warfarin and Thrombocythemia--Essential

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

Chronic myeloproliferative disorders share a stem cell-derived clonal myeloproliferation. This group of disorders include essential thrombocythemia (ET), polycythemia vera (PV), chronic myeloid leukemia, and primary myelofibrosis (PMF), with the respective features of thrombocytosis, erythrocytosis, and bone marrow fibrosis. These disorders can be associated with genetic mutations affecting protein tyrosine kinases, resulting in different configurations of abnormal signal transduction. The Janus tyrosine kinase 2 mutation can be used as a key diagnostic tool for diagnosing MPDs, specifically, ET, PV, and PMF. Patients with ET and PV are at an increased risk for thromboembolic and hemorrhagic events. We present a unique case of ET causing extensive arterial thromboembolism, despite being on adequate antithrombotic agents including warfarin and aspirin.

Topics: Anticoagulants; Arterial Occlusive Diseases; Blood Coagulation; Blood Coagulation Tests; Computed Tomography Angiography; Drug Substitution; Enoxaparin; Humans; Hydroxyurea; Male; Middle Aged; Thrombocythemia, Essential; Thromboembolism; Treatment Failure; Treatment Outcome; Warfarin

A 69-year-old man who had essential thrombocythemia, for which he was taking no medications, suddenly developed aphasia and right hemiplegia and was admitted to the hospital. He was thought to have had an embolic stroke and was initially treated with warfarin. Although the international normalized ratio was in the therapeutic range, he had 3 additional ischemic stroke episodes with the same symptoms after the index stroke. Magnetic resonance angiographic examinations revealed serial changes in middle cerebral artery stenosis. After administration of an antiplatelet agent and hydroxyurea, he had no additional strokes.

Topics: Aged; Anticoagulants; Aphasia; Brain Ischemia; Cerebral Angiography; Cilostazol; Diffusion Magnetic Resonance Imaging; Hemiplegia; Humans; Hydroxyurea; Infarction, Middle Cerebral Artery; International Normalized Ratio; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Perceptual Disorders; Platelet Aggregation Inhibitors; Stroke; Tetrazoles; Thrombocythemia, Essential; Warfarin

Topics: Cavernous Sinus Thrombosis; Compartment Syndromes; Decompression, Surgical; Eye Pain; Fibrinolytic Agents; Hirudins; Humans; Intraocular Pressure; Male; Middle Aged; Orbital Diseases; Protein C Deficiency; Recombinant Proteins; Thrombocythemia, Essential; Tomography, X-Ray Computed; Visual Acuity; Warfarin

Essential thrombocytosis is extremely rare in children. However, when present, it is associated with increased prevalence of antiphospholipid antibodies and thrombo-hemorrhagic complications. The authors report here a child with Budd-Chiari Syndrome resulting from essential thrombocytosis and associated antiphospholipid antibodies. A 13- y-old boy presented with microcytic hypochromic anemia, hepatosplenomegaly and thrombocytosis. CT scan demonstrated calcified thrombus in inferior vena cava (IVC). Diagnosis of essential thrombocytosis was considered in view of persistent thrombocytosis, antiphospholipid antibodies, bone marrow showing increased number, clusters and giant forms of megakaryocytes and IVC thrombosis. He was started on warfarin prophylaxis and did not have thrombotic recurrence on follow up.

Topics: Adolescent; Anticoagulants; Antiphospholipid Syndrome; Budd-Chiari Syndrome; Chronic Disease; Developing Countries; Diagnosis, Differential; Humans; Male; Thrombocythemia, Essential; Tomography, X-Ray Computed; Warfarin

Essential thrombocythemia is a hematological disorder characterized by clonal hemopoiesis in the bone marrow and increased number of circulating platelets. It is usually discovered accidentally at the time of routine blood examinations or can become clinically evident with either thrombotic or hemorrhagic complications. In the present article, we describe the case of a 66-year-old woman with pneumonia due to Pneumocystis carinii, who experienced deep vein thrombosis and pulmonary embolism during hospitalization with a subsequent heparin-induced thrombocytopenia. Bone marrow examination performed after clinical improvement revealed the patient to be affected by essential thrombocythemia.

Topics: Aged; Anticoagulants; Female; Fondaparinux; Heparin; Humans; Incidental Findings; Platelet Factor 4; Pneumonia, Pneumocystis; Polysaccharides; Pulmonary Embolism; Thrombocythemia, Essential; Thrombocytopenia; Thrombophlebitis; Warfarin

Mesenteric vein thrombosis is a rare disorder that is often the first manifestation of a systemic condition such as a hypercoagulable state or cancer. In particular, myeloproliferative disorders can present as mesenteric vein thrombosis even in the setting of relatively normal peripheral blood counts. A recent novel mutation in the Janus activated kinase 2 gene involving a gain-of-function substitute of valine to phenylalanine at position 617 (JAK2 V617F) has been discovered to be prevalent in patients with mesenteric vein thrombosis and myeloproliferative disorders. This article reports a patient who presented with mesenteric vein thrombosis and relatively normal peripheral blood counts. He was diagnosed with essential thrombocythemia after he tested positive for the JAK2 V617F mutation.

Topics: Aged; Anticoagulants; DNA Mutational Analysis; Genetic Predisposition to Disease; Genetic Testing; Humans; Janus Kinase 2; Male; Mesenteric Vascular Occlusion; Mesenteric Veins; Point Mutation; Thrombocythemia, Essential; Tomography, X-Ray Computed; Venous Thrombosis; Warfarin

Topics: Adult; Aspirin; Disease Management; Female; Humans; Hydroxyurea; Interferon-alpha; Leg Ulcer; Male; Middle Aged; Pipobroman; Platelet Count; Pregnancy; Pregnancy Complications, Hematologic; Quinazolines; Thrombocythemia, Essential; 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

Although essential thrombocythemia (ET) is usually primarily considered a disorder of middle age, it has been observed in children and young adults. However, the real risk for thrombosis in these patients has not been clearly established.. Prospective analysis of consecutive patients younger than 40 at the time of the diagnosis of ET and followed in our department between 1980 and 1998.. Sixty-eight patients (28 males and 40 females, median follow-up 99.14 months) affected by ET diagnosed in agreement with the Polycythemia Vera Study Group criteria.. Asymptomatic ET patients were not treated. In contrast, patients with associated atherosclerotic risk factors, microvascular disturbances, or a previous major arterial thrombosis were given acetyl salicylic acid (ASA 100 mg/day). Only patients with major thrombotic complications and a platelet count > 1,000 x 10(9)/L received cytoreductive therapy.. (1) to evaluate thrombotic complications in young patients with ET, (2) to relate thrombotic risk to the presence of general atherosclerotic risk factors, and (3) to adopt treatment, and (4) to report the outcome of the pregnancies monitored in our population.. Fifteen patients had major thrombosis, 11 of which were the presenting features of ET. No rethrombosis has been observed. Only one patient with thrombotic complications was under efficient treatment. Atherosclerotic risk factors are more common in patients with major arterial thrombosis than in asymptomatic subjects. Thirteen normal babies were delivered out of 16 pregnancies, 6 of the pregnant women were on ASA therapy.. Most thrombosis in young ET patients occurred at the time of the diagnosis, and venous thrombotic events represent one-third of total thrombosis. Cardiovascular risk factors seem to be concurrent stimuli for arterial thrombosis in ET. The thrombotic complication rate was 2.6/100 patients/year ASA reduces microvascular disturbances, thrombosis, and rethrombosis and possibly reduces obstetric complications in women with ET.

Topics: Acute Disease; Adult; Age Factors; Arteriosclerosis; Aspirin; Busulfan; Cohort Studies; Disease-Free Survival; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Hydroxyurea; Leukemia; Male; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Pregnancy Outcome; Primary Myelofibrosis; Prospective Studies; Risk Factors; Splenectomy; Thrombocythemia, Essential; Venous Thrombosis; Warfarin

The 78-year-old male underwent coronary angiography because of angina pectoris. He was revealed to have essential thrombocythemia with a platelet count of over 1,000,000/mm3. Essential thrombocythemia belongs to the group of chronic myeloproliferative disorders. It displays both thrombogenic and bleeding tendency due to the increased platelet count, as well as to dysfunction. CABG was performed using the left internal thoracic artery and the right gastroepiploic artery. Hydroxycarbamide was taken to regulate the platelet count before surgery. There was no difficulty with hemostasis during surgery. Warfarin and hydroxycarbamide were used as anticoagulant therapies after surgery. Postoperative CAG demonstrated both grafts to be patients. The patient remained in good condition until he died suddenly on the 159th postoperative day. The cause of death was not clear because no autopsy was carried out. The death may have been associated with a thromboembolism, acute graft thrombosis or cerebral infarction, or pulmonary embolism. This patient did not take antiplatelet drugs because the platelet count and prothrombin time was well controlled. Nonetheless, an antiplatelet agent might reduce the risk of thromboembolism in such patients. It is suggested that meticulous anticoagulation therapy must be important for a patient with essential thrombocythemia, especially in the postoperative period.

Topics: Aged; Angina Pectoris; Coronary Artery Bypass; Fatal Outcome; Humans; Hydroxyurea; Male; Omentum; Stomach; Thoracic Arteries; Thrombocythemia, Essential; Warfarin

This report deals with clinical experience of urologic surgery of patients with hemostatic disorder or hemolytic disease. In the past 5 years from May 1986, 14 operations were conducted in our clinic on 13 patients, consisting of 4 with von Willebrand disease (vWd), 1 with hemophilia B, 4 who had warfarin administration, 3 with essential thrombocythemia and 2 with spherocytosis. Almost all patients were treated hematologically before the urological operations. Except in 1 case, the post-operative course was favorable and under hematologic control. Massive bleeding in 1 case was obviously attributable to over-dosage of warfarin. It is difficult to determine the optimal dose of warfarin under an unstable hemostatic condition during the operation and recovery periods. However, it is possible to carry out urologic surgery for these patients under appropriate hematologic control, and ESWL was safely performed without medical treatment on 3 patients; 1 with vWd, 1 treated with warfarin and 1 with spherocytosis.

Topics: Adult; Aged; Blood Coagulation Factors; Blood Transfusion, Autologous; Child; Child, Preschool; Factor VIII; Female; Fibrinogen; Hemophilia B; Humans; Hydroxyurea; Lithotripsy; Male; Middle Aged; Spherocytosis, Hereditary; Thrombocythemia, Essential; Urologic Diseases; von Willebrand Diseases; Warfarin