Excessive prolongation of the bleeding time by aspirin in essential thrombocythemia is related to a decrease of large von Willebrand factor multimers in plasma

Abstract

Patients with essential thrombocythemia (ET), who frequently have bleeding complications, may manifest an excessive prolongation of the bleeding time (BT) after ingestion of aspirin (ASA). The reason for this excessive prolongation of the BT is unknown, but it is attributed to qualitative platelet defects. Since patients with ET may also have acquired abnormalities of plasma and platelet von Willebrand factor (vWF), we questioned whether the excessive prolongation of the BT by ASA was related to changes in either plasma or platelet vWF. To that end, we studied BT and plasma and platelet vWF in ten ET patients, ten patients with reactive thrombocytosis (RT), and ten normal individuals, both before and after administration of 500 mg ASA for 7 days. In a second study, the effect of DDAVP infusion on plasma vWF in relation to the BT was studied in ten normal individuals and ten ET patients after treatment with 100 mg ASA for 3 days. In the first study, treatment with ASA resulted in a significant prolongation of the BT in normal subjects, RT patients, and ET patients. However, in five ET patients an excessive (`2 SD) prolongation of the BT by ASA was observed. Although ASA induced no direct changes in either plasma or platelet vWF levels in either normal subjects, RT patients, or ET patients, all five ET patients who showed an excessive prolongation of the BT by ASA had significantly decreased levels of large vWF multimers in plasma. In the second study, infusion with DDAVP resulted in a significant increase in plasma large vWF multimers, paralleled by a normalization of (excessively) prolonged BT. Our data suggest that in ET inhibition of platelet function by ASA in the presence of concurrently decreased levels of large vWF multimers in plasma may have provoked the excessive BT prolongation.

Romiplostim administration shows reduced megakaryocyte response-capacity and increased myelofibrosis in a mouse model of MYH9-RD

“…These may include of course the decrease in the GPIb complex, and in GPVI, but also an increase in VWF consumption resulting from the high amount of circulating platelets, as already reported for thrombocythemia. 30 A direct effect of romiplostim on platelet function is unlikely because romiplostim administration for 6 hours did not increase the bleeding time.…”

“…These may include of course the decrease in the GPIb complex, and in GPVI, but also an increase in VWF consumption resulting from the high amount of circulating platelets, as already reported for thrombocythemia. 30 A direct effect of romiplostim on platelet function is unlikely because romiplostim administration for 6 hours did not increase the bleeding time.A potential limitation of our study is that we used Myh9 Ϫ/Ϫ mice and not mice showing a heterozygous mutation of the Myh9 gene, which would reflect the exact situation in patients with MYH9-RDs. Furthermore, in our mouse model Myh9 is knocked out in the megakaryocytic lineage only, whereas in affected humans other organs are also affected.…”

Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia

“…One study attempted to define the bleeding tendency in relation to thrombocytosis as well as VWF abnormalities in patients with ET and reactive thrombocytosis compared with normal controls by assessment of the effect of aspirin on the bleeding time (van Genderen et al , 1997c). Treatment with aspirin resulted in bleeding time prolongation in all subjects but was more excessive in ET.…”

Approach to patients with essential thrombocythaemia and very high platelet counts: what is the evidence for treatment?

“…In addition, the panel recommended considering treatment with platelet‐lowering agents for platelet counts ≥ 1500 × 10 9 /l (Barbui et al , ). The latter recommendation and the specific choice of a platelet count threshold of 1500 × 10 9 /l were largely based on pathophysiologic considerations (van Genderen et al , ). While the recognized goal of therapy is to decrease the risk of vascular events, the endpoint of treatment in clinical studies is the achievement of a so‐called ‘clinicohaematological response.’ However, the correlation between the former and the latter has remained unproven (Barosi et al , ).…”