Anticoagulant-resistant thrombophilia in a patient with polycythemia vera: a case report

Mechanical valve thrombosis is a rare condition in an adequately anticoagulated patient in the absence of underlying thrombophilia. We report a case of a 76-year-old male with mechanical prosthetic mitral valve thrombosis as the presenting feature of polycythemia vera. The patient was treated with thrombolysis at the time of acute presentation and subsequently maintained on low molecular weight heparin, low-dose aspirin, phlebotomy and hydroxyurea. Hemoglobin, leucocytosis and platelet count were controlled for almost 4 years after which the patient suffered a second, fatal episode in the setting of therapeutic anti-Xa level. This case report highlights the thrombotic risks associated with polycythemia vera. The proposed mechanisms of hypercoagulability in polycythemia vera are reviewed. To the best of our knowledge, mechanical valve thromboses as the presenting feature of polycythemia vera has not been reported previously.     

Aspirin-responsive painful red,blue, black toe,or finger syndrome in polycythemia vera associated with thrombocythemia

Five patients with red, purple blue, or black toes or fingers due to thrombocythemia associated with polycythemia vera (polycythemia and thrombocythemia vera) in four and essential thrombocythemia (thrombocythemia vera) in one are described. The microvascular erythromelalgic syndrome of thrombocythemia was overlooked and progressed to cold blue swollen and painful fingers or black toes in three patients with polycythemia and thrombocythemia vera due to arteriographically documented occlusions of digital or large peripheral arteries with no evidence of preexistent atherosclerotic vascular disease. Concomitant erythromelalgia of the hand palm could be confirmed by the histopathological findings of arteriolar thrombotic lesions in the reticular dermis in two patients with polycythemia and thrombocythemia vera. The increased hematocrit in the presented patients with polycythemia and thrombocythemia vera contributed to the progression of the microvascular syndrome of thrombocythemia to major occlusive ischemic events of the extremities. Standard therapy with oral anticoagulants and reduction of the hematocrit to normal by bloodletting did not affect the platelet-mediated microvascular erythromelalgic, ischemic symptoms in the patients with polycythemia vera because thrombocythemia vera persisted. Complete relief of pain and restoration of the ischemic acral circulation disturbances in patients with thrombocythemia vera or thrombocythemia associated with polycythemia vera in maintained remission by bloodletting could be obtained by long-term treatment with low-dose aspirin.     

Intraventricular thrombosis in polycythemia vera: A cause of intractable cardiac failure

The occurrence of thrombotic events is central to the course of polycythemia vera.^1–5 Myocardial, cerebral, peripheral, and pulmonary infarctions are frequent and are consequences of thromboses in small and medium caliber arteries. Thrombosis in large caliber arteries is a rare event. Thrombosis within the chambers of the heart has not been hitherto reported.This report documents the occurrence of massive left ventricular thrombosis in a patient with polycythemia vera. The thrombus reduced the left ventricular capacity by about 75% and caused intractable congestive heart failure.     

Decreased platelet aggregation but increased thromboxane A2 generation in polycythemia vera

Patients with polycythemia vera have been described to have hemorrhagic as well as thrombotic tendencies. In a patient with polycythemia vera and angina pectoris, we observed markedly decreased platelet aggregation response to epinephrine but increased platelet and whole-blood thromboxane A2 generation compared with normal subjects. Electron microscopy mostly showed partially activated forms of platelets, which may account for decreased aggregation response in vitro and hemorrhagic tendencies. Young and large platelets found in this disease, however, can generate large amounts of vasoconstrictor and platelet proaggregatory prostanoid thromboxane A2 in response to endogenous thrombin, which may be a basis for thrombotic tendencies.     

Mutation of the prothrombin gene and thrombotic events in patients with polycythemia vera or essential thrombocythemia: a cohort study

The association between a prothrombin mutation and the risk of thrombosis was analyzed in 214 patients with polycythemia vera or essential thrombocythemia. The rate for venous thrombotic events was 14.7/100 patient-years in patients with the prothrombin mutation compared to 0.8 in patients without the mutation (rate ratio 17.5).     

Hemostatic gene polymorphisms and the prevalence of thrombotic complications in polycythemia vera and essential thrombocythemia.

Patients with polycythemia vera and essential thrombocythemia are at risk for thrombotic and bleeding complications. Currently, no diagnostic test can predict thrombohemorrhagic complications. In a prospective study of 86 patients with polycythemia vera (43 patients) or essential thrombocythemia (43 patients), we examined the possible role of polymorphisms of platelet adhesion receptors [glycoprotein (GP) Ibalpha, GPIa, GPIIIa) and clotting factor II (prothrombin's G20210A mutation) and clotting factor V (Leiden mutation) in determining the risk of thrombotic or bleeding complications. Except for an association between vasomotor symptoms and prothrombin mutation (P < 0.001), no significant correlation between polymorphism of clotting factors and thrombohemorrhagic complications was identified. When the entire patient cohort was considered, the polymorphisms of platelet adhesion receptors were not associated with the risk for thrombotic or bleeding complications. However, among patients with polycythemia vera, the presence of the PlA2 allele of GPIIIa was associated with an increased risk of arterial thrombosis. In view of previous studies linking the presence of the PlA2 allele of GPIIIa to a higher risk for coronary artery thrombosis, our data have physiologic relevance. However, they need to be confirmed in a larger study.     

Evidence-based management of polycythemia vera

The clinical course of polycythemia vera is marked by significant thrombotic complications and a variable risk of the disease turning either into myeloid metaplasia with myelofibrosis or into acute myeloid leukemia. Cytoreductive treatment of blood hyperviscosity by phlebotomy or chemotherapy and antiplatelet therapy with low-dose aspirin have dramatically reduced the number of thrombotic complications and substantially improved survival. However, there is concern that certain myelosuppressive drugs accelerate the disease progression to acute leukemia. Thus, the objective of management is two-fold: first, to minimize the risk of thrombotic complications; second, to prevent progression to myelofibrotic or leukemic transformation. This chapter provides updated estimates of the risk of thrombosis and disease progression and evaluates the various randomized and observational studies in polycythemia vera, according to an evidence-based approach.     

A clinical update in polycythemia vera and essential thrombocythemia

Polycythemia vera and essential thrombocythemia pose specific management issues that distinguish them from other chronic myeloproliferative disorders. They are associated with a better prognosis, as well as a variable risk of thrombohemorrhagic complications. In addition, essential thrombocythemia occurs comparatively more often in young people and women. Treatment strategies for patients with polycythemia vera and essential thrombocythemia must consider the possibility of long-term survival, morbidity from thrombotic complications, transformation into myelofibrosis with myeloid metaplasia or acute myeloid leukemia, and the effect of specific therapies on the incidence of leukemic transformation and on pregnancy. There is increasing concern about the possible leukemogenic effect of hydroxyurea. Newer therapeutic agents, including interferon alpha and anagrelide, are being used more often. Ongoing studies are reexamining the effects of low-dose aspirin in preventing thrombotic complications.     

Identification and treatment of arterial thrombophilia

Opinion statement Once the diagnosis of a thrombophilic state has been established, management must include one or more strategies designed to attenuate thrombotic risk and the likelihood of clinical events. In the case of drug-induced arterial thrombosis provoked by oral contraceptives, hormone replacement therapy, heparinoids, cocaine, or thienopyridine-related thrombotic thrombocytopenic purpura (TTP), the offending agent should be discontinued immediately. Anticoagulant therapy and platelet-directed therapies, either alone or in combination, should be considered for patients experiencing a single arterial or venous thrombosis (secondary prevention), with treatment duration determined by diagnostic studies and the persistence of a prothrombotic state. Other specific therapies should be directed at the underlying thrombophilic disorder. These treatments include direct thrombin inhibitors such as argatroban for heparin-induced thrombocytopenia (HIT), myelosuppressive drugs such as hydroxyurea for essential thrombocytosis, plasma exchange for thrombotic thrombocytopenic purpura, and phlebotomy for polycythemia vera. Additionally, the treating physician must seek input early from a hematologist or rheumatologist when managing patients with known or suspected HIT, TTP, and myeloproliferative disorders, or the antiphospholipid syndrome, respectively. This interdisciplinary interface is critical to ensure an optimal outcome when treating patients with arterial thrombophilia.     

Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols

The PVSG was organized in 1967 to establish effective diagnostic criteria for polycythemia vera, to study the natural history of the disease and to define the optimal treatment. Although polycythemia vera and the other myeloproliferative diseases are relatively uncommon, the PVSG was able to accumulate well over 1,000 patients with these various disorders and to study them according to a total of 15 different protocols. PVSG-01, a long-term randomized controlled study of phlebotomy alone compared with the myelosuppressive agents, 32P or chlorambucil supplemented by phlebotomy, continues to receive follow-up data on 93% of surviving patients 18 years after initiation of the study. During its lifetime, PVSG has developed a widely accepted and highly effective set of criteria for the specific diagnosis of polycythemia vera as well as useful criteria for the diagnosis of essential thrombocythemia. It has gathered an enormous volume of data on the natural history of the myeloproliferative diseases and in particular on the nature of the prevalent complications, such as thrombotic events and hematologic and nonhematologic malignancies. With respect to the final question, the optimal treatment for polycythemia vera, it is apparent that the expectation of a single optimal therapy that would apply to all patients at all ages and stages of the disease was naive. Nevertheless considerable progress has been made. Moreover, the group has defined more precisely than ever before the nature of the complications of the disease and the association of the risks of specific complications with specific forms of therapy. It thus has made it possible to pose the next series of therapeutic questions that must be addressed in this disorder with a greater degree of sophistication than was previously possible.     

Trends in the incidence of polycythemia vera among olmsted county,Minnesota residents, 1935–1989

To investigate the suggestion that the incidence of polycythemia vera has increased in recent decades, we ascertained secular trends in the incidence of polycythemia vera in Olmsted County, Minnesota, over the 55-year period, 1935–1989. The inpatient and outpatient medical records of all potential cases of polycythemia vera in Olmsted County residents were reviewed and the diagnostic criteria of the Polycythemia Vera Study Group were applied. We found no indication of an increase in the age- and sex-adjusted incidence of polycythemia vera, which averaged 1.9 per 100,000 person-years (95% C.I., 1.4–2.5) over the study period. Incidence rates increased with age, and age-adjusted incidence rates were greater for men (2.8 per 100,000 person-years; 95% C.I., 1.8–3.9) than for women (1.3 per 100,000 person-years; 95% C.I., 0.7–1.9), with the highest incidence rate (23.5 per 100,000 person-years) among men aged 70–79 years. Survival was reduced in this inception cohort of 50 cases, compared to that expected for individuals of like age and sex (P < 0.0001); median survival following diagnosis was 7.2 years. © 1994 Wiley-Liss, Inc.     

Risk stratification, staging, and treatment of patients with polycythemia vera: Italian and European collaboration on low-dose aspirin in polycythemia data

The clinical course of polycythemia vera (PV) is marked by a high incidence of thrombotic complications, which represent the main cause of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use increases the risk of transformation into acute leukemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients should be treated with phlebotomy and low-dose aspirin based on the results of the European Collaboration on Low-Dose Aspirin in Polycythemia study. Cytotoxic therapy is indicated in high-risk patients, and the drug of choice is hydroxyurea because its leukemogenicity is low. New therapeutic options, that theoretically are devoid of leukemic risk (such as interferon alpha and imatinib), should be reserved for selected patients and require additional clinical experience.     

Therapy for polycythemia vera and essential thrombocythemia is driven by the cardiovascular risk

The clinical course of polycythemia vera (PV) and essential thrombocythemia (ET) is characterized by an increased incidence of thrombotic and hemorrhagic complications and an inherent tendency to progress into myelofibrosis or acute myeloid leukemia. Major predictors of vascular events are increasing age and previous thrombosis. Myelosuppressive drugs can reduce the rate of thromboses and hemorrhages, but there is concern that their use accelerates the rate of leukemic transformation. Thus, a risk-oriented management strategy is recommended. Low-risk patients with PV should be treated with phlebotomy and low-dose aspirin, whereas those with ET can be left untreated. Cytotoxic agents are recommended in high-risk cases and hydroxyurea is the drug of choice in most patients. Interferon alpha or anagrelide could be considered in selected young patients or as second-line therapy in those refractory or intolerant of hydroxyurea. The recent identification of JAK2V617F mutation in a substantial proportion of patients with PV and ET raises new questions regarding both risk classification and management, but additional studies on these issues are required.     

JAK2V617F mutation and hydroxyurea treatment as determinants of immature platelet parameters in essential thrombocythemia and polycythemia vera patients

Immature platelets (IPFs), which are hemostatically more active than mature platelets, have been found elevated in essential thrombocythemia and polycythemia vera, 2 myeloproliferative neoplasms (MPN) characterized by an increased risk of thrombosis. It is not known whether the IPF levels are influenced by pathogenetic factors, including JAK2V617F mutational status, or by treatment regimen. To address this point, in 46 essential thrombocythemia and 38 polycythemia vera consecutive patients, we measured IPF and correlated the results to JAK2V617F mutation and myelosuppressive treatment with hydroxyurea. This analysis provides 2 new elements regarding IPF and MPN. The first finding is that the JAK2V617F mutation is linked to the quantity of IPF in patients with MPN, which might contribute to the prothrombotic phenotype in these patients. The second finding is that IPF is susceptible to myelosuppressive treatment, which may additionally explain the favorable effect of hydroxyurea therapy on MPN outcome as well as the associated thrombotic risk.     

Extent of hematopoietic involvement by TET2 mutations in JAK2V⁶¹⁷F polycythemia vera

TET2 mutations are found in polycythemia vera and it was initially reported that there is a greater TET2 mutational burden than JAK2(V617F) in polycythemia vera stem cells and that TET2 mutations precede JAK2(V617F). We quantified the proportion of TET2, JAK2(V617F) mutations and X-chromosome allelic usage in polycythemia vera cells, BFU-Es and in vitro expanded erythroid progenitors and found clonal reticulocytes, granulocytes, platelets and CD34(+) cells. We found that TET2 mutations may also follow rather than precede JAK2(V617F) as recently reported by others. Only a fraction of clonal early hematopoietic precursors and largely polyclonal T cells carry the TET2 mutation. We showed that in vitro the concomitant presence of JAK2(V617F) and TET2 mutations favors clonal polycythemia vera erythroid progenitors in contrast with non-TET2 mutated progenitors. We conclude that loss-of-function TET2 mutations are not the polycythemia vera initiating events and that the acquisition of TET2 somatic mutations may increase the aggressivity of the polycythemia vera clone.     

Megakaryopoiesis and platelet function in polycythemia vera and essential thrombocythemia patients with JAK2 V617F mutation

Patients with Ph chromosome negative myeloproliferative disease (Ph-MPD) have an increased risk of vascular complications. It remains controversial whether patients with the JAK2 V617F mutation (V617F) exhibit increased risk, while recent growing evidence has shown a critical role for V617F in clonal erythropoiesis in Ph-MPD. We studied 53 patients with Ph-MPD especially in relation to megakaryopoiesis, the thrombotic complications and the presence of V617F. Using novel mutation-specific PCR which is a highly sensitive PCR-based assay for detection of JAK2 mutated allele(s), we identified V617F in 38 Ph-MPD, which include 13 polycythemia vera (PV), 23 essential thrombocythemia (ET) and 2 chronic idiopatic myelofibrosis. The numbers of megakaryocytes were significantly increased in PV and ET patients with V617F, but the platelet counts were slightly lower. Although statistically not significant, the incidence of thrombotic events was higher in the group with V617F compared to in those without the mutation. Agonist-induced in vitro platelet aggregation and platelet adhesion were not affected by the presence of this mutation. Nonetheless, we found a hypercoagulable state in Ph-CMPD with V617F by employing whole blood thromboelastography. It suggests pre-thrombotic tendencies in CMPD are complex and JAK2 V617F mutation might have a role in vivo blood coagulation by altering not only the number, but function(s) of all three myeloid cells, including red blood cells, white blood cells and platelets in Ph-CMPD.     

Aspirin for the control of platelet activation and prevention of thrombosis in essential thrombocythemia and polycythemia vera: current insights and rationale for future studies

Polycythemia vera and essential thrombocythemia are chronic myeloproliferative disorders characterized by a relatively benign clinical course that may be complicated by arterial and venous thromboses. A thrombotic diathesis often manifests at diagnosis or in the preclinical phase of the myeloproliferative disease. Peculiar microcirculatory disturbances such as erythromelalgia and visual and hearing symptoms also commonly occur in these patients, and are highly responsive to aspirin. In a placebo-controlled trial in relatively low-risk polycythemic subjects, low-dose aspirin recently was shown to reduce the incidence of both arterial and venous thrombosis with a limited increase of the hemorrhagic risk. Due to its favorable benefit/risk profile, low-dose aspirin should be prescribed to all patients with polycythemia vera who have no contraindication to this treatment. Future studies should assess primarily the efficacy and safety of aspirin in essential thrombocythemia, and test the possible use of more aggressive antithrombotic strategies in high-risk polycythemic patients.     

Tissue plasminogen activator levels in different types of polycythemia

The plasma level of tissue plasminogen activator antigen (t-PA-Ag) was examined in 86 patients with polycythemia (29 polycythemia vera, 11 secondary polycythemia and 46 with spurious polycythemia) and 24 healthy volunteers. Tissue plasminogen activator antigen was significantly decreased in patients with polycythemia vera in comparison with healthy controls. On the other hand, in patients with spurious polycythemia and secondary polycythemia t-PA-Ag concentration was significantly increased. There was no significant difference in t-PA-Ag levels in polycythemic patients with or without thromboembolic disease. A significant correlation was detected between t-PA-Ag level and hemoglobin or hematocrit concentration in patients with polycythemia vera (p = 0.02, r = 0.43). However, in patients with secondary polycythemia and spurious polycythemia, no significant correlation between t-PA-Ag and hemoglobin level was found. Plasminogen activator inhibitor (PAI) levels in patients with polycythemia vera and healthy volunteers did not differ significantly.     

Occlusion of the superior mesenteric artery in a patient with Polycythemia vera: Resolution with percutaneous transluminal angioplasty

The case is reported of a 46-year-old male patient with polycythemia vera (PV) treated with phlebotomy who developed an occlusive thrombosis of the superior mesenteric artery 2 years after the diagnosis. He was successfully managed with percutaneous transluminal angioplasty. The patient did not develop any other thrombotic phenomena. To our knowledge, there are no previous reports on the use of percutaneous transluminal angioplasty in the management of arterial thrombotic complications in PV patients.     

Successful anticoagulation with hirudin in a patient with mesenteric venous thrombosis and multiple coagulation abnormalities

A case of multiple thrombotic diatheses discovered in the setting of mesenteric venous infarction is discussed. The patient had deficiencies of protein C, protein S, antithrombin III; was heterozygous for factor V Leiden; and had polycythemia vera. Adequate anticoagulation could not be established with heparin administration and hirudin was used. The diagnosis of mesenteric venous infarction, thrombotic tendency of multiple coagulation diatheses, and use of hirudin are discussed.