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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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Submitted June 19, 2008
Accepted July 23, 2008
Thrombin generation and activated protein C resistance in patients with Essential Thrombocythemia and Polycythemia Vera
Marina Marchetti*, Elisabetta Castoldi, Henri MH Spronk, Rene van Oerle, Donatella Balducci, Tiziano Barbui, Jan Rosing, Hugo ten Cate, and Anna Falanga
Department of Internal Medicine, Laboratory for Clinical Thrombosis and Haemostasis, (CARIM), Maastricht University, Maastricht, Netherlands
Department of Biochemistry, (CARIM), Maastricht University, Maastricht, Netherlands
Thrombosis and Hemostasis Center, Department of Hematology-Oncology, Ospedali Riuniti, Bergamo, Italy
Research Foundation, Ospedali Riuniti, Bergamo, Italy
Department of Internal Medicine, Division of Haematology, University Hospital Maastricht, Maastricht, Netherlands
* Corresponding author; email: marina.r.marchetti{at}gmail.com.
We used the thrombin generation assay to evaluate the hypercoagulable state according to JAK2V617F mutational status in patients with Essential Thrombocythemia (ET), and Polycythemia Vera (PV). 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), FII, FV and neutrophil elastase were measured in plasma; CD11b was measured on neutrophils. Compared to normal control subjects, patients had a lower endogenous thrombin potential (ETP) in the absence of APC, but had a higher ETP in the presence of APC, showing the occurrence of APC-resistance. The nAPCsr values significantly increased in JAK2V617F carriers compared to non carriers, and were highest in JAK2V617F homozygous patients. FII, FV, free-PS, and TFPI levels were reduced in patients, and mainly in JAK2V617F carriers. Multiple regression analysis indicated the low free PS level as major determinant of the increased nAPCsr. Elastase was significantly increased in patients and was inversely correlated with free PS. In conclusion, these data indicate the occurrence of acquired APC-resistance in ET and PV patients, likely due to a reduction in free-PS levels. The APC resistant phenotype is influenced by the JAK2V617F mutational load, as shown by the more pronounced APC-resistance in homozygous subjects.
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