A. Introduction. A predisposition to bleeding can result from problems with platelets (either number or function) or problems with coagulation (factor deficiency or factor inhibitors).
B. Clinical Manifestations of Bleeding Disorders
a. Recurrent bleeding since childhood or a family history of bleeding suggests an inherited problem.
b. Mucocutaneous petechiae or ecchymoses are usually indicative of platelet problems.
c. Spontaneous bleeding into organs, body cavities, and joints (hemarthroses), or delayed bleeding after trauma (including surgery) is suggestive of coagulation problems.
C. Approach to the Patient. Figure 66.1 summarizes the general approach to a patient with a bleeding disorder.
a. Platelet count. Although affected by a number of variables, the platelet count is usually <100,000 cells/μL before the bleeding time becomes prolonged. Therefore, mildly decreased platelet counts are usually not responsible for clinically overt bleeding. Rather, a concurrent problem of platelet function or coagulation should be considered.
b. Prothrombin time (PT)/partial thromboplastin time (PTT). There are three types of PT/PTT abnormalities: increased PT/normal PTT, increased PT/increased PTT, or normal PT/increased PTT.
i. Increased PT/normal PTT
1. Differential diagnosis
a. Early disseminated intravascular coagulation (DIC)
b. Liver disease
c. Warfarin therapy
d. Vitamin K deficiency
e. Factor VII deficiency (isolated factor VII deficiency is a rare cause of an elevated PT/normal PTT)
2. Recommended workup
a. Patient history. Ask about medications and note factors that may predispose a patient to vitamin K deficiency (e.g., malnutrition, pancreatic insufficiency, liver disease, recent antibiotic use).
b. DIC panel (D-dimer, fibrinogen, PT/PTT, and platelet count) and peripheral smear. Evidence for DIC includes a prolonged PT and/or PTT, low fibrinogen level (<150 mg/dL), an elevated D-dimer, and the presence of schistocytes on the peripheral blood smear. D-dimer levels can also be elevated in patients with myocardial infarction, stroke, venous thromboembolism, preeclampsia, sepsis, renal failure, or severe liver disease. Hypofibrinogenemia may also occur in patients with severe liver dysfunction or those receiving certain medications (e.g., L-asparaginase).
c. Liver function tests. Bilirubin, albumin, and transaminase levels are often obtained to assess for liver failure, as the liver produces many of the different clotting factors.
Because of many overlapping findings between liver disease and DIC, the presence of schistocytes may be the only distinguishing feature of DIC in a patient with concomitant liver failure.
e. Factor VII level. An isolated factor VII level is rarely indicated but can be obtained if the cause of the increased PT is still unknown.
ii. Increased PT/increased PTT
1. Differential diagnosis. The differential diagnosis for this abnormality is generally the same as for an isolated elevated PT, but the conditions are more severe.
b. Severe liver disease
c. Warfarin overdose
d. Heparin overdose
e. Severe vitamin K deficiency
f. Factor I, II, V, or X inhibitor or deficiency (extremely rare causes of an elevated PT/PTT)
2. Recommended workup. The recommended initial evaluation is the same as that for increased PT/normal PTT. However, individual factor inhibitors or deficiencies can be identified with a mixing study and factor-specific quantitative analyses. Additionally, dysfibrinogenemia can be characterized through an assessment of both the fibrinogen antigen and activity levels as well as with the thrombin clotting time and reptilase time.
iii. Normal PT/increased PTT
1. Differential diagnosis. After excluding the obvious cause (i.e., heparin therapy), you need to consider four possibilities.
a. Coagulation factor deficiency
b. Coagulation factor inhibitor
c. Antiphospholipid antibodies
d. von Willebrand’s disease (VWD; especially types IIN and III)
2. Recommended workup
a. Patient history. The patient history can provide valuable information. If the patient has a history of bleeding, then a factor deficiency, a factor inhibitor, or vWD is most likely. If the patient has a history of clotting rather than bleeding, an antiphospholipid antibody may be present.
b. Mixing study. Only 50% factor activity is needed to have a normal PT or PTT. By mixing the patient’s plasma with an equal amount of plasma with a normal PT and PTT, enough factor will be provided to correct for any factor deficiency, but this often will not correct for an inhibitor of the specific clotting factor.
i. If the PTT corrects, a factor deficiency is diagnosed. The most common factor deficiencies are factor VIII (hemophilia A), factor IX (hemophilia B), and factor XI deficiencies; therefore, factor VIII, IX, and XI levels should be assessed after the mixing study corrects the PTT.
ii. If the PTT does not correct, an antiphospholipid antibody may be present. Laboratory tests to identify an antiphospholipid antibody include a lupus anticoagulant, an anticardiolipin antibody, a β2-glycoprotein (GP) 1 antibody, and a dilute Russell’s viper venom time (see III. D. 1.).
iii. A factor inhibitor can also prolong the PTT and may be suspected with a prolonged PTT and a mixing study that does not correct. Some inhibitors function better at 37° C, and therefore the mixing study always includes an immediate mixing value and one obtained after warming the sample to 37° C for 30 to 60 minutes. The results are reported as Bethesda units (BU), which indicates the number of titrations required to dilute out the inhibitor; a higher BU implies a higher amount of the inhibitor.
c. vWD can result in a qualitative or quantitative decrease in proteins required to form a functional clot. In vWD type IIN, there is a decreased ability of factor VIII to bind to the von Willebrand antigen, resulting in a decreased level of factor VIII, which may prolong the PTT. Likewise, in vWD type III, there is a near absence of the von Willebrand antigen, resulting in a near absence of factor VIII.
Because hemophilia A is an X-linked disorder, consider a type III vWD in females presenting with a near absence of factor VIII.
c. Patients with mucocutaneous bleeding or ecchymoses whose coagulation studies are normal may have a congenital or acquired platelet disorder or vWD. Historically, a bleeding time was used to assess for an underlying platelet disorder, but because this test is affected by a number of nonpathologic variables, including skin temperature, age, sex, anxiety, cuff pressure, and size and depth of the incision, its use has diminished significantly. More recently, the platelet function analyzer (PFA-100) has been used to screen for platelet disorders, mainly in the perioperative setting. The most accurate assessments include platelet aggregometry and agonist-induced platelet secretory testing, but these tests are limited to advanced specialized laboratories .
i. If the coagulation tests are normal and the platelet count is >100,000 cells/μL, platelet dysfunction, vWD, or vascular abnormality may be implicated.
1. Acquired platelet dysfunction
a. Differential diagnosis. Acquired platelet disorders are usually systemic.
i. Severe renal disease (i.e., uremia)
ii. Advanced chronic liver disease
iii. Malignancy. Multiple myeloma and Waldenström’s macroglobulinemia can both lead to platelet dysfunction due to either paraprotein interfering with platelet function or hyperviscosity.
iv. Myeloproliferative neoplasms can be associated with an increased risk for bleeding even when platelet levels are elevated
v. DIC. The fibrin split products produced in DIC can inhibit platelet function.
vi. Acquired storage pool disease. Cardiopulmonary bypass surgery or vasculitis can cause platelets to release all their granules, resulting in dysfunctional platelets.
vii. Aspirin irreversibly inhibits platelet function for the life of the platelet (7–10 days); other nonsteroidal antiinflammatory drugs (NSAIDs) reversibly inhibit platelet function, and the effect is more transient.
viii. Additional medications: clopidogrel, ticlopidine, abciximab, and eptifibatide are increasingly being used in patients with cardiovascular disease and can be associated with an increased risk for bleeding.
b. Recommended workup
i. Patient history. A history of renal, hepatic, or malignant disease should be sought. A medication history (including all over-the-counter drugs) should also always be elicited.
ii. Complete blood count (CBC) with platelets and differential. A CBC will help evaluate the possibility of a myeloproliferative neoplasm (see Chapter 70) and may provide some evidence of a plasma cell dyscrasia (see Chapter 72).
iii. DIC panel.
iv. Renal and liver tests (blood urea nitrogen [BUN], creatinine, aspartate aminotransferase [AST], alanine aminotransferase [ALT], protein, albumin, and alkaline phosphatase) may help identify medical reasons for the bleeding disorder.
v. Serum protein electrophoresis with immunofixation, urine Bence Jones protein, or serum free light-chain analysis may be used to evaluate the presence of paraproteinemia (see Chapter 72).
2. Inherited platelet dysfunction. Platelet activity in clotting is dependent on platelet adherence, activation, aggregation, and release of granular products. Dysfunction in any of these steps may lead to clinical bleeding.
a. Differential diagnosis. The first two disorders involve problems with platelet adherence, and the second two involve problems with platelet aggregation.
i. vWD. von Willebrand factor (vWF) is elaborated by megakaryocytes and endothelial cells, but then undergoes extensive post-translational modification. It circulates in the plasma in multimers of varying size, bound to factor VIII (which vWF stabilizes). vWF binds to the GP Ib receptor on platelets and helps platelets adhere to endothelium.
1. In type I vWD (75% of vWD cases; autosomal dominant), there is a mild to moderate quantitative decrease in the amount of vWF.
2. In type II vWD (10–15% of vWD cases; most are autosomal dominant), there is a qualitative decrease in vWF activity.
a. In type IIA vWD (autosomal dominant), there is an increased susceptibility to cleavage of vWF large multimers by the vWF cleaving protease (ADAMTS13), resulting in a relative decrease in intermediate and large multimers of vWF, which are most responsible for inducing platelet adhesion.
b. In type IIB vWD (autosomal dominant), there is increased spontaneous binding of the high-molecular-weight multimers to platelets, resulting in a decrease in free large multimers and a mild decrease in platelet numbers.
c. In type IIM vWD (autosomal dominant), there is decreased binding of vWF to GP Ib with an apparently normal multimer analysis.
d. Type IIN vWD (autosomal recessive) results from an altered binding of factor VIII to vWF, resulting in decreased factor VIII levels.
ii. Bernard-Soulier syndrome results from a loss in the platelet receptor for vWF (GP Ib) and thus can be confused with type IIM vWD.
iii. Glanzmann’s thrombasthenia results from the loss of the GP IIb/IIIa platelet receptor, which leads to decreased fibrinogen binding and, therefore, defective platelet aggregation.
iv. Congenital storage pool diseases are caused by defects in the formation of or the signaling mechanisms that induce the release of platelet granules. These include gray platelet syndrome (deficient α-granules), Wiskott-Aldrich syndrome (due to mutations in the X-linked WAS protein), Chediak-Higashi syndrome, and Hermansky-Pudlak syndrome.
b. Recommended workup
i. Patient history. vWD is a largely autosomal dominant disorder, and Bernard-Soulier syndrome and Glanzmann’s thrombasthenia are autosomal recessive disorders; therefore, obtaining a thorough family history is important. Several of the storage pool diseases have coexisting physical findings including albinism (Chediak-Higashi and Hermansky-Pudlak) or coexisting immune disorders (Wiskott-Aldrich).
ii. vWD panel. Screen for vWD first because vWD is the most common inherited disorder of platelet function. A vWD panel includes the following tests:
1. Von Willebrand factor antigen (VWF:Ag) can be quantified using a number of methods.
2. Von Willebrand antigen activity is often assessed using the ristocetin cofactor activity (VWF:RCo). Ristocetin is an antibiotic that binds the platelet receptor GP Ib to vWF, especially the high-molecular-weight multimers. The patient’s plasma is mixed with normal platelets and ristocetin, which should cause the patient’s vWF to bind to the platelet surface and produce platelet aggregation. The absence of platelet aggregation implies a quantitative or qualitative decrease in vWF. Patients with type II vWD and decreased large multimers (IIA and IIB) often have a depressed VWF:RCo compared with the VWF:Ag.
3. Factor VIII antigen/factor VIII activity. Since vWF binds factor VIII and stabilizes the protein, decreased vWF can lead to decreased factor VIII levels and decreased activity.
4. Ristocetin-induced platelet aggregation (RIPA) is an analysis of the affinity of binding of vWF to GP Ib. Interestingly, the vWF in type IIB binds to GP Ib with increased affinity, and it is the one vWD that has an elevated RIPA. Alternatively, Bernard-Soulier syndrome demonstrates a normal vWD panel but a decreased RIPA due to an absent GP Ib protein.
5. vWF multimer analysis uses gel electrophoresis to visualize the size and quantity of the various vWF multimers.
Type I vWD often shows a moderate parallel quantitative decrease in all parts of the panel, whereas type III vWD demonstrates a significant parallel quantitative decrease in all parts of the panel. In type II vWD, there are qualitative changes in the von Willebrand pathways leading to changes in either the multimer analysis, VWF:RCo activity, or factor VIII levels.
iii. Platelet aggregometry, agonist-induced platelet secretory testing, and electron microscopy can be used to diagnose Glanzmann’s thrombasthenia and many of the other congenital storage pool diseases.
1. In many storage pool diseases, platelets will demonstrate an initial aggregation response to agonists, but then disassociate. Electron microscopy can help identify abnormal granule formation.
2. In Glanzmann’s thrombasthenia, most platelet agonists other than ristocetin fail to induce any aggregation because the necessary IIb–IIIa receptor is missing.
iv. If there is a clinical history of bleeding and the prior testing is normal, a few rare disorders still need to be considered. All these involve a defect in crosslinking of fibrin, leading to a poor stability of the clot.
1. Differential diagnosis
a. Factor XIII (“fibrin-stabilizing factor”) deficiency
c. Deficiency of inhibitors to fibrinolysis (i.e., plasminogen activator inhibitor or α2-plasmin inhibitor)
2. Recommended workup
a. Increased clot solubility in urea, acetic acid, or monochloroacetic acid is seen in factor XIII deficiency, but a quantitative analysis is required to confirm the diagnosis.
b. Increased thrombin time and reptilase time is evidence of a possible dysfibrinogenemia.
c. Quantitative and functional assessments of plasminogen activator inhibitor and α2-plasmin inhibitor can be performed to diagnose deficiency of inhibitors to fibrinolysis.
d. Other tests
i. Dilute Russell’s viper venom time (dRVVT). Russell’s viper venom activates factor X, leading to activation of factor II (thrombin) and subsequently factor I (fibrinogen), but still requires phospholipid. The dRVVT may therefore be prolonged when antiphospholipid antibodies are present.
ii. Thrombin time measures the time for the blood to clot after thrombin is directly added to plasma and therefore assesses thrombin’s conversion of fibrinogen to fibrin. The thrombin time will be prolonged when thrombin is inhibited (as in heparin therapy), when there is low fibrinogen (as in afibrinogenemia or DIC), or when there is abnormal fibrinogen (as in dysfibrinogenemia).
iii. Reptilase time is just like thrombin time, except it is not sensitive to the effect of heparin. If the thrombin time is prolonged, but the reptilase time is normal, then a heparin effect is diagnosed. If the reptilase time is also prolonged, then afibrinogenemia, DIC, or dysfibrinogenemia should be considered.
iv. Nonhematologic causes of bleeding. A number of vascular abnormalities noted in Figure 66.1 have been associated with clinically-relevant bleeding. These include congenital or acquired structural and connective tissue disorders involving the vascular wall as well as vasculitides that result in increased blood vessel fragility or permeability. Diagnosis and treatment depend on the etiology identified, although some congenital disorders have no specific therapy available.
a. Platelet problems
i. Quantitative problems. The treatment of thrombocytopenia is discussed in Chapter 60.
ii. Qualitative problems are usually only treated when the patient is acutely bleeding or if surgery is planned. Specific therapies may include dialysis for uremia, myelosuppression for myeloproliferative neoplasms, or platelet transfusions for platelet storage pool diseases. Other commonly used treatments include:
1. Desmopressin (DDAVP) (0.3 μg/kg/day) works presumably by increasing the release of stored vWF and factor VIII from endothelial cells. DDAVP is useful as prophylaxis before surgery in patients with type I vWD or hemophilia A. It may also be useful in other disorders of platelet dysfunction (e.g., uremia, drug-induced platelet dysfunction, and some storage pool disease, such as Bernard-Soulier syndrome), but not Glanzmann’s thrombasthenia.
a. A test dose of desmopressin (given while the patient is not bleeding) should always be administered to ensure that adequate levels of vWF are induced 60 minutes and 3–4 hours after the infusion. Use in emergent situations without prior testing is not recommended because some patients will not respond.
b. Stores of vWF are depleted in 2–3 days, so desmopressin is usually only effective as a short-term treatment. Moreover, desmopressin is an antidiuretic, and prolonged use or use in children younger than 2 years can lead to hyponatremia and risk for seizures.
c. Desmopressin is ineffective in type III vWD. In type IIB vWD, abnormal large multimers of vWF have a high affinity to platelets, and treatment with desmopressin can trigger paradoxical thromboses and thrombocytopenia (from splenic removal). Therefore, the use of desmopressin should be avoided in patients with these subtypes.
2. Intermediate purity factor VIII concentrates also contain vWF that are coprecipitated with factor VIII and are pasteurized to reduce the risk for viral transmission.
3. Cryoprecipitate (10–15 units every 12 hours) is effective in raising vWF levels 30–50% (approximately 3% per unit) and therefore can be used in patients with vWD. However, cryoprecipitate carries an elevated risk for transmitting viral infections and has a higher risk for transfusion-associated allergic reactions, and therefore its use in hemophiliac patients or in those with vWD has fallen out of favor.
4. Platelet transfusions can be used for refractory bleeding.
a. Coagulation problems
i. Increased PT/normal PTT and increased PT/increased PTT
1. With significant acute bleeding
a. Fresh-frozen plasma is given to correct the PT/PTT regardless of the underlying etiology.
b. Cryoprecipitate can be used for patients with DIC to restore the fibrinogen level to >150 mg/dL.
c. Vitamin K (10 mg subcutaneously or orally daily for 3 days) can be administered in cases in which vitamin K deficiency plays a primary or contributing role in the patient’s coagulopathy.
Fresh-frozen plasma contains all factors but only small amounts of fibrinogen. Cryoprecipitate contains concentrated factor VIII, vWF, and fibrinogen.
2. Without significant acute bleeding. Treatment takes into account the underlying cause.
a. DIC. In patients with DIC but no acute bleeding, the elevated PT is not treated. Instead, treatment is aimed at correcting the cause of the DIC (e.g., antibiotics for sepsis).
b. Warfarin therapy. The mechanism used to correct the international normalized ratio (INR) is dependent on both the degree of the elevation of the INR and the presence of bleeding.
i. If the INR is <5 and the patient is not bleeding, the warfarin dose is usually withheld temporarily and the PT is rechecked daily. No specific reversal is warranted.
ii. If the INR is >5 but <9 and the patient is not bleeding, the warfarin dose may be withheld temporarily and the PT is rechecked daily or vitamin K (1–2.5 mg) may be given orally or subcutaneously until the INR is reduced.
iii. If the INR is >9 and the patient is not bleeding, the warfarin dose is withheld temporarily and vitamin K (2.5–5 mg) is given orally or subcutaneously until the INR is reduced.
iv. If the patient is bleeding, fresh-frozen plasma is given to correct the INR and vitamin K is also given (10 mg) orally, subcutaneously, or intravenously.
Remember, there is approximately a 2- to 3-day delay between the changes in warfarin dose and changes in the PT. If warfarin is held, do not wait until the PT is in the appropriate range to resume therapy because the PT will continue to drop. Therapy is best reinitiated when the PT is slightly higher than desired.
c. Vitamin K deficiency or liver failure. Frequently, it is unclear whether the patient’s elevated PT is from vitamin K deficiency, liver disease, or both (especially in alcoholic patients, who are prone to both disorders). Vitamin K therapy is often both diagnostic and therapeutic.
d. Factor deficiency is not treated unless trauma has occurred and there is a risk for bleeding, bleeding is occurring, or surgery is planned.
ii. Normal PT/increased PTT
1. Factor deficiency is only treated if trauma has occurred and there is a risk for bleeding, the patient is acutely bleeding, or the patient is about to undergo surgery. Hemophilia A and hemophilia B are treated with factor VIII and IX concentrates, respectively(either plasma purified or recombinant) Other factor deficiencies are typically replaced with fresh-frozen plasma because many do not yet have a purified product available.
2. Factor inhibitors
a. Acute treatment. Factor inhibitors associated with active bleeding can be extremely difficult to treat. Treatment algorithms have been created that take into account the concentration of the inhibitor (Bethesda units).
i. Aggressive factor replacement (to “overwhelm” a low-titer inhibitor) and/or plasmapheresis (to remove the low-titer inhibitor) can be used.
ii. Bypassing products that circumvent the inhibitor can be used to stop bleeding but carry an increased risk for unwanted thromboses. Choices include prothrombin complex concentrates, activated prothrombin complex concentrate, or recombinant activated clotting factors.
iii. Chronic treatment. Steroids, immunosuppressive chemotherapy (e.g., cyclophosphamide, rituximab), or immune tolerance induction may be used in an attempt to decrease the titer of the inhibitor.
3. Antiphospholipid antibodies have a tendency to cause thromboses, not bleeding. Therefore, treatment is anticoagulation therapy if clotting occurs (see Chapter 67). Because the patient’s PT or PTT may be abnormal at baseline, monitoring for therapeutic levels of anticoagulation may be difficult and typically requires chromogenic factor assays.
Suggested Further Readings
Bolton-Maggs PHB, Pasi KJ. Haemophilias A and B. Lancet 2003;361:1801–9. (Classic Article.)Find this resource:
Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med 2014;370:847–59.Find this resource:
Hunt BJ, Levi M. Engineering reversal—finding an antidote for direct oral anticoagulants. N Engl J Med 2016;375:1185–6.Find this resource:
Leebeek FWG, Eikenboom JCJ. Von Willebrand’s disease. N Engl J Med 2016;375:2067–80.Find this resource: