Acquired haemophilia A may be associated with clopidogrel
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《英国医生杂志》
1 Department of Haematology, University Hospital of Wales, Cardiff CF14 4XN
Correspondence to: P W Collins peter.collins@cardiffandvale.wales.nhs.uk
Acquired haemophilia A is a rare bleeding disorder caused by autoantibodies against factor VIII.1 Bleeding is often severe and may be life threatening. In half of patients, no underlying disorder is found, however, common associations are with autoimmune disease, malignancy, dermatological disorders, pregnancy, and drugs.1-3
Two women aged 70 and 67 presented with a history of excessive bruising and soft tissue bleeding 2-3 months after starting clopidogrel (Plavix; Bristol-Myers Squibb, Sanofi-Synthelabo) for peripheral vascular disease. Their drugs had not changed recently in any other way. They had no clinical symptoms or signs of malignancy, antiphosphpolipid syndrome, or collagen vascular disease.
One patient had had a documented normal activated partial thromboplastin time at the time of starting clopidogrel; the other had not been tested. Investigation showed that the women had a normal platelet count, peripheral blood film, and prothrombin time. Both had a prolonged activated partial thromboplastin time of 48.6 and 77.6 seconds (normal range 23-33 seconds). Tests for lupus anticoagulant, anticardiolipin antibody, antinuclear factor, double stranded DNA, and rheumatoid factor were negative. The women had low factor VIII (3.9 and 1 IU/dl) with normal von Willebrand factor levels and a detectable antifactor VIII inhibitor (2.2 and 17.6 Bethesda units). We treated both patients with 1 mg/kg of prednisolone. Concentrations of factor VIII rose to 119 and 136 IU/dl, and the inhibitor became undetectable (< 0.4 Bethesda units) within eight weeks of treatment. The factor VIII inhibitor relapsed in one patient when the steroid dose was reduced, but we induced and sustained remission with azathioprine.
A possible link between autoimmune acquired haemophilia and clopidogrel has not been previously reported. Clopidogrel has been associated with microangiopathic haemolytic anaemia and thrombocytopenia,4 5 suggesting other possible immune mediated adverse events.
Increased bruising should not be ascribed to the antiplatelet action of clopidogrel unless a platelet count and coagulation screen have been found to be normal. Investigation for an antifactor VIII inhibitor should be done if indicated by a prolonged activated partial thromboplastin time.
Funding: None.
Competing interests: None declared.
References
Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemostas 1981;45: 200-3.
Hay CRM. Acquired haemophilia. In: Bailliere's clinical haematology. London: Bailliere Tindall, 1998: 287-303.
Morrison AE, Ludlam CA. Acquired haemophilia and its management. Br J Haematol 1995;89: 231-6.
Bennett CL, Connors JM, Carwile JM, Moake JL, Bell WR, Tarantolo SR, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000;342: 1773-7.
Elmi F, Peacock T, Schiavone J. Isolated profound thrombocytopenia associated with clopidogrel. J Invas Cardiol 2000;12: 532-5.(Montaser Haj, specialist )
Correspondence to: P W Collins peter.collins@cardiffandvale.wales.nhs.uk
Acquired haemophilia A is a rare bleeding disorder caused by autoantibodies against factor VIII.1 Bleeding is often severe and may be life threatening. In half of patients, no underlying disorder is found, however, common associations are with autoimmune disease, malignancy, dermatological disorders, pregnancy, and drugs.1-3
Two women aged 70 and 67 presented with a history of excessive bruising and soft tissue bleeding 2-3 months after starting clopidogrel (Plavix; Bristol-Myers Squibb, Sanofi-Synthelabo) for peripheral vascular disease. Their drugs had not changed recently in any other way. They had no clinical symptoms or signs of malignancy, antiphosphpolipid syndrome, or collagen vascular disease.
One patient had had a documented normal activated partial thromboplastin time at the time of starting clopidogrel; the other had not been tested. Investigation showed that the women had a normal platelet count, peripheral blood film, and prothrombin time. Both had a prolonged activated partial thromboplastin time of 48.6 and 77.6 seconds (normal range 23-33 seconds). Tests for lupus anticoagulant, anticardiolipin antibody, antinuclear factor, double stranded DNA, and rheumatoid factor were negative. The women had low factor VIII (3.9 and 1 IU/dl) with normal von Willebrand factor levels and a detectable antifactor VIII inhibitor (2.2 and 17.6 Bethesda units). We treated both patients with 1 mg/kg of prednisolone. Concentrations of factor VIII rose to 119 and 136 IU/dl, and the inhibitor became undetectable (< 0.4 Bethesda units) within eight weeks of treatment. The factor VIII inhibitor relapsed in one patient when the steroid dose was reduced, but we induced and sustained remission with azathioprine.
A possible link between autoimmune acquired haemophilia and clopidogrel has not been previously reported. Clopidogrel has been associated with microangiopathic haemolytic anaemia and thrombocytopenia,4 5 suggesting other possible immune mediated adverse events.
Increased bruising should not be ascribed to the antiplatelet action of clopidogrel unless a platelet count and coagulation screen have been found to be normal. Investigation for an antifactor VIII inhibitor should be done if indicated by a prolonged activated partial thromboplastin time.
Funding: None.
Competing interests: None declared.
References
Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemostas 1981;45: 200-3.
Hay CRM. Acquired haemophilia. In: Bailliere's clinical haematology. London: Bailliere Tindall, 1998: 287-303.
Morrison AE, Ludlam CA. Acquired haemophilia and its management. Br J Haematol 1995;89: 231-6.
Bennett CL, Connors JM, Carwile JM, Moake JL, Bell WR, Tarantolo SR, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000;342: 1773-7.
Elmi F, Peacock T, Schiavone J. Isolated profound thrombocytopenia associated with clopidogrel. J Invas Cardiol 2000;12: 532-5.(Montaser Haj, specialist )