Polycythemia vera‐associated acquired von Willebrand syndrome despite near‐normal platelet count
Authors: Ayalew Tefferi, Kristi J. Smock, Ajit B. Divgi
Journal: American Journal of Hematology (2010)

Polycythemia vera-associated acquired von Willebrand syndrome despite near-normal platelet countTo the editor: The pathogenesis of bleeding diathesis associated with myeloproliferative neoplasms (MPN) is not well understood; implicated mechanisms include acquired von Willebrand syndrome (AVWS), platelet storage pool deficiency, and defective aggregation [1].Because MPN is also associated with abnormal clotting, antithrombotic measures including use of aspirin exacerbate the underlying bleeding diathesis.AVWS also occurs in the setting of other unrelated conditions including lymphoma, plasma cell dyscrasia, cardiovascular disease, and autoimmune disorders [2].Implicated pathogenetic mechanisms include targeting and selective clearance of large von Willebrand factor (VWF) multimers by clonal cells, abnormal vessels/valves, and autoimmune antibodies [3,4].VWF antigen (VWF:Ag) assays measure VWF monomer content but not its multimeric composition; in other words, they are helpful in detecting VWF deficiency but not dysfunction.Decreased VWF:Ag is usually accompanied by decreased factor VIII coagulant activity (FVIII:C) since the former carries and stabilizes the latter in the circulation.Laboratory assays used to assess VWF function include ristocetin cofactor activity (VWF:RCoA), which measures binding of VWF to platelet GP Ib, and VWF multimer analysis, which measures multimer distribution.In AVWS, because of selective loss of the largest VWF multimers, VWF:RCoA is decreased despite normal levels of VWF:Ag and VWF:RCoA/VWF:Ag ratio is usually <0.7 (normal ratio is 1.0).In a recent study, none of the above-listed assays, other than VWF multimer analysis, had adequate sensitivity to detect the presence of a clinically relevant (i.e., associated with bleeding symptoms) AVWS [5].More than 50% of patients with polycythemia vera (PV) or essential thrombocythemia (ET) display laboratory evidence AVWS, which is sometimes accompanied by clinically overt mucocutaneous bleeding [6,7].The underlying mechanism is believed to include an abnormally increased VWF proteolysis that results in selective depletion of the largest multimers [8].There is evidence to support the role of platelets in this regard, especially in ET and reactive thrombocytosis, and therapeutic lowering of the platelet count has been shown to correct the laboratory abnormality in some patients [9,10].Herein, we describe a patient with PV who experienced bleeding complications associated with AVWS despite a platelet count of <500 3 10 9 /L.A 61-year-old patient with JAK2V617F-positive PV presented with a hemoglobin level of 21 g/dL (hematocrit 66%), white blood cell count (WBC) of 13.6 3 10 9 /L, and platelet count of 481 3 10 9 /L, in October 2009.During treatment with phlebotomy in November 2009, the patient displayed several areas of ecchymoses and localized bleeding despite optimal venipuncture techniques and absence of treatment with aspirin.Laboratory studies at the time showed complete absence of the large VWF multimers (Fig. 1, lane 4): FVIII:C (89%; normal range 56-191), VWF:Ag (166%; normal range 52-214), VWF:RCoA (92%; normal range 51-215), and VWF:RCoA/VWF:Ag 0.6.On that same day, his WBC was 13.6 3 10 9 /L, hemoglobin 17.9 g/dL (hematocrit 56%), and platelet count 488 3 10 9 /L.After aggressive phlebotomy and treatment with hydroxyurea, resolution of bleeding symptoms and correction of VWF multimer distribution was documented by January 2010 (Fig. 2, lane 8): hemoglobin 16.4 g/dL (hematocrit 50%), WBC 8.4 3 10 9 /L, platelets 276 3 10 9 /L; FVIII:C 166%, VWF:Ag 157%, VWF:RCoA 109%, and VWF:RCoA/VWF:Ag 0.7.Increased clearance of the larger VWF multimers in ET has been proposed by some investigators to be the result of enhanced proteolytic degradation of VWF as a direct result of platelet excess [8,9], which may facilitate the interaction between platelet surface receptor GP Ib and VWF, thus inducing the appropriate conformational changes in VWF that allows ADAMTS13 to gain access to its cleavage site.In our patient with PV, despite the near-normal platelet count, a similar pathogenetic contribution from platelets cannot be excluded and the platelet-VWF complex-induced accelerated proteolysis might have been enhanced by high shear stress from increased blood hyperviscosity [11].Regardless, there are two important practical points that are illustrated by our case report: (i) clinically relevant AVWS can occur in PV despite near-normal platelet count and (ii) VWF multimer analysis is essential for accurate diagnosis of AVWS.