The currently available anticoagulants include unfractionated heparin, LMWHs, fondaparinux, vitamin K antagonists (ie, warfarin), and direct-acting oral anticoagulants (DOACs) (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). (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 biologic product most commonly derived from porcine intestinal tissue rich in heparin-bearing mast cells. It is heterogeneous with respect to sulfation and polymer length; individual molecules may range from 3000 to 30,000. Only about one-third of the molecules in a given preparation of unfractionated heparin contain the crucial pentasaccharide sequence necessary for binding of antithrombin and exerting its anticoagulant effect upon thrombin. 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 degree of anticoagulation with unfractionated heparin is typically monitored by aPTT or anti-Xa level in patients who are receiving the drug in therapeutic doses, although the pharmacokinetics of unfractionated heparin are poorly predictable. Only a fraction of an infused dose of heparin is metabolized by the kidneys, 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. LMWHs are associated with a lower frequency of heparin-induced thrombocytopenia and thrombosis (approximately 0.6%) than unfractionated heparin (3%).
Fondaparinux is a synthetic molecule consisting of the highly active pentasaccharide sequence found in LMWHs. 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.
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 is taken orally, leading to a significant advantage over the heparins and heparin derivatives, interindividual differences in 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, 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 14–10). While the DOACs have fewer drug interactions than warfarin, if DOACs are given with potentially interacting medications, there is no reliable way to measure the impact on anticoagulant activity of the concomitant administration. There is also no reliable way to measure adherence. Data remain limited on use of DOACs in morbidly obese patients (more than 120 kg or BMI greater than or equal to 40) in VTE treatment. The clinician must carefully consider kidney function, concomitant medications, indication for use, candidacy for lead-in parenteral therapy (as required for acute VTE treatment with edoxaban and dabigatran only) and anticipated patient adherence. Providers must be careful to dose each DOAC properly for the indication, kidney function, and weight of patient, and to check for drug interactions. (See Table 14–10 for details.) There is a reversal agent available for dabigatran and for the anti-Xa inhibitors apixaban and rivaroxaban (Table 14–11).
Table 14–10.Direct-acting oral anticoagulants (DOACs) for VTE treatment and prevention.1 ||Download (.pdf) Table 14–10. Direct-acting oral anticoagulants (DOACs) for VTE treatment and prevention.1
| ||Dabigatran ||Rivaroxaban ||Apixaban ||Edoxaban ||Betrixaban |
|Mechanism ||Oral direct thrombin inhibitor ||Oral direct factor Xa inhibitor ||Oral direct factor Xa inhibitor ||Oral direct factor Xa inhibitor ||Oral direct factor Xa inhibitor |
|Approved uses for VTE || |
VTE treatment and secondary prevention
VTE prophylaxis post-hip replacement
VTE treatment and secondary prevention
VTE prophylaxis post-hip or knee replacement
VTE prophylaxis in select adult patients hospitalized for acute medical illness
VTE treatment and secondary prevention
VTE prophylaxis post-hip or knee replacement
|VTE treatment and secondary prevention ||Prophylaxis of VTE in select adults hospitalized for acute medical illness |
|Frequency of dosing for VTE ||Twice daily || |
Twice daily for first 21 days of acute VTE therapy, then daily
Once daily for DVT prophylaxis
|Twice daily ||Once daily ||Once daily |
|Food ||With or without food ||With food (for 15- and 20-mg tablets) ||With or without food ||With or without food ||With 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% ||15% |
|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 ||t ½ = 19–27 hours; tmax = 3 hours |
|Impact on INR ||↑ (or →) ||↑↑ (or → at low concentrations) ||↑ (or →) ||↑ ||Unknown |
|Impact on aPTT ||↑↑ ||↑ ||↑ ||↑ ||Unknown |
|Drug interactions (list not comprehensive) || |
Avoid rifampin, St John’s wort, and possibly carbamazepine
Caution with amiodarone, clarithromycin, dronedarone, ketoconazole, quinidine, verapamil
No dose adjustment 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) particularly in patients with impaired kidney function
Avoid carbamazepine, clarithromycin, phenytoin, rifampin, St John’s wort,
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 (eg, amiodarone, azithromycin, verapamil, ketoconazole, clarithromycin). Use has not been studied with many other P-gp inhibitors and inducers.
Some experts recommend avoiding concurrent use altogether
|Reduce dose to 40 mg orally daily with concurrent use of P-gp inhibitors (eg, amiodarone, azithromycin, verapamil, ketoconazole, clarithromycin) |
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 warfarin concomitantly
For 30-mg dose, reduce dose to 15 mg and start warfarin concomitantly
Stop edoxaban when INR ≥ 2.0
|No data available |
|Warfarin to DOAC ||Start when INR < 2.0 ||Start when INR < 3.0 ||Start when INR < 2.0 ||Start when INR ≤ 2.5 ||Start when INR < 2.5 |
|Special considerations || |
Dyspepsia is common and starts within first 10 days
GI bleeding risk higher with dabigatran than with warfarin
|GI bleeding risk higher with rivaroxaban than with warfarin || ||Do not use if CrCl < 15 mL/min || |
Table 14–11.Medications to consider for reversing anticoagulant effect during life-threatening bleeding.1 ||Download (.pdf) Table 14–11. Medications to consider for reversing anticoagulant effect during life-threatening bleeding.1
|Anticoagulants ||Guidance |
|Heparins || |
Protamine provides total (for unfractionated heparin) or partial (for LMWHs) reversal of anticoagulant effect.
Administration: Very slow infusion
Maximum dose: 50 mg intravenously
Caution: risk of anaphylactoid reactions and true hypersensitivity reactions, especially if allergy to other protamine-containing medications (such as NPH insulin) or to fish (black box warning)
Dosing depends on dose given and time elapsed
Dosing calculator at https://clincalc.com/Protamine/
|Unfractionated heparin || |
Protamine (100% neutralization)
|LMWH (enoxaparin, dalteparin) || |
Protamine (approximately 60% neutralization)
|DOACs || |
Guidance for all DOAC-associated major bleeding:
Supportive measures recommended for all patients
If ingested within 2 hours, administer activated charcoal
Reversal agent is recommended ONLY if bleeding is life-threatening or into a critical organ
Reversal agent not recommended for DOAC overdose without bleeding
|Dabigatran || |
Idarucizamab 5 g intravenously once
If idarucizamab is not available: administer APCC 50 units/kg intravenously
|Apixaban || |
Last dose ≤ 5 mg AND within 8 hours: low dose2
Last dose > 5 mg AND within 8 hours: high dose3
Last dose > 8 hours ago: low dose2
If andexanet alfa is not available: administer four-factor PCC 2000 units
|Rivaroxaban || |
Last dose ≤ 10 mg AND within 8 hours: low dose2
Last dose > 10 mg AND within 8 hours: high dose3
Last dose > 8 hours ago: low dose2
If andexanet alfa is not available: administer four-factor PCC 2000 units
|Warfarin ||See Table 14–21 |
Routine monitoring is not recommended for patients taking DOACs. However, there are clinical scenarios where assessing anticoagulant activity may be helpful, including active bleeding, pending urgent surgery, suspected therapeutic failure, or concern for accumulation. Drug-specific anti-Xa levels are not widely available, and guidance is lacking regarding clinical approach to the results. DOACs have varying effects on the PT and aPTT. In the absence of drug-specific levels, a normal dilute thrombin time excludes the presence of clinically relevant dabigatran levels; an elevated aPTT suggests clinically relevant levels of dabigatran. An elevated PT suggests clinically relevant levels of rivaroxaban. However, a normal aPTT or normal PT does not rule out clinically significant amounts of dabigatran or rivaroxaban, respectively.
et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost. 2018;16:209.
PREVENTION OF VENOUS THROMBOEMBOLIC DISEASE
The frequency of venous thromboembolic disease (VTE) among hospitalized patients ranges widely. Up to 60% of VTE cases occur during or after hospitalization, with especially high incidence among critical care patients and high-risk surgical patients.
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 anticoagulation regimens differ in their recommended duration of use. 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 in portable form with at least an 18-hour daily wear time.
Table 14–12.Risk stratification for DVT/VTE among surgical inpatients. ||Download (.pdf) Table 14–12. Risk stratification for DVT/VTE among surgical inpatients.
Recent major orthopedic surgery/arthroplasty/fracture
Abdominal/pelvic cancer undergoing surgery
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. ||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 ||Download (.pdf) Table 14–14. Pharmacologic prophylaxis of VTE in selected clinical scenarios.1
|Anticoagulant ||Dose ||Frequency ||Clinical Scenario ||Comment |
|LMWH and Fondaparinux |
|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 abdominopelvic 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, TKR, 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, TKR, 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. Consider continuing for 4 weeks total duration after abdominopelvic cancer surgery. |
| || || ||Medical inpatients ||— |
|Fondaparinux ||2.5 mg subcutaneously ||Once daily ||Orthopedic surgery2 ||Give for at least 10 days. For THR, TKR, or HFS, consider continuing up to 1 month after surgery in high-risk patients. |
|Direct-Acting Oral Anticoagulants |
|Rivaroxaban ||10 mg orally ||Once daily ||Orthopedic surgery: THR, TKR ||Give for 12 days following TKR; give for 35 days following THR. |
|Apixaban ||2.5 mg orally ||Twice daily ||Following THR or TKR ||Give for 12 days following TKR; give for 35 days following THR. |
|Dabigatran ||110 mg orally first day, then 220 mg ||Once daily ||Following THR ||For patients with CrCl > 30 mL/min. Consider continuing up to 1 month after surgery in high-risk patients. |
|Betrixaban || |
160 mg orally first dose, then 80 mg with food
Reduce dose for patients with severe renal impairment or taking P-gp inhibitors
|Once daily ||Medical inpatients with moderately to severely restricted mobility and other risk factors for VTE ||Recommended duration of treatment is 35–42 days. |
|Unfractionated Heparin |
|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 and Aspirin |
|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, TKR, or HFS, consider continuing up to 1 month after surgery. |
|Aspirin ||81 mg orally ||Twice daily ||TKR, THR ||For patients at otherwise low VTE risk following major orthopedic surgery. Give for at least 14 days. |
Table 14–15.Contraindications to VTE prophylaxis for medical or surgical hospital inpatients at high risk for VTE. ||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 [50 × 109/L])
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. Risk assessment models like the Padua Risk Score (Table 14–13) and the IMPROVE risk score can help clinicians identify patients who may benefit from DVT prophylaxis. The IMPROVE investigators also developed a bleeding risk model that may aid in identifying acutely ill medical inpatients at increased risk for bleeding: https://www.outcomes-umassmed.org/IMPROVE/risk_score/index.html. While two of the anti-Xa oral anticoagulants (betrixaban and rivaroxaban) have been approved for extended duration prophylaxis after discharge for medically ill patients, how to identify those who will have clinical benefit from this practice is still unclear.
The Caprini score may help guide decisions in surgical patients about VTE prophylaxis (https://www.mdcalc.com/caprini-score-venous-thromboembolism-2005). In addition, certain high-risk surgical patients should be considered for extended-duration prophylaxis of up to 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 mechanical devices such as intermittent pneumatic compression devices and graduated compression stockings.
A. Primary VTE Prevention in Patients with Active Cancer
Some ambulatory cancer patients undergoing chemotherapy who are at moderate to high risk of VTE (Khorana risk score ≥ 2) (https://www.mdcalc.com/khorana-risk-score-venous-thromboembolism-cancer-patients) may benefit from pharmacologic DVT prophylaxis, although bleeding risk is increased and caution should be taken, particularly in patients with gastrointestinal or intracranial malignancy, and other risk factors for anticoagulant-related bleeding (such as thrombocytopenia and kidney dysfunction). DOACs should be avoided when there are possible interactions with chemotherapeutic agents.
B. Primary VTE Prevention, Diagnosis, and Treatment in Patients with Severe COVID-19
Patients with severe COVID-19 appear to have an increased incidence of thrombotic complications, including venous (DVT, PE) and arterial (stroke, limb occlusion) events. Risk is especially high in the critical care setting. Although the reasons for this hypercoagulability are not yet well understood, the profound systemic inflammatory response associated with severe COVID-19 is thought to play a role. While the hypercoagulability in COVID-19 resembles DIC, laboratory and clinical findings are somewhat different. Laboratory findings in patients with severe COVID-19 may include markedly elevated D-dimer and modestly prolonged prothrombin time. However, patients with COVID-19 tend to have elevated fibrinogen levels; thrombocytopenia is rare and nonsevere; and bleeding complications are unusual. Thrombosis in patients with COVID-19 is associated with a poor prognosis and often occurs despite standard pharmacologic prophylaxis.
1. Risk stratification and initial prognostication of patients with severe COVID-19
Given the prevalence and prognostic value of abnormal laboratory findings at presentation, patients with COVID-19 should have RP/INR, PTT, D-dimers, and fibrinogen measured. When results are abnormal, especially significantly elevated D-dimers or decreased fibrinogen, admission for monitoring should be considered even in patients who are otherwise clinically stable. Worsening laboratory parameters during hospitalization should prompt consideration of transfer to a higher level of care and heightened clinical suspicion for thrombosis.
2. VTE prophylaxis for patients with severe COVID-19
In the absence of strong contraindications, all patients hospitalized with COVID-19 should receive pharmacologic VTE prophylaxis. LMWH is preferred over unfractionated heparin to minimize staff exposure and the chance of heparin-induced thrombocytopenia.
For patients with a prior history of VTE who take an oral anticoagulant for secondary prevention at the time of admission, transition to LMWH should be considered due to its shorter half-life and potential anti-inflammatory properties.
For updated recommendations regarding pharmacologic dosing and post-discharge prophylaxis, refer to professional society guidance (links at end of this section) since guidance in this area is evolving rapidly.
3. Diagnosis and management of thromboembolic disease in patients with severe COVID-19
Logistical challenges complicate the diagnosis of thromboembolism in patients with COVID-19 due to patient instability and risks of staff exposures. D-dimers are generally elevated in hospitalized patients who have COVID-19. A substantial increase in D-dimers may suggest COVID-19–associated coagulopathy with or without thrombotic events. Clinicians should remain vigilant for signs and symptoms of thrombosis and consider obtaining surveillance laboratory testing at least every 3–4 days with low threshold for imaging. Ideally, thrombosis should be confirmed radiographically, but in situations where these studies cannot safely be obtained and clinical suspicion is very high, empiric treatment may be considered.
Guidance from the Anticoagulation Forum (https://acforum.org/web/), the International Society for Thrombosis and Haemostasis (https://academy.isth.org/isth/#!*menu=8*browseby=2*sortby=1*label=19794), and the American Society for Hematology (https://www.hematology.org/covid-19) is evolving and should be frequently consulted.
et al. Direct oral anticoagulants for extended thromboprophylaxis in medically ill patients: meta-analysis and risk/benefit assessment. J Blood Med. 2018;9:25.
et al; AVERT Investigators. Apixaban
to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380:711.
et al. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033.
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;141:e278S.
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;141:e227S.
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;141:e195S.
et al; CASSINI Investigators. Rivaroxaban
for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380:720.
et al. Anticoagulation in COVID-19: a systematic review, meta-analysis, and rapid guidance from Mayo Clinic. Mayo Clin Proc. 2020;95:2467.
et al. External validation of the IMPROVE Bleeding Risk Assessment Model in medical patients. Thromb Haemost. 2016 Aug 30;116(3):530–6.
et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv. 2018;2:3198.
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 ||Download (.pdf) Table 14–16. Initial anticoagulation for VTE.1
| || ||Clinical Scenario || |
|Anticoagulant ||Dose/Frequency ||DVT, Lower Extremity ||DVT, Upper Extremity ||PE ||VTE, With Concomitant Severe Kidney Disease2 ||VTE, Cancer-Related ||Comment |
|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 or heparin anti-Xa 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
1.5 mg/kg subcutaneously daily
|× ||× ||× || || ||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 ||× ||× ||× || ||× ||Preferred LMWH for cancer patients; administer for at least 3–6 months (no transition to warfarin) |
|Fondaparinux ||5–10 mg subcutaneously once daily; 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
Monotherapy without need for initial parenteral therapy
Caution in luminal gastrointestinal or genitourinary cancer
|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 begin 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
Initial need for parenteral therapy
Caution in luminal gastrointestinal or genitourinary cancer
B. Selecting Appropriate Initial 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. ||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
Confirmed ability to pay for medication (either by insurance or out-of-pocket)
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)
Comorbid conditions requiring inpatient management
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
Weight < 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 reliably take medication at home, recognize changes in health status, or understand or follow directions
Among patients with PE, risk stratification at time of diagnosis should 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 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 and/or in centers with expertise. Low-risk patients have a mortality rate less than 3% and are candidates for expedited discharge or outpatient therapy.
For hemodynamically stable patients, additional assessment focusing on right ventricular dysfunction is warranted to differentiate between low-risk, low-intermediate risk, and high-intermediate risk PE. The Bova score (https://www.mdcalc.com/bova-score-pulmonary-embolism-complications) and the simplified PE severity index accurately identify patients at low risk for 30-day PE-related mortality (Table 14–18) (eTable 14–3) who are potential candidates for expedited discharge or outpatient treatment. Because the Bova score includes serum troponin and evidence of right ventricular dysfunction (by CT or echocardiography), it also identifies patients with high-intermediate risk PE who warrant close monitoring and may require escalation of therapy. 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. Echocardiography may provide better assessment of right ventricular dysfunction when there is concern. 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.
Table 14–18.Simplified Pulmonary Embolism Severity Index (PESI). ||Download (.pdf) Table 14–18. Simplified Pulmonary Embolism Severity Index (PESI).
| ||Points |
|Age > 80 years old ||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 14–3.Pulmonary Embolism Severity Index (PESI). ||Download (.pdf) eTable 14–3. 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, active cancer, thrombosis location) as described in Table 14–16.
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; they 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. 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 on LMWH. Use of unfractionated heparin leads to heparin-induced thrombocytopenia and thrombosis in approximately 3% of patients, so daily complete blood counts are recommended 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.
A. DIRECT-ACTING ORAL ANTICOAGULANTS
DOACs have a predictable dose effect, few drug-drug interactions, rapid onset of action, and freedom from laboratory monitoring (Table 14–10). 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 treated with dabigatran or edoxaban must first receive 5–10 days of parenteral anticoagulation and then be transitioned to the oral agent per prescribing information. Unlike warfarin, DOACs do not require an overlap since these agents are immediately active; the DOAC is started when the parenteral agent is stopped. Compared to warfarin and LMWH, the DOACs are all noninferior with respect to prevention of recurrent VTE; both rivaroxaban and apixaban have a lower bleeding risk than warfarin with LMWH bridge. While DOACs are recommended as first-line therapy for acute VTE according to the CHEST 2016 VTE guidelines, agent selection should be individualized with consideration of kidney function, concomitant medication use, indication, ability to use LMWH bridge therapy, cost, and adherence.
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 14–4). Conversely, individuals of African descent, those with larger body mass index or hypothyroidism, and those who are receiving medications that increase warfarin metabolism (eg, rifampin) 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 during the initial period of therapy (Table 14–19). Web-based warfarin dosing calculators incorporating clinical and genetic factors are available to help clinicians choose appropriate starting doses (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 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 14–4.Commonly used agents and their potential effect on the INR. ||Download (.pdf) eTable 14–4. Commonly used agents and their potential effect on the INR.
Table 14–19.Warfarin dosing adjustment guidelines for initiation of warfarin therapy. ||Download (.pdf) Table 14–19. Warfarin dosing adjustment guidelines for initiation of warfarin therapy.
|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. ||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. ||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 || || |
C. Duration of Anticoagulation Therapy
Recurrence rates of VTE after discontinuation of 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. Men have a greater than twofold higher risk of recurrent VTE compared to women; 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 proximal DVT has a higher recurrence risk than distal DVT.
Table 14–22.Duration of treatment of VTE. ||Download (.pdf) Table 14–22. Duration of treatment of VTE.
|Scenario ||Suggested Duration of Therapy ||Comments |
|Provoked by major transient risk factor (eg, major surgery, major trauma, major hospitalization) ||3 months ||VTE prophylaxis upon future exposure to transient risk factors |
|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
Consider transition to DOAC secondary prevention dose after initial treatment period
|Recurrent unprovoked ||Indefinite ||If recurrent despite therapeutic anticoagulation, consider hematology consultation for further evaluation and guidance |
|Cancer-related ||≥ 3–6 months or as long as cancer is active, whichever is longer ||LMWH or carefully selected DOAC recommended for initial treatment (see Table 14–16) |
|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 |
1. Provoked versus unprovoked VTE
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 for unprovoked PE will not reduce risk of recurrence once anticoagulation is stopped; if anticoagulants are stopped after 3, 6, 12, or 18 months in such a patient, 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.
2. Risk scoring systems to guide therapy duration
The HERDOO2 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 (https://www.mdcalc.com/herdoo2-rule-discontinuing-anticoagulation-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.
LMWH has been the mainstay of treatment for cancer-related VTE based on lower VTE recurrence in cancer patients treated with dalteparin compared with warfarin. Studies have also shown that DOACs (edoxaban, rivaroxaban, and apixaban) are at least as effective as LMWH for VTE treatment. The use of edoxaban and rivaroxaban is at the expense of increased bleeding, particularly for patients with gastrointestinal cancer. The International Society for Thrombosis and Haemostasis suggests use of specific DOACs for cancer patients with a diagnosis of acute VTE, no drug-drug interactions, and a low risk of bleeding but suggests use of LMWH for those with a high risk of bleeding, including patients with luminal gastrointestinal cancers with an intact primary tumor, and those at risk for bleeding from the genitourinary or gastrointestinal tract. For patients with intracranial malignancy and VTE, bleeding risk depends on tumor type (primary versus metastatic) and other characteristics; whenever possible, interdisciplinary consultation is recommended to help determine risk of initiating anticoagulation. DOACs do not appear to confer higher bleeding risk compared to LMWH in patients with brain tumors. Clinicians must be aware that 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.
4. Thrombophilia workup in determining duration
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 because these patients have a marked increase in recurrence rates, are at risk for both arterial and venous disease, in general receive bridge therapy during any interruption of anticoagulation, and should not receive DOACs as first-line antithrombotic therapy due to increased arterial events compared to warfarin. 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 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. Bleeding risk scores, such as the Riete score (https://www.mdcalc.com/riete-score-risk-hemorrhage-pulmonary-embolism-treatment) have been developed to estimate risk of these complications. Their performance, however, may not offer any advantage over a clinician’s subjective assessment, particularly in older individuals. Consideration 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.
Table 14–23.Candidates for thrombophilia workup if results will influence management. ||Download (.pdf) Table 14–23. Candidates for thrombophilia workup if results will influence management.
Patients < 50 years of age
Strong family history of VTE
Clot in unusual locations
Women of childbearing age
Suspicion for APS (avoid DOACs if APS is strongly suspected or confirmed)
Table 14–24.Laboratory evaluation of thrombophilia. ||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 before age 50 years
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, antithrombin activity2; if free protein S is normal, check protein S activity
|Acute thrombosis can result in decreased protein C, S and antithrombin activity. Warfarin can decrease protein C and S activity; heparin can 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 |
Antithrombotic therapy offered after the initial 3–6 months of treatment should be considered in patients with VTE that is not majorly provoked; it is most compelling for those with unprovoked VTE. For most patients who continue to take a DOAC to prevent recurrence, the dose can be reduced to prophylactic intensity after the initial 6–12 months of therapy. In patients deemed poor candidates for ongoing DOAC or warfarin use but who warrant some secondary prevention, low-dose (81–100 mg) aspirin may be used; however, this will provide far less reduction in risk of recurrent VTE with similar bleeding risk.
et al; Bova Score Validation Study Investigators. A prospective validation of the Bova score in normotensive patients with acute pulmonary embolism. Thromb Res. 2018;165:107.
JM. Thrombophilia testing and venous thrombosis. N Engl J Med. 2017;377:2298.
et al. Reversal of direct oral anticoagulants: guidance from the Anticoagulation Forum. Am J Hematol. 2019;94:697.
et al. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018;378:2010.
et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315.
et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16:1891.
et al. The 2019 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2019;40:3453.
et al. Direct oral anticoagulant for the prevention of thrombosis in ambulatory patients with cancer: a systematic review and meta-analysis. J Thromb Haemost. 2019;17:2141.
et al. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin
(LMWH) for treatment of cancer associated thrombosis (CAT): a systematic review and meta-analysis. Thromb Res. 2019;173:158.
et al. NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018. J Natl Compr Canc Netw. 2018;16:1289.
et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2:3257.
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 (Table 14–25), require immediate thrombolysis in combination with anticoagulation (Table 14–26). Systemic thrombolytic therapy has been used in carefully 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 lower dose of tPA commonly used for PE treatment has been evaluated in small trials but additional data are needed to recommend its use. 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.Contraindications to thrombolytic therapy for pulmonary embolism. ||Download (.pdf) Table 14–25. Contraindications to thrombolytic therapy for pulmonary embolism.
History of hemorrhagic stroke or stroke of unknown origin
Ischemic stroke in previous 6 months
Central nervous system neoplasm
Major trauma, surgery, or head injury in previous 3 weeks
Transient ischemic attack in previous 6 months
Pregnancy or first postpartum week
Noncompressible puncture sites
Refractory hypertension (systolic blood pressure > 180 mm Hg)
Advanced liver disease
Active peptic ulcer
Table 14–26.Thrombolytic therapies for high risk (massive) pulmonary embolism. ||Download (.pdf) Table 14–26. Thrombolytic therapies for high risk (massive) pulmonary embolism.
|Thrombolytic Agent ||Dose ||Frequency ||Comment |
|Alteplase (r-TPA) (preferred) ||100 mg ||Continuous intravenous infusion over 2 hours ||Follow with continuous intravenous infusion of unfractionated heparin (see Table 14–16 for dosage) |
|Urokinase ||4400 international units/kg ||Intravenous bolus × 1 followed by 4400 international units/kg continuous intravenous infusion for 12 hours || |
|Streptokinase ||250,000 international units ||250,000 international units intravenously loading dose over 30 min, followed by 100,000 international units/h over 12–24 h || |
In patients with large proximal iliofemoral DVT, data from randomized controlled trials are conflicting on the benefit of catheter-directed thrombolysis in addition to treatment with anticoagulation; the CaVenT trial showed some reduction in risk of postthrombotic syndrome, but the larger ATTRACT trial failed to show reduction in postthrombotic syndrome but did find an increased risk of major bleeding.
et al. Thrombolytic therapy in acute venous thromboembolism. Hematology Am Soc Hematol Educ Program. 2020;2020:612.
et al. Outcomes of catheter-directed therapy plus anticoagulation versus anticoagulation alone for submassive and massive pulmonary embolism. Am J Med. 2019;132:240.
et al. Half-dose versus full-dose alteplase
for treatment of pulmonary embolism. Crit Care Med. 2018;46:1617.
et al. 2019 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2019;40:3453.
et al; ATTRACT Trial Investigators. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med. 2017;377:2240.
F. Nonpharmacologic Therapy
1. Graduated compression stockings
Graduated compressions stockings may provide symptomatic relief to selected patients with ongoing swelling but do not reduce risk of postthrombotic syndrome at 6 months. 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 proximal DVT plus at least one additional risk factor for severity received full intensity 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 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.
Presence of large iliofemoral VTE, unprovoked upper extremity DVT, 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.
Clots in unusual locations (eg, renal, hepatic, or 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, low-risk PE at high risk for bleeding, poor candidate for outpatient treatment.
DVT with poorly controlled pain, high bleeding risk, or 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.
Suspected Paget-Schroetter syndrome (spontaneous upper extremity thrombosis related to thoracic outlet syndrome).
et al. Systematic review of efficacy and safety of retrievable inferior vena caval filters. Thromb Res. 2018;165:79.
et al; SOX trial investigators. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880.
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;313:1627.