A Progressive Acquired Von Willebrand Factor Inhibitor in a Patient with Type 1 Von Willebrand's Disease, Persistent Antiphospholipid Antibodies and An IgA Paraprotein

Abstract

Acquired von Willebrand's disease (AVWD) is a rare bleeding disorder with similar clinical and laboratory findings to the inherited disorder. It can be caused by specific or non-specific antibodies, adsorption of von Willebrand factor (VWF) onto malignant cell clones, hypothyroidism or loss of high molecular weight multimers under conditions of high sheer stress. AVWD is commonly diagnosed using standard laboratory tests for inherited VWD in the absence of a family history of bleeding. In this abstract we present an unusual case of development of antibodies in a 76 year old white caucasian lady with documented desmopressin responsive Type 1 VWD and a family history of VWD. Her baseline laboratory parameters were VWF: Ag of 26.6 IU/dL (RR 45–160 IU/dL), Factor VIII:C of 52.6 IU/dL (RR 50–200 IU/dL) and normal VWF multimer distribution. She presented with undetectable VWF:RCo, VWF:CB 2.9 IU/dL, VWF:Ag 8.2 IU/dL, FVIII:C 8.4 IU/dL and unmeasurable PFA-100 closure times during routine work-up prior to planned elective surgery. There had been no significant change in her clinical symptomatology. The lupus anticoagulant and moderately elevated IgM anticardiolipin antibodies which had been detected three years previously remained positive and a Bethesda assay for FVIII inhibitor was negative. Her rheumatoid factor, antinuclear antibody and double stranded DNA antibody tests were negative. She was extensively investigated for an underlying malignancy but the only positive finding was that of an IgG kappa paraprotein band. The IgG level was 7.5 g/L (RR 6–16 g/L) without any evidence of immune paresis. Assay for VWF:RCo inhibitor on a 1:1 mixture of patient and normal plasma after 5 minute incubation at 37°C was negative. The patient was infused with VWF concentrate Haemate 8000 RCo units and serial assays of VWF:RCo, VWF:Ag and FVIII:C were undertaken. At 10 minutes post-infusion the levels were 173.0, 161.6 and 70.3 IU/dL respectively and 88.2, 131.1 and 39.8 IU/dL respectively at 20 minutes. The VWF:RCo dropped to 10.0 IU/dL by 4 hours whereas the VWF:Ag was 43.1 IU/dL at that point and 27.2 IU/dL at 8 hours, when the VWF:RCo had reduced further to 6.8 IU/dL. The FVIII:C continued to fall until it levelled off at 27.5 IU/dL at 2 hours. The VWF:RCo inhibitor assay was repeated on an incubated 1:1 mixture of patient and normal plasma. The normal plasma was manipulated to have a value at the start of the assay of 130.0 IU/dL once mixed with patient plasma, which fell to 92.0, 87.0 and 78.0 IU/dL after 30 minutes, 4 hours and 18 hours incubation respectively, revealing a progressive inhibitor of VWF:RCo activity. The antibody demonstrated is likely to be an acquired autoantibody rather than an antibody to previously infused von Willebrand factor concentrate as the pre-infusion VWF activity and antigen levels in the patient were undetectable. Also, the additional presence of antiphospholipid antibodies may indicate the inherent propensity of the patient to produce autoantibodies. Further, the additional presence of an IgA paraprotein band may also have contributed to the low VWF activity levels. It is interesting to speculate on the multifactorial nature of the pathogenic mechanism of development of multiple auto-antibodies in this patient. AVWD associated with paraproteinemia is well described. However, in this case the AVWD and paraprotenemia developed on a background of lifelong history of inherited VWD. To our knowledge this is the first reported case of development of acquired antibodies in a patient with pre-existing inherited VWD. Her forthcoming surgery will provide further challenges for management.