Ala‐10 Mutations in the Factor Ix Propeptide and Haemorrhage in a Patient Treated With Warfarin

Oral anticoagulant therapy is dangerous, with 1–2% of patients suffering a major haemorrhage each year ( Palareti et al, 1996 ). Two mutations that are associated with haemorrhage in patients treated with warfarin have been described at Ala-10 in the factor IX propeptide, i.e. Ala to Thr ( Chu et al, 1996 ; Oldenburg et al, 1997 ) and Ala to Val ( Oldenburg et al, 1997 ). These mutations interfere with a recognition site for γ-glutamylcarboxylase, the enzyme that carboxylates the glutamic acids in the gla-domain. This means that when warfarin therapy is given to maintain a therapeutic International Normalized Ratio (INR), with factors VII, X and prothrombin 20–40% of normal, the factor IX level falls to < 3%. These reports raised the question of whether male patients on warfarin should have an activated partial thromboplastin time (aPTT) screening test. In our anticoagulant clinic, we decided against this after Peters et al (1997 ) screened 750 patients (412 males) and found no cases, and we simply resolved to measure the aPTT in patients who haemorrhaged without an excessive INR. This policy was recently supported by another group ( van der Meer et al, 1999 ), who screened 734 patients and again found no cases. We report a further case. A 56-year-old man presented with an axillary vein thrombosis secondary to carcinoma of the stomach. He was initiated on warfarin therapy, but suffered extensive bruising and a right leg haematoma within 4 weeks of commencement. His INR was consistently maintained between 2 and 3 but his aPTT was disproportionately prolonged, ranging from 104 to 170 s [normal range (NR) 22–34 s]. When his INR was 2.2, his factor VII level was 20 u/dl (NR 50–150 u/dl) and his factor IX level < 1 u/dl (NR 50–150 u/dl). The warfarin was discontinued, his bruising stopped and the factor IX level rose to 65 u/dl. Sequencing of the patient's factor IX gene revealed the G6346A mutation that results in the Ala-10→Thr substitution. Problems due to mutations at Ala-10 are likely to be manifest soon after warfarin therapy is initiated, therefore the screening of long-term stable patients may be selecting against the likelihood of finding these mutations which may not be so rare as supposed. This case shows that the aPTT should be measured in patients on warfarin who bleed despite a therapeutic INR, and one should be particularly vigilant soon after treatment is initiated. If this problem is identified, warfarin must be discontinued. Vitamin K will normalize coagulation, but if more urgent reversal is required for serious haemorrhage then prothrombin complex concentrates are likely to be more effective than FFP in a patient with very low levels of factor IX. In patients who need continued anticoagulation, we would recommend using low molecular weight heparin. Family studies should be undertaken to identify other male carriers of the mutation so that they can be warned of the risk of anticoagulant therapy.