warfarin and Polycythemia-Vera

Estimating and modifying thrombotic risk is currently the mainstay of care for patients with polycythemia vera (PV) and essential thrombocythemia (ET). In recent years, however, increased attention has shifted towards quality of life and disease modification. In this review, we discuss recent advances in risk stratification, present updated results for ruxolitinib and interferon randomized clinical trials, discuss new approaches in antiplatelet and anticoagulant treatment, and summarize early phase trials of novel agents and emerging therapeutic concepts for the treatment of PV and ET.. International collaborations and novel technologies, i.e., next-generation sequencing and machine learning techniques, have demonstrated excellent abilities to improve thrombotic risk stratification in PV and ET. Updated results from ruxolitinib and interferon randomized clinical trials have confirmed excellent efficacy and safety of these agents, both as first- and second-line treatments. Early trials of novel agents (histone deacetylase inhibitors, telomerase inhibitors, lysine-specific demethylase-1 inhibitors, human double-minute 2 inhibitors, and hepcidin mimetics) have shown encouraging efficacy and safety in blood count control, reduction of splenomegaly, and alleviation of disease-related symptoms. Finally, accumulating evidence suggested that direct oral anticoagulants may be a valid therapeutic alternative to warfarin for prolonged thromboprophylaxis. International collaborations ("big data") with the help of new technologies represent an exciting new approach to analyze rare outcomes in rare diseases, especially for identifying novel prognostic biomarkers in PV and ET. Randomized clinical trials are also needed to fully elucidate whether novel agents may establish new standards of care.

Topics: Anticoagulants; Biomarkers; Hepcidins; Histone Deacetylase Inhibitors; Humans; Interferons; Lysine; Nitriles; Polycythemia Vera; Pyrazoles; Pyrimidines; Quality of Life; Risk Assessment; Telomerase; Thrombocythemia, Essential; Thrombosis; Venous Thromboembolism; Warfarin

Topics: Aspirin; Biomarkers; Female; Hematologic Neoplasms; Humans; Janus Kinase 2; Male; Middle Aged; Nitriles; Polycythemia Vera; Pyrazoles; Pyrimidines; Pyrrolidines; Sulfonamides; Thrombocythemia, Essential; Thrombosis; Warfarin

We report the case of a 59 year old woman who presented with a six week history of worsening bifrontal headache. On CT brain the only abnormal finding was a partially empty sella potentially indicative of increased intracranial pressure. MRI found a large cerebral venous sinus thrombosis in the superior sagittal sinus. Blood tests and a bone marrow biopsy revealed a diagnosis of JAK2 positive primary polycythaemia rubra vera. The lack of sensitivity and specificity of CT in the diagnosis of CVST should engender a low threshold for MRI in patients with risk factors and/or non-diagnostic abnormalities on initial CT. Management of this dual pathology involves both the immediate treatment of the thrombus with heparin bridging to warfarin and the long treatment for polycythaemia involving repeat venesections and cytoreductive therapy.

Topics: Diagnosis, Differential; Empty Sella Syndrome; Female; Headache; Heparin; Humans; Middle Aged; Polycythemia Vera; Sella Turcica; Sinus Thrombosis, Intracranial; Warfarin

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Polycythemia Vera; Proportional Hazards Models; Risk Factors; Smoking; Thrombophilia; Thrombosis; Warfarin

Microvascular circulation disturbances including erythromelalgia, its microvascular ischemic complications, and migraine-like atypical or typical transient ischemic cerebral, ocular, and coronary ischemic attacks are specific clinical manifestations in patients with essential thrombocythemia (ET), and polycythemia vera (PV) associated with thrombocythemia. Thrombocythemia (ET and PV) patients with microvascular disturbances have shortened platelet survival, increased beta-thromboglobulin (beta-tg), platelet factor 4 (PF4), and thrombomoduline (TM) levels, and increased urinary thromboxane B2 (TxB2) excretion indicating platelet-mediated processes in vivo. Inhibition of platelet cyclooxygenase (COX 1) by aspirin is followed by relief of microvascular disturbances, correction of shortened platelet survival, and return of plasma levels of beta-tg, PF4, TM levels and TxB2 excretion to normal. The transient ischemic attacks and thrombotic complications in thrombocythemia are very likely caused by hypersensitive platelets produced by spontaneously proliferating enlarged megakaryocytes in the bone marrow of ET and PV patients. In contrast to normal platelets in healthy individuals the circulating hypersensitive thrombocythemic platelets spontaneously activate and secrete their products, thus forming aggregates that transiently plug the microcirculation, or result in occlusive platelet thrombi in arterioles or small arteries. Clear evidence is presented that the microvascular transient ischemic and occlusive thrombotic complications in thrombocythemia patients are relieved by treatment with aspirin and by reduction of platelet counts to normal (<400 x 109/l), but not by coumadin. In patients with thrombocythemia associated with PV, increased hematocrit and whole blood viscosity aggravate the platelet-mediated microvascular ischemic and thrombotic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Correction of hematocrit and blood viscosity by phlebotomy significantly reduces the major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated microvascular circulation disturbances in PV patients because thrombocythemia persists. Complete relief and prevention of microvascular and major thrombosis in PV patients are obtained by treatment with low-dose aspirin on top of phlebotomy or by treatment with the platelet lowering agents, anagrelide, interferon or hydroxyurea.

Topics: Aged; Anticoagulants; Aspirin; Drug Resistance; Erythromelalgia; Female; Humans; Ischemia; Male; Microcirculation; Middle Aged; Phlebotomy; Platelet Aggregation Inhibitors; Polycythemia Vera; Thrombocythemia, Essential; Thrombophilia; Thrombosis; Warfarin

Polycythemia Vera (PV) and Essential Thrombocythemia (ET) are chronic myeloproliferative disorders complicated by a high incidence of thrombotic complications. Extensive coagulation studies failed to demonstrate a consistent pattern of abnormalities associated with thrombosis. Recently, a poor anticoagulant response to activated protein C (APC), due to a mutation of factor V (FV Leiden), has been identified as the most frequent hereditary disorder associated with venous thrombophilia. We investigated in 304 patients with PV and ET whether the presence of FV Leiden could be a risk factor for thrombosis. FV Leiden was found in 14/304 patients (4.6%) and was associated with venous thromboembolism (VTE) occurred before and at diagnosis (5/27,16%, with a significant difference of prevalence in comparison of that observed in asymptomatic patients, 9/263, 3%, p = 0.003). Carriership of FV Leiden was associated with VTE relapse, with a prevalence of 3.6% in asymptomatic patients, 6.9% in patients with a single episode of VTE and 18.1% in patients with recurrent VTE. The prevalence of FV Leiden in patients with and without arterial thrombosis was similar (5/79, 6% and 9/211, 4%, respectively, p = 0.337). This study indicates that the prevalence of the FV Leiden mutation in patients with PV and ET is comparable with that observed in the general population. FV Leiden mutation is a risk factor for VTE before and at time of diagnosis and for VTE recurrences. Screening for FV Leiden may be considered to identify PV and ET patients at higher risk of recurrences.

Topics: Activated Protein C Resistance; Anticoagulants; Austria; Cardiovascular Diseases; Cohort Studies; Comorbidity; Factor V; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Male; Middle Aged; Polycythemia Vera; Prevalence; Recurrence; Risk Factors; Thrombocythemia, Essential; Thrombophilia; Venous Thrombosis; Warfarin

A 42-year-old man presented with acute anterior myocardial infarction and hemoglobin of 248 g/L. Laboratory studies suggested the diagnosis of polycythemia rubra vera (PRV). Management of this condition with acetylsalisylic acid, heparin, warfarin and phlebotomy constitutes a therapeutic dilemma. This case also brings up the question of the appropriateness of thrombolysis and angioplasty in the treatment of myocardial infarction in the presence of PRV. Due to the rarity of this hematological disease, a call for international collaboration for assessing the efficacy and safety of these treatment modalities is recommended.

Topics: Adult; Anticoagulants; Aspirin; Cardiac Catheterization; Coronary Angiography; Electrocardiography; Fibrinolytic Agents; Heparin; Humans; Male; Myocardial Infarction; Phlebotomy; Platelet Aggregation Inhibitors; Polycythemia Vera; Warfarin

Topics: Female; Humans; Intracranial Embolism and Thrombosis; Middle Aged; Myocardial Infarction; Polycythemia Vera; Warfarin