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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4061-4068.
Prepublished online as a Blood First Edition Paper on September 3, 2008; DOI 10.1182/blood-2008-06-164087.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera
Marina Marchetti1,2,
Elisabetta Castoldi3,
Henri M. H. Spronk1,
René van Oerle1,
Donatella Balducci2,
Tiziano Barbui4,
Jan Rosing3,
Hugo ten Cate1,5, and
Anna Falanga2
1 Department of Internal Medicine, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands;
2 Thrombosis and Hemostasis Center, Department of Hematology-Oncology, Ospedali Riuniti di Bergamo, Bergamo, Italy;
3 Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands;
4 Research Foundation, Ospedali Riuniti di Bergamo, Bergamo, Italy; and
5 Department of Internal Medicine, Division of Haematology, University Hospital Maastricht, Maastricht, The Netherlands
We used the thrombin generation assay to evaluate the hypercoagulable state according to JAK2V617F mutational status in essential thrombocythemia (ET) and polycythemia vera (PV) patients. Thrombin generation was determined in the presence and absence of activated protein C (APC), and APC resistance was expressed as normalized APC sensitivity ratio (nAPCsr). Tissue factor pathway inhibitor (TFPI), total and free protein S (PS), prothrombin (FII), factor V (FV), and neutrophil elastase were measured in plasma; CD11b was measured on neutrophils. Compared with normal controls, patients had a lower endogenous thrombin potential in the absence of APC but had a higher endogenous thrombin potential in the presence of APC, showing the occurrence of APC resistance. The nAPCsr increased in JAK2V617F carriers compared with noncarriers and was highest in JAK2V617F homozygous patients. FII, FV, free PS, and TFPI levels were reduced in patients, mainly in JAK2V617F carriers. Multiple regression analysis indicated the low free PS level as major determinant of the increased nAPCsr. Elastase was increased in patients and inversely correlated with free PS. In conclusion, these data indicate the occurrence of acquired APC resistance in ET and PV patients, probably because of a reduction in free PS levels. The APC-resistant phenotype is influenced by the JAK2V617F mutational load.
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