8: Bleeding Disorders

The framework for bleeding distinguishes between structural causes (ie, an injury to the tissue or organ), platelet-related causes, and clotting factor–related causes. Bleeding due to platelet abnormalities, whether due to reduced number or abnormal function of platelets, is usually small vessel bleeding, and produces such findings as petechiae, bruising, gum bleeding, or nosebleeds. The bleeding occurs immediately upon the injury that induces it. Platelet-related bleeding is generally not quantitatively significant (ie, platelet-related bleeding tends not to cause serious blood loss requiring red cell transfusions). Nonetheless, platelet-related bleeding can still be clinically important if a patient bleeds a small amount into the brain (unusual unless the platelet count is < 10,000/mcL) or induces an abdominal hematoma from vigorous coughing, for example. By contrast, bleeding due to coagulation factor deficiencies or inhibitors tends to be delayed; that is, a platelet plug slows or stops the bleeding immediately after an injury, but the platelet plug is then not bolstered by the stable fibrin clot that is meant to definitively stop the bleeding. Bleeding due to coagulation factor abnormalities is more likely to be quantitatively significant, generally occurring in joints, the gastrointestinal tract, brain, retroperitoneum, or at sites of recent injury or medical or surgical intervention.

1. Structural causes

   1. Tissue injury from trauma

   2. Abnormality of the tissue such that minor trauma causes bleeding, such as a toothbrush causing gum bleeding from inflammatory gingival disease

2. Bleeding due to platelet disorders

   1. Disorders of platelet number (thrombocytopenia)

      1. Decreased production of platelets

         • (1) Medications (examples include valproic acid, linezolid, thiazide diuretics, gold compounds, antineoplastic chemotherapy drugs)

         • (2) Bone marrow replacement by malignancy, fibrosis, granulomas

         • (3) Bone marrow aplasia

         • (4) Alcohol

         • (5) B₁₂ deficiency

      2. Increased loss or consumption of platelets

         • (1) Splenic sequestration

         • (2) Autoimmune thrombocytopenia

           • (a) Idiopathic (also called idiopathic thrombocytopenic purpura [ITP])

           • (b) HIV

           • (c) Systemic lupus erythematosus (SLE)

           • (d) Lymphoproliferative disorders

           • (e) Medications (examples include heparin, phenytoin, carbamazepine, sulfonamides, quinine, antiplatelet drugs used for coronary syndromes such as abciximab or tirofiban)

         • (3) Disseminated intravascular coagulation (DIC)

         • (4) Thrombotic thrombocytopenic purpura (TTP)

         • (5) Sepsis

   2. Disorders of platelet function

      1. Congenital

         • (1) von Willebrand disease

         • (2) Other rare genetic abnormalities

      2. Acquired

         • (1) Medications, such as aspirin, nonsteroidal antiinflammatory drugs (NSAIDs)

         • (2) Myeloproliferative disorders, such as essential thrombocythemia, polycythemia vera

         • (3) Coating of platelets by abnormal proteins, such as in multiple myeloma and, occasionally, immune thrombocytopenia

         • (4) Uremia

3. Bleeding due to clotting factor abnormalities

   1. Congenital

      1. Hemophilia A (the most common)

      2. Other clotting factor deficiencies

   2. Acquired

      1. Deficiency of a factor or factors

         • (1) Liver disease

         • (2) Vitamin K deficiency (nutritional or due to warfarin therapy)

         • (3) Abnormal adsorption of a factor, eg, factor X adsorption to amyloid fibrils

         • (4) Consumption of factors, eg, DIC

         • (5) Dilution of factors, eg, massive transfusion

      2. Acquired inhibitor to clotting factor or factors

Figure 8-1 shows the diagnostic approach to bleeding disorders.

There are several pivotal points in Ms. A’s presentation that suggest her bleeding is due to a platelet disorder: the bleeding occurs immediately after the trauma of tooth brushing, she has petechiae on her skin, and the bleeding is small volume.

The second pivotal point is that her history further suggests that her platelet disorder is acquired. If she had a congenital platelet disorder, such as von Willebrand disease, she might have had life-long heavy menses and other manifestations of bleeding. In this case, her symptoms just began 2 weeks ago. A platelet count will confirm that her bleeding is related to thrombocytopenia, rather than platelet dysfunction, which is less commonly seen. (When platelet dysfunction is suspected, a test such as the PFA-100 assay should be ordered. This test is a reproducible screening tool for platelet function abnormalities. It measures the time to formation of a platelet plug in response to collagen along with adenosine diphosphate [ADP] or epinephrine.) The most common cause of thrombocytopenia in a young woman with no signs of systemic illness is idiopathic autoimmune thrombocytopenia. Although Ms. A’s headache is mild and she looks well, TTP can present with headache and thrombocytopenia and also tends to occur in young women. Finally, it is critical to remember that the platelets are only 1 of the cell lines affected by bone marrow disorders, and that a serious bone marrow condition (eg, leukemia) might first manifest as thrombocytopenia. A key step, then, is to decide if the thrombocytopenia is isolated or part of a pancytopenia picture, such as one might encounter with acute leukemia.

Table 8-1 lists the differential diagnosis.

Leading Hypothesis: ITP

Textbook Presentation

The classic presentation is a previously healthy person not exposed to medications that can cause thrombocytopenia in whom gum bleeding or petechiae are present. The platelet count is low, with large platelets seen on peripheral blood smear; other cell lines are normal. Physical exam, other than the minor bleeding, is normal.

Disease Highlights

1. ITP is an autoimmune disorder primarily of young women. This is the demographic group that commonly suffers from other autoimmune disorders.

2. A better term might be autoimmune thrombocytopenic purpura, as some cases are secondary to other conditions, such as lymphoproliferative disorders, collagen vascular disorders such as SLE, or infectious or inflammatory disorders such as chronic hepatitis, HIV infection, or Crohn disease.

3. The prevalence is approximately 100 cases per million persons.

Evidence-Based Diagnosis

1. ITP is a clinical diagnosis.

2. A bone marrow examination is not required for diagnosis.

   1. If performed, it would likely show normal or increased megakaryocytes, indicating adequate platelet production and suggesting the thrombocytopenia is due to peripheral destruction of platelets in the reticuloendothelial system.

   2. A bone marrow examination should be done when the presentation is atypical: patient has splenomegaly or significant lymphadenopathy or other cytopenias or the patient is older.

3. Serum antiplatelet antibody tests are about 50–60% sensitive, and not sufficiently specific to make the diagnosis of ITP.

   1. They are not considered sufficiently reliable for general use in diagnosing ITP.

   2. If there is serious consideration of a drug-induced cause of immune thrombocytopenia, it may be possible to demonstrate drug-related antiplatelet antibodies.

4. A successful clinical trial of corticosteroid therapy may also serve as strong evidence of the correct diagnosis of ITP.

5. Serologic studies to evaluate for lupus erythematosus or HIV infection would also be indicated if there is any clinical suspicion for their presence.

Treatment

1. Prednisone is the initial treatment for all patients.

2. Patients who do not respond to prednisone or whose thrombocytopenia recurs when the prednisone is stopped undergo splenectomy, which removes a site of antibody production as well as a site of reticuloendothelial system destruction of antibody-coated platelets.

3. In refractory cases, other immunosuppressants may be used, such as rituximab, azathioprine, or cyclophosphamide.

4. Thrombopoietin analogues such as romiplostim and eltrombopag have recently become available for treatment of refractory cases of ITP.

Alternative Diagnosis: TTP

Textbook Presentation

Patients with TTP appear systemically ill. The 5 classic manifestations are thrombocytopenia; microangiopathic hemolytic anemia; neurologic abnormalities such as confusion, headache, lethargy, or seizures; fever; and acute kidney injury.

Disease Highlights

1. Only 2 or 3 of the classic manifestations are present in many patients.

2. Thrombocytopenia and microangiopathic hemolytic anemia must be present to diagnose TTP, regardless of whether the other manifestations are present.

3. Neurologic abnormalities are present in about two-thirds of patients, acute kidney injury or renal failure in about half, and fever in about one-quarter.

4. Pathophysiology

   1. The ADAMTS13 enzyme is responsible for cleaving ultra-large von Willebrand factor multimers into smaller components.

   2. An anti-ADAMTS13 antibody inactivates the enzyme; the trigger for antibody formation is unknown.

   3. The lack of the enzyme leads to the ultra-large multimers causing platelet aggregation and clumping in the microcirculation, leading to thrombocytopenia.

   4. These clumps cause red blood cells passing over them to be physically damaged, leading to the characteristic finding on the blood smear of schistocytes, or fragmented red blood cells.

Evidence-Based Diagnosis

1. A serum test demonstrating reduced ADAMTS13 activity and a positive test for the anti-ADAMTS13 antibody reliably establish the diagnosis.

2. The diagnosis of TTP is made clinically, since the ADAMTS13 assay result may take several days to return, and the disease has critical morbidity and mortality if treatment is delayed.

   1. Any patient with thrombocytopenia (usually below 30,000/mcL) and evidence of microangiopathic hemolysis (schistocytes on peripheral blood smear, elevated serum lactate dehydrogenase (LD) level, reduced serum haptoglobin level) should raise concern about TTP.

   2. If neurologic signs or acute kidney injury is present, the diagnosis becomes even more likely.

Think about TTP in patients with thrombocytopenia and signs of hemolytic anemia.

Treatment

1. Plasma exchange is the treatment of TTP. While it is complicated and expensive, it does not carry substantial medical risk.

   1. Large volumes of plasma are removed from the patient and fresh plasma reinfused.

   2. This removes the antibody to ADAMTS13, and provides plasma with a normal complement of the enzyme.

   3. It is possible to treat TTP with plasma infusion alone, but plasma exchange allows for infusion of much higher volumes of plasma.

   4. Plasma exchange is performed daily, typically for 7–14 days, while monitoring the platelet count and LD levels.

   5. Prior to the advent of plasma exchange, the mortality rate for TTP was about 90%. With plasma exchange, the survival rate is now about 90%.

2. Immunosuppressive drugs such as prednisone or rituximab are also used in an effort to reduce the production of the anti-ADAMTS13 antibody.

It is essential to treat TTP as soon as it is suspected, even if the diagnosis is not absolutely firm.

The goal of therapy in ITP is a safe platelet count, typically a count above 30,000/mcL, rather than a normal count. If it is not possible to taper prednisone off, or to a very low dose, while maintaining a safe platelet count, alternative therapies such as splenectomy or thrombopoietin analogues are indicated, since the long-term risks of corticosteroids (infections, osteoporosis, adrenal suppression, muscle weakness, electrolyte disturbances) should be avoided if possible.

The most common causes of new thrombocytopenia in hospitalized patients are medications, heparin-induced thrombocytopenia (HIT), and sepsis. Therefore, the first steps in diagnosing thrombocytopenia in a hospitalized patient are to review previous platelet counts to determine whether the thrombocytopenia is new, review the medication list, and look for vital signs suggestive of sepsis. Because Mr. J has a history of autoimmune hemolytic anemia, it is also important to consider autoimmune thrombocytopenia as an accompanying autoimmune phenomenon (also called Evans syndrome, characterized by seeing spherocytes rather than schistocytes in the peripheral smear), although this would otherwise be uncommon in his age group. Finally, he could have cirrhosis due to his extensive alcohol intake over the years, with hypersplenism causing mild-to-moderate thrombocytopenia. Chronic autoimmune hemolytic anemia might also cause splenic enlargement. If hypersplenism is the cause, his platelet count at admission would probably have been somewhat low, typically between 40,000/mcL and 120,000/mcL. Table 8-2 lists the differential diagnosis.

Mr. J’s thrombocytopenia is new, and he is receiving heparin, a very common cause of medication-related thrombocytopenia. He is clinically stable, and so sepsis is not a serious consideration.

Leading Hypothesis: HIT

Textbook Presentation

The classic presentation of HIT is a hospitalized patient receiving heparin whose platelet count falls by more than 50% from baseline, though generally to a level still above 50,000/mcL. There may be associated thrombosis, more commonly venous (deep venous thrombosis, pulmonary embolism, venous limb gangrene) than arterial (cold digits or extremity). Skin necrosis at the site of heparin injections may also be seen.

Disease Highlights

1. Caused by the development of an antibody directed against a heparin-platelet factor 4 complex; the antibody occurs more commonly with unfractionated heparin than with low-molecular-weight heparin.

2. Develops in about 5% of patients who receive heparin.

3. Surgical patients are at higher risk.

4. HIT manifests between 5 and 10 days after starting any kind of heparin—full dose intravenous heparin, low-dose prophylactic heparin, or even just heparin flushes to maintain patency of indwelling intravascular catheters. Thrombocytopenia may develop earlier in patients with recent heparin exposure.

5. Thrombosis develops in about 50% of patients who have HIT, and the thrombosis may be evident at the same time as the platelet count drop. Thrombosis may be arterial (previously called the white clot syndrome), although it is more often venous.

6. The platelet count does not usually drop below 50,000/mcL in HIT; a lower platelet count suggests another etiology.

Evidence-Based Diagnosis

1. The most sensitive, readily available, screening test is an enzyme-linked immunosorbent assay (ELISA) assay for anti-PF4 antibody.

   1. It is nearly 100% sensitive, although specificity is between 75% and 85%. Thus, a negative test is very reassuring that HIT is not present, but false-positive tests are not uncommon.

   2. The serotonin-release assay is more specific but not readily available.

2. Because the poor specificity of the anti-PF4 assay leads to overdiagnosis of HIT, a pretest probability scoring system (the 4“T’s”) has been validated.

   1. Thrombocytopenia

      1. Fall of platelets by > 50% and nadir > 20,000/mcL = 2 points

      2. Fall of platelets by 30–50% or nadir 10–19,000/mcL =1 point

      3. Fall by < 30% or nadir < 10,000/mcL = 0 points

   2. Timing of platelet fall

      1. Clear onset between days 5 and 10 after exposure, or < 1 day if prior heparin exposure within 30 days = 2 points

      2. Consistent with fall between 5 and 10 days, but some data missing, or fall > 10 days, or < 1 day if prior heparin exposure within 30–100 days = 1 point

      3. Fall at < 4 days and without recent exposure = 0 points.

   3. Thrombosis or other sequelae

      1. Confirmed new thrombosis, skin necrosis, or acute systemic reaction after IV unfractionated heparin bolus = 2 points

      2. Progressive or recurrent thrombosis, non-necrotizing skin lesions or suspected thrombosis that has not been proven = 1 point

      3. None of the above = 0 points.

   4. OTher causes for thrombocytopenia present:

      1. None apparent = 2 points

      2. Possible = 1 point

      3. Definite = 0 points.

   5. Test interpretation: 0–3 points: low probability; 4–5 points: intermediate probability; 6–8 points: high probability.

      1. In 1 large series of 111 patients with a low pretest probability of HIT using this scoring system, only 1 had clinically significant HIT antibodies (0.9%).

      2. In contrast, the overall rate of clinically significant HIT antibodies was 11.4% and 34% in those with intermediate and high scores, respectively.

   6. An online calculator is available at http://www.qxmd.com/calculate-online/hematology/hit-heparin-induced-thrombocytopenia-probability

Treatment

1. Heparin must be discontinued whenever HIT is suspected, even when the anti-PF4 assay result is not yet available.

2. An alternative anticoagulant must be started to prevent HIT-associated thrombosis, regardless of whether the initial indication for anticoagulation is still present; generally, a direct thrombin inhibitor such as argatroban or lepirudin is used.

   1. Low-molecular-weight heparin may not be substituted: although the incidence of HIT with low-molecular-weight heparin is much lower than with unfractionated heparin, once HIT occurs, there is too much risk for cross-reactivity.

   2. Similarly, warfarin should not be used until the platelet count has recovered (this takes a few days) but can then be started while the direct thrombin inhibitor is being given.

   3. Anticoagulation should continue for 2–3 months.

3. Although not approved for this indication, fondaparinux, a factor X inhibitor, has sometimes been used as an alternative anticoagulant in patients with HIT.

4. Surprisingly, patients with a history of HIT may safely be reexposed to heparin if necessary after a year has passed and the antibody has presumably disappeared.

The findings of a painful, cool, and dusky toe suggest arterial occlusion. While post cardiac surgery patients can have arterial emboli from a left ventricular clot or postoperative atrial fibrillation, the combination of new thrombocytopenia, heparin exposure, and thrombosis points toward HIT. Mr. J’s “4T” score is 8, consistent with a high probability of HIT: 2 points for the degree of thrombocytopenia, 2 points for the time course, 2 points for the presence of new thrombosis, and 2 points for lack of other apparent causes of thrombocytopenia (despite his alcohol history, his liver tests are normal, making cirrhosis and hypersplenism unlikely, and ITP is not associated with thrombosis).

Ms. W’s presentation suggests that she is having an upper gastrointestinal (GI) bleed. In addition to the specific GI causes of upper GI bleeding discussed in Chapter 19, GI Bleeding, it is important to consider whether patients who are bleeding have an underlying platelet or coagulation disorder contributing to the bleeding. Ms. W does have cirrhosis with splenomegaly that could lead to thrombocytopenia due to splenic sequestration; however, the large volume of the bleeding may suggest a coagulation factor disorder.

The prothrombin time (PT) measures what is commonly called the extrinsic clotting pathway (Figure 8-2), wherein tissue factor from an injury activates factor VII, followed by activation of the coagulation cascade through the "common pathway" factors (factors V, X, II [prothrombin] and I [fibrinogen]). Because the source of tissue factor reagents used in the laboratory to trigger the cascade vary, the PT will vary among different laboratories when testing the same sample. To overcome this problem of PT results not being comparable from one lab to another, the international normalized ratio (INR) was developed, to standardize PT results based on a constant associated with each laboratory reagent. The INR, which is routinely reported along with the PT, allows the clinician to feel confident that the data from different laboratories are comparable.

The activated partial thromboplastin time (aPTT) measures what is commonly called the intrinsic clotting pathway, starting with factor XII and working through factors XI, IX and VIII before entering the "common pathway."

In the evaluation of a prolonged clotting time, either PT or aPTT, one considers whether only 1 test is prolonged, and which factors contribute to each test. For example, an isolated prolonged PT suggests a deficiency of factor VII, since that is the only factor unique to the PT assay. An isolated prolonged aPTT raises concern about the 4 factors that are unique to the aPTT—factors, XII, XI, IX, and VIII. Prolongation of both the PT and aPTT raises concern either about the factors in the common pathway—I, II, V, and X—or a defect in multiple factors. Table 8-3 summarizes commonly seen patterns of factor deficiencies.

In clinical practice, prolongation of clotting times is most commonly acquired, either due to acquired deficiencies (eg, from malnutrition or liver disease) or acquired factor inhibitors. (While congenital factor deficiencies such as hemophilia certainly cause prolonged clotting times, these are far less commonly seen, and patients are well aware of them, making complex diagnostic evaluations unnecessary.) In order to distinguish between a factor deficiency and an inhibitor, it is often helpful to perform a mixing study, wherein one mixes 1:1 the patient’s plasma and normal plasma, to see if the clotting time corrects. If it does correct, the normal plasma has provided the missing factor to the patient’s plasma, indicating the abnormality is due to a factor deficiency. If it does not correct, the implication is that an inhibitor in the patient’s plasma is inactivating the clotting factor(s) from the normal plasma. Such inhibitors may be exogenous, such as inadvertent heparin in the mixture; or endogenous, such as an acquired factor inhibitory antibody.

Based on the data we have so far, Ms. W’s GI bleeding is most likely from the upper GI tract, probably induced by use of the NSAID ibuprofen. The severity of the bleeding may be exacerbated by a coagulopathy related to her cirrhosis. The history of poor appetite for a few weeks raises the consideration of vitamin K deficiency, and the presence of splenomegaly on examination suggests that thrombocytopenia due to splenic sequestration may also be contributing.

Table 8-4 lists the differential diagnosis.

Ms. W has the stable, moderate thrombocytopenia generally seen in patients with portal hypertension and hypersplenism. Moderate thrombocytopenia such as this does not substantially increase the risk of bleeding, especially not the large volume GI bleeding she is experiencing. The coagulation abnormalities she has can certainly contribute to large volume bleeding.

Leading Hypothesis: Liver Disease–Induced Coagulopathy

Textbook Presentation

The classic presentation of liver disease–induced coagulopathy is variable. Patients may be asymptomatic, only discovered to have a coagulopathy incidentally on coagulation laboratory studies. Spontaneous bleeding is uncommon, but anything that stresses the patient (such as an injury, an operative procedure, or perhaps drug-induced gastritis) may lead to more bleeding than one might normally anticipate with that event in someone without liver disease.

Disease Highlights

1. Patients with liver disease–induced coagulopathy typically have a disproportionately longer PT (and therefore higher INR) than aPTT.

2. The coagulopathy is caused by impaired production of clotting factors by the diseased liver; the clotting factor with the shortest half-life, namely factor VII, would be expected to be most prominently affected. Since the PT/INR is so sensitive to factor VII levels, that test is more notably abnormal.

3. Coagulopathy is seen primarily in patients with severe liver disease. The liver has considerable reserve, and only when the impairment is severe does one find significant coagulopathy.

Evidence-Based Diagnosis

1. In a patient with liver disease who is bleeding or in whom an invasive procedure is planned, the PT/INR and aPTT should be checked in order to screen for coagulation factor deficiencies.

   1. If the screening tests are prolonged, it may be worth checking the levels of factor VII, factor V, factor II, factor IX, and factor X as well as fibrinogen to help determine which replacement therapy is most appropriate.

   2. If factor VII is low but factor V normal, it suggests that vitamin K deficiency may be playing a role, whereas in severe liver impairment, both factors V and VII are reduced.

   3. Because all the clotting factors except factor VIII are produced in the hepatocytes, all of them except factor VIII may be low in severe liver disease. Factor VIII is typically normal or even elevated in liver disease, a finding that may distinguish liver disease from DIC, in which factor VIII is low.

2. Another finding that may contribute to bleeding risk in severe liver disease is excessive fibrinolysis, the cause of which is a complex interplay between the production of and hepatic clearance of fibrinolytic activators and inhibitors.

3. While it may seem paradoxical, there may also be increased risk of thrombosis in liver disease. Several findings may account for this: reduction of the vitamin K-dependent anticoagulant proteins, protein C and protein S; and increases in factor VIII and sometimes von Willebrand factor.

Treatment

1. Correct the coagulopathy using fresh frozen plasma to replete clotting factors. If the plasma fibrinogen level is particularly low (eg, < 100 mg/dL), infusion of cryoprecipitate may be helpful.

2. In severe cases, administration of recombinant activated factor VIIa may help stop the bleeding associated with liver disease; it is extremely expensive, however, and carries some risk of inducing thrombosis.

Alternative Diagnosis: Vitamin K Deficiency

Textbook Presentation

The usual presentation of vitamin K deficiency is a hospitalized patient who is found to have a prolonged PT/INR, rarely with bleeding manifestations.

Disease Highlights

1. The most common cause of vitamin K deficiency is inadequate oral intake.

2. Patients who have been hospitalized and need to start warfarin therapy may require smaller than expected doses to achieve therapeutic levels, because they may be unduly sensitive as a result of baseline vitamin K deficiency.

3. Vitamin K deficiency can also occur with the recent use of antibiotics that alter the gut flora’s ability to convert vitamin K to an absorbable form.

Evidence-Based Diagnosis

1. As with liver disease, patients with vitamin K deficiency have PT/INR levels disproportionately longer than aPTT levels.

2. This is due to factor VII having the shortest half-life of the vitamin K–dependent factors (II, VII, IX, and X), thus making the factor VII–dependent PT/INR more sensitive to vitamin K alterations.

3. The aPTT will also go up eventually, as the levels of factors II, IX and X, with much longer half-lives, fall.

Treatment

1. Vitamin K repletion, either orally or parenterally, is the treatment of choice.

   1. If parenteral treatment is chosen, it should be administered subcutaneously or intravenously—not intramuscularly.

   2. Intramuscular injections should be avoided in patients with coagulopathies, in order to avoid the development of hematomas in muscles that can lead to neuropathy if a major nerve traverses the area.

   3. Vitamin K administration takes 18–24 hours to have its effect, so if a patient with vitamin K deficiency is bleeding, fresh frozen plasma may be required.

Alternative Diagnosis: DIC

Textbook Presentation

Disseminated intravascular coagulation (DIC, also called consumptive coagulopathy) is a catastrophic activation of the coagulation system that classically presents as the abrupt onset of uncontrolled spontaneous diffuse bleeding from multiple sites (venipuncture sites, catheter sites, endotracheal tubes, recent surgical sites) in patients with severe illness such as shock states, major trauma, sepsis, obstetric emergencies, and advanced cancer.

Disease Highlights

1. The common denominator of conditions that cause DIC is tissue injury and activation of the clotting cascade via entry of procoagulants into the circulation.

2. A variety of conditions activate the clotting cascade.

   1. Trauma

   2. Advanced adenocarcinomas of any site, such as colon, pancreas, or lung.

   3. Obstetric crises such as amniotic fluid embolism or placental abruption.

   4. Acute promyelocytic leukemia, wherein the granules of the malignant promyelocytes activate the clotting system.

3. Although the classic presentation is major bleeding due to activation of the clotting cascade leading to secondary consumption of clotting factors, in some cases clotting manifestations may predominate.

   1. Patients with advanced cancer may have recurrent deep venous thrombosis or pulmonary embolism or arterial emboli in the extremities, without signs of bleeding.

   2. This is considered chronic DIC.

4. Renal, hepatic, and pulmonary dysfunction may accompany acute DIC.

Evidence-Based Diagnosis

1. In acute DIC, consumption of clotting factors is demonstrated by thrombocytopenia, prolongation of the PT/INR and aPTT, reduction of plasma fibrinogen level, and increases in D-dimer and fibrin degradation products (FDP).

2. The D-dimer and FDP reflect fibrinolytic activity acting upon fibrin formed during the clotting process.

   1. D-dimer is the product of lysis of cross-linked fibrin.

   2. FDP is the product of lysis of both fibrin and fibrinogen.

   3. Fibrinogen levels below 100 mg/dL may correlate with bleeding risk.

If DIC is suspected, testing should include platelet count, PT/INR, aPTT, fibrinogen, and D-dimer.

Treatment

1. Treat the underlying condition if possible.

2. Replete clotting factors that have been depleted, with platelet transfusions, fresh frozen plasma, and cryoprecipitate if fibrinogen is particularly low.

3. In rare instances, the use of low-dose heparin is considered. While it is logical to consider undertaking anticoagulation if the initiation of the process was coagulation, the additional bleeding risk is of great concern, and efforts are generally focused more on providing clotting factors while addressing the underlying cause.