Clopidogrel and acquired haemophilia

Clopidogrel is a thienopyridine, inhibiting platelet activation and aggregation. It is indicated for prevention of:

• atherothrombotic events in patients with acute coronary syndrome, ischaemic stroke, or established peripheral arterial disease
• atherothrombotic and thromboembolic events in patients with atrial fibrillation and at least one other risk factor, who are unsuitable for treatment with vitamin K antagonists

Acquired haemophilia is a very rare condition that affects between one and four men or women per million people per year; it generally occurs in the elderly

• about half of cases are idiopathic and half associated with illness (eg, rheumatoid arthritis, cancer). Occasionally, cases of acquired haemophilia may occur in association with drug treatment
• acquired hemophilia A is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII)
  • is diagnosed in patients without previous or familial histories of bleeding who have isolated prolongation of the activated partial thromboplastin time (aPTT) that cannot be corrected by mixing study and who have reduced FVIII levels as well as evidence of FVIII inhibitor activity
  • FVIII autoantibodies occur in patients in the postpartum period and those with concomitant diseases or conditions (i.e., autoimmune disorders, malignancies, and drug abuse). However, up to 50% of cases develop without any relevant medical illness

Morbidity and mortality associated with acquired haemophilia are high

• the condition tends to cause bleeding into the skin and soft tissues; by contrast with severe congenital haemophilia, bleeding into the joints is unusual
• mortality rate of AHA is as high as 16%

A total of 11 cases of acquired haemophilia A and one case of acquired haemophilia B have been received worldwide by the licence (marketing authorisation) holder in association with clopidogrel, four of which were published case reports (1)

• this number of reports should be considered in the context of the very high use of clopidogrel (more than 153 million patients worldwide).
• case reports described patients aged between 65 years and 81 years, with no previous history of abnormal haemostasis. In six cases, it was reported that symptoms of acquired haemophilia resolved after stopping clopidogrel and corrective treatment (including steroids). Although no cases had a fatal outcome, two were considered life-threatening. Although these events are very rare, it is important to be aware of the possibility that a patient may develop acquired haemophilia, as distinct from the risk of bleeding associated with clopidogrel

Advice for healthcare professionals regarding clopidogrel and acquired haemophilia:

• Healthcare professionals should be aware of the risk of acquired haemophilia in association with clopidogrel
• Prompt diagnosis is required to minimise the time the patient is at risk of bleeding and to avoid major bleeding
• Acquired haemophilia should be considered in the event of isolated prolonged activated partial thromboplastin time (aPTT)
• Patients with confirmed acquired haemophilia should be managed by specialists, and clopidogrel should be discontinued. Invasive procedures should be avoided

Reference:

• MHRA (December 2013). Drug Safety Update - Clopidogrel: risk of acquired haemophilia
• Hwang HW et al. A patient with acquired hemophilia A induced by clopidogrel. Korean J Hematol. 2012 Mar;47(1):80-2.