Abstract Number: PB0916
Meeting: ISTH 2021 Congress
Background: Essential thrombocythemia (ET) is a BCR/ABL1-negative myeloproliferative neoplasm characterized by thrombocytosis and an elevated incidence of thrombosis. Paradoxically, when platelet count is markedly increased, bleeding is often observed. Extreme thrombocytosis is associated with reduced von Willebrand factor (VWF) large multimers. This condition is known as acquired von Willebrand syndrome.
Aims: We investigated whether VWF degradation by ADAMTS13 is enhanced in ET patients.
Methods: VWF antigen (Ag), VWF multimers, and ADAMTS13 activity were analyzed in 50 ET patients before and after starting treatment. VWF multimers were divided into three classes (high-, medium-, and low-molecular weight multimers [HMW-, MMW-, and LMW-VWFMs]), and ratios of prevalence of each class in each patient to that in healthy subjects (multimer index) was calculated using densitometric analysis. VWF-degradation product (DP) was measured by ELISA, using a monoclonal antibody that specifically recognizes Y1605 at the C-terminal boundary of the VWF A2 domain (a determinant of cleavage by ADAMTS13).
Results: Fifty ET patients were divided into low platelet (<750×103/μl, n=28) and high platelet (≥ 750×103/μl, n=22) cohorts. Compared to the low platelet group, the high platelet group showed a significant reduction in their HMW-VWFM index and an increase in their LMW-VWFM index. The VWF-DP/Ag ratio was significantly higher in the high platelet group than in the low platelet group (Fig 1). Of the 50 patients, 25 received cytoreduction therapy (hydroxyurea, anagrelide, and busulfan). The group that received cytoreduction therapy had significantly lower platelet counts, a higher HMW-VWFM index, a lower LMW-VWFM index, and a lower VWF-DP/Ag ratio than the group that did not receive cytoreduction therapy (Table 1).
|Cytoreduction therapy group (n=25)||No cytoreduction therapy group (n=25)||P value|
|Age, years median (IQR)||75(67-78)||65(40-71)||<0.01|
|Sex (Female: Male)||8:17||14:11||0.15|
|JAK2 V617F mutation, n(%)||11/22(50%)||12/23(52%)||1.0|
|WBCs, /μL median(IQR)||6300(5400-7700)||9000(7600-10400)||<0.01|
|Platelets, ×103/μL median(IQR)||582(482-736)||884(727-1107)||<0.01|
|VWF:Ag, % median(IQR)||117.7(104.1-149.0)||94.0(53.5-111.3)||<0.01|
|HMW-VWFMs index, % median(IQR)||66.5(49.0-80.0)||48.4(32.3-55.1)||<0.01|
|VWF-DP/Ag ratio, median(IQR)||1.14(0.91-1.89)||2.16(1.90-3.15)||<0.01|
|ADAMTS13 activity, % median(IQR)||53.3(42.2-68.4)||65.3(48.7-81.4)||0.09|
Conclusions: In ET patients with pronounced thrombocytosis, increased cleavage of the Tyr1605-Met1606 bond in the VWF A2 domain lead to a reduction in HMW-VWFM. This condition can be ameliorated using cytoreduction therapy.
To cite this abstract in AMA style:Kubo M, Kashiwagi H, Yagi H, Seki Y, Hasegawa A, Tanaka H, Amano I, Tomiyama Y, Matsumoto M. Increased Cleavage of VWF by ADAMTS13 Might Reduce High-molecular-weight VWF Multimers, Leading to Acquired von Willebrand Syndrome in Patients with Essential Thrombocythemia [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/increased-cleavage-of-vwf-by-adamts13-might-reduce-high-molecular-weight-vwf-multimers-leading-to-acquired-von-willebrand-syndrome-in-patients-with-essential-thrombocythemia/. Accessed August 19, 2022.
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