Publication Only: Myeloproliferative neoplasms - Clinical
Thrombotic complications contribute significantly to morbidity and mortality in Ph-negative myeloproliferative neoplasms, including primary myelofibrosis (PMF). The majority of PMF patients have JAK2V617F mutation that is associated with increased thrombotic risk, CALR gene mutations are also common in PMF. Clonal myeloproliferation in PMF followed by secondary inflammation with pathologic cytokine production induce endothelium, leukocytes and platelets activation resulting in coagulation activation. Natural anticoagulants protein C (PC) and protein S (PS) deficiencies with activated protein C resistance development are supposed among the crucial procoagulant features in Polycythemia Vera and Essential Thrombocythemia, while the data on hemostatic abnormalities in PMF and their relationship with JAK2V617F burden is scarce.
To evaluate the hemostatic parameters in PMF patients, predisposing high thrombosis risk, and their relationship with JAK2V617F presence and allele burden.
The study included 36 PMF patients (age 30-86 years, median 60 years). Somatic mutations (JAK2V617F and CALR) presence and JAK2V617F allele burden were assessed using allele specific polymerase-chain reaction. The control group consisted of 68 healthy persons (30-73 years, median 46 years). Coagulation assays (factors VIII, V, von Willebrand (VWF), antithrombin and PC activities, fibrinogen concentration, VWF antigen and free PS level) were performed by standard clotting, chromogenic and immunoturbidimetric techniques. STATISTICA 6.0 was used for data analysis. The results were presented as median with 95% confidence interval (CI). Mann-Whitney and Spearman rank tests were applied, the differences considered statistically significant with p < 0.05(*).
23 (63.9%) PMF patients in the study were JAK2V617F-positive, 8 (22.2%) had mutation in CALR gene. JAK2V617F allele burden data was available in 13 PMF patients with median 8.1% (95%CI 3.4-43.8%). The results of hemostatic parameters in PMF patients and controls are shown in Table 1.
Unexpectedly there were no significant differences in studied parameters between PMF patients with JAK2V617F and CALR mutations. However, a statistically significant inverse correlation was revealed between JAK2V617F allele burden and PC activity (r = -0.68301, p = 0.01).
PC and, especially, PS activities were decreased in PMF, predisposing hypercoagulation. The increased FVIII activity and fibrinogen in PMF patients confirm the hypercoagulability and also reflect high inflammation level, while VWF:Ag increase suggests the endothelium damage and dysfunction, enhancing prothrombotic state in PMF. An inverse relationship between JAK2V617F allele burden and PC activity can serve as one of the mechanisms contributing to the higher thrombosis incidence depending on JAK2V617F burden.