Thromboprophylaxis with reviparin in a patient with acquired hemophilia

Reviparin sodium is a low–molecular weight heparin with an anti–factor Xa:anti–factor IIa ratio of ≥3.6 and negligible effects on global clotting tests. It has been shown to be as effective as unfractioned heparin in different prophylactic indications, causing fewer injection-site hematomas as well [1]. Here we report the case of a patient with acquired hemophilia successfully treated with standard therapy plus reviparin. A 65-year-old man with a history of renal adenocarcinoma was hospitalized with extensive subcutaneous hematomas; he was under treatment with antipsychotic drugs. Hemoglobin was 80 g/L, bilirubin 60.2 µmol/L (indirect: 34.7 µmol/L), and lactate dehydrogenase (LDH) 14.7 µkat/L. Activated partial thromboplastin time (aPTT) was 97 seconds, prothrombin time was normal, fibrinogen level was 6.60 g/L and D-dimer 1751 ng/mL. The patient received fresh frozen plasma, packed red blood cells, and methylprednisolone (0.5 mg/kg per day) without any benefit, then he was transferred to our department. Positive direct antiglobulin test results and low haptoglobin indicated the diagnosis of autoimmune hemolytic anemia. The prolonged aPTT of a mixture of a 1:1 volume of patient’s plasma with normal plasma at 37°C for 2 hours suggested the presence of coagulation inhibitors [2]. Specificity for factor VIII was shown by incubating serial dilutions of the patient’s plasma with an equal volume of normal plasma and performing assays of factor VIII, IX, and XI at 0, 60, and 120 minutes on each mixed dilution [3]. Only factor VIII decreased over time, and the inhibitor titer was 2.6 Bethesda units. The discrepancy between severe bleeding and low titer of antibodies was not surprising; in fact, Bethesda assay underestimates the levels of acquired inhibitors, because of the complexity of reaction kinetics and variation in antibody affinities [4]. On day 3, the patient’s hemoglobin level was 47 g/L; computed tomography revealed a hemothorax and a sub capsular hepatic hematoma. The patient received fresh frozen plasma, packed red blood cells, human factor VIII (bolus of 150 IU/kg plus continuous infusion of 10 IU/kg per hour, to a maximum of 9000 IU), prednisone (1 mg/kg per day), and antifibrinolytic treatment with tranexamic acid (500 mg intravenously 3 times a day) [4,5]. Antipsychotic drugs were withdrawn, because acquired inhibitors may be associated with these drugs. Thromboprophylaxis with subcutaneous reviparin (4200 IU/d) was started, because of the evidence of ongoing intravascular fibrin formation (D-dimer elevation), risk factors for thrombosis (eg, immobilization), and the hemostatic imbalance induced by antifibrinolytic treatment. Although thrombotic events are unusual in acquired hemophilia, there has been a case report concerning pulmonary embolism associated with tranexamic acid therapy [6]. On day 9 aPTT was 85 seconds; there were no signs of active bleeding, but persisting hemolysis was demonstrated by laboratory tests. The patient was started on high-dose intravenous immunoglobulin G (400 mg/kg per day x 5 days, followed by periodic maintenance doses), which resulted in a sudden shortening of aPTT and reduction of the inhibitor titer [7]. On day 63, aPTT was 43 seconds, hemoglobin 108 g/ L, and inhibitors were undetectable. Any recurrence of renal malignancy was ruled out. One month after discharge the aPTT was 30 seconds, fibrinogen 4.46 g/L, D-dimer 342 ng/ mL, bilirubin 5.0 µmol/L, LDH 4.3 µkat/L, haptoglobin 1.83 g/L, and hemoglobin 127 g/L, showing a complete recovery. In conclusion, antifibrinolytic therapy is of proven benefit in the treatment of bleeding episodes in patients with acquired hemophilia [5]. Nevertheless, tranexamic acid contributes to an increased thromboembolic risk in this setting. In our patient, prophylaxis with reviparin was safe and effective in the prevention of thrombotic events, without any evidence of bleeding complications.