Clinical efficacy of
recombinant activated factor VII (rFVIIa) during acute bleeding
episode and surgery in a patient with acquired hemophilia A with
high inhibitor titer.
Massimo Franchini,* Franco Capra,° Carla Capelli,°
Elena de Maria,° Giuseppe Lippi,# Giorgio Gandini*
*Servizio di Immunoematologia e Trasfusione - Centro Emofilia,
Ospedale Policlinico, Azienda Ospedaliera di Verona,
°Istituto di Medicina e Sanità Pubblica, Sezione di
Medicina, Università di Verona, #Istituto di Chimica e
Microscopia Clinica, Università di Verona, Verona, Italy.
Correspondence: Dr. Massimo Franchini, Servizio di
Immunoematologia e Trasfusione - Centro Emofilia, Ospedale
Policlinico, Azienda Ospedaliera di Verona, Verona, Italy. Tel.:
+39 045 8074321, FAX: +39 045 8074626, E-mail: giorgio.gandini@mail.azosp.vr.it
Abstract
In this report we describe the case of an elderly woman with severe acquired haemophilia A with high inhibitor titer successfully treated with activated recombinat factor VII (rFVIIa) for an acute bleeding episode and for an antihaemorrhage prophylaxis before surgery.
Text
Acquired hemophilia A is an uncommon hemorrhagic disorder caused by the spontaneous occurrence of an auto-antibody directed against the coagulation factor VIII.1,2 The disease is occasionally associated with post-partum condition, auto-immune diseases, as well as various types of neoplasia and drugs, but in most cases it occurs spontaneously in elderly people.3,4 The clinical picture is often severe and life-threatening, with a death rate between 10% and 22%, depending on case series.2,5 The therapeutic strategy has 2 goals:4-6 long-term suppression of the auto-antibody and hemorrhage control. In order to eradicate the antibody immunosuppressive drugs are used, such as prednisone and cyclophosphamide, and/or immunomodulators, such as immunoglobulins at high dosage. The antihaemorrhagic therapy depends on the anti-FVIII inhibitor titer: patients with a low inhibitor titer (< 5 BU) can be treated with high doses of human factor VIII concentrates and/or desmopressin, whereas patients with a high inhibitor titer (> 10 BU) are generally treated with porcine factor VIII or activated prothrombin complex concentrates. In recent times the activated recombinant factor VII (rFVIIa) has also been used in these patients.7-9 Thanks to its FVIII bypassing activity this drug has proved efficient and safe in the treatment of bleeding episodes in patients with high inhibitor titer. We report the case of a female patient suffering from severe acquired hemophilia A associated with an autoimmune disorder who was successfully treated with rFVIIa. The patient, a 74-year-old woman, was admitted to emergency at our city hospital with headache, nausea, vomiting, an significant superficial face haematoma and massive muscle haematomas on the right arm and left thigh. The admission tests showed significant anemia (hemoglobin 6.5 g/dl) and lengthening of the APTT (3.5) with PT; fibrinogen and platelet count were within the norm. The family and personal history was negative for hereditary haemorrhagic pathologies; the patient had given birth to 2 children, respectively 44 and 42 years before, and had undergone hysterectomy 22 years before without any bleeding complication. The patient reported getting haematomas as a result of minor traumas during the 2 months before admission. The absence of a familiar and personal bleeding history, together with the fact that the APTT was not corrected following the addition of normal plasma, led us to suspect that a coagulation inhibitor was involved. Considering the emergency of the initial clinical picture we decided to immediately start a transfusion therapy with red blood cell concentrates and an antihaemorrhage treatment with rFVIIa in a 120 mcg/Kg intravenous bolus followed by 90 mcg/Kg after 2 hours, the same dose then being administered every 3 hours. We also gave the patient 1 g tranexamic acid every 8 hours intravenously. The laboratory tests (Table 1) performed after admission showed an extremely low value of coagulant FVIII (FVIII:C <1 UI/dl) and confirmed the involvement of a high titer inhibitor directed against the human factor VIII (220 BU). This inhibitor also cross-reacted towards the porcine FVIII (55 BU). The high levels of antinucleus antibodies (titer 5000) reinforced the hypothesis of an underlying auto-immune disease. An immunosuppressive therapy was started at the same time with 1 mg/Kg prednisone per day and 100 mg cyclophosphamide per day orally. Thanks to the antihaemorrhage therapy with rVIIa the bleeding was quickly put under control; as a result, haemoglobin levels stabilized, the need for transfusion blood decreased and the haematomas stopped progressing. From the third hospital day the rVIIa was decreased to 90 mcg/Kg every 4 hours, the same dose being administered every 6 hours form the sixth day on. Over this period the patient's dependence on transfusions ceased, haemoglobin stabilized around 11 g/dl and a slow but progressive resorption of haematomas was observed. From the twelfth day the rVIIa was further decreased to 90 mcg/Kg every 8 hours, and on the sixteenth day it was discontinued, because the haematomas had almost completely disappeared. For the whole duration of the treatment with rFVIIa the levels of platelets, fibrinogen and D-dimerous were monitored, and resulted stable. Since the levels of the inhibitor stayed high with low factor VIII values despite the protracted immunosuppressive therapy, on the 25th hospital day we started administering immunoglobulins intravenously (IVIG) at a dosage of 400 mg/Kg per day for 5 days. On the 27th day the clinical picture was complicated by a biliary colic with jaundice (bilirubin up to 15 mg/dl, mainly direct) and hyperamylasaemia due to the impaction of a stone in the common bile duct. Papillosphinterectomy (ERCP) was performed in emergency after resuming the therapy with 120 mcg/Kg rVIIa, followed 2 hours later by 90 mcg/Kg, the same dose being then administered every 3 hours. The post-op course was regular and free from bleeding complications. From the +4 day after surgery the rFVIIa was decreased to 90 mcg/Kg every 4 hours until it was discontinued on the 8th day (35th hospital day). From the 30th day the patient had shown a progressive improvement of coagulation parameters. On the 32th day the per os cyclophosphamide therapy was discontinued (3.2 g had been administered altogether) because of the onset of leuco-thrombocytopenia. From the 35th day, after documented full remission of the disease (the APTT was back to normal and the inhibitor had disappeared), the steroid was gradually reduced by 5 mg per week. On the 45th day, following a resurgence of the disease documented by laboratory tests, the steroid therapy was brought back to full dosage (prednisone 1 mg/Kg per day per os) and the treatment with cyclophosphamide (500 mg bolus intravenously) and with IVIG (400 mg/Kg per day, scheduled for a 5 day administration) was resumed. On the 47th day the patient died because of the sudden onset of a severe bleeding picture characterized by melena, spontaneous superficial and muscle haematomas, brain haemorrhage in the left temporo-occipital area (the post-mortem confirmed the CT scan findings). The prognosis of acquired haemophilia A depends on the underlying disorder and on the inhibitor titer: post-partum and idiopathic forms, as well as those with low titer inhibitor, tend to have a more favorable prognosis. Unfortunately in our case the underlying auto-immune disease and the high inhibitor titer, not eradicable through the immunosuppressive therapy, determined the fatal outcome of the disease despite the clinical success of the rFVIIa in controlling bleeding episodes.
