Selected causes of thrombocytopenia are shown in Table 14–2. The age of the patient and presence of any comorbid conditions may help direct the diagnostic workup.
Table 14–2.Selected causes of thrombocytopenia. |Favorite Table|Download (.pdf) Table 14–2. Selected causes of thrombocytopenia.
Decreased production of platelets
Congenital bone marrow failure (eg, Fanconi anemia, Wiskott-Aldrich syndrome; congenital amegakaryocytic thrombocytopenia)
Acquired bone marrow failure (eg, aplastic anemia, myelodysplasia, leukemia)
Exposure to chemotherapy, irradiation
Marrow infiltration (neoplastic, infectious)
Nutritional (deficiency of vitamin B12, folate)
Other: HIV infection, alcohol
Increased destruction of platelets
Immune thrombocytopenia (primary)
Immune thrombocytopenia (secondary), including drug-induced or related to hepatitis C virus, Epstein-Barr virus, or HIV
Disseminated intravascular coagulation
Neonatal alloimmune thrombocytopenia
Mechanical (aortic valvular dysfunction; extracorporeal bypass)
von Willebrand disease, type 2B
Increased sequestration of platelets
Hypersplenism (eg, related to cirrhosis, myeloproliferative disorders, lymphoma)
Other conditions causing thrombocytopenia
Bernard-Soulier syndrome, gray platelet syndrome, May-Hegglin anomaly
The risk of spontaneous bleeding (including petechial hemorrhage and bruising) does not typically increase appreciably until the platelet count falls below 10,000–20,000/mcL, although patients with dysfunctional platelets may bleed with higher platelet counts. Suggested platelet counts to prevent spontaneous bleeding or to provide adequate hemostasis around the time of invasive procedures are found in Table 14–3. However, most medical centers develop their own local guidelines to have a consistent approach to such complex situations.
Table 14–3.Desired platelet count ranges. |Favorite Table|Download (.pdf) Table 14–3. Desired platelet count ranges.
|Clinical Scenario ||Platelet Count (/mcL) |
|Prevention of spontaneous mucocutaneous bleeding ||> 10,000–20,000 |
|Insertion of central venous catheters ||> 20,000–50,0001 |
|Administration of therapeutic anticoagulation ||> 30,000–50,000 |
|Minor surgery and selected invasive procedures2 ||> 50,000–80,000 |
|Major surgery ||> 80,000–100,000 |
DECREASED PLATELET PRODUCTION
Congenital conditions that cause thrombocytopenia include amegakaryocytic thrombocytopenia, the thrombocytopenia-absent radius syndrome, and Wiskott-Aldrich syndrome; these disorders usually feature isolated thrombocytopenia, whereas patients with Fanconi anemia and dyskeratosis congenita typically include cytopenias in other blood cell lineages.
Acquired causes of bone marrow failure (see Chapter 13) leading to thrombocytopenia include acquired aplastic anemia, myelodysplastic syndrome (MDS), acquired amegakaryocytic thrombocytopenia (albeit a rare disorder), alcohol, and drugs. Unlike aplastic anemia, MDS is more common among older patients.
Acquired aplastic anemia typically presents with reductions in multiple blood cell lineages, and the CBC reveals pancytopenia. A bone marrow biopsy is required for diagnosis and reveals marked hypocellularity. Myelodysplastic syndrome (MDS) also presents as cytopenias and can have pancytopenia, but the marrow cellularity is not decreased; the marrow typically demonstrates hypercellularity. The presence of macrocytosis, ringed sideroblasts on iron staining of the bone marrow aspirate, dysplasia of hematopoietic elements, or cytogenetic abnormalities (especially monosomy 5 or 7, and trisomy 8) are more suggestive of MDS.
Adult patients with acquired amegakaryocytic thrombocytopenia (rare) have isolated thrombocytopenia and reduced or absent megakaryocytes in the bone marrow, which (along with failure to respond to immunomodulatory regimens typically administered in immune thrombocytopenia [ITP]) distinguishes them from patients with ITP.
Treatment is varied but may include blood product support, blood cell growth factors, androgens and, in some cases, allogeneic hematopoietic stem cell transplantation.
Patients with severe aplastic anemia are treated with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation. Allogeneic hematopoietic stem cell transplantation is the preferred therapy for patients younger than age 40 who have an HLA-matched sibling donor (see Chapter 13), and immunosuppressive therapy is preferred for older patients and those who lack an HLA-matched sibling donor. Eltrombopag has been shown to induce multilineage responses (some of which are durable after discontinuing the medication) in selected patients with severe aplastic anemia that is unresponsive to immunosuppressive therapy.
Treatment of thrombocytopenia due to MDS, if clinically significant bleeding is present or if the risk of bleeding is high, is limited to chronic transfusion of platelets in most instances (Table 14–3). Immunomodulatory agents such as lenalidomide do not produce increases in the platelet count in most patients. The thrombopoietin receptor agonists eltrombopag and romiplostim have shown efficacy as an adjunct to hypomethylating agents in low-risk MDS in clinical trials. However, these agents are typically avoided in moderate- and high-risk MDS patients due to possibility of accelerating leukemic transformation.
et al. Eltrombopag
restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014 Mar 20;123(12):1818–25.
et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma. 2013 Feb;54(2):321–8.
et al. Management of the refractory aplastic anemia patient: what are the options? Blood. 2013 Nov 21;122(22):3561–7.
et al. Development and validation of a model to predict platelet response to romiplostim in patients with lower-risk myelodysplastic syndromes. Br J Haematol. 2014 Nov;167(3):337–45.
2. Bone Marrow Infiltration
Replacement of the normal bone marrow elements by leukemic cells, myeloma, lymphoma, or other nonhematologic tumors, or by infections (such as mycobacterial disease or ehrlichiosis) may cause thrombocytopenia; however, abnormalities in other blood cell lines are usually present. These entities are easily diagnosed after examining the bone marrow biopsy and aspirate or determining the infecting organism from an aspirate specimen, and they often lead to a leukoerythroblastic peripheral blood smear (left-shifted myeloid lineage, nucleated red blood cells, and teardrop-shaped red blood cells). Treatment of thrombocytopenia is directed at eradication of the underlying infiltrative disorder, but platelet transfusion may be required if clinically significant bleeding is present.
3. Chemotherapy & Irradiation
Chemotherapeutic agents and irradiation may lead to thrombocytopenia by direct toxicity to megakaryocytes, hematopoietic progenitor cells, or both. The severity and duration of chemotherapy-induced depressions in the platelet count are determined by the specific regimen used, although the platelet count typically resolves more slowly following a chemotherapeutic insult than does neutropenia or anemia, especially if multiple cycles of treatment have been given. Until recovery occurs, patients may be supported with transfused platelets if bleeding is present or the risk of bleeding is high (Table 14–3). Clinical trials to determine the role of the platelet growth factors eltrombopag and romiplostim in the treatment of chemotherapy-induced thrombocytopenia have not shown clinically significant responses in the majority of treated patients.
DJ. Managing thrombocytopenia associated with cancer chemotherapy. Oncology (Williston Park). 2015 Apr;29(4):282–94.
4. Nutritional Deficiencies
Thrombocytopenia, typically in concert with anemia, may be observed when a deficiency of folate (that may accompany alcoholism) or vitamin B12 is present (concomitant neurologic findings may be manifest). In addition, thrombocytopenia rarely can occur in very severe iron deficiency, but thrombocytosis is more common. Replacing the deficient vitamin or mineral results in improvement in the platelet count.
et al. Cobalamin deficiency: clinical picture and radiological findings. Nutrients. 2013 Nov 15;5(11):4521–39.
5. Cyclic Thrombocytopenia
Cyclic thrombocytopenia is a very rare disorder that produces cyclic oscillations of the platelet count, usually with a periodicity of 3–6 weeks. The exact pathophysiologic mechanisms responsible for the condition may vary from patient to patient. Severe thrombocytopenia and bleeding typically occur at the platelet nadir. Oral contraceptive medications, androgens, azathioprine, and thrombopoietic growth factors have been used successfully in the management of cyclic thrombocytopenia.
INCREASED PLATELET DESTRUCTION
1. Immune Thrombocytopenia
ESSENTIALS OF DIAGNOSIS
Isolated thrombocytopenia (rule out pseudothrombocytopenia by review of peripheral smear).
Assess for any new causative medications and HIV and hepatitis C infections.
ITP is a diagnosis of exclusion.
ITP is an autoimmune condition in which pathogenic antibodies bind platelets, accelerating their clearance from the circulation. Many patients with ITP also lack appropriate compensatory platelet production, thought, at least in part, to reflect the antibody’s effect on megakaryocytopoiesis and thrombopoiesis. The disorder is primary and idiopathic in most adult patients, although it can be associated with connective tissue disease (such as systemic lupus erythematosus), lymphoproliferative disease (such as lymphoma), medications, and infections (such as hepatitis C virus and HIV infections). Targets of antiplatelet antibodies include glycoproteins IIb/IIIa and Ib/IX on the platelet membrane, although antibodies are demonstrable in only two-thirds of patients. In addition to production of antiplatelet antibodies, HIV and hepatitis C virus may lead to thrombocytopenia through additional mechanisms (for instance, by direct suppression of platelet production [HIV] and cirrhosis-related splenomegaly [hepatitis C virus]).
Mucocutaneous bleeding may be present, depending on the platelet count. Clinically relevant spontaneous bruising, nosebleeds, gingival bleeding, or other types of hemorrhage generally do not occur until the platelet count has fallen below 10,000–20,000/mcL. Individuals with secondary ITP (such as due to collagen vascular disease, HIV or HCV infection, or lymphoproliferative malignancy) may have additional disease-specific findings.
Typically, patients have isolated thrombocytopenia. If bleeding has occurred, anemia may also be present. Hepatitis B and C viruses and HIV infections should be excluded by serologic testing. Bone marrow should be examined in patients with unexplained cytopenias, in patients older than 60 years, or in those who do not respond to primary ITP-specific therapy. A bone marrow biopsy is not necessary in all cases to make a diagnosis in younger patients. Megakaryocyte abnormalities and hypocellularity or hypercellularity are not characteristic of ITP. If there are clinical findings suggestive of a lymphoproliferative malignancy, a CT scan should be performed. In the absence of such findings, otherwise asymptomatic patients younger than 40 years with unexplained isolated thrombocytopenia of recent onset may be considered to have ITP. Chronic thrombocytopenia will develop in most adult patients with newly diagnosed ITP.
Individuals with platelet counts less than 20,000–30,000/mcL or those with significant bleeding should be treated; the remainder may be monitored serially for progression, but that is a patient-specific decision. The mainstay of initial treatment of new-onset primary ITP is a short course of corticosteroids with or without intravenous immunoglobulin (IVIG) or anti-D (WinRho) (Figure 14–1). Responses are generally seen within 3–5 days of initiating treatment, with responses to IVIG typically seen in 24–36 hours. Platelet transfusions may be given concomitantly if active bleeding is present. The addition of the monoclonal anti-B cell antibody rituximab to corticosteroids as first-line treatment may improve the initial response rate, but it is associated with increased toxicity and is not regarded as standard first-line therapy in most centers.
Management of immune thrombocytopenia (ITP).
Although over two-thirds of patients with ITP respond to initial treatment, most relapse following reduction of the corticosteroid dose. Patients with a persistent platelet count less than 30,000/mcL or clinically significant bleeding are appropriate candidates for second-line treatments (Figure 14–1). These treatments are chosen empirically, bearing in mind potential toxicities and the patient’s preference. IVIG or anti-D (WinRho) temporarily increases platelet counts (duration, up to 3 weeks or longer), although serial anti-D treatment (platelet counts less than 30,000/mcL) may allow adult patients to delay or avoid splenectomy. Rituximab leads to clinical responses in about 50% of adults with corticosteroid-refractory chronic ITP, which decrease to about 20% at 5 years. Romiplostim (administered subcutaneously weekly) and eltrombopag (taken orally daily) are approved for use in adult patients with chronic ITP who have not responded durably to corticosteroids, IVIG, or splenectomy and are typically taken indefinitely to maintain the platelet response. Splenectomy has a durable response rate of over 50% and may be considered for cases of severe thrombocytopenia that fail to respond durably to initial treatment or are refractory to second-line agents; patients should receive pneumococcal, Haemophilus influenzae type b, and meningococcal vaccination at least 2 weeks before therapeutic splenectomy. If available, laparoscopic splenectomy is preferred. Additional treatments for ITP are found in Figure 14–1.
The goals of management of pregnancy-associated ITP are a platelet count of 10,000–30,000/mcL in the first trimester, greater than 30,000/mcL during the second or third trimester, and greater than 50,000/mcL prior to cesarean section or vaginal delivery. Moderate-dose oral prednisone or intermittent infusions of IVIG are standard. Splenectomy is reserved for failure to respond to these therapies and may be performed in the first or second trimester.
For thrombocytopenia associated with HIV or hepatitis C virus, effective treatment of either infection leads to an amelioration of thrombocytopenia in most cases; refractory thrombocytopenia may be treated with infusion of IVIG or anti-D (HIV and hepatitis C virus), splenectomy (HIV), or interferon-alpha or eltrombopag (hepatitis C virus, including eradication). Treatment with corticosteroids is not recommended in hepatitis C virus infection. Occasionally, ITP treatment response is impaired due to Helicobacter pylori infection, so that should be ruled out in the appropriate situation.
All patients with ITP should be referred to a subspecialist for evaluation at the time of diagnosis.
Patients with major hemorrhage or very severe thrombocytopenia associated with bleeding should be admitted and monitored in-hospital until the platelet count has stably risen to more than 20,000–30,000/mcL and hemodynamic stability has been achieved.
et al; ELEVATE Study Group. Eltrombopag
before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med. 2012 Aug 23;367(8):716–24.
et al. Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review. J Thromb Haemost. 2015 Mar;13(3):457–64.
et al. Safety and efficacy of eltrombopag
for treatment of chronic immune thrombocytopenia (ITP): results of the long-term, open-label EXTEND study. Blood. 2013 Jan 17;121(3):537–45.
2. Thrombotic Microangiopathy
ESSENTIALS OF DIAGNOSIS
Microangiopathic hemolytic anemia and thrombocytopenia, in the absence of another plausible explanation, are sufficient for the diagnosis of thrombotic microangiopathy (TMA).
Fever, neurologic abnormalities, and kidney disease may occur concurrently but are not required for diagnosis.
Kidney dysfunction is more common and more severe in hemolytic-uremic syndrome (HUS).
The TMAs include, but are not limited to, thrombotic thrombocytopenic purpura (TTP) and HUS. These disorders are characterized by thrombocytopenia due to the incorporation of platelets into thrombi in the microvasculature, and microangiopathic hemolytic anemia, which results from shearing of erythrocytes in fibrin networks in the microcirculation.
In idiopathic TTP, autoantibodies against ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeat, member 13), also known as the von Willebrand factor cleaving protease (vWFCP), lead to accumulation of ultra-large von Willebrand factor (vWF) multimers. These multimers bridge and aggregate platelets in the absence of hemostatic triggers, which in turn leads to the vessel obstruction and various organ dysfunctions seen in TTP. In some cases of pregnancy-associated TMA, an antibody to ADAMTS-13 is present. In contrast, the activity of the ADAMTS-13 in congenital TTP is decreased due to a mutation in the gene encoding the molecule. Classic HUS, also called Shiga toxin–mediated HUS, is thought to be secondary to toxin-mediated endothelial damage and is often contracted through the ingestion of undercooked ground beef contaminated with Escherichia coli (especially types O157:H7 or O145).
Atypical HUS (aHUS), now termed complement-mediated HUS, is not related to Shiga toxin. It is a chronic disorder that typically leads to acute kidney injury and often kidney failure. Patients with complement-mediated HUS often have genetic defects in proteins that regulate complement activity. Mutations in complement genes (such as factor H, a complement regulator) account for the uncontrolled activation of complement that characterizes the condition. Damage to endothelial cells—such as the damage that occurs in endemic HUS due to presence of toxins from E coli (especially type O157:H7 or O145) or in the setting of cancer, hematopoietic stem cell transplantation, or HIV infection—may also lead to TMA. Certain drugs (eg, cyclosporine, quinine, ticlopidine, clopidogrel, mitomycin C, and bleomycin) have been associated with the development of TMA, possibly by promoting injury to endothelial cells, although inhibitory antibodies to ADAMTS-13 have been demonstrated in some cases.
Microangiopathic hemolytic anemia and thrombocytopenia are presenting signs in all patients with TTP and most patients with HUS; in a subset of patients with HUS, the platelet count remains in the normal range. Only approximately 25% of patients with TMA manifest all components of the original pentad of findings (microangiopathic hemolytic anemia, thrombocytopenia, fever, kidney disease, and neurologic system abnormalities) (Table 14–4). Most patients (especially children) with HUS have a recent or current diarrheal illness, often bloody. Neurologic manifestations, including headache, somnolence, delirium, seizures, paresis, and coma, may result from deposition of microthrombi in the cerebral vasculature.
Table 14–4.Presentation and management of thrombotic microangiopathies. |Favorite Table|Download (.pdf) Table 14–4. Presentation and management of thrombotic microangiopathies.
| ||TTP ||Complement-Mediated HUS ||Shiga toxin–Mediated HUS |
|Patient population ||Adult patients ||Children (occasionally adults) ||Usually children, often following bloody diarrhea |
|Pathogenesis ||Acquired auto-antibody to ADAMTS-13 ||Some cases: heritable deficiency in function of complement regulatory proteins ||Bacterial (such as enterotoxogenic Escherichia coli; Shiga toxin) |
|Thrombocytopenia ||Typically severe, except in very early clinical course ||Variable ||May be mild/absent in a minority of patients |
|Fever ||Typical ||Variable ||Atypical |
|Kidney disease ||Typical, but may be mild ||Typical ||Typical |
|Neurologic impairment ||Variable ||Less than half of cases ||Less than half of cases |
|Laboratory investigation ||Decreased activity of ADAMTS-13; inhibitor usually identified ||Defects in complement regulatory proteins || |
Typically normal ADAMTS-13 activity
Positive stool culture for E coli 0157:H7 or detectable antibody to Shiga toxin
|Management || |
Hemodialysis for severe renal impairment
Platelet transfusions contraindicated unless TPE underway
Immediate TPE in most cases
Hemodialysis for severe renal impairment
Eculizumab (selected cases)
Hemodialysis for severe renal impairment
TPE rarely beneficial (exception: selected cases in adults)
Laboratory features of TMA include those associated with microangiopathic hemolytic anemia (anemia, elevated lactate dehydrogenase [LD], elevated indirect bilirubin, decreased haptoglobin, reticulocytosis, schistocytes on the blood smear, and a negative direct antiglobulin test); thrombocytopenia; elevated creatinine; positive stool culture for E coli O157:H7 or stool assays for Shiga toxin–producing E coli to detect non-O157:H7 such as E coli O145 (HUS only); reductions in ADAMTS-13 activity (idiopathic TTP); and mutations of genes encoding complement proteins (complement-mediated HUS; specialized laboratory assessment). Routine coagulation studies are within the normal range in most patients with TTP or HUS.
Immediate administration of plasma exchange is essential in most cases because the mortality rate is more than 95% without treatment. With the exception of children or adults with endemic diarrhea-associated HUS, who generally recover with supportive care only, plasma exchange must be initiated as soon as the diagnosis of TMA is suspected and in all cases of TTP. Plasma exchange usually is administered once daily until the platelet count and LD have returned to normal for at least 2 days, after which the frequency of treatments may be tapered slowly while the platelet count and LD are monitored for relapse. In cases of insufficient response to once-daily plasma exchange, twice-daily treatments can be considered. Fresh frozen plasma (FFP) may be administered if immediate access to plasma exchange is not available or in cases of familial TMA. Platelet transfusions are contraindicated in the treatment of TMA due to reports of worsening TMA, possibly due to propagation of platelet-rich microthrombi. In cases of documented life-threatening bleeding, however, platelet transfusions may be given slowly and after plasma exchange is underway. Red blood cell transfusions may be administered in cases of clinically significant anemia. Hemodialysis should be considered for patients with significant kidney disease.
In cases of TTP relapse following initial treatment, plasma exchange should be reinstituted. If ineffective, or in cases of primary refractoriness, second-line treatments should be considered including rituximab (which has shown efficacy when administered preemptively in selected cases of relapsing TTP), corticosteroids, IVIG, vincristine, cyclophosphamide, and splenectomy.
Cases of complement-mediated HUS may respond to plasma infusion initially; however, once this diagnosis is strongly suspected, apheresis is typically stopped and serial infusions of the anti-complement C5 antibody eculizumab are provided, which have produced sustained remissions in some patients. If irreversible kidney disease has occurred, hemodialysis or kidney transplantation may be necessary.
Consultation by a hematologist or transfusion medicine specialist familiar with plasma exchange is required at the time of presentation. Patients with refractory or relapsing TMA require ongoing care by a hematologist.
All patients with newly suspected or diagnosed TMA should be hospitalized immediately.
et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood. 2013 Sep 19;122(12):2023–9.
et al. Syndromes of thrombotic microangiopathy associated with pregnancy. Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):644–8.
et al; French Thrombotic Microangiopathies Reference Centre. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood. 2014 Jul 10;124(2):204–10.
et al. How I treat refractory thrombotic thrombocytopenic purpura. Blood. 2015 Jun 18;125(25):3860–7.
et al; International Working Group for Thrombotic Thrombocytopenic Purpura. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost. 2017 Feb;15(2):312-22.
3. Heparin-Induced Thrombocytopenia
ESSENTIALS OF DIAGNOSIS
Thrombocytopenia within 5–14 days of exposure to heparin.
Decline in baseline platelet count of 50% or greater.
Thrombosis occurs in up to 50% of cases; bleeding is uncommon.
Heparin-induced thrombocytopenia (HIT) is an acquired disorder that affects approximately 3% of patients exposed to unfractionated heparin and 0.6% of patients exposed to low-molecular-weight heparin (LMWH). The condition results from formation of IgG antibodies to heparin-platelet factor 4 (PF4) complexes; the antibody:heparin-PF4 complex binds to and activates platelets independent of physiologic hemostasis, which leads to thrombocytopenia and thromboses.
Patients are usually asymptomatic, and due to the pro-thrombotic nature of HIT, bleeding usually does not occur. Thrombosis (at any venous or arterial site), however, may be detected in up to 50% of patients, up to 30 days post-diagnosis.
A presumptive diagnosis of HIT is made when new-onset thrombocytopenia is detected in a patient (frequently a hospitalized patient) within 5–14 days of exposure to heparin; other presentations (eg, rapid-onset HIT) are less common. A decline of 50% or more from the baseline platelet count is typical. The 4T score (http://www.qxmd.com/calculate-online/hematology/hit-heparin-induced-thrombocytopenia-probability) is a clinical prediction rule for assessing pretest probability for HIT, although low scores have been shown to be more predictive of excluding HIT, than are intermediate or high scores of predicting its presence. Once HIT is clinically suspected, the clinician must establish the diagnosis by performing a screening PF4-heparin antibody enzyme-linked immunosorbent assay (ELISA). If the PF4-heparin antibody ELISA is positive, the diagnosis must be confirmed using a functional assay (such as serotonin release assay). The magnitude of a positive ELISA result correlates with the clinical probability of HIT, but even high optical density values on the PF4 may be falsely positive. The confirmatory assay is essential.
Treatment should be initiated as soon as the diagnosis of HIT is suspected, before results of laboratory testing are available.
Management of HIT (Table 14–5) involves the immediate discontinuation of all forms of heparin. If thrombosis has not already been detected, duplex Doppler ultrasound of the lower extremities should be performed to rule out subclinical deep venous thrombosis (DVT). Despite thrombocytopenia, platelet transfusions are rarely necessary and should be avoided. Due to the substantial frequency of thrombosis among HIT patients, an alternative anticoagulant, typically a direct thrombin inhibitor (DTI) such as argatroban or bivalirudin should be administered immediately. The DTI should be continued until the platelet count has recovered to at least 100,000/mcL, at which point treatment with a vitamin K antagonist (warfarin) may be initiated. The DTI should be continued until therapeutic anticoagulation with the vitamin K antagonist warfarin has been achieved (ie, international normalized ratio [INR] of 2.0–3.0); the infusion of argatroban must be temporarily discontinued for 2 hours before the INR is obtained so that it reflects the anticoagulant effect of warfarin alone. There is growing use of the subcutaneous indirect anti-Xa inhibitor fondaparinux for initial treatment of HIT. In all patients with HIT, some form of anticoagulation (warfarin or other) subsequently should be continued for at least 30 days, due to a persistent risk of thrombosis even after the platelet count has recovered, but in patients in whom thrombosis has been documented, anticoagulation should continue for 3–6 months.
Table 14–5.Management of suspected or proven HIT. |Favorite Table|Download (.pdf) Table 14–5. Management of suspected or proven HIT.
| I. Discontinue all forms of heparin. Send PF4-heparin ELISA (if indicated). |
| II. Begin treatment with direct thrombin inhibitor. |
|Agent ||Indication ||Dosing |
|Argatroban ||Prophylaxis or treatment of HIT ||Continuous intravenous infusion of 0.5–1.2 mcg/kg/min, titrate to aPTT = 1.5 to 3 × the baseline value.1 Max infusion rate ≤ 10 mcg/kg/min. |
|Bivalirudin ||Percutaneous coronary intervention2 ||Bolus of 0.75 mg/kg intravenously followed by initial continuous intravenous infusion of 1.75 mg/kg/h. Manufacturer indicates monitoring should be by ACT. |
| III. Perform Doppler ultrasound of lower extremities to rule out subclinical thrombosis (if indicated). |
|IV. Follow platelet counts daily until recovery occurs. |
| V. When platelet count has recovered, transition anticoagulation to warfarin; treat for 30 days (HIT) or 3–6 months (HITT). |
|VI. Document heparin allergy in medical record (confirmed cases). |
Subsequent exposure to heparin should be avoided in all patients with a prior history of HIT, if possible. If its use is regarded as necessary for a procedure, it should be withheld until PF4-heparin antibodies are no longer detectable by ELISA (usually as of 100 days following an episode of HIT), and exposure should be limited to the shortest time period possible.
Due to the tremendous thrombotic potential of the disorder and the complexity of use of the DTI, all patients with HIT should be evaluated by a hematologist.
Most patients with HIT are hospitalized at the time of detection of thrombocytopenia. Any outpatient in whom HIT is suspected should be admitted because the DTIs must be administered by continuous intravenous infusion.
et al. Emerging therapy options in heparin-induced thrombocytopenia. Cardiovasc Hematol Agents Med Chem. 2014;12(1):50–8.
et al. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012 Nov 15;120(20):4160–7.
et al. Advances in the pathophysiology and treatment of heparin-induced thrombocytopenia. Curr Opin Hematol. 2014 Sep;21(5):380–7.
et al. Serological investigation of patients with a previous history of heparin-induced thrombocytopenia who are reexposed to heparin. Blood. 2014 Apr 17;123(16):2485–93.
4. Disseminated Intravascular Coagulation
ESSENTIALS OF DIAGNOSIS
A frequent cause of thrombocytopenia in hospitalized patients.
Prolonged activated partial thromboplastin time and prothrombin time.
Thrombocytopenia and decreased fibrinogen levels.
Disseminated intravascular coagulation (DIC) is caused by uncontrolled local or systemic activation of coagulation, which leads to depletion of coagulation factors and fibrinogen, and often results in thrombocytopenia as platelets are activated and consumed.
The numerous disorders that are associated with DIC include sepsis (in which coagulation is activated by presence of lipopolysaccharide), cancer, trauma, burns, and pregnancy-associated complications (in which tissue factor is released). Aortic aneurysm and cavernous hemangiomas may promote localized intravascular coagulation, and snake bites may result in DIC due to the introduction of exogenous toxins.
Bleeding in DIC usually occurs at multiple sites, such as intravenous catheters or incisions, and may be widespread (purpura fulminans). Malignancy-related DIC may manifest principally as thrombosis (Trousseau syndrome).
In early DIC, the platelet count and fibrinogen levels may remain within the normal range, albeit reduced from baseline levels. There is progressive thrombocytopenia (rarely severe), prolongation of the prothrombin time (PT), decrease in fibrinogen levels, and eventually elevation in the activated partial thromboplastin time (aPTT). D-dimer levels typically are elevated due to the activation of coagulation and diffuse cross-linking of fibrin. Schistocytes on the blood smear, due to shearing of red cells through the microvasculature, are present in 10–20% of patients. Laboratory abnormalities in the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), a severe form of DIC with a particularly high mortality rate that occurs in peripartum women, include elevated liver transaminases and kidney injury due to gross hemoglobinuria and pigment nephropathy. Malignancy-related DIC may feature normal platelet counts and coagulation studies, but clinicians often see a dropping platelet count and fibrinogen, with a rising INR.
The underlying causative disorder must be treated (eg, antimicrobials, chemotherapy, surgery, or delivery of conceptus). If clinically significant bleeding is present, hemostasis must be achieved (Table 14–6).
Table 14–6.Management of DIC. |Favorite Table|Download (.pdf) Table 14–6. Management of DIC.
|I. Assess for underlying cause of DIC and treat. |
|II. Establish baseline platelet count, PT, aPTT, D-dimer, fibrinogen. |
|III. Transfuse blood products only if ongoing bleeding or high risk of bleeding: ||Platelets: goal > 20,000/mcL (most patients) or > 50,000/mcL (severe bleeding, eg, intracranial hemorrhage) |
| ||Cryoprecipitate: goal fibrinogen level > 80–100 mg/dL |
| ||Fresh frozen plasma: goal PT and aPTT < 1.5 × normal |
| ||Packed red blood cells: goal hemoglobin > 8 g/dL or improvement in symptomatic anemia |
|IV. Follow platelets, aPTT/PT, fibrinogen every 4–6 hours or as clinically indicated. |
|V. If persistent bleeding, consider use of heparin1 (initial infusion, 5–10 units/kg/h); do not administer bolus. |
|VI. Follow laboratory parameters every 4–6 hours until DIC resolved and underlying condition successfully treated |
Blood products should be administered only if clinically significant hemorrhage has occurred or is thought likely to occur without intervention (Table 14–6). The goal of platelet therapy for most cases is greater than 20,000/mcL or greater than 50,000/mcL for serious bleeding, such as intracranial bleeding. FFP should be given only to patients with a prolonged aPTT and PT and significant bleeding. Cryoprecipitate may be given for bleeding or for fibrinogen levels less than 80–100 mg/dL. The clinician should correct the fibrinogen level with cryoprecipitate prior to giving FFP for prolonged PT and aPTT, to see if the fibrinogen replacement alone corrects the PT and aPTT. The PT, aPTT, fibrinogen, and platelet count should be monitored at least every 6–8 hours in acutely ill patients with DIC.
In some cases of refractory bleeding despite replacement of blood products, administration of low doses of heparin can be considered. The clinician must remember that DIC is primarily excessive clotting with secondary fibrinolysis, and heparin can interfere with thrombin generation, which could then lead to a lessened consumption of coagulation proteins and platelets. An infusion of 5–10 units/kg/h (no bolus) may be used with appropriate clinical judgement. Heparin, however, is contraindicated if the platelet count cannot be maintained at 50,000/mcL or more and in cases of central nervous system hemorrhage, gastrointestinal bleeding, placental abruption, and any other condition that is likely to require imminent surgery. Fibrinolysis inhibitors may be considered in some patients with refractory DIC, but this can promote dangerous clotting and should be undertaken with great caution and only in consultation with a hematologist.
The treatment of HELLP syndrome must include evacuation of the uterus (eg, delivery of a term or near-term infant or removal of retained placental or fetal fragments). Patients with Trousseau syndrome require treatment of the underlying malignancy and administration of unfractionated heparin or subcutaneous therapeutic-dose LMWH as treatment of thrombosis, since warfarin typically is ineffective at secondary prevention of thromboembolism in the disorder. Typically, the heparin or LMWH treatment will gradually return the fibrinogen, PT (INR), aPTT, and platelet count back to normal, but it can take days.
Immediate initiation of chemotherapy (usually within 24 hours of diagnosis) is required for patients with acute promyelocytic leukemia (APL)–associated DIC, along with administration of blood products as clinically indicated.
Most patients with DIC are hospitalized when DIC is detected.
DI. Disseminated intravascular coagulation in patients with solid tumors. Oncology (Williston Park). 2015 Feb;29(2):96–102.
et al. Anticoagulant therapy for sepsis-associated disseminated intravascular coagulation: the view from Japan. J Thromb Haemost. 2014 Jul;12(7):1010–9.
M. Diagnosis and treatment of disseminated intravascular coagulation. Int J Lab Hematol. 2014 Jun;36(3):228–36.
et al. Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. Cochrane Database Syst Rev. 2011 Jun 15;(6):CD008562.
et al. Trends in the incidence and outcomes of disseminated intravascular coagulation in critically ill patients (2004–2010): a population-based study. Chest. 2013 May;143(5):1235–42.
et al. Disseminated intravascular coagulation: testing and diagnosis. Clin Chim Acta. 2014 Sep 25;436:130–4.
OTHER CONDITIONS CAUSING THROMBOCYTOPENIA
1. Drug-Induced Thrombocytopenia
The mechanisms underlying drug-induced thrombocytopenia are thought in most cases to be immune, although exceptions exist (such as chemotherapy). Table 14–7 lists medications associated with thrombocytopenia. The typical presentation of drug-induced (or drug-related) thrombocytopenia is severe thrombocytopenia and mucocutaneous bleeding 7–14 days after exposure to a new drug, although a range of presentations is possible. Discontinuation of the offending agent leads to resolution of thrombocytopenia within 7–10 days in most cases, but recovery kinetics depends on rate of drug clearance, which can be affected by liver and kidney function. Patients with severe thrombocytopenia should be given platelet transfusions with (immune cases only) or without IVIG.
Table 14–7.Selected medications causing drug-associated thrombocytopenia. |Favorite Table|Download (.pdf) Table 14–7. Selected medications causing drug-associated thrombocytopenia.
|Class ||Examples |
|Chemotherapy ||Most agents |
|Antiplatelet agents || |
|Antimicrobial agents || |
Adefovir, indinavir, ritonavir
|Cardiovascular agents || |
|Gastrointestinal agents ||Cimetidine, famotidine, ranitidine |
|Neuropsychiatric agents || |
|Analgesic agents || |
Diclofenac, ibuprofen, sulindac
|Anticoagulant agents || |
|Immunomodulator agents || |
|Immunosuppressant agents || |
|Other agents || |
Iodinated contrast dye
2. Posttransfusion Purpura
Posttransfusion purpura (PTP) is a rare disorder that features sudden-onset thrombocytopenia in an individual who received transfusion of red cells, platelets, or plasma within 1 week prior to detection of thrombocytopenia. Antibodies against the human platelet antigen PlA1 are detected in most individuals with PTP. Patients with PTP often are either multiparous women or persons who have received transfusions previously. Severe thrombocytopenia and bleeding are typical. Initial treatment consists of administration of IVIG (1 g/kg/day for 2 days), which should be administered as soon as the diagnosis is suspected. Platelets are not indicated unless severe bleeding is present, but if they are to be administered, HLA-matched platelets are preferred. A second course or IVIG, plasma exchange, corticosteroids, or splenectomy may be used in case of refractoriness. PlA1-negative or washed blood products are preferred for subsequent transfusions, but data supporting various treatment options are limited.
3. von Willebrand Disease Type 2B
von Willebrand disease (vWD) type 2B leads to chronic, characteristically mild to moderate thrombocytopenia via an abnormal vWF molecule that binds platelets with increased affinity, resulting in aggregation and clearance.
4. Platelet Sequestration
At any given time, one-third of the platelet mass is sequestered in the spleen. Splenomegaly, due to a variety of conditions (eTable 14–1), may lead to thrombocytopenia of variable severity. Whenever possible, treatment of the underlying disorder should be pursued, but splenectomy, splenic embolization, or splenic irradiation may be considered in selected cases.
eTable 14–1.Selected causes of splenomegaly. |Favorite Table|Download (.pdf) eTable 14–1. Selected causes of splenomegaly.
Chronic lymphocytic leukemia
Chronic myeloid leukemia
Paroxysmal nocturnal hemoglobinuria
Collagen vascular disease
Felty syndrome, Systemic lupus erythematosus
Autoimmune lymphoproliferative disorder
Cytomegalovirus, Epstein Barr virus
Inborn errors of metabolism
Gestational thrombocytopenia is thought to result from progressive expansion of the blood volume that typically occurs during pregnancy, leading to hemodilution. Cytopenias result, although production of blood cells is normal or increased. Platelet counts less than 100,000/mcL, however, are observed in less than 10% of pregnant women in the third trimester; decreases to less than 70,000/mcL should prompt consideration of pregnancy-related ITP as well as preeclampsia or a pregnancy-related thrombotic microangiopathy.
Both immune- and platelet production–mediated defects are possible, and there may be significant overlap with concomitant DIC. Regardless, the platelet count typically improves with effective antimicrobial treatment or after the infection has resolved. In some critically ill patients, a defect in immunomodulation may lead to bone marrow macrophages (histiocytes) engulfing cellular components of the marrow in a process also called hemophagocytosis. The phenomenon typically resolves with resolution of the infection, but with certain infections (Epstein-Barr virus) immunosuppression may be required. Hemophagocytosis also may arise in the setting of malignancy, in which case the disorder is usually unresponsive to treatment with immunosuppression. Sepsis-related thrombocytopenia may be due to increased hepatic clearance of platelets caused by loss of asialoglycoprotein moieties on the platelet surface.
Pseudothrombocytopenia results from EDTA anticoagulant-induced platelet clumping; the phenomenon typically disappears when blood is collected in a tube containing citrate anticoagulant. Pseudothrombocytopenia diagnosis requires review of the peripheral blood smear.
et al. Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20218–23.
et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med. 2015 Jan;21(1):47–54.
et al. Clinical features of gestational thrombocytopenia difficult to differentiate from immune thrombocytopenia diagnosed during pregnancy. J Obstet Gynaecol Res. 2015 Jan;41(1):44–9.
et al. Posttransfusion purpura occurrence and potential risk factors among the inpatient US elderly, as recorded in large Medicare databases during 2011 through 2012. Transfusion. 2015 Feb;55(2):284–95.
et al. Quinine-induced thrombocytopenia: drug-dependent GPIb/IX antibodies inhibit megakaryocyte and proplatelet production in vitro. Blood. 2011 Jun 2;117(22):5975–86.
QUALITATIVE PLATELET DISORDERS
CONGENITAL DISORDERS OF PLATELET FUNCTION
ESSENTIALS OF DIAGNOSIS
Usually diagnosed in childhood.
Family history usually is positive.
May be diagnosed in adulthood when there is excessive bleeding.
Heritable qualitative platelet disorders are far less common than acquired disorders of platelet function and lead to variably severe bleeding, often beginning in childhood. Occasionally, however, disorders of platelet function may go undetected until later in life when excessive bleeding occurs following a sufficient hemostatic challenge. Thus, the true incidence of hereditary qualitative platelet disorders is unknown.
Bernard-Soulier syndrome (BSS) is a rare, autosomal recessive bleeding disorder due to reduced or abnormal platelet membrane expression of glycoprotein Ib/IX (vWF receptor).
Glanzmann thrombasthenia results from a qualitative or quantitative abnormality in glycoprotein IIb/IIIa receptors on the platelet membrane, which are required to bind fibrinogen and vWF, both of which bridge platelets during aggregation/platelet plug formation. Inheritance is autosomal recessive.
Under normal circumstances, activated platelets release the contents of platelet granules to reinforce the aggregatory response. Storage pool disease includes a spectrum of defects in release of alpha or dense (delta) platelet granules, or both (alpha-delta storage pool disease).
In patients with Glanzmann thrombasthenia, the onset of bleeding is usually in infancy or childhood. The degree of deficiency in IIb/IIIa may not correlate well with bleeding symptoms. Patients with storage pool disease are affected by variable bleeding, ranging from mild and trauma-related to spontaneous.
In Bernard-Soulier syndrome, there are abnormally large platelets (approaching the size of red cells), moderate thrombocytopenia, and a prolonged bleeding time. Platelet aggregation studies show a marked defect in response to ristocetin, whereas aggregation in response to other agonists is normal; the addition of normal platelets corrects the abnormal aggregation. The diagnosis can be confirmed by platelet flow cytometry.
In Glanzmann thrombasthenia, platelet aggregation studies show marked impairment of aggregation in response to stimulation with various agonists.
Storage pool disease describes defects in the number, content, or function of platelet alpha or dense granules, or both. The gray platelet syndrome comprises abnormalities of platelet alpha granules, thrombocytopenia, and marrow fibrosis. The blood smear shows agranular platelets, and the diagnosis is confirmed with electron microscopy.
Albinism-associated storage pool disease involves defective dense granules in disorders of oculocutaneous albinism, such as the Hermansky-Pudlak and Chediak-Higashi syndromes. Electron microscopy confirms the diagnosis.
Non–albinism-associated storage pool disease results from quantitative or qualitative defects in dense granules and is seen in Ehlers-Danlos and Wiskott-Aldrich syndromes, among others.
The Quebec platelet disorder comprises mild thrombocytopenia, an abnormal platelet factor V molecule, and a prolonged bleeding time. Patients typically experience moderate bleeding. Interestingly, platelet transfusion does not ameliorate the bleeding. Patients have a prolonged bleeding time. Platelet aggregation studies characteristically show platelet dissociation following an initial aggregatory response, and electron microscopy confirms the diagnosis.
The mainstay of treatment (including periprocedural prophylaxis) is transfusion of normal platelets, although desmopressin acetate (DDAVP), antifibrinolytic agents, and recombinant human activated factor VII each have a role in selected clinical situations.
et al. Bernard-Soulier syndrome: an update. Semin Thromb Hemost. 2013 Sep;39(6):656–62.
MP. What to do when you suspect an inherited platelet disorder. Hematology Am Soc Hematol Educ Program. 2011;2011:377–83.
ACQUIRED DISORDERS OF PLATELET FUNCTION
Platelet dysfunction is more commonly acquired than inherited; the widespread use of platelet-altering medications accounts for most of the cases of qualitative defects (Table 14–8). In cases where platelet function is irreversibly altered, platelet inhibition typically recovers within 7–9 days following discontinuation of the drug. In cases where platelet function is non-irreversibly affected, platelet inhibition recovers with clearance of the drug from the system. Transfusion of platelets may be required if clinically significant bleeding is present.
Table 14–8.Causes of acquired platelet dysfunction. |Favorite Table|Download (.pdf) Table 14–8. Causes of acquired platelet dysfunction.
|Cause ||Mechanism(s) ||Treatment of Bleeding |
|Salicylates (eg, aspirin) ||Irreversible inhibition of platelet cyclooxygenase ||Discontinuation of drug; platelet transfusion |
|NSAIDs (eg, ibuprofen) ||Reversible inhibition of cyclooxygenase || |
|Glycoprotein IIb/IIIa inhibitors (eg, abciximab, tirofiban, eptifibatide) ||↓ Binding of fibrinogen to PM IIb/IIIa receptor || |
|Thienopyridines (eg, clopidogrel, ticlopidine) ||↓ ADP binding to PM receptor || |
|Dipyridamole ||↓ Intracellular cAMP metabolism || |
|SSRIs (eg, paroxetine, fluoxetine) ||↓ Serotonin in dense granules || |
|Omega-3 fatty acids (eg, DHA, EHA) ||Disruption of PM phospholipid || |
|Antibiotics (eg, high-dose penicillin, nafcillin, ticarcillin, cephalothin, moxalactam) ||Not fully elucidated; PM binding may interfere with receptor-ligand interactions || |
|Alcohol ||↓ TXA2 release || |
|Uremia ||↑ Nitric oxide; ↓ release of granules ||DDAVP, high-dose estrogens; platelet transfusion, dialysis |
|Myeloproliferative disorder/myelodysplastic syndrome ||Abnormal PM receptors, signal transduction, and/or granule release ||Platelet transfusion; myelosuppressive treatment (myeloproliferative disorder) |
|Surgical Procedure–Related |
|Cardiac bypass ||Platelet activation in bypass circuit ||Platelet transfusion |
Laboratory manifestations of aspirin toxicity include a prolonged epinephrine cartridge closure time in the platelet function analyzer (PFA)-100 system, or a decreased aggregation to low-dose collagen and thrombin (and preserved aggregation in response to high-dose collagen and thrombin) on platelet aggregation studies. Abnormal platelet aggregation studies may be observed in the setting of qualitative platelet defects induced by other conditions, but specific defects vary considerably.
CONGENITAL DISORDERS OF COAGULATION
ESSENTIALS OF DIAGNOSIS
Hemophilia A: congenital deficiency of coagulation factor VIII.
Hemophilia B: congenital deficiency of coagulation factor IX.
Recurrent hemarthroses and arthropathy.
Risk of development of inhibitory antibodies to factor VIII or factor IX.
In many older patients, infection with HIV or hepatitis C virus from receipt of contaminated blood products.
The frequency of hemophilia A is 1 per 5000 live male births, whereas hemophilia B occurs in approximately 1 in 25,000 live male births. Inheritance is X-linked recessive, leading to affected males and carrier females. There is no race predilection. Testing is indicated for male infants with a hemophilic pedigree who are asymptomatic or who experience excessive bleeding, or for an otherwise asymptomatic adolescent or adult who experiences unexpected excessive bleeding with trauma or invasive procedures.
Inhibitors to factor VIII will develop in approximately 30% of patients with severe hemophilia A, and inhibitors to factor IX will develop in less than 5% of patients with severe hemophilia B. The risk of development of an inhibitor to factor VIII or factor IX is highest in patients with severe hemophilia who have a sibling in whom inhibitor formation occurred; the characteristics of initiation of administration of factor replacement in childhood, as well as mutation type, also may be influential. Recent data suggest that recombinant products may have an increased risk of inhibitor formation than products made from pooled plasma.
A substantial proportion of older patients with hemophilia acquired infection with HIV or HCV or both in the 1980s due to exposure to contaminated factor concentrates and blood products.
Severe hemophilia (factor VIII activity less than 1%) presents in infant males or in early childhood with spontaneous bleeding into joints, soft tissues, or other locations. Spontaneous bleeding is rare in patients with mild hemophilia (factor VIII activity greater than 5%), but bleeding may occur with a significant hemostatic challenge (eg, surgery, trauma). Intermediate clinical symptoms are seen in patients with moderate hemophilia (factor VIII activity 1–5%). Female carriers of hemophilia are usually asymptomatic.
Significant hemophilic arthropathy is usually avoided in patients who have received long-term prophylaxis with factor concentrate starting in early childhood, whereas joint disease is common in adults who have experienced recurrent hemarthroses.
Inhibitor development to factor VIII or factor IX is characterized by bleeding episodes that are resistant to treatment with clotting factor VIII or IX concentrate, and by new or atypical bleeding.
Hemophilia is diagnosed by demonstration of an isolated reproducibly low factor VIII or factor IX activity level, in the absence of other conditions. If the aPTT is prolonged, it typically corrects upon mixing with normal plasma. A variety of mutations, including inversions, large and small deletions, insertions, missense mutations, and nonsense mutations may be causative. Depending on the level of residual factor VIII or factor IX activity and the sensitivity of the thromboplastin used in the aPTT coagulation reaction, the aPTT may or may not be prolonged (although it typically is markedly prolonged in severe hemophilia). Hemophilia is classified according to the level of factor activity in the plasma. Severe hemophilia is characterized by less than 1% factor activity, mild hemophilia features greater than 5% factor activity, and moderate hemophilia features 1–5% factor activity. Female carriers may become symptomatic if significant lyonization has occurred favoring the defective factor VIII or factor IX gene, leading to factor VIII or factor IX activity level markedly less than 50%. Typically, a clinical bleeding diathesis occurs once the factor activity is less than 20%, but bleeding can occur in trauma, surgery, and delivery if the factor activity is less than 50%.
In the presence of an inhibitor to factor VIII or factor IX, there is accelerated clearance of and suboptimal or absent rise in measured activity of infused factor, and the aPTT does not correct on mixing. The Bethesda assay measures the potency of the inhibitor.
Plasma-derived or recombinant factor VIII or IX products are the mainstay of treatment. The standard of care for most individuals with severe hemophilia is primary prophylaxis: by the age of 4 years, most children with severe hemophilia have begun twice- or thrice-weekly infusions of factor to prevent the recurrent joint bleeding that otherwise would characterize the disorder and lead to severe musculoskeletal morbidity. In selected cases of nonsevere hemophilia, or as an adjunct to prophylaxis in severe hemophilia, treatment with factor products is given periprocedurally, prior to high-risk activities (such as sports), or as needed for bleeding episodes (Table 14–9). Recombinant factor VIII and factor IX molecules that are bioengineered to have an extended half-life may allow for extended dosing intervals in patients who are treated prophylactically. The decision to switch to a long-acting product is patient specific. The long-acting factor IX products have clear added value in reducing frequency of factor injections. This is not so clear with the long-acting factor VIII products. Patients with mild hemophilia A may respond to as-needed intravenous or intranasal treatment with DDAVP. Antifibrinolytic agents may be useful in cases of mucosal bleeding and are commonly used adjunctively, such as following dental procedures. Delivery of a functional factor IX gene using modified viral vectors continues to be explored in clinical trials, with early results among patients with severe hemophilia B showing encouraging results with improvement in the baseline factor IX to levels that will transform the patient’s lives and reduce or eliminate the need for prophylactic infusions of factor IX protein.
Table 14–9.Treatment of bleeding in selected inherited disorders of hemostasis. |Favorite Table|Download (.pdf) Table 14–9. Treatment of bleeding in selected inherited disorders of hemostasis.
|Disorder ||Subtype ||Treatment for Minor Bleeding ||Treatment for Major Bleeding ||Comment |
|Hemophilia A ||Mild ||DDAVP1 ||DDAVP1 or factor VIII product ||Treat for 3–10 days for major bleeding or following surgery, keeping factor activity level 50–80% initially. Adjunctive aminocaproic acid (EACA) may be useful for mucosal bleeding or procedures |
| ||Moderate or severe ||Factor VIII product ||Factor VIII product |
|Hemophilia B ||Mild, moderate, or severe ||Factor IX product ||Factor IX product |
|von Willebrand disease ||Type 1 ||DDAVP ||DDAVP, vWF product |
| ||Type 2 ||DDAVP,1 vWF product ||vWF product |
| ||Type 3 ||vWF product ||vWF product |
|Factor XI deficiency ||— ||FFP or EACA ||FFP ||Adjunctive EACA should be used for mucosal bleeding or procedures |
It may be possible to overcome low-titer inhibitors (less than 5 Bethesda units [BU]) by giving larger doses of factor, whereas treatment of bleeding in the presence of a high-titer inhibitor (more than 5 BU) requires infusion of an activated prothrombin complex concentrate (such as FEIBA [factor eight inhibitor bypassing activity]) or recombinant activated factor VII. Inhibitor tolerance induction, achieved by giving large doses (50–300 units/kg intravenously of factor VIII daily) for 6–18 months, succeeds in eradicating the inhibitor in 70% of patients with hemophilia A and in 30% of patients with hemophilia B. Patients with hemophilia B who receive inhibitor tolerance induction, however, are at risk for development of nephrotic syndrome and anaphylactic reactions, making eradication of their inhibitors less feasible. Additional immunomodulation may allow for eradication in selected inhibitor tolerance induction–refractory patients.
The cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drug, celecoxib, may be used to treat arthritis symptoms; generally, other NSAIDs and aspirin should be avoided due to the increased risk of bleeding from inhibition of platelet function. Oral opioid medications are commonly used to control pain, including joint pain and surgical pain from the often-needed total joint replacements.
Antiretroviral treatment is almost universally administered to individuals with HIV infection. Patients with hepatitis C infection should be referred for treatment to eradicate the virus.
All patients with hemophilia should be seen regularly in a comprehensive hemophilia treatment center.
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2. von Willebrand Disease
ESSENTIALS OF DIAGNOSIS
The most common inherited bleeding disorder.
von Willebrand factor binds platelets to subendothelial surfaces, aggregates platelets, and prolongs the half-life of factor VIII.
vWF is an unusually large multimeric glycoprotein that binds to its receptor, platelet glycoprotein Ib, bridging platelets to the subendothelial matrix at the site of vascular injury and contributing to linking them together in the platelet plug. vWF also has a binding site for factor VIII, prolonging its half-life in the circulation.
Between 75% and 80% of patients with vWD have type 1, a quantitative abnormality of the vWF molecule that usually does not feature an identifiable causal mutation in the vWF gene.
Type 2 vWD is seen in 15–20% of patients with vWD. In type 2A or 2B vWD, a qualitative defect in the vWF molecule is causative. Type 2N and 2M vWD are due to defects in vWF that decrease binding to factor VIII or to platelets, respectively. Importantly, type 2N vWD clinically resembles hemophilia A, with the exception of a family history that shows affected females. Factor VIII activity levels are markedly decreased, and vWF activity and antigen (Ag) are normal. Type 2M vWD features a normal multimer pattern. Type 3 vWD is rare, and like type 1, is a quantitative defect, with mutational homozygosity or double heterozygosity yielding undetectable levels of vWF and severe bleeding in infancy or childhood.
Patients with type 1 vWD usually have mild or moderate platelet-type bleeding (especially involving the integument and mucous membranes). Patients with type 2 vWD usually have moderate to severe bleeding that presents in childhood or adolescence. Patient with type 3 vWD demonstrate a severe bleeding phenotype.
In type 1 vWD, the vWF activity (by ristocetin co-factor assay) and the vWF Ag are mildly depressed, whereas the vWF multimer pattern is normal (Table 14–10). Laboratory testing of type 2A or 2B vWD typically shows a ratio of vWF Ag:vWF activity of approximately 2:1 and a multimer pattern that lacks the highest molecular weight multimers. Thrombocytopenia is common in type 2B vWD due to a gain-of-function mutation of the vWF molecule, which leads to increased binding to its receptor on platelets, resulting in clearance; a ristocetin-induced platelet aggregation (RIPA) study shows an increase in platelet aggregation in response to low concentrations of ristocetin. Except in the more severe forms of vWD that feature a significantly decreased factor VIII activity, the aPTT and PT in vWD are usually normal.
Table 14–10.Laboratory diagnosis of von Willebrand disease. |Favorite Table|Download (.pdf) Table 14–10. Laboratory diagnosis of von Willebrand disease.
|Type ||vWF Activity ||vWF Antigen ||Factor VIII ||RIPA ||Multimer Analysis |
|1 || ||↓ ||↓ ||Nl or ↓ ||↓ ||Normal pattern; uniform ↓ intensity of bands |
|2 ||A ||↓↓ ||↓ ||↓ ||↓ ||Large and intermediate multimers decreased or absent |
| ||B ||↓↓ ||↓ ||↓ ||↑ ||Large multimers decreased or absent |
| ||M ||↓ ||↓ ||↓ ||↓ ||Normal pattern; uniform ↓ intensity of bands |
| ||N ||Nl ||Nl ||↓↓ ||Nl ||Nl |
|3 || ||↓↓↓ ||↓↓↓ ||↓↓↓ ||↓↓↓ ||Multimers absent |
The treatment of vWD is outlined in Table 14–9. DDAVP is useful in the treatment of mild bleeding in most cases of type 1 and some cases of type 2 vWD. DDAVP causes release of vWF and factor VIII from storage sites, leading to increases in vWF and factor VIII twofold to sevenfold that of baseline levels. A therapeutic trial to document sufficient vWF levels posttreatment is strongly recommended. Due to tachyphylaxis and the risk of significant hyponatremia secondary to fluid retention, more than two doses should not be given in a 48-hour period. vWF-containing factor VIII concentrates or recombinant VWF products are used in all other clinical scenarios, and when bleeding is not controlled with DDAVP. Cryoprecipitate should not be given due to lack of viral inactivation. Antifibrinolytic agents (eg, aminocaproic acid or tranexamic acid) may be used adjunctively for mucosal bleeding or procedures. Pregnant patients with vWD usually do not require treatment at the time of delivery because of the natural physiologic increase in vWF levels (up to threefold that of baseline) that are observed by parturition. However, levels need to be confirmed in late pregnancy, and if they are low or if excessive bleeding is encountered, vWF products may be given. Moreover, patients are at risk for significant bleeding for a few days postpartum when vWF levels fall secondary to the fall in estrogen levels.
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Factor XI deficiency (also called hemophilia C) is inherited in an autosomal recessive manner, leading to heterozygous or homozygous defects. It is most prevalent among individuals of Ashkenazi Jewish descent. Levels of factor XI, while variably reduced, do not correlate well with bleeding symptoms. Mild bleeding is most common, and surgery or trauma may expose or worsen the bleeding tendency. FFP is the mainstay of treatment in locales where the plasma-derived factor XI concentrate is not available. Administration of adjunctive aminocaproic acid or tranexamic acid is regarded as mandatory for procedures or bleeding episodes involving the mucosa (Table 14–9).
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4. Less Common Heritable Disorders of Coagulation
Congenital deficiencies of clotting factors II, V, VII, and X are rare and typically are inherited in an autosomal recessive pattern. A prolongation in the PT (and aPTT for factor X, factor V, and factor II deficiency) that corrects upon mixing with normal plasma is typical. Definitive diagnosis requires testing for specific factor activity. The treatment of factor II deficiency is with a prothrombin complex concentrate; factor V deficiency is treated with infusions of FFP or platelets (which contain factor V in alpha granules); factor VII deficiency is treated with recombinant human activated factor VII at 15–30 mcg/kg every 4–6 hours. Factor X deficiency, previously treated with FFP, can now be treated with a FDA-approved plasma-derived factor X product (Coagadex).
Deficiency of factor XIII, a transglutamase that cross-links fibrin, characteristically leads to delayed bleeding that occurs hours to days after a hemostatic challenge (such as surgery or trauma). The condition is usually life-long, and spontaneous intracranial hemorrhages as well as recurrent pregnancy loss appear to occur with increased frequency in these patients compared with other congenital deficiencies. Cryoprecipitate or infusion of a plasma-derived factor XIII concentrate (appropriate for patients with A-subunit deficiency only) is the treatment of choice for bleeding or surgical prophylaxis. Factor XIII deficiency does not cause a prolongation of the PT or aPTT.
Alpha-2-antiplasmin deficiency is a rare disorder that leads to accelerated fibrinolysis via insufficient inhibition of plasmin. Heterozygosity for the condition usually produces a mild bleeding tendency, while bleeding symptoms in homozygotes may be severe. The diagnosis is made by a documented antiplasmin level below the reference range; the aPTT and PT are normal. In some cases, treatment of bleeding or surgical prophylaxis is with aminocaproic acid. A congenital deficiency of plasminogen activator I (PAI-1) is extremely rare and can lead to mild to moderate bleeding; testing for the disorder can be difficult due to the extremely low extension of the normal reference range for PAI-1.
Congenital afibrinogenemia is exceedingly rare and produces mild to severe bleeding; the frequency of first trimester miscarriage is increased among women with the disorder. The PT is more typically prolonged than the aPTT, and a functional fibrinogen assay shows reduced activity. Treatment is with a fibrinogen concentrate (RiaSTAP) (preferred and now FDA approved), cryoprecipitate, or FFP and is aimed at increasing the plasma fibrinogen concentration to greater than 80 mg/dL.
Congenital deficiencies of factor XII, prekallikrein, high molecular-weight kininogen may lead to a prolonged aPTT that corrects with extended incubation but do not lead to bleeding.
et al. Rare coagulation disorders: fibrinogen, factor VII and factor XIII. Haemophilia. 2016 Jul;22(Suppl 5):61–5.
et al. Rare bleeding disorders: worldwide efforts for classification, diagnosis, and management. Semin Thromb Hemost. 2013 Sep;39(6):579–84.
ACQUIRED DISORDERS OF COAGULATION
1. Acquired Antibodies to Factor VIII
Spontaneous antibodies to factor VIII occasionally occur in adults without a prior history of hemophilia; older adults and patients with lymphoproliferative malignancy or connective tissue disease and those who are postpartum or postsurgical are at highest risk. The clinical presentation typically includes extensive soft tissue ecchymoses, hematomas, and mucosal bleeding, as opposed to hemarthrosis in congenital hemophilia A. The aPTT is typically prolonged and does not correct upon mixing; factor VIII activity is found to be low and a Bethesda assay reveals the titer of the inhibitor. Inhibitors of low titer (less than 5 BU) may often be overcome by infusion of high doses of factor VIII concentrates, whereas high-titer inhibitors (greater than 5 BU) must be treated with serial infusions of activated prothrombin complex concentrates, recombinant human activated factor VII, or recombinant porcine factor VIII (hemophilia A patients only). Along with establishment of hemostasis by one of these measures, immunosuppressive treatment with corticosteroids and oral cyclophosphamide should be instituted; treatment with IVIG, rituximab, or plasmapheresis can be considered in refractory cases. Unlike in congenital factor VIII deficiency, the patient’s bleeding does not correlate well with the factor VIII activity level, so the clinician must be concerned with any elevation of aPTT secondary to acquired factor VIII inhibitor. All such patients require referral to a hematologist.
et al. Laboratory diagnosis of acquired hemophilia A: limitations, consequences, and challenges. Semin Thromb Hemost. 2014 Oct;40(7):803–11.
et al. Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. Blood. 2015 Feb 12;125(7):1091–7.
et al. Interventions for treating acute bleeding episodes in people with acquired hemophilia A. Cochrane Database Syst Rev. 2014 Aug 28;8:CD010761.
2. Acquired Antibodies to Factor II
Patients with antiphospholipid antibodies occasionally manifest specificity to coagulation factor II (prothrombin), leading typically to a severe hypoprothrombinemia and bleeding. Mixing studies may or may not reveal presence of an inhibitor, as the antibody typically binds a non-enzymatically active portion of the molecule that leads to accelerated clearance, but characteristically the PT is prolonged and levels of factor II are low. FFP should be administered for treatment of bleeding. Treatment is immunosuppressive.
3. Acquired Antibodies to Factor V
Products containing bovine factor V (such as topical thrombin or fibrin glue, frequently used in surgical procedures) can lead to formation of an anti–factor V antibody that cross-reacts with human factor V. Clinicopathologic manifestations range from a prolonged PT in an otherwise asymptomatic individual to severe bleeding. Mixing studies suggest the presence of an inhibitor, and the factor V activity level is low. In cases of serious or life-threatening bleeding, IVIG or platelet transfusions, or both, should be administered, and immunosuppression (as for acquired inhibitors to factor VIII) may be offered.
Vitamin K deficiency may occur as a result of deficient dietary intake of vitamin K (from green leafy vegetables, soybeans, and other sources), malabsorption, or decreased production by intestinal bacteria (due to treatment with chemotherapy or antibiotics). Vitamin K is required for normal function of vitamin K epoxide reductase that assists in posttranslational gamma-carboxylation of the coagulation factors II, VII, IX, and X, which is necessary for their activity. Thus, vitamin K deficiency typically features a prolonged PT (activity of the vitamin K–dependent factors is more reflected than in the aPTT) that corrects upon mixing; activity levels of individual clotting factors II, VII, IX, and X typically are low. Importantly, a concomitantly low factor V activity level is not indicative of isolated vitamin K deficiency, and may indicate an underlying defect in liver synthetic function.
For treatment, vitamin K1 (phytonadione) may be administered via intravenous or oral routes; the subcutaneous route is not recommended due to erratic absorption. The oral dose is 5–10 mg/day and absorption is typically excellent; at least partial improvement in the PT should be observed within 1 day of administration. Intravenous administration (1–5 mg/day) results in even faster normalization of a prolonged PT than oral administration; due to descriptions of anaphylaxis, parenteral doses should be administered at lower doses and slowly (eg, over 30 minutes) with concomitant monitoring.
5. Coagulopathy of Liver Disease
Impaired hepatic function due to cirrhosis or other causes leads to decreased synthesis of clotting factors, including factors II, V, VII, and IX, and fibrinogen, whereas factor VIII levels may be elevated in spite of depressed levels of other coagulation factors. The PT (and with advanced disease, the aPTT) is typically prolonged and usually corrects on mixing with normal plasma. A normal factor V level, in spite of decreases in the activity of factors II, VII, IX, and X, however, suggests vitamin K deficiency rather than liver disease. Qualitative and quantitative deficiencies of fibrinogen also are prevalent among patients with advanced liver disease, typically leading to a prolonged PT, thrombin time, and reptilase time.
The coagulopathy of liver disease usually does not require hemostatic treatment until bleeding occurs. Infusion of FFP may be considered if active bleeding is present and the aPTT and PT are markedly prolonged; however, the effect is transient and concern for volume overload may limit infusions. Patients with bleeding and a fibrinogen level consistently below 80–100 mg/dL should receive cryoprecipitate. Liver transplantation, if feasible, results in production of coagulation factors at normal levels. The use of recombinant human activated factor VII in patients with bleeding varices is controversial, although some patient subgroups may experience benefit.
et al. Coagulopathy in liver diseases: complication or therapy? Dig Dis. 2014;32(5):609–14.
et al. Acquired factor V inhibitors: a systematic review. J Thromb Thrombolysis. 2011 May;31(4):449–57.
et al. The coagulopathy of liver disease: does vitamin K help? Blood Coagul Fibrinolysis. 2013 Jan;24(1):10–7.
et al. The coagulopathy of chronic liver disease. N Engl J Med. 2011 Jul 14;365(2):147–56.
7. Disseminated Intravascular Coagulation
The consumptive coagulopathy of DIC is typically initiated by excessive tissue factor exposure or release and results in decreases in the activity of clotting factors. The result can be bleeding or thrombosis in any given patient. The aPTT and PT are characteristically prolonged, and platelets and fibrinogen levels are reduced from baseline.
8. Heparin/Fondaparinux/Direct-Acting Oral Anticoagulant Use
The thrombin time is dramatically prolonged in the presence of heparin. Patients who are receiving heparin and who have bleeding should be managed by discontinuation of the heparin and, in some cases, administration of protamine sulfate; 1 mg of protamine neutralizes approximately 100 units of heparin sulfate, and the maximum dose is 50 mg intravenously. LMWHs typically do not prolong clotting times and are poorly or incompletely reversible with protamine. There is no reversal agent for fondaparinux, although some experts have suggested using recombinant human activated factor VIIa for cases of life-threatening bleeding. The direct-acting oral anticoagulants (DOACs) include DTIs (eg, dabigatran) and factor Xa inhibitors (eg, rivaroxaban, apixaban, and edoxaban). Dabigatran has a reversal agent, a monoclonal antibody called idarucizumab. Reversal agents for the factor Xa inhibitors are still in development or awaiting FDA approval (eg, andexanet alfa, a recombinant modified human factor Xa decoy protein).
et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131–41.
et al. Novel antidotes for target specific oral anticoagulants. Exp Hematol Oncol. 2015 Sep 15;4:25.
et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015 Dec 17;373(25):2413–24.
Lupus anticoagulants prolong clotting times (aPTT) by binding proteins associated with phospholipid, which is a necessary component of coagulation reactions, but they do not lead to bleeding. In fact, they predispose to thrombosis. Lupus anticoagulants were so named because of their early identification in patients with connective tissue disease, although they also occur with increased frequency in individuals with underlying infection, inflammation, or malignancy, and they also can occur in asymptomatic individuals in the general population. A prolongation in the aPTT is observed that does not correct completely on mixing but that normalizes with excessive phospholipid. Specialized testing such as the hexagonal phase phospholipid neutralization assay, the dilute Russell viper venom time, and platelet neutralization assays can confirm the presence of a lupus anticoagulant.
M. Measurement of lupus anticoagulants: an update on quality in laboratory testing. Semin Thromb Hemost. 2013 Apr;39(3):267–71.
Occasionally, abnormalities of the vasculature and integument may lead to bleeding despite normal hemostasis; congenital or acquired disorders may be causative. These abnormalities include Ehlers-Danlos syndrome, osteogenesis imperfecta, Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia), and Marfan syndrome (heritable defects) and integumentary thinning due to prolonged corticosteroid administration or normal aging, amyloidosis, vasculitis, and scurvy (acquired defects). The bleeding time often is prolonged. The bleeding time reflects the integrity of the vasculature (which is abnormal in collagen synthesis disorders) in addition to activity of platelets and coagulation factors. If possible, treatment of the underlying condition should be pursued, but if this is not possible or feasible (ie, congenital syndromes), globally hemostatic agents such as DDAVP can be considered for treatment of bleeding. Topical bevacizumab has been effective in some patients with refractory nosebleeds.
et al; ATERO Study Group. Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. J Thromb Haemost. 2014 Sep;12(9):1494–502.
et al. Bevacizumab in the treatment of hereditary hemorrhagic telangiectasia. Expert Opin Biol Ther. 2013 Sep;13(9):1315–23.
et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011 Jul;13(7):607–16.
The currently available anticoagulants include unfractionated heparin, LMWHs, fondaparinux, vitamin K antagonist (ie, warfarin), and DOACs (ie, dabigatran, rivaroxaban, apixaban, edoxaban). (For a discussion of the injectable DTIs, see section Heparin-Induced Thrombocytopenia above.)
Classes of Anticoagulants
A. Unfractionated Heparin and LMWHs
Unfractionated heparin is a repeating polymer of sulfated glycosaminoglycans that is most commonly derived from porcine intestinal tissue, which is rich in heparin-bearing mast cells. A biologic product, it is extremely heterogeneous with respect to sulfation and polymer length; individual molecules may range from 3000 to 30,000. In addition, only about one-third of the molecules in a given preparation of unfractionated heparin contain the crucial pentasaccharide sequence that is necessary for binding of antithrombin and, through conversion of thrombin from a slow inhibitor of coagulation factor activity to a rapid inhibitor, exertion of its anticoagulant effect. Heparin is highly negatively charged, and upon intravenous infusion, it binds to a large array of blood components, such as endothelial cells, platelets, mast cells, and plasma proteins. The pharmacokinetics of unfractionated heparin are poorly predictable, and the degree of anticoagulation is typically monitored (by aPTT or anti-Xa level) in patients who are receiving the drug in therapeutic doses. Only a fraction of an infused dose of heparin is metabolized by the kidneys, however, making it safe to use in most patients with significant kidney disease.
The LMWHs are produced from chemical depolymerization of unfractionated heparin, resulting in products of lower molecular weight (mean molecular weight, 4500–6500d, depending on the LMWH). Due to less protein and cellular binding, the pharmacokinetics of the LMWHs are much more predictable than those of unfractionated heparin, allowing for fixed weight-based dosing. All LMWHs are principally renally cleared and must be avoided or used with extreme caution in individuals with creatinine clearance less than 30 mL/min. A longer half-life permits once- or twice-daily subcutaneous dosing, allowing for greater convenience and outpatient therapy in selected cases. Most patients do not require monitoring, although monitoring using the anti-Xa activity level is appropriate for patients with moderate kidney disease, those with elevated body mass index or low weight, and selected pregnant patients. About 30% of the molecules in a dose of LMWH are long enough (ie, sufficiently negatively charged) to bind protamine sulfate, allowing for some neutralization of anticoagulant effect. LMWHs are associated with a lower frequency of HIT (approximately 0.6%) than unfractionated heparin.
Fondaparinux, which is chemically related to LMWHs, is a synthetic molecule consisting of the highly active pentasaccharide sequence. As such, it exerts almost no thrombin inhibition and works to indirectly inhibit factor Xa through binding to antithrombin. Fondaparinux, like the LMWHs, is almost exclusively metabolized by the kidneys, and should be avoided in patients with creatinine clearance less than 30 mL/min. Predictable pharmacokinetics allow for weight-based dosing. A particularly long half-life (17–21 hours) allows for once-daily subcutaneous dosing, but the absence of necessary charge characteristics leads to a lack of binding to protamine sulfate; therefore, unlike heparin, no effective neutralizing agent exists.
C. Vitamin K Antagonist (Warfarin)
The vitamin K antagonist warfarin inhibits the activity of the vitamin K–dependent carboxylase that is important for the posttranslational modification of coagulation factors II, VII, IX, and X. Although warfarin may be taken orally, leading to a significant advantage over the heparins and heparin derivatives, which must be given parenterally or subcutaneously, interindividual differences in response to the agent related to nutritional status, comorbid diseases, concomitant medications, and genetic polymorphisms lead to a poorly predictable anticoagulant response. Individuals taking warfarin must undergo periodic monitoring to verify the intensity of the anticoagulant effect. The intensity of anticoagulant effect is reported as the INR, which corrects for differences in potency of commercially available thromboplastin used to perform the PT.1
D. Direct-Acting Oral Anticoagulants
Unlike warfarin, the DOACs (1) have a predictable dose effect and therefore do not require laboratory monitoring, (2) have anticoagulant activity independent of vitamin K with no need for dietary stasis, and (3) are renally metabolized to varying degrees so there are restrictions or dose reductions related to reduced kidney function (Table 14–11). While the DOACs have fewer drug interactions than warfarin, if DOACs are given with a potentially interacting medication, there is no reliable way to measure the impact on anticoagulant activity of the concomitant administration. Providers must consider these features when choosing between warfarin and DOAC for each patient.
Table 14–11.Direct-acting oral anticoagulants (DOACs) for VTE treatment and prevention.1 |Favorite Table|Download (.pdf) Table 14–11. Direct-acting oral anticoagulants (DOACs) for VTE treatment and prevention.1
| ||Dabigatran ||Rivaroxaban ||Apixaban ||Edoxaban |
|Mechanism ||Oral direct thrombin inhibitor ||Oral direct factor Xa inhibitor ||Oral direct factor Xa inhibitor ||Oral direct factor Xa inhibitor |
|Approved uses || |
VTE treatment and secondary prevention
VTE replacement prophylaxis following hip replacement
VTE treatment and secondary prevention
VTE prophylaxis post-hip or knee replacement
VTE treatment and secondary prevention
VTE prophylaxis post-hip or knee replacement
VTE treatment and secondary prevention
|Frequency of dosing ||Twice daily || |
Twice daily for first 21 days of acute VTE therapy, then daily
Once daily for DVT prevention
|Twice daily ||Once daily |
|Food ||With or without food ||With food (for 15- and 20-mg tablets) ||With or without food ||With or without food |
|Crushable? ||No ||Can crush; do not administer via J tube ||Can crush and administer orally or via NG tube ||No data |
|Renal clearance ||80% ||30–60% ||25% ||50% |
|Kinetics ||t ½ = 12–17 hours; tmax = 2 hours ||t ½ = 5–9 hours; tmax = 3 hours ||t ½ = 12 hours; tmax = 3 hours ||t ½ = 10–14 hours; tmax = 2 hours |
|Influences INR? ||↑ (or →) ||↑↑ (or → at low concentrations) ||↑ (or →) ||↑ |
|Influences aPTT? ||↑↑ ||↑ ||↑ ||↑ |
|Drug interactions (list not comprehensive) || |
Avoid rifampin, St John’s wort, and possibly carbamazepine
Caution with amiodarone, clarithromycin, dronedarone, ketoconazole, quinidine, verapamil. No dosage adjustment of dabigatran is recommended if CrCl > 50 mL/min
Reduce dose to 75 mg orally twice daily if CrCl 30–50 mL/min and concurrent use of dronedarone or ketoconazole
Avoid carbamazepine, conivaptan, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, phenytoin, rifampin, ritonavir, St John’s wort
Caution with the concurrent use of combined P-gp inhibitors and/or weak or moderate inhibitors of CYP3A4 (eg, amiodarone, azithromycin, diltiazem, dronedarone, erythromycin, felodipine, quinidine, ranolazine, verapamil) with rivaroxaban, particularly in patients with impaired kidney function
Avoid carbamazepine, phenytoin, rifampin, St John’s wort
Avoid clarithromycin, itraconazole, ketoconazole, and ritonavir in patients already taking apixaban even at a reduced dose of 2.5 mg twice daily
Caution with clarithromycin, itraconazole, ketoconazole, and ritonavir
Reduce dose with certain P-gp inhibitors. Use has not been studied with many other P-gp inhibitors and inducers
Some recommend avoiding concomitant use altogether
Switching from DOAC to warfarin
(per AC Forum Clinical Guidance: either approach [ie, stop DOAC then
start LMWH and warfarin; or overlap warfarin with DOAC] can be used for all DOAC to warfarin transitions.
If overlapping warfarin and DOAC, measure INR just before next DOAC dose and stop DOAC when INR ≥ 2.0)
Start warfarin and overlap with dabigatran;
CrCl C50 mL/min, overlap 3 days
CrCl 30–50 mL/min, overlap 2 days
CrCl 15–30 mL/min, overlap 1 day
Stop DOAC; start warfarin and LMWH at time of
next scheduled DOAC dose and bridge until
INR ≥ 2.0
Stop DOAC; start warfarin and LMWH at time of
next scheduled DOAC dose and bridge until
INR ≥ 2.0
For 60-mg dose, reduce dose to 30 mg and start
For 30-mg dose reduce dose to 15 mg and start
Stop edoxaban when INR ≥ 2.0
|Warfarin to DOAC ||Start when INR < 2.0 ||Start when INR < 3.0 ||Start when INR < 2.0 ||Start when INR ≤ 2.5 |
|Special considerations || |
Dyspepsia is common and starts within first 10 days
GI bleeding risk higher with dabigatran vs warfarin
|GI bleeding risk higher with rivaroxaban vs warfarin || ||Do not use if CrCl ≥ 95 mL/min |
|Management of life-threatening bleeding ||Idarucizumab 2 doses of 2.5 g intravenously no more than 15 min apart ||Activated charcoal, supportive care, consider 4-component PCC ||Activated charcoal, supportive care, consider 4-component PCC ||Activated charcoal, supportive care, consider 4-component PCC |
Dabigatran etexilate is an oral DOAC that is approved for use in the United States for the following indications: (1) preventing stroke and systemic embolism in nonvalvular atrial fibrillation, (2) treating DVT and pulmonary embolism (PE) in patients who have been received a parenteral anticoagulant for 5–10 days, (3) reducing the risk of recurrence of DVT and PE in patients who have been previously treated, and (4) prophylaxis against DVT and PE following hip replacement surgery. It prevents thrombus formation by inhibiting both clotbound and free thrombin and thrombin-induced platelet aggregation. It is a prodrug that is converted to dabigatran with peak effect within 2 hours. Steady state is reached within 3 days. As renal excretion accounts for about 80% of clearance, dose adjustment is required for creatinine clearance of 15–30 mL/min in patients with nonvalvular atrial fibrillation; this agent cannot be recommended for patients with creatinine clearances less than 15–30 mL/min depending on indication (Table 14–11). As a substrate of the p-glycoprotein (P-gp) transport system, concomitant use of strong inducers, eg, rifampin, should be avoided and caution is advised with concomitant use of strong P-gp inhibitors (eg, ketoconazole and dronedarone) in patients with normal kidney function while drug dose reduction or avoidance is recommended for concomitant use in those with creatinine clearances less than 30–50 mL/min or less depending on indication (Table 14–11). The half-life of the dabigatran etexilate is 12–17 hours. Non–life-threatening bleeding may be treated by holding dabigatran, maintaining diuresis, providing supportive measures, and administering charcoal (if a dose was recently ingested). Idarucizumab is an antibody fragment that binds to dabigatran to neutralize its activity, reversing the anticoagulant effect in minutes. It is indicated when reversal of the anticoagulant effect of dabigatran is needed for emergency surgery, urgent procedures, or in life-threatening or uncontrolled bleeding.
Rivaroxaban is an oral direct factor Xa inhibitor that is approved in the United States for the following indications: (1) preventing venous thrombosis following hip or knee replacement, (2) preventing nonvalvular atrial fibrillation–associated stroke, (3) treating acute venous thrombosis, and (4) reducing the risk of recurrence of VTE. Its half-life ranges from 5 hours to 13 hours (longer in elderly patients). As renal excretion accounts for about 35% of clearance, dose adjustment is required for creatinine clearances 30–50 mL/min in patients with atrial fibrillation. This agent cannot be recommended for patients with creatinine clearances less than 15–30 mL/min (Table 14–11). Concomitant use of agents that are strong inducers or inhibitors of P-gp should be avoided and caution is recommended with the concomitant administration of combined P-gp inhibitors and/or weak or moderate inhibitors of CYP3A4 (eg, amiodarone, azithromycin, diltiazem, dronedarone, erythromycin, felodipine, quinidine, ranolazine, verapamil) particularly in patients with impaired renal function. As it has no antidote, rivaroxaban-associated bleeding may be treated by withholding the drug while the anticoagulant effect dissipates and by administration of activated charcoal (if a dose was recently ingested). For patients with life-threatening bleeding, use of prothrombin complex concentrate, 4-component prothrombin complex concentrate, recombinant factor VIIa may be considered. Protamine and vitamin K are not expected to affect the anticoagulant activity of the DOACs.
Apixaban is an oral direct factor Xa inhibitor approved in the United States for the following indications: (1) preventing stroke in nonvalvular atrial fibrillation, (2) prophylaxis of DVT following hip and knee surgery, (3) treating acute VTE, and (4) preventing recurrent VTE. It has a half-life of about 12 hours in patients with normal kidney function. Simultaneous use of strong inducers of CYP3A4 and P-gp reduces blood levels of apixaban, and concomitant use should be avoided. Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of apixaban, and concomitant use should be avoided but if necessary dose reduction is recommended. While all four of the currently approved DOACs are renally cleared, apixaban, relies least on the kidneys; only 25% is renally excreted. However, dose reduction is still recommended in patients with nonvalvular atrial fibrillation with two of three of the following: older than 80 years and less than 60 kg or serum creatinine greater than 1.5 mg/dL. This agent cannot be recommended for patients with creatinine clearances less than 15 mL/min (Table 14–11.) The approach to life-threatening bleeding is the same as outlined for rivaroxaban.
Edoxaban is an oral direct factor Xa inhibitor approved in the United States for the following indications: (1) reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and (2) treating DVT and PE after 5–10 days of initial therapy with a parenteral anticoagulant. Its onset of action is 1–2 hours and half-life is 10–14 hours. Edoxaban should not be used in patients with creatinine clearance greater than 95 mL/min as therapy for nonvalvular atrial fibrillation because of an increased risk of ischemic stroke compared to warfarin. As renal excretion accounts for about 50% of clearance, dose adjustment is required for patients taking edoxaban for nonvalvular atrial fibrillation and creatinine clearances less than 15–50 mL/min and in patients being treated for VTE with creatinine clearances 15–50 mL/min or body weight less than or equal to 60 kg or who use certain P-gp inhibitors. Edoxaban is not recommended in those with creatinine clearances less than 15 mL/min (Table 14–11). The approach to life-threatening bleeding is the same as rivaroxaban.
Routine monitoring is not recommended for patients taking DOACs. However, there are clinical scenarios where assessing anticoagulant activity would be helpful, including active bleeding, pending urgent surgery, suspected therapeutic failure, or concern for accumulation. There is no standardized laboratory assay to measure anticoagulant effect of the DOACs. They have varying effects on the PT and aPTT. A normal thrombin time excludes the presence of clinically relevant dabigatran levels; a normal aPTT likely excludes excess drug levels of dabigatran. A negative anti-Xa level likely excludes clinically relevant levels of rivaroxaban, apixaban, or edoxaban; a normal PT likely excludes excess drug levels of rivaroxaban but not apixaban or edoxaban. The INR is unreliable for the evaluation of factor Xa activity.
et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e44S–88S.
et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016 Jan;41(1):206–32.
A. Laboratory measurement of the non-vitamin K antagonist oral anticoagulants: selecting the optimal assay based on drug, assay availability, and clinical indication. J Thromb Thrombolysis. 2016 Feb;41(2):241–7.
et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e24S–43S. Erratum in: Chest. 2012 May;141(5):1369. Dosage error in article text.
et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015 Oct;17(10):1467–507.
et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e152S–84S.
et al. Oral direct thrombin
inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database Syst Rev. 2015 Jun 30;6:CD010956.
et al. Oral direct thrombin
inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism. Cochrane Database Syst Rev. 2015 Dec 4;12:CD010957.
et al. Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016 Jan;41(1):187–205.
Prevention of Venous Thromboembolic Disease
The frequency of venous thromboembolic disease (VTE) among hospitalized patients ranges widely; up to 20% of medical patients and 80% of critical care patients and high-risk surgical patients have been reported to experience this complication, which includes DVT and PE.
Avoidance of fatal PE, which occurs in up to 5% of high-risk inpatients as a consequence of hospitalization or surgery is a major goal of pharmacologic prophylaxis. Tables 14–12 and 14–13 provide risk stratification for DVT/VTE among hospitalized surgical and medical inpatients. Standard pharmacologic prophylactic regimens are listed in Table 14–14. Prophylactic strategies should be guided by individual risk stratification, with all moderate- and high-risk patients receiving pharmacologic prophylaxis, unless contraindicated. Contraindications to VTE prophylaxis for hospital inpatients at high risk for VTE are listed in Table 14–15. In patients at high risk for VTE with absolute contraindications to pharmacologic prophylaxis, mechanical devices such as intermittent pneumatic compression devices should be used, ideally portable devices with at least an 18-hour daily wear time.
Table 14–12.Risk stratification for DVT/VTE among surgical inpatients. |Favorite Table|Download (.pdf) Table 14–12. Risk stratification for DVT/VTE among surgical inpatients.
Recent major orthopedic surgery/arthroplasty/fracture
Abdominal/pelvic cancer undergoing surgery
Recent spinal cord injury or major trauma within 90 days
More than three of the intermediate risk factors (see below)
Not ambulating independently outside of room at least twice daily
Active infectious or inflammatory process
Major surgery (nonorthopedic)
History of VTE
Central venous access or PICC line
Inflammatory bowel disease
Prior immobilization (> 72 hours) preoperatively
Obesity (BMI > 30)
Patient age > 50 years
Hormone replacement or oral contraceptive therapy
HF (systolic dysfunction)
Minor procedure and age < 40 years with no additional risk factors
Ambulatory with expected length of stay of < 24 hours or minor surgery
Table 14–13.Padua Risk Assessment Model for VTE prophylaxis in hospitalized medical patients. |Favorite Table|Download (.pdf) Table 14–13. Padua Risk Assessment Model for VTE prophylaxis in hospitalized medical patients.
|Condition ||Points1 |
|Active cancer, history of VTE, immobility, laboratory thrombophilia ||3 points each |
|Recent (≤ 1 mo) trauma and/or surgery ||2 points each |
|Age ≥ 70, acute MI or CVA, acute infection, rheumatologic disorder, BMI ≥ 30, hormonal therapy ||1 point each |
Table 14–14.Pharmacologic prophylaxis of VTE in selected clinical scenarios.1 |Favorite Table|Download (.pdf) Table 14–14. Pharmacologic prophylaxis of VTE in selected clinical scenarios.1
|Anticoagulant ||Dose ||Frequency ||Clinical Scenario ||Comment |
|Enoxaparin ||40 mg subcutaneously ||Once daily ||Most medical inpatients and critical care patients ||— |
| || || ||Surgical patients (moderate risk for VTE) || |
| || || ||Abdominal/pelvic cancer surgery ||Consider continuing for 4 weeks total duration after abdomino-pelvic cancer surgery |
| || ||Twice daily ||Bariatric surgery ||Higher doses may be required |
| ||30 mg subcutaneously ||Twice daily ||Orthopedic surgery2 ||Give for at least 10 days. For THR, TKA, or HFS, consider continuing up to 1 month after surgery in high-risk patients |
| || || ||Major trauma ||Not applicable to patients with isolated lower extremity trauma |
| || || ||Acute spinal cord injury ||— |
|Dalteparin ||2500 units subcutaneously ||Once daily ||Most medical inpatients ||— |
| || || ||Abdominal surgery (moderate risk for VTE) ||Give for 5–10 days |
| ||5000 units subcutaneously ||Once daily ||Orthopedic surgery2 ||First dose = 2500 units. Give for at least 10 days. For THR, TKA, or HFS, consider continuing up to 1 month after surgery in high-risk patients |
| || || ||Abdominal surgery (higher-risk for VTE) ||Give for 5–10 days |
| || || ||Medical inpatients ||— |
|Fondaparinux ||2.5 mg subcutaneously ||Once daily ||Orthopedic surgery2 ||Give for at least 10 days. For THR, TKA, or HFS, consider continuing up to 1 month after surgery in high-risk patients |
|Rivaroxaban ||10 mg orally ||Once daily ||Orthopedic surgery: total hip and total knee replacement ||Give for 12 days following total knee replacement; give for 35 days following total hip replacement |
|Apixaban ||2.5 mg orally ||Twice daily ||Following hip or knee replacement surgery ||Give for 12 days following total knee replacement; give for 35 days following total hip replacement |
|Dabigatran || |
110 mg orally first day, then
220 mg once daily
|Once daily ||Following hip replacement surgery ||For patients with CrCl > 30 mL/min |
|Unfractionated heparin ||5000 units subcutaneously ||Three times daily ||Higher VTE risk with low bleeding risk ||Includes gynecologic surgery for malignancy and urologic surgery, medical patients with multiple risk factors for VTE |
| ||5000 units subcutaneously ||Twice daily ||Hospitalized patients at intermediate risk for VTE ||Includes gynecologic surgery (moderate risk) |
| || || ||Patients with epidural catheters ||LMWHs usually avoided due to risk of spinal hematoma |
| || || ||Patients with severe kidney disease3 ||LMWHs contraindicated |
|Warfarin ||(variable) oral ||Once daily ||Orthopedic surgery2 ||Titrate to goal INR = 2.5. Give for at least 10 days. For high-risk patients undergoing THR, TKA, or HFS, consider continuing up to 1 month after surgery |
|Aspirin ||variable || ||Hip and knee replacement || |
Table 14–15.Contraindications to VTE prophylaxis for medical or surgical hospital inpatients at high risk for VTE. |Favorite Table|Download (.pdf) Table 14–15. Contraindications to VTE prophylaxis for medical or surgical hospital inpatients at high risk for VTE.
Acute hemorrhage from wounds or drains or lesions
Intracranial hemorrhage within prior 24 hours
Heparin-induced thrombocytopenia (HIT): consider using fondaparinux
Severe trauma to head or spinal cord or extremities
Epidural anesthesia/spinal block within 12 hours of initiation of anticoagulation (concurrent use of an epidural catheter and anticoagulation other than low prophylactic doses of unfractionated heparin should require review and approval by service who performed the epidural or spinal procedure, eg, anesthesia/pain service, and in many cases, should be avoided entirely)
Currently receiving warfarin or heparin or LMWH or direct thrombin inhibitor for other indications
Coagulopathy (INR > 1.5)
Intracranial lesion or neoplasm
Severe thrombocytopenia (platelet count < 50,000/mcL)
Intracranial hemorrhage within past 6 months
Gastrointestinal or genitourinary hemorrhage within past 6 months
It is recommended that VTE prophylaxis be used judiciously in hospitalized medical patients who are not critically ill since a comprehensive review of evidence suggested harm from bleeding in low-risk patients given low-dose heparin and skin necrosis in stroke patients given compression stockings. The Padua Risk Score provides clinicians with a simple approach to risk stratification in medical patients (Table 14–13). The IMPROVE risk score offers clinicians another standardized approach to risk assessment although both scores require further validation. Certain high-risk surgical patients should be considered for extended-duration prophylaxis of approximately 1 month, including those undergoing total hip replacement, hip fracture repair, and abdominal and pelvic cancer surgery. If bleeding is present, if the risk of bleeding is high, or if the risk of VTE is high for the inpatient (Table 14–12) and therefore combined prophylactic strategies are needed, some measure of thromboprophylaxis may be provided through use of mechanical devices, including intermittent pneumatic compression devices, or graduated compression stockings.
et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010 Nov;8(11):2450–7.
et al. Deep venous thrombosis and venous thromboembolism prophylaxis. Surg Clin North Am. 2015 Apr;95(2):285–300.
et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e278S–325S.
et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e227S–77S. Erratum in: Chest. 2012 May;141(5):1369.
et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e195S–226S.
et al. Apixaban for the prophylaxis and treatment of deep vein thrombosis and pulmonary embolism: an evidence-based review. Ther Clin Risk Manag. 2015 Aug 26;11:1273–82.
et al. Oral direct Factor Xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: a systematic review and meta-analysis. Ann Intern Med. 2012 May 15;156(10):710–9.
et al. Venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011 Nov 1;155(9):625–32.
et al. Graduated compression stockings for prevention of deep vein thrombosis. Cochrane Database Syst Rev. 2014 Dec 17;12:CD001484.
et al. Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence. Ann Pharmacother. 2013 Jan;47(1):63–74.
et al. Update on edoxaban for the prevention and treatment of thromboembolism: clinical applications based on current evidence. Adv Hematol. 2015;2015:920361.
Treatment of Venous Thromboembolic Disease
Treatment for VTE should be offered to patients with objectively confirmed DVT or PE, or to those in whom the clinical suspicion is high for the disorder but who have not yet undergone diagnostic testing (see Chapter 9). The management of VTE primarily involves administration of anticoagulants; the goal is to prevent recurrence, extension and embolization of thrombosis and to reduce the risk of post-thrombotic syndrome. Suggested anticoagulation regimens are found in Table 14–16.
Table 14–16.Initial anticoagulation for VTE.1 |Favorite Table|Download (.pdf) Table 14–16. Initial anticoagulation for VTE.1
|Anticoagulant ||Dose/Frequency ||Clinical Scenario ||Comment |
|DVT, Lower Extremity ||DVT, Upper Extremity ||PE ||VTE, With Concomitant Severe Kidney Disease2 ||VTE, Cancer-Related |
|Unfractionated Heparin |
|Unfractionated heparin ||80 units/kg intravenous bolus, then continuous intravenous infusion of 18 units/kg/h ||× ||× ||× ||× || ||Bolus may be omitted if risk of bleeding is perceived to be elevated. Maximum bolus, 10,000 units. Requires aPTT monitoring. Most patients: begin warfarin at time of initiation of heparin. |
| ||330 units/kg subcutaneously × 1, then 250 units/kg subcutaneously every 12 hours ||× || || || || ||Fixed-dose; no aPTT monitoring required |
|LMWH and Fondaparinux |
|Enoxaparin3 ||1 mg/kg subcutaneously every 12 hours ||× ||× ||× || || ||Most patients: begin warfarin at time of initiation of LMWH |
|Dalteparin3 ||200 units/kg subcutaneously once daily for first month, then 150 units/kg/day ||× ||× ||× || ||× ||Cancer: administer LMWH for ≥ 3–6 months; reduce dose to 150 units/kg after first month of treatment |
|Fondaparinux ||5–10 mg subcutaneously once daily (see Comment) ||× ||× ||× || || ||Use 7.5 mg for body weight 50–100 kg; 10 mg for body weight > 100 kg |
|Direct-Acting Oral Anticoagulants (DOACs) |
|Rivaroxaban ||15 mg orally twice daily with food for 21 days then 20 mg orally daily with food ||× ||× ||× || || ||Contraindicated if CrCl < 30 mL/min |
|Apixaban ||10 mg orally twice daily for first 7 days then 5 mg twice daily ||× ||× ||× || || || |
Contraindicated if CrCl < 25 mL/min
Monotherapy without need for initial parenteral therapy
|Dabigatran ||5–10 days of parenteral anticoagulation, then 150 mg orally twice daily ||× ||× ||× || || || |
Contraindicated if CrCl < 15 mL/min
Initial need for parenteral therapy
|Edoxaban ||5–10 days of parenteral anticoagulation, then 60 mg orally once daily; 30 mg once daily recommended if CrCl is between 15 and 50 mL/min, if weight ≤ 60 kg, or if certain P-gp inhibitors are present ||× ||× ||× || || || |
Contraindicated if CrCl < 15 mL/min or > 95 mL/min
Initial need for parenteral therapy
B. Selecting Appropriate Anticoagulant Therapy
Most patients with DVT alone may be treated as outpatients, provided that their risk of bleeding is low, and they have good follow-up. Table 14–17 outlines proposed selection criteria for outpatient treatment of DVT.
Table 14–17.Patient selection for outpatient treatment of DVT. |Favorite Table|Download (.pdf) Table 14–17. Patient selection for outpatient treatment of DVT.
Patients considered appropriate for outpatient treatment
No clinical signs or symptoms of PE and pain controlled
Motivated and capable of self-administration of injections
Confirmed prescription insurance that covers injectable medication or patient can pay out-of-pocket for injectable agents
Capable and willing to comply with frequent follow-up
Initially, patients may need to be seen daily to weekly
Potential contraindications for outpatient treatment
DVT involving inferior vena cava, iliac, common femoral, or upper extremity vein (these patients might benefit from vascular intervention)
Active peptic ulcer disease, GI bleeding in past 14 days, liver synthetic dysfunction
Brain metastases, current or recent CNS or spinal cord injury/surgery in the last 10 days, CVA ≤ 4–6 weeks
Familial bleeding diathesis
Active bleeding from source other than GI
Creatinine clearance < 30 mL/min
Patient weighs < 55 kg (male) or < 45 kg (female)
Recent surgery, spinal or epidural anesthesia in the past 3 days
History of heparin-induced thrombocytopenia
Inability to inject medication at home, reliably follow medication schedule, recognize changes in health status, understand or follow directions
Among patients with PE, risk stratification should be done at time of diagnosis to direct treatment and triage. Patients with persistent hemodynamic instability are classified as high-risk patients (previously referred to as having “massive PE”) and have an early PE-related mortality of more than 15%. These patients should be admitted to an intensive care unit and generally receive thrombolysis (both full-dose and half-dose regimens have been shown to be effective) and anticoagulation with intravenous heparin. Intermediate-risk patients (previously, “submassive PE”) have a mortality rate of up to 15% and should be admitted to a higher level of inpatient care, with consideration of thrombolysis on a case-by-case basis. Catheter-directed techniques, if available, may be an option for patients who are poor candidates for systemic thrombolysis. Low-risk patients have a mortality rate less than 3% and are candidates for expedited discharge or outpatient therapy.
Because both intermediate- and low-risk patients are hemodynamically stable, additional assessment is necessary to differentiate the two. Echocardiography can be used to identify patients with right ventricular dysfunction, which connotes intermediate risk. An RV/LV ratio less than 1.0 on chest CT angiogram has been shown to have good negative predictive value for adverse outcome but suffers from inter-observer variability. Serum biomarkers such as B-type natriuretic peptide and troponin are most useful for their negative predictive value, and mainly in combination with other predictors. The PE severity index (PESI) and simplified PESI clinical risk scores, which do not require additional testing, accurately identify patients at low risk for 30-day PE-related mortality (Table 14–18) (eTable 14–2) and thus potential candidates for expedited discharge or outpatient treatment. The PESI48 and sPESI48 scores identify a subgroup of patients hospitalized with intermediate-risk PE who are reclassified as low risk by 48 hours and may be appropriate for early discharge.
Table 14–18.Simplified Pulmonary Embolism Severity Index (PESI). |Favorite Table|Download (.pdf) Table 14–18. Simplified Pulmonary Embolism Severity Index (PESI).
| ||Points |
|Age > 80 ||1 |
|Cancer ||1 |
|Chronic cardiopulmonary disease ||1 |
|Systolic blood pressure < 100 mm Hg ||1 |
|Oxygen saturation ≤ 90% ||1 |
|Severity Class ||Points ||30-Day Mortality |
|Low risk ||0 ||1% |
|High risk ||≥ 1 ||10% |
eTable 14–2.Pulmonary Embolism Severity Index (PESI). |Favorite Table|Download (.pdf) eTable 14–2. Pulmonary Embolism Severity Index (PESI).
|Risk factor ||Points |
|Age ||No. of years of age |
|Male sex ||10 |
|Cancer ||30 |
|Heart failure ||10 |
|Chronic lung disease ||10 |
|Heart rate > 110 bpm ||20 |
|Systolic blood pressure < 100 mm Hg ||20 |
|Respiratory rate > 30 breaths per minute ||20 |
|Temperature < 36°C ||20 |
|Change in mental status ||60 |
|Oxygen saturation < 90% ||20 |
|Severity class ||Points ||30-day mortality |
|I ||0–65 ||< 1.6% |
|II ||66–85 ||< 3.5% |
|III ||86–105 ||< 7.1% |
|IV ||106–125 ||4–11.4% |
|V ||> 125 ||10–24.5% |
Selection of an initial anticoagulant should be determined by patient characteristics (kidney function, immediate bleeding risk, weight) and the clinical scenario (eg, whether thrombolysis is being considered).
1. Parenteral anticoagulants
In patients in whom parenteral anticoagulation is being considered, LMWHs are more effective than unfractionated heparin in the immediate treatment of DVT and PE and are preferred as initial treatment because of predictable pharmacokinetics, which allow for subcutaneous, once- or twice-daily dosing with no requirement for monitoring in most patients. Monitoring of the therapeutic effect of LMWH may be indicated in pregnancy, compromised kidney function, and extremes of weight. Accumulation of LMWH and increased rates of bleeding have been observed among patients with severe kidney disease (creatinine clearance less than 30 mL/min), leading to a recommendation to use intravenous unfractionated heparin preferentially in these patients. If concomitant thrombolysis is being considered, unfractionated heparin is indicated. Patients with VTE and a perceived higher risk of bleeding (ie, post-surgery) may be better candidates for treatment with unfractionated heparin than LMWH given its shorter half-life and reversibility. Unfractionated heparin can be effectively neutralized with the positively charged protamine sulfate while protamine may only have partial reversal effect at best on LMWH. Use of unfractionated heparin leads to HIT in approximately 3% of patients, so most individuals require serial platelet count determinations during the initial 10–14 days of exposure.
Weight-based, fixed-dose daily subcutaneous fondaparinux (a synthetic factor Xa inhibitor) may also be used for the initial treatment of DVT and PE, with no increase in bleeding over that observed with LMWH. Its lack of reversibility, long half-life, and renal clearance limit its use in patients with an increased risk of bleeding or kidney disease.
Patients with DVT with or without PE require a minimum of 3 months of anticoagulation in order to reduce the risk of recurrence of thrombosis. Patients initiated on parenteral therapy will be transitioned to an oral agent to complete the course of therapy although patients with cancer-related thrombosis may benefit from remaining on long-term LMWH.
If warfarin is chosen as the oral anticoagulant it will be initiated along with the parenteral anticoagulant, which is continued until INR is in therapeutic range. Most patients require 5 mg of warfarin daily for initial treatment, but lower doses (2.5 mg daily) should be considered for patients of Asian descent, older adults, and those with hyperthyroidism, heart failure, liver disease, recent major surgery, malnutrition, certain polymorphisms for the CYP2C9 or the VKORC1 genes or who are receiving concurrent medications that increase sensitivity to warfarin (eTable 14–3). Conversely, individuals of African descent, those with larger body mass index or hypothyroidism, and those who are receiving medications that increase warfarin metabolism may require higher initial doses (7.5 mg daily). Daily INR results should guide dosing adjustments in the hospitalized patient while at least biweekly INR results guide dosing in the outpatient (Table 14–19). Web-based warfarin dosing calculators that consider these clinical and genetic factors are available to help clinicians choose the appropriate starting dose (eg, see www.warfarindosing.org). Because an average of 5 days is required to achieve a steady-state reduction in the activity of vitamin K–dependent coagulation factors, the parenteral anticoagulant should be continued for at least 5 days and until the INR is more than 2.0. Meticulous follow-up should be arranged for all patients taking warfarin because of the bleeding risk that is associated with initiation of therapy. Once stabilized, the INR should be checked at an interval no longer than every 6 weeks and warfarin dosing should be adjusted by guidelines (Table 14–20) since this strategy has been shown to improve the time patients spend in the therapeutic range and their clinical outcomes. Supratherapeutic INRs should be managed according to evidence-based guidelines (Table 14–21).
eTable 14–3.Commonly used agents and their potential effect on the INR.
Table 14–19.Warfarin adjustment guidelines. |Favorite Table|Download (.pdf) Table 14–19. Warfarin adjustment guidelines.
|Measurement Day ||INR ||Action |
|For Hospitalized Patients Newly Starting Therapy |
|Day 1 || ||5 mg (2.5 or 7.5 mg in select populations1) |
|Day 2 ||< 1.5 ||Continue dose |
| ||≥ 1.5 ||Decrease or hold dose2 |
|Day 3 ||≤ 1.2 ||Increase dose2 |
| ||> 1.2 and < 1.7 ||Continue dose |
| ||≥ 1.7 ||Decrease dose2 |
|Day 4 until therapeutic ||Daily increase < 0.2 units ||Increase dose2 |
| ||Daily increase 0.2–0.3 units ||Continue dose |
| ||Daily increase 0.4–0.6 units ||Decrease dose2 |
| ||Daily increase ≥ 0.7 units ||Hold dose |
|For Outpatients Newly Starting Therapy |
|Measure PT/INR on Day 1 ||Baseline ||Start treatment with 2–7.5 mg |
|Measure PT/INR on Day 3–4 ||< 1.5 ||Increase weekly dose by 5–25% |
| ||1.5–1.9 ||No dosage change |
| ||2.0–2.5 ||Decrease weekly dose by 25–50% |
| ||> 2.5 ||Decrease weekly dose by 50% or HOLD dose |
|Measure PT/INR on Day 5–7 ||< 1.5 ||Increase weekly dose by 10–25% |
| ||1.5–1.9 ||Increase weekly dose by 0–20% |
| ||2.0–3.0 ||No dosage change |
| ||> 3.0 ||Decrease weekly dose by 10–25% or HOLD dose |
|Measure PT/INR on Day 8–10 ||< 1.5 ||Increase weekly dose by 15–35% |
| ||1.5–1.9 ||Increase weekly dose by 5–20% |
| ||2.0–3.0 ||No dosage change |
| ||> 3.0 ||Decrease weekly dose by 10–25% or HOLD dose |
|Measure PT/INR on Day 11–14 ||< 1.6 ||Increase weekly dose by 15–35% |
| ||1.6–1.9 ||Increase weekly dose by 5–20% |
| ||2.0–3.0 ||No dosage change |
| ||> 3.0 ||Decrease weekly dose by 5–20% or HOLD dose |
Table 14–20.Warfarin-dosing adjustment guidelines for patients receiving long-term therapy, with target INR 2–3. |Favorite Table|Download (.pdf) Table 14–20. Warfarin-dosing adjustment guidelines for patients receiving long-term therapy, with target INR 2–3.
|Patient INR ||Weekly Dosing Change |
|Dose change ||Follow-up INR |
|≤ 1.5 ||Increase by 10–15% ||Within 1 week |
|1.51–1.79 ||If falling or low on two or more occasions, increase weekly dose by 5–10%. ||7–14 days |
|1.80–2.29 ||Consider not changing the dose unless a consistent pattern has been observed. ||7–14 days |
|2.3–3.0 (in range) ||No change in dosage. ||28 days (42 days if INR in range three times consecutively) |
|3.01–3.20 ||Consider not changing the dose unless a consistent pattern has been observed. ||7–14 days |
|3.21–3.69 ||Do not hold warfarin. If rising or high on two or more occasions, decrease weekly dose by 5–10%. ||7–14 days |
|3.70–4.99 ||Hold warfarin for 1 day and decrease weekly dose by 5–10%. ||Within 1 week, sooner if clinically indicated |
|5.0–8.99 ||Hold warfarin. Clinical evaluation for bleeding. When INR is therapeutic, restart at lower dose (decrease weekly dose by 10–15%). Check INR at least weekly until stable. ||Within 1 week, sooner if clinically indicated, then weekly until stabilized |
|≥ 9 ||See Table 14–21 || |
Table 14–21.American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Management of Supratherapeutic INR. |Favorite Table|Download (.pdf) Table 14–21. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Management of Supratherapeutic INR.
|Clinical Situation ||INR ||Recommendations |
|No significant bleed ||Above therapeutic range but < 5.0 || |
| ||≥ 5.0 but < 9.0 || |
| || || |
| || || |
| ||≥ 9.0 || |
| || || |
| || || |
|Serious/life-threatening bleed || || |
b. Direct-acting oral anticoagulants
DOACs have a predictable dose effect, few drug-drug interactions, rapid onset of action, and freedom from laboratory monitoring (Table 14–11). Dabigatran, rivaroxaban, apixaban, and edoxaban are approved for treatment of acute DVT and PE. While rivaroxaban and apixaban can be used as monotherapy eliminating the need for parenteral therapy, patients who will be treated with dabigatran or edoxaban must first receive 5–10 days of parenteral anticoagulation and then be transitioned to the oral agent. Unlike warfarin, parenteral therapies do not require an overlap or “bridge,” since these agents are immediately active; the patient first receives a course of a parenteral agent, the agent is then stopped and the DOAC is started. Compared to warfarin and LMWH, the DOACs are all “noninferior” with respect to prevention of recurrent VTE; both rivaroxaban and apixaban boast a lower bleeding risk than warfarin and LMWH. Agent selection for acute treatment of VTE should be individualized and consider kidney function, concomitant medications, ability to use LMWH bridge therapy, cost, and adherence.
There are limited data available regarding the use of DOACs in cancer patients. LMWH is still the preferred agent for treatment of cancer-related VTE. If a patient declines LMWH, it is reasonable to use DOAC or warfarin. Clinicians must be aware, however, that many chemotherapeutic agents may interact with DOACs and their use should be avoided in cases of potential interactions because there is no easily accessible and reliable way to measure the anticoagulant effect of DOACs. Due to lack of safety data, DOACs should be avoided in patients with severe thrombophilia (ie, antiphospholipid antibody syndrome), splanchnic vein thrombosis as well as in patients in whom anticoagulation fails and thrombosis develops during treatment with LMWH or warfarin.
3. Duration of anticoagulation therapy
The clinical scenario in which the thrombosis occurred is the strongest predictor of recurrence and, in most cases, guides duration of anticoagulation (Table 14–22). In the first year after discontinuation of anticoagulation therapy, the frequency of recurrent VTE among individuals whose thrombosis occurred in the setting of a transient, major, reversible risk factor (such as surgery) is approximately 3% after completing 3 months of anticoagulation, compared with at least 8% for individuals whose thrombosis was unprovoked, and greater than 20% in patients with cancer. Patients with provoked VTE are generally treated with a minimum of 3 months of anticoagulation, whereas unprovoked VTE should prompt consideration of indefinite anticoagulation provided the patient is not at high risk for bleeding. Merely extending duration of anticoagulation beyond 3 months will not reduce risk of recurrence once anticoagulation is stopped; if anticoagulants are stopped after 3, 6, 12, or 18 months in a patient with unprovoked VTE the risk of recurrence after cessation of therapy is similar. Individual risk stratification may help identify patients most likely to suffer recurrent disease and thus most likely to benefit from ongoing anticoagulation therapy. Normal D-dimer levels 1 month after cessation of anticoagulation are associated with lower recurrence risk, although some would argue not low enough to consider stopping anticoagulant therapy, particularly in men. One risk scoring system uses body mass index, age, D-dimer, and post-phlebitic symptoms to identify women at lower risk for recurrence after unprovoked VTE. The Vienna Prediction Model, a simple scoring system based on age, sex, D-dimer, and location of thrombosis, can help estimate an individual’s recurrence risk to guide duration of therapy decisions. The following facts are important to consider when determining duration of therapy: (1) men have a greater than twofold higher risk of recurrent VTE compared to women, (2) recurrent PE is more likely to develop in patients with clinically apparent PE than in those with DVT alone and has a case fatality rate of nearly 10%, and (3) proximal DVT has a higher recurrence risk than distal DVT. Laboratory workup for thrombophilia is not recommended routinely for determining duration of therapy because clinical presentation is a much stronger predictor of recurrence risk. The workup may be pursued in patients younger than 50 years, with a strong family history, with a clot in unusual locations, or with recurrent thromboses (Table 14–23). In addition, a workup for thrombophilia may be considered in women of childbearing age in whom results may influence fertility and pregnancy outcomes and management or in those patients in whom results will influence duration of therapy. An important hypercoagulable state to identify is antiphospholipid syndrome [APS] because these patients have a marked increase in recurrence rates, are at risk for both arterial and venous disease, and in general receive bridge therapy during any interruption of anticoagulation. Due to effects of anticoagulants and acute thrombosis on many of the tests, the thrombophilia workup should be delayed in most cases until at least 3 months after the acute event, if it is indicated at all (Table 14–24). The benefit of anticoagulation must be weighed against the bleeding risks posed, and the benefit-risk ratio should be assessed at the initiation of therapy, at 3 months, and then at least annually in any patient receiving prolonged anticoagulant therapy. While bleeding risk scores have been developed to estimate risk of these complications, their performance may not offer any advantage over a clinician’s subjective assessment, particularly in older individuals. Assessment of bleeding risk is of particular importance when identifying candidates for extended duration therapy for treatment of unprovoked VTE; it is recommended that patients with a high risk of bleeding receive a defined course of anticoagulation, rather than indefinite therapy, even if the VTE was unprovoked. Compared with placebo, aspirin has been shown to reduce risk of recurrent VTE by 30% in patients with idiopathic VTE. Low-dose aspirin therapy (81 mg/day) should be considered in patients with unprovoked VTE who are not candidates for ongoing anticoagulation, but it is inferior to anticoagulation for risk reduction and is not an equivalent alternative.
Table 14–22.Duration of treatment of VTE. |Favorite Table|Download (.pdf) Table 14–22. Duration of treatment of VTE.
|Scenario ||Suggested Duration of Therapy ||Comments |
|Major transient risk factor (eg, major surgery, major trauma, major hospitalization) ||3 months ||VTE prophylaxis upon future exposure to transient risk factors |
|Cancer-related ||≥ 3–6 months or as long as cancer active, whichever is longer ||LMWH recommended for initial treatment (see Table 14–16) |
|Unprovoked ||At least 3 months; consider indefinite if bleeding risk allows ||May individually risk-stratify for recurrence with D-dimer, clinical risk scores and clinical presentation |
|Recurrent unprovoked ||Indefinite || |
|Underlying significant thrombophilia (eg, antiphospholipid antibody syndrome, antithrombin deficiency, protein C deficiency, protein S deficiency, ≥ two concomitant thrombophilic conditions) ||Indefinite ||To avoid false positives, consider delaying investigation for laboratory thrombophilia until 3 months after event |
Table 14–23.Candidates for thrombophilia workup if results will influence management. |Favorite Table|Download (.pdf) Table 14–23. Candidates for thrombophilia workup if results will influence management.
Patients younger than 50 years
Strong family history of VTE
Clot in unusual locations
Women of childbearing age
Suspicion for APS
Table 14–24.Laboratory evaluation of thrombophilia. |Favorite Table|Download (.pdf) Table 14–24. Laboratory evaluation of thrombophilia.
|Hypercoagulable State ||When to Suspect ||Laboratory Workup ||Influence of Anticoagulation and Acute Thrombosis |
|Antiphospholipid antibody syndrome || |
CVA/TIA age < 50
Recurrent thrombosis (despite anticoagulation)
Thrombosis at an unusual site
Arterial and venous thrombosis
Livedo reticularis, Raynaud phenomenon, thrombocytopenia, recurrent early pregnancy loss
Anti-cardiolipin IgG and/or IgM medium or high titer (ie, > 40 GPL or MPL, or > the 99th percentile)1
Anti-beta-2 glycoprotein I IgG and/or IgM medium or high titer (> the 99th percentile)1
|Lupus anticoagulant can be falsely positive or falsely negative on anticoagulation |
|Protein C, S, antithrombin deficiencies ||Thrombosis < 50 years of age with family history of VTE ||Screen with protein C activity, free protein S, protein S activity, antithrombin activity ||Acute thrombosis can result in decreased protein C, S and antithrombin activity. Warfarin can decrease protein C and S activity, heparin can cause decrease antithrombin activity. DOACs can increase protein C, S, and antithrombin activity |
|Factor V Leiden, prothrombin gene mutation ||Thrombosis on OCPs, cerebral vein thrombosis, DVT/PE in white population ||PCR for factor V Leiden or prothrombin gene mutation ||No influence |
|Hyperhomocysteinemia || ||Fasting homocysteine ||No influence |
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Anticoagulation alone is appropriate treatment for most patients with PE; however, those with high-risk, massive PE, defined as PE with persistent hemodynamic instability, have an in-hospital mortality rate that approaches 30% and absent contraindications require immediate thrombolysis in combination with anticoagulation (Table 14–25). Systemic thrombolytic therapy has been used in selected patients with intermediate-risk, submassive PE, defined as PE without hemodynamic instability but with evidence of right ventricular compromise and myocardial injury. Thrombolysis in this cohort decreases risk of hemodynamic compromise but increases the risk of major hemorrhage and stroke. A “safe dose” of tPA (50% or less of the standard dose [100 mg] commonly used for the treatment of PE) has been evaluated in small trials of both high- and intermediate-risk PE showing similar efficacy and a better safety profile. The use of thrombolysis in hemodynamically stable intermediate risk PE patients should be considered on a case-by-case basis. The use of catheter-directed therapy for acute PE may be considered for high-risk or intermediate-risk PE when systemic thrombolysis has failed or as an alternative to systemic thrombolytic therapy.
Table 14–25.Thrombolytic therapies for pulmonary embolism. |Favorite Table|Download (.pdf) Table 14–25. Thrombolytic therapies for pulmonary embolism.
|Thrombolytic Agent ||Dose ||Frequency ||Comment |
|High Risk (Massive Pulmonary Embolism) |
|Alteplase ||100 mg ||Continuous intravenous infusion over 2 hours ||Follow with continuous intravenous infusion of unfractionated heparin (see Table 14–16 for dosage) |
| ||100 mg ||Intravenous bolus × 1 ||Appropriate for acute management of cardiac arrest and suspected pulmonary embolism |
|Urokinase ||4400 international units/kg ||Intravenous bolus × 1 followed by 4400 international units/kg continuous intravenous infusion for 12 hours ||Unfractionated heparin should be administered concurrently (see Table 14–16 for dosage) |
|Intermediate Risk (Submassive Pulmonary Embolism) |
|rt-PA ||50 mg/2 hours ||Continuous infusion over 2 hours || |
|Tenecteplase ||30–50 mg ||Intravenous bolus × 1 || |
|Alteplase ||100 mg ||(10-mg intravenous bolus, followed by a 90-mg intravenous infusion 2 hours) || |
Limited data suggest that patients with large proximal iliofemoral DVT may also benefit from catheter-directed thrombolysis in addition to treatment with anticoagulation. However, standardized guidelines are lacking, and use of the intervention may be limited by institutional availability and provider experience. Importantly, thrombolytics should be considered only in patients who have a low risk of bleeding, as rates of bleeding are increased in patients who receive these products compared with rates of hemorrhage in those who are treated with anticoagulation alone.
et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414–21.
LS. Thrombolytic therapy for submassive pulmonary embolus? PRO viewpoint. Thorax. 2014 Feb;69(2):103–5.
et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011 Apr 26;123(16):1788–830. Erratum in: Circulation. 2012 Aug 14;126(7):e104. Circulation. 2012 Mar 20;125(11):e495.
et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S–94S.
et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402–11.
et al. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013 Jan 15;111(2):273–7.
AJ. Thrombolysis for acute submassive pulmonary embolism: CON viewpoint. Thorax. 2014 Feb;69(2):105–7.
et al. Guidance for the use of thrombolytic therapy for the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016 Jan;41(1):68–80.
et al. The role of thrombolytic therapy in pulmonary embolism. Blood. 2015 Apr 2;125(14):2191–9.
et al. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev. 2014 Jan 23;1:CD002783.
D. Nonpharmacologic Therapy
1. Graduated compression stockings
Although use of graduated compression stockings with 30–40 mm Hg pressure at the ankle in patients with DVT on the affected lower extremity had been advocated for 1–2 years after diagnosis, a randomized placebo-controlled trial failed to show a reduction in the postthrombotic syndrome at 6 months. Stockings may provide symptomatic relief to selected patients with ongoing swelling; however, they are contraindicated in patients with peripheral vascular disease.
2. Inferior vena caval (IVC) filters
There is a paucity of data to support the use of IVC filters for the prevention of PE in any clinical scenario. There are two randomized, controlled trials of IVC filters for prevention of PE. In the first study, patients with documented DVT received full intensity, time-limited anticoagulation with or without placement of a permanent IVC filter. Patients with IVC filters had a lower rate of nonfatal asymptomatic PE at 12 days but an increased rate of DVT at 2 years. In the second study, patients with symptomatic PE and residual DVT plus at least one additional risk factor for severity received anticoagulation with or without a retrievable IVC filter. IVC filter use did not reduce the risk of symptomatic recurrent PE at 3 months. Most experts agree with placement of an IVC filter in patients with acute proximal DVT and an absolute contraindication to anticoagulation despite lack of evidence to support this practice. While IVC filters were once commonly used to prevent VTE recurrence in the setting of anticoagulation failure, many experts now recommend switching to an alternative agent or increasing the intensity of the current anticoagulant regimen instead. The remainder of the indications (submassive/intermediate-risk PE, free-floating iliofemoral DVT, perioperative risk reduction) are controversial. If the contraindication to anticoagulation is temporary (active bleeding with subsequent resolution), placement of a retrievable IVC filter may be considered so that the device can be removed once anticoagulation has been started and has been shown to be tolerated. Rates of IVC filter retrieval are very low, often due to a failure to arrange for its removal. Thus, if a device is placed, removal should be arranged at the time of device placement.
Complications of IVC filters include local thrombosis, tilting, migration, fracture, and inability to retrieve the device. When considering placement of an IVC filter, it is best to consider both short- and long-term complications, since devices intended for removal may become permanent. To improve patient safety, institutions should develop systems that guide appropriate patient selection for IVC filter placement, tracking, and removal.
et al. Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial. Thromb Haemost. 2014 Dec 1;112(6):1137–41.
et al. Procedural and indwelling complications with inferior vena cava filters: frequency, etiology, and management. Semin Intervent Radiol. 2015 Mar;32(1):34–41.
et al; PREPIC2 Study Group. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015 Apr 28;313(16):1627–35.
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et al. Indications, complications, and management of inferior vena cava filters: the experience in 952 patients at an academic hospital with a level I trauma center. JAMA Intern Med. 2013 Apr 8;173(7):513–7.
Presence of large iliofemoral VTE, IVC thrombosis, portal vein thrombosis, or Budd-Chiari syndrome for consideration of catheter-directed thrombolysis.
High-risk PE for urgent embolectomy or catheter-directed therapies.
Intermediate-risk PE if considering thrombolysis.
History of HIT or prolonged PTT plus renal failure for alternative anticoagulation regimens.
Consideration of IVC filter placement.
Presence of clots in unusual locations (eg, renal vein, hepatic vein, cerebral vein), or simultaneous arterial and venous thrombosis, to assess possibility of a hypercoagulable state.
Recurrent VTE while receiving therapeutic anticoagulation.
Documented or suspected intermediate- or high-risk PE and low-risk PE at high risk for bleeding or poor candidate for outpatient treatment.
DVT with poorly controlled pain, high bleeding risk, concerns about follow-up.
Large iliofemoral DVT for consideration of thrombolysis.
Acute DVT and absolute contraindication to anticoagulation for IVC filter placement.
Venous thrombosis despite therapeutic anticoagulation.