Thrombohemorrhagic complications of myeloproliferative disorders

doi:10.1016/j.blre.2010.08.002

Blood Reviews

Volume 24, Issue 6, November 2010, Pages 227-232

https://doi.org/10.1016/j.blre.2010.08.002 Get rights and content

Abstract

Myeloproliferative disorders are commonly associated with thrombohemorrhagic manifestations. The current review highlights recent advances in understanding the epidemiology and pathogenetic mechanisms of thrombotic and bleeding complications. Therapeutic modalities and prophylactic interventions corresponding to the specific disease states are also discussed.

Introduction

Myeloproliferative disorders (MPD) constitute a cluster of clonal hematological diseases, initially described as a group by William Dameshek in 1951.¹ They are characterized by increased hematopoiesis and overproduction of mature and differentiated blood cells, leading to splenomegaly, myelofibrosis and an augmented risk of transformation to acute leukemia, but foremost, to an increased risk of thrombotic and hemorrhagic complications.² In polycythemia vera (PV) and essential thrombocythemia (ET) the rate of thrombosis (arterial and venous) can approach 50%.[3], [4], [5], [6], [7], [8], [9] Hence, thrombotic disorders have been most extensively investigated in PV and ET and will be the focus of the current work, while data related to myelofibrosis will not be discussed in detail in the present review.¹⁰ Mechanisms involved in thrombotic tendency have been recently attributed in part to JAK-2, a molecular hallmark of PV and ET. However, further research is needed to explore the pathogenesis of thrombosis in these disorders.

Section snippets

Epidemiology and clinical presentations

Large retrospective published studies on the frequency of thrombotic and hemorrhagic events in PV and ET[11], [12] have demonstrated that thrombotic risk (arterial, venous, or microvascular) constantly outweighs the risk for hemorrhage at diagnosis as well as during the follow-up period (Table 1, Table 2). According to epidemiological studies, there is a broad variation in the probability of major thrombosis that ranges between 7.6–29.4% and 11.2–38.6%, for newly diagnosed ET[13], [14], [15],

Erythrocytosis and red cell functional disorders

Patients with PV and an increased hematocrit are at an augmented thrombotic risk due in part to the reported correlation of high hematocrit with hyperviscosity (Table 3).³⁹ This correlation is further enhanced by the fact that earlier diagnosis of PV and a prompt treatment of blood hyperviscosity result in reduction of thrombotic events. Earlier clinical studies in PV showed an incidence of thrombosis reaching 60% in PV patients with a hematocrit above 60%, and a dramatically reduced survival.³⁹

Risk factors

In the assessment of thrombotic risk in ET or PV patients the multifactorial nature of arterial and venous thromboembolic disease should be considered.

Risk assessment

Vascular risk assessment is regarded as the main determinant of the therapeutic approach in ET and PV patients. The use of aspirin alone or in combination with cytoreduction (hydroxyurea, anagrelide and interferon) is considered after the estimation of thrombotic and hemorrhagic risk in these patients.

The antithrombotic efficacy of low-dose (100 mg) aspirin in PV⁷⁶ along with the thromboxane role⁷⁷ in ET leads to the established use of aspirin in MPD patients. Prior to aspirin administration, a

Conclusion

The prothrombotic condition occurs in ET and PV patients when the disease interplays with common vascular risk factors. Platelet and leukocyte activation appears to have a major impact on the thrombotic risk, while advanced age is the major common risk factor predisposing to thrombosis. Bleeding risk, on the other hand, is more prominent in MPD patients with very high platelet counts and therefore, it should be carefully evaluated in those receiving antithrombotic therapy. Low-dose aspirin is

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Thrombosis and platelet dysfunction in myeloproliferative neoplasms
2020, Revue de Medecine Interne
Les néoplasies myéloprolifératives sont un ensemble d’hémopathies acquises touchant le plus souvent l’adulte et dont la morbi-mortalité découle, en grande partie, de troubles de l’hémostase. Les complications les plus fréquemment retrouvées sont des thromboses affectant préférentiellement le territoire artériel, mais également des localisations plus atypiques telles que des thromboses des veines splanchniques. La physiopathologie en est complexe et fait intervenir différents acteurs : cellules sanguines, endothélium, conditions de flux. De nombreuses études ont été menées afin d’identifier les facteurs de risque de thromboses. À ce jour, seuls deux facteurs de risque sont validés sur des études prospectives (âge supérieur à 60 ans et un antécédent d’évènements thrombotiques) et permettent la classification des patients en « bas risque » ou « haut risque », base des recommandations thérapeutiques actuelles. Les manifestations hémorragiques, moins fréquentes que les thromboses, sont principalement liées à une altération de l’hémostase primaire et se manifestent par des saignements cutanéo-muqueux. On retrouve chez ces patients des thrombopathies et des syndromes de Willebrand acquis. La physiopathologie des thromboses et thrombopathies au cours des néoplasies myéloprolifératives reste toutefois à ce jour partiellement méconnue. Dans cette revue, nous nous proposons de faire le point sur les différents mécanismes physiopathologiques ainsi que sur les dernières avancées dans la compréhension de ceux-ci.
Myeloproliferative neoplasms are acquired hematological malignancies, mainly affecting the adult and whose morbidity and mortality stems from haemostasis disorders. The most frequently encountered complications include thrombosis, affecting preferentially the arterial territory, but also atypical locations such as splanchnic vein thrombosis. The pathophysiology of these thromboses is complex and involves different actors: blood cells, endothelium and flow conditions. Numerous studies have been conducted to identify risk factors for thrombosis. To date, only two risk factors have been validated through prospective studies (age over 60 years old, history of thrombotic events) and allow classification of patients as “low risk” and “high risk” as the basis for current treatment recommendations. Haemorrhagic manifestations, less frequent than thrombosis, are mainly related to an alteration of primary haemostasis and are therefore manifested by mucocutaneous bleeding. In these patients, platelet dysfunctions and/or acquired Willebrand syndromes can be found. The pathophysiology of thrombosis and platelet dysfunction during myeloproliferative neoplasms remains to date partially unknown. In this review, we offer to focus on physiopathological mechanisms as well as the latest advances in their understanding.
Cerebral Hemorrhage of a 50-Year-Old Female Patient with Polycythemia Vera
2019, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
According to some literature, approximately one third of patients with PV have thrombotic events prior to or at diagnosis.3 On the contrary, bleeding events as an initial presenting symptom at an estimated prevalence of between 3% and 8.1% in PV.4 Although the exact mechanism of hemorrhagic manifestation remains unclear, it is believed that acquired von Willebrand disease from excessive binding of von Willebrand factor with the abnormal platelets is the most likely pathogenesis.5
Polycythemia vera is a chronic myeloproliferative neoplasm, which is primarily characterized by elevated erythrocyte count with the risk of thrombosis, hemorrhage, and vasomotor symptoms. More common reported about bleeding events are gastrointestinal, mucosal, and cutaneous bleeding. Spontaneous cerebral hemorrhage/bleeding is seldom reported. Here, we report the case of a 50-year-old female with polycythemia vera who developed a spontaneous cerebral hemorrhage. She improved significantly after hydroxyurea agent and red cell apheresis, and the hematocrit decreased from 74% to 40%.
Acquired disorders of platelet function
2019, Platelets
Platelet function can be abnormally increased, as in association with vascular events, or defective, as in a variety of clinical settings, or display converse phenotypes with increased and decreased platelet responsiveness, as in myeloproliferative neoplasms. Drugs represent the most frequent cause of platelet dysfunction. While aspirin, ADP receptor antagonists, and integrin αIIbβ3 inhibitors are well-known prototypes of antiplatelet agents, other widely used agents (e.g., nonsteroidal antiinflammatory drugs, antibiotics, serotonin reuptake inhibitors, and volume expanders) and supplements can also impair platelet function and cause or aggravate hemorrhage. Certain clinical conditions are often associated with qualitative platelet disorders and a bleeding diathesis. Consequently, acquired platelet function defects are far more common in clinical practice than inherited platelet disorders. Their pathogenesis is heterogeneous. Platelet dysfunction, sometimes in association with quantitative abnormalities, is present in uremia, liver disease, hematologic disorders, cardiac valvular disease and extracorporeal settings. Due to their heterogeneity, acquired platelet function disorders will be discussed in relation to their underlying clinical conditions.
Incidence of venous thromboembolism and use of anticoagulation in hematological malignancies: Critical review of the literature
2018, Critical Reviews in Oncology/Hematology
Citation Excerpt :
In primary myelofibrosis, non-fatal VTE was reported in 0.76% of patients per year (Barbui et al., 2010). At diagnosis, the prevalence of clinically relevant thrombosis has been reported to vary from 11 to 39% in PV and from 8 to 29% in ET (Papadakis et al., 2010; Elliot and Tefferi, 2005; Tefferi and Barbui, 2015). Chronic myeloproliferative neoplasms (MPN) are characterized by the occurrence of VTE in atypical sites, in particular splanchnic vein thrombosis (SVT) and Budd-Chiari syndrome.
Venous Thromboembolism (VTE) frequently complicates the course of hematologic malignancies (HM) and its incidence is similar to that observed in high-risk solid tumors. Despite that, pharmacologic prophylaxis and treatment of VTE in patients with HM is challenging, mainly because a severe thrombocytopenia frequently complicates the course of treatments or may be present since diagnosis, thus increasing the risk of bleeding. Therefore, in this setting, safe and effective methods of VTE prophylaxis and treatment have not been well defined and hematologists generally refer to guidelines produced for cancer patients that give indications on anticoagulation in patients with thrombocytopenia. In this review, besides to summarize the incidence and the available data on prophylaxis and treatment of VTE in HM, we give some advices on how to use antithrombotic drugs in patients with HM according to platelets count.
Unusual clinical course of polycythemia vera - Case report
2014, Acta Haematologica Polonica
Polycythemia vera is mainly diagnosed in the age of 40–80. In people under 20 years of age, it is very rare. A typical marker for confirmation of the diagnosis of polycythemia vera is a mutation of gene JAK 2 in exon 14, in position 617, which is found in about 95% of patients with this diagnosis.
Patients without the mutation require additional examination to state the final diagnosis. A search for the mutations in other exons due to the diversity of mutations and the related complexity of molecular testing is not applicable in routine laboratory diagnostics. Here we present a case of polycythemia vera diagnosed in a patient aged 19 without typical mutation of gene JAK 2 in exon 14. Conducted additional tests revealed presence of the mutation in exon 12 of gene JAK 2. The most common complication of polycythemia vera is the arterial and venous thrombosis, which could be the result of not only an increased hematocrit, but also coexisting congenital disorders leading to thrombophilia, as occurred in the presented case.
Platelet Disorders
2014, Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
Platelets are key members of the hemostatic cascade, integrating vascular endothelial disruption with adhesion, activation, aggregation, and finally interaction with between the thrombotic plug with factors of the coagulation cascade. Platelets have other functions beyond promoting hemostasis and thrombosis formation, including protein storage and inflammatory and immune responses. Discovery into the pathogenesis of platelet disorders has provided a better understanding of the function and interaction of platelets. This article will provide a review of normal platelet function and a review of the mechanisms of platelet dysfunction in human disease.

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REVIEWThrombohemorrhagic complications of myeloproliferative disorders

Abstract

Introduction

Section snippets

Epidemiology and clinical presentations

Erythrocytosis and red cell functional disorders

Risk factors

Risk assessment

Conclusion

Blood

Semin Hem

Am J Med

Am J Med

Mayo Clin Proc

Crit Rev Onc-Hem

Blood

Lancet

Blood

Am J Med

Lancet

Biophys J

Blood

Bailliere's Best Practice in Clinical Haematology

Blood

Blood

Blood

Blood

Lancet

Cancer Cell

J Biol Chem

Exp Hematol

Blood

Blood

Mayo Clin Proc

Chest

Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia

Br J Haematol

Polycythemia vera: the natural history of 1213 patients followed for 20 years

Ann Intern Med

Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia

J Clin Oncol

Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients

Leukemia

Clinical course of essential thrombocythemia in 147 cases

Cancer

Thrombotic and hemorrhagic complications in essential thrombocythemia. A retrospective study of 103 patients

Cancer

Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area

Eur J Haematol

Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia

Arch Intern Med

Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients

Haematologica

Vascular and neoplastic risk in a large cohort of patients with polycythemia vera

J Clin Oncol

Budd–Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases

Klin Wochenschr

Polycytemia vera in young people: an analysis of 58 cases diagnosed before 40 year

Br J Hem

REVIEW
Thrombohemorrhagic complications of myeloproliferative disorders