Risk Factors and Predictors of Thrombosis in Myeloprolferative Neoplasms
Risk Factors and Predictors of Thrombosis in Myeloprolferative Neoplasms
To assess the clinical risk factors and predictable biomarkers of thrombotic complications in
 cases of philadelphia negative myeloproliferative disorders.
Classic BCR-ABL negative chronic myeloproliferative neoplasms (MPN) are stem cell disorders
 characterized by abnormal myeloid proliferation and increased blood cell counts and comprise
 polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).

 Myeloproliferative neoplasms (MPN) are common malignancies in elderly individuals as the
 combined annual incidence rates of classical MPNs were reported to be 0.84, 1.03, and 0.47
 per 100,000 respectively for PV, ET, and PMF but with a wide variation in prevalence rates
 reported in different studies. The 5-year relative survival rates are 84.8, 89.9, and 39% for
 PV, ET and PMF patients, respectively.

 Thromboembolic complications represent a major cause of morbidity and mortality in MPN,
 particularly in PV and ET. The mechanisms underlying increased thrombotic risk in chronic
 myeloproliferative neoplasms (MPN) are incompletely understood.

 Several pathophysiological mechanisms help explain the increased likelihood of thrombosis in
 these patients. Factors, such as leukocyte and platelet activation leading to the formation
 of leukocyte-platelet aggregates, activation of the coagulation cascade by microparticles,
 high levels of inflammatory cytokines, and endothelial dysfunction have a crucial role in
 thrombosis in MPN patients.

 Accurate prediction of the thrombotic risk still represents a challenge and adequate
 predictive biomarkers are not available. The mechanisms underlying thrombosis involve a
 complex interplay among blood cells, the endothelium and the coagulation system. Both
 increased blood counts and cellular activation, which is due to hyperactivation of
 intracellular signaling pathways and enhanced interaction between blood cells, are implicated
 in the thrombotic predisposition.

 The JAK2V617F mutation is a diagnostic marker for MPN and it also plays an important role in
 patient treatment since inhibition of JAK2-associated proliferative pathways has the
 potential to inhibit cell proliferation in MPNs. This mutation is present in ~95% of PV
 patients and 50% of ET or PMF patients. Thrombosis and hemostasis are major complications
 that affect the life expectancy of patients with MPN.

 Current guidelines recommend testing for JAK2 mutations in any patient suspected to have an
 MPN. JAK2 mutation leads to distinct changes in hematopoietic cells that increase the
 likelihood of thrombus formation.

 The risk of thrombosis, in both PV and ET, exceeds 20% and a substantial proportion of
 patients experience vasomotor disturbances (e.g. headaches, lightheadedness, acral
 paresthesias, erythromelalgia, atypical chest pain, ocular disturbances, tinnitus) and in
 case of PV, pruritus.

 Mean platelet volume (MPV) is largely considered as a useful indirect marker of platelet
 activation. Larger platelets are metabolically and enzymatically more active, and have a
 greater prothrombotic potential. Elevated MPV is associated with other markers of platelet
 activity, including increased platelet aggregation, increased thromboxane synthesis and
 beta-thromboglobulin release, and increased expression of adhesion molecules.

 High sensitivity CRP is an inflammatory marker might be useful to reflect a condition of
 chronic inflammation which is associated with the disease severity .

 In addition, Elevated CRP and elevated LDH are risk factors for survival in MPN patients.

 Elevated γ-Glutamyl (γ-GT) transferase is an independent risk factor for Splanchnic venous
 thrombosis (SVT) presence in MPN.

 About 30% of vascular events in Ph-negative MPN patients are VTE, which generally present as
 lower limb deep vein thrombosis or pulmonary artery embolism. However, in Ph-negative MPN,
 VTE characteristically occurs in uncommon locations such as splanchnic veins, including
 hepatic veins (presenting Budd-Chiari syndrome), portal and mesenteric veins, or, less
 frequently, cerebral veins or sinuses. In patients with MPN, the prevalence of CVT is 3-7% of
 cases.

 Myeloproliferative neoplasms are known to be pro-thrombotic diseases (arterial and venous).
 For both of ET and PV, thromboses occur more frequently in arterial sites (between 64 and 75%
 for PV, and between 72 and 91% for ET).

 JAK2 mutation can affect cardiac arteries and veins in ET and PV, which results in
 thrombosis, ischemia and other cardiovascular events. JAK/STAT signaling pathway plays an
 important role in heart diseases. High incidence of atrial arrhythmias among patients with ET
 or PV. The patients were older, cumulating more cardiovascular risk factors inducing more
 thrombotic events mainly in arteries, and have a higher incidence of death.

 The importance of treatment compliance has now been clearly established in many pathological
 conditions as poor adherence has a negative impact on clinical evolution and non-adherence to
 cytoreductive therapy was associated with a significant reduction in the complete
 haematological remission rate but no significant association between thrombosis or death and
 non-adherence was found. This may be related to the fact that thrombosis is a more acute
 event, depending on the immediate hemostatic status at the time of thrombus constitution,
 whereas the phenotypic evolution of chronic haematological malignancies may be more the
 result of long term evolution of the clone, reflecting its exposure to therapeutic pressure.

 Patients with MPN should also avoid factors that are known to increase risk of VTE, including
 systemic hormone therapy such as oral contraceptive pills and smoking, and optimize
 cardiovascular risk factors, including control of blood pressure, diabetes, and cholesterol,
 in order to minimize thrombotic complications.
Inclusion Criteria:

 age > 18 years

 All patients diagnosed as BCR-ABL negative myeloproliferative neoplasm e.g:

 Polycythemia vera Essential thrombocythemia Primary myelofibrosis

 Exclusion Criteria:

 -  BCR- ABL positive MPN e.g CML

 -  Secondary erythrocytosis.

 -  Secondary thrombocytosis.

 -  Secondary bone marrow fibrosis.