PROTEOLYSIS OF VON-WILLEBRAND-FACTOR IS DECREASED IN ACUTE PROMYELOCYTIC LEUKEMIA BY TREATMENT WITH ALL-TRANS-RETINOIC ACID

Plasma von Willebrand factor (VWF) was investigated in five patients w ith acute promyelocytic leukaemia (APL) before and after administratio n of the differentiating agent all-trans-retinoic acid (ATRA). The pur pose of the study was to see how the proteolytic state associated with APL affects VWF structure and function and whether ATRA reverses any abnormality. At the onset of APL, multimeric analysis of plasma VWF re vealed a lack of the largest multimers. After ATRA, there was a progre ssive correction of the multimeric pattern in all cases, with transien t appearance of ultralarge multimers in two cases. Proteolysis was inv estigated with immunopurified and reduced VWF from each patient's plas ma. This was electrophoresed and probed with two monoclonal antibodies that identify the 225 kD native subunit and the three native fragment s of 189, 176 and 140 kD and differentiate novel proteolytic fragments produced by different proteinases. At the onset of APL, the 225 kD na tive subunit was relatively decreased, with the appearance of an array of novel VWF proteolytic fragments, ranging in size from <140 to <225 kD. These novel fragments observed in patients were similar to those produced in vitro by digestion of purified VWF with plasmin or elastas e. After ATRA therapy, proteolysis diminished progressively in paralle l with the improvement of other haemostatic measurements, but persiste d to some extent. We conclude that VWF proteolysis in APL is produced by plasmin and elastase. Changes of VWF structure and function might a dversely affect haemostasis in APL. Therefore, improvement of VWF afte r ATRA administration might explain in part the effectiveness of this drug in reducing haemorrhagic complications.