Acqumed hemophilia and other disorders of Circulating Inhibitors
In addition to the hemorrhage caused by the circulating al-loantibody inhibitors in severe hemophilias A and B, clinical hemorrhage is occasionally caused by circulating inhibitors directed against specific clotting factors, which seem to appear spontaneously. Because acquired autoantibody to factor VIII, which gives rise to the clinical picture of acquired hemophilia, is the most common of these circulating inhibitors, it will be described here in some detail, but many of the same principles apply to other inhibitors.
Autoantibodies to factor VIII are usually IgGa and, frequently, IgG4 and thus do not fix complement. They are usually directed against the functionally important A2 and C2 domains43 on factor VIII. About half of the patients with an acquired factor VIII inhibitor have no identifiable associated disorder, but many disease states have been identified in the other patients, including autoimmune disorders such as systemic lupus erythemato-sus, lymphoproliferative disorders, plasma cell malignancies, drug reactions (e.g., reaction to penicillin), the postpartum state, and skin disorders.
Diagnosis
Patients with an acquired factor VIII inhibitor commonly present with new-onset mucosal hemorrhages, hematomas, and ec-chymoses but have a negative bleeding history. Typically, the clinical picture of acquired hemophilia caused by factor VIII inhibitor occurs in an elderly patient or in a young woman during pregnancy or in the postpartum period. The laboratory hallmark of an acquired inhibitor to a clotting factor is a prolonged clotting time that is not corrected by mixing equal parts of the patient’s plasma with normal plasma. In the case of factor VIII inhibitor, the PTT is prolonged and the PT and TT are normal. The antibody binds to factor VIII with complex kinetics such that the inhibitory effect becomes apparent only after prolonged incubation. Therefore, if an acquired factor VIII inhibitor is suspected, mixing studies should be performed after 5-minute and 60-minute incubations. The diagnosis can be confirmed by demonstration of a very low factor VIII level when other clotting factor levels are normal. Determination of the titer of the factor VIII inhibitor (expressed in Bethesda units [BU] per milliliter, with 1 BU/ml indicating a sufficient number of inhibitors to cause the complete inhibition of factor VIII in 1 ml of blood) is useful in choosing the appropriate therapy.
Treatment
The hemorrhage caused by circulating inhibitors may be clinically life threatening. Attempts at factor replacement are usually not successful, because the inhibitor inactivates the exogenous factor VIII. Occasionally, if the inhibitor has a low titer (e.g., < 2 to 3 BU/ml), massive factor VIII replacement can overwhelm the inhibitor. However, this treatment may trigger a significant anamnestic response resulting in increased levels of antibody, which complicates further management. Immunosuppressive therapy with a combination of cyclophosphamide (given either as a monthly intravenous pulse therapy or orally on a daily basis) and prednisone has been successful in most cases.45,46 The inhibitor usually becomes undetectable after three or four monthly cycles of chemotherapy. In the case of severe or life-threatening hemorrhage in which there is insufficient time to reduce the level of inhibitor, porcine factor VIII can be administered, because the antibody usually displays low cross-reactivity.
Another alternative therapy for acute bleeding is the administration of procoagulant complexes, which may bypass the inhibitor block by providing large amounts of factor X and factor VII.47 Still other therapeutic options include plasmapheresis and high-dose intravenous IgG, although the response rate for intravenous immune globulin (IVIg) appears to be quite low.48 Recombinant activated factor VII (90 Mg/kg given as an I.V. bolus every 2 to 3 hours) has been used successfully in patients with this condition. There is growing evidence that rituximab, given intravenously at 375 mg/m2 once weekly for 4 weeks, is effective.49,50 In patients with a very high titer inhibitor (>100 BU/ml), a combination of rituximab and cyclophosphamide may be required.
Acquired Von Willebrand Disease
Diagnosis
Patients with acquired von Willebrand disease, who are generally in their 50s and 60s and do not have a personal or family history of a bleeding disorder, present with mucocutaneous-type bleeding.51 The workup is the same as that for vWD. The acquired form of the disease frequently occurs in the setting of underlying lymphoproliferative, myeloproliferative, or cardiovascular disease. A study showed that acquired vWD is quite common in patients with severe aortic stenosis. vWF abnormalities are directly related to the severity of aortic stenosis and improve after valve replacement.52 Acquired vWD is also occasionally associated with angiodysplasia in patients with recurrent gastrointestinal bleeding. Frequently, a small monoclonal gammopathy is found on serum protein electrophoresis. The plasma antibody to vWF is functional in a minority of cases, as demonstrated by inhibition of vWF in a functional assay by mixing studies.53 However, most cases involve nonneutralizing antibodies to vWF, which can be demonstrated by enzyme-linked immunosorbent assay (ELISA). Presumably, the antibody binds to vWF and causes its rapid clearance, leading to a low plasma vWF level. Nonim-mune mechanisms (e.g., adsorption of vWF onto tumor cells) have also been described. Multimeric analysis of plasma vWF typically shows a decrease in the high-molecular-weight multi-mers, resembling type 2A vWD.
Treatment
DDAVP is useful in correcting the bleeding diathesis in about one third of cases of acquired vWD. High-dose intravenous IgG (1 g/kg I.V. daily for 1 to 2 days) generally garners a good temporary response, with an increase in the vWF level and a shortening of the aPTT, lasting from a few days to 2 weeks. If the patient has a defined lymphoproliferative, myeloproliferative, or autoimmune disease, the underlying disease should be treated. However, the response of acquired vWD to immunosuppressive therapy with cyclophosphamide and prednisone is generally not as favorable as the response in the case of acquired factor VIII inhibitor.
Hemorrhage Caused by Severe Liver Disease
Patients with severe liver disease may suffer life-threatening hemorrhages. The most frequent types are esophageal and gastrointestinal hemorrhages related to varices, gastritis, or peptic ulcer. There may also be bleeding from biopsy sites and during and after surgery. Mucosal and soft tissue bleeding may occur, but generally, this is not the dominant bleeding problem.
The coagulopathy of severe liver disease is complex and not well delineated. Because the liver is the major site of synthesis for all the clotting factors, decreased levels of multiple clotting factors are observed, including fibrinogen, prothrombin, factor V, and factor VII; factor VIII is excepted, presumably because it is an acute-phase reactant. An increased level of abnormal fibrino-gen with reduced clotting capability is also observed in patients with cirrhosis.54 In addition, there is reduced clearance of activated clotting factors by the liver. DIC appears to occur commonly in patients with cirrhosis55 (presumably because of triggering of the clotting cascade by hepatic tissue damage), but its precise role in both acute fulminant hepatitis and chronic liver disease has not been firmly established. Moderate thrombocytopenia is common, resulting from a combination of decreased platelet production (from relative deficiency of thrombopoietin [TPO], because the liver is the major site of TPO synthesis) and increased platelet destruction from hypersplenism. Platelet function is generally maintained. There is also evidence of hyperfibri-nolysis, but its contribution to the overall hemostatic defect is uncertain. The liver also synthesizes most of the natural anticoagulant proteins. AT, protein C, and protein S levels are decreased. The best screening tests for this disorder include the PT, aPTT, platelet count, fibrinogen level, and D-dimer level. Specific assays that may guide therapy include factor V, factor VII, and AT. Replacement for active bleeding is accomplished by administering fresh frozen plasma, cryoprecipitates, and platelets as required. Prothrombin-complex concentrates are not recommended, because they do not replenish all the deficient clotting factors and may exacerbate the DIC. In general, although the multiple hemostatic defects contribute to the bleeding diathesis in severe liver disease, hemodynamic and anatomic factors are the primary determinants in this situation.
Primary fibrinolysis
Cases of generalized primary fibrinolysis are rare. Many of the early reports of primary fibrinolysis probably represented secondary fibrinolysis associated with DIC. Postprostatectomy hematuria may constitute a true example of hemorrhage caused by localized fibrinolysis. The high concentration of urokinase in the urine in this condition causes plasminogen to be converted to plasmin with resulting clot lysis. If other causes of persistent postoperative hematuria can be ruled out, the condition can be treated with oral or intravenous EACA. Local instillation of EACA by urethral catheter is also effective.
Bleeding after cardiopulmonary bypass
A mild thrombocytopenia (approximately 100,000/ ^l) commonly occurs in patients after cardiopulmonary bypass sur-gery.56 A significant acquired platelet function disorder develops in some patients, probably caused by contact between the platelets and the oxygenator apparatus, which in turn leads to partial platelet degranulation.57 In addition to the release of platelet granule contents, activation of fibrinolysis may occur together with modest clotting factor depletion.58 The hemorrhage in such cases generally responds to platelet transfusions. The use of DDAVP in this setting has been reported to reduce postoperative blood loss; however, a meta-analysis of 17 clinical trials showed only a modest beneficial effect.
The bovine protease inhibitor aprotinin has been shown to reduce bleeding and transfusion requirements in patients undergoing cardiopulmonary bypass.60 Aprotinin inhibits plasmin and may also attenuate the systemic inflammatory response by inhibition of the proinflammatory mediator kallikrein.61 It reduces plasmin-mediated proteolysis of platelet membrane proteins and preserves platelet function.62 Randomized clinical trials showed that the two antifibrinolytic agents EACA and tranexamic acid are equally efficacious as aprotinin in this set-ting.63,64 Aprotonin should be reserved for patients who are likely to require blood transfusion, especially those undergoing second operations and those with preexisting hemostatic defects.
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Table 4 Differential Diagnosis of Postoperative Hemorrhage |
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Dilutional thrombocytopenia caused by massive transfusion |
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Acquired platelet function defect after cardiopulmonary bypass |
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Inadequate heparin neutralization |
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Disseminated intravascular coagulation |
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Coagulopathy caused by shock liver |
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Acquired antithrombin and anti-factor V inhibitors after exposure to fibrin glue |
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Heparin-induced thrombocytopenia |
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Thrombocytopenia caused by GPIIb-IIIa inhibitors (e.g., abciximab) |
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Hyperfibrinolysis after prostate surgery |
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Undiagnosed von Willebrand disease or hemophilia |
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Thrombocytopenia caused by posttransfusion purpura |
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False abnormalities in coagulation test results |
Preoperative testing of hemostasis appears not to be useful.
During bypass surgery, patients are sometimes exposed to topical thrombin (fibrin glue), which is used for local hemostasis control. Generally, bovine thrombin and trace amounts of other clotting factors to which patients may develop antibodies are used in these preparations. The antibodies against bovine throm-bin cause a prolongation of the TT but are innocuous in themselves. However, potentially serious complications arise when the antibodies cross-react with human thrombin. Some patients develop antibodies against bovine factor V that cross-react with human factor V and may lead to clinical bleeding.65,66 A review of reported cases found that bovine thrombin-associated factor V antibodies developed in 40% to 66% of cardiac surgery patients and in 20% of neurosurgery patients, and clinical bleeding complications occurred in about one third of these cases.67 Mixing studies utilizing the patient’s plasma and normal plasma will reveal the presence of the inhibitors, and the measurement of the appropriate factor levels will allow the correct diagnosis to be made. Sometimes, plasmapheresis is required to control the acute bleeding.
Evaluation of postoperative bleeding
Serious hemorrhage during or after surgery is a complicated clinical problem requiring rapid diagnosis and prompt intervention. The first question is whether the bleeding has a local anatomic cause (e.g., unligated vessel) or is the result of a systemic hemostatic failure. If the patient is bleeding only in the operative area, it would suggest a local anatomic cause, such as an unligated bleeding vessel. The patient’s bleeding history, especially with the results of prior surgical procedures, is extremely useful, but the available history may be inadequate or incomplete. A revealing clue to a systemic malfunction is bleeding at multiple sites, particularly areas other than that of the surgical wound. Bleeding around a catheter, from venipuncture sites, and from venous cutdowns is highly indicative of a hemorrhag-ic disorder.
Rapid assessment of the total clinical setting is imperative. The following questions should be addressed:
• Does the patient have underlying renal, hepatic, or malignant disease?
• Has the surgery required pump bypass techniques or the induction of hypothermia, or has the patient been in shock or been hypothermic?
• How many units of blood and blood products have been given and over what period of time?
• Were baseline screening procoagulant tests obtained before surgery, and is the patient’s frozen plasma still available?
The differential diagnosis of postoperative hemorrhage should include a number of bleeding disorders [see Table 4].
Prompt resolution of postoperative bleeding requires a panel of coagulation tests—including aPTT, PT, TT, fibrinogen assay, and D-dimer—a platelet count, and a well-stained blood smear for evaluation of platelet and red cell morphology. This battery of tests should be performed immediately. More specialized studies can be obtained if there is evidence of a specific disorder.
