Keith McCrae, MD
Director, Benign Hematology, Taussig Cancer Institute, Professor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine
Dr. McCrae indicated no relevant conflicts of interest.
(Editor’s Note: This question was submitted through the Consult-a-Colleague Program. Dr. McCrae was asked to respond.)
How often do you see immune thrombocytopenia (ITP) with pulmonary embolism (PE) and deep-vein thrombosis (DVT)? The patient is a 60-year-old woman who had pneumonia about a month ago and now is presenting with a platelet count of 30,000/μl with DVT and PE. A hypercoagulable diagnostic panel, including tests for heparin-induced thrombocytopenia (HIT) and antiphospholipid antibodies, are pending. Would you perform a bone marrow aspirate and biopsy? A pulmonologist inserted an inferior vena cava filter; was that appropriate?
ITP is a fascinating disorder with a complex pathogenesis that has only recently begun to be understood in detail.1,2 While a number of immune abnormalities underlie the development of ITP, the disease is largely mediated by antibodies reactive with glycoproteins expressed on platelets and megakaryocytes. These antibodies cause accelerated platelet destruction in the spleen as well as deficient platelet production secondary to impaired maturation of megakaryocytes.
The most common clinical presentation of ITP is bleeding, the severity of which correlates with the degree of thrombocytopenia.3 However, many patients with ITP have few bleeding complications even with very low platelet counts, an observation that may be related to the presence of young, highly functional platelets, increased levels of plasma microparticles, or other factors. Surprisingly, recent studies have also demonstrated that patients with ITP have an increased risk of thrombosis. The data concerning ITP and thrombosis are derived from several sources. A retrospective study from Aledort et al. suggested an increased risk of thrombosis in patients with ITP, with 18 thromboembolic events occurring in 186 adults (the majority after the diagnosis of chronic ITP).4 In another retrospective study reported in an abstract by Bennett et al., a 6.9 percent cumulative incidence of thromboembolic events in patients with ITP was seen over a 15-month period. Sarpatwari et al. prospectively analyzed the incidence of thromboembolic events in patients with ITP using the UK General Practice Research Database, identifying 1,070 adults >18 years of age with primary ITP that were matched with 4,280 ITP-free patients.5 Over a median of 47.6 months, the adjusted hazard ratio for venous, arterial, or combined thromboembolic events in patients with ITP was 1.58 (95% CI, 1.01-2.48), 1.37 (95% CI, 0.94-2.00), and 1.41 (95% CI, 1.04-1.91), respectively. Subgroup analysis suggested a strikingly increased risk of myocardial infarction in the ITP cohort. Also suggested was a direct relationship between the severity of thrombocytopenia and the risk of thrombosis. Another recent study utilizing a matched ITP cohort obtained from the Danish National Patient Registry observed an incidence rate ratio for venous thromboembolism in patients with ITP of 2.04 (95% CI, 1.45 2.87).6 Two of the ITP patients with VTE had severe thrombocytopenia, although one was ultimately diagnosed with lung cancer.
Taken together, these studies provide evidence that the incidence of thromboembolism is increased in patients with ITP, even in the presence of very low platelet counts. While acute portal vein thrombosis has been reported in up to 15 percent of ITP patients undergoing splenectomy, and an increased risk of subsequent thrombosis has been associated with splenectomy for thalassemia,7 the review from Sarpatwari et al. demonstrates a similar incidence of thrombosis in splenectomized and nonsplenectomized ITP patients.
The mechanisms underlying the paradoxical development of thrombosis in patients with ITP have not been defined, though several have been postulated. The incidence of antiphospholipid antibodies (APLA) appears to be increased in patients with ITP, and several studies suggest that ITP patients with APLA develop thrombosis more frequently. In a prospective study, Diz-Küçükkaya assessed 82 newly diagnosed patients with ITP, finding 31 (37.8%) positive for APLA.8 After five years, the cumulative thrombosis-free survival of APLA-positive and APLA-negative patients was 39 percent and 97.7 percent, respectively (p=0.004). Though current guidelines do not recommend routine screening of ITP patients for APLA,9,10 this should be considered in those who develop thrombi. Additional factors contributing to the development of thrombosis in patients with ITP may include elevated levels of platelet-derived microparticles11 and complement activation on antibody-coated platelets.12
The management of thrombosis in thrombocytopenic patients with ITP is challenging and not addressed by current guidelines. Likewise, there are no evidence-based data on which to draw from for recommendations. Many experts suggest that the risk of anticoagulation is acceptable at platelet counts above 40,000 to 50,000/μl, although the severity of the thrombotic event and clinical characteristics of the patient should be considered. In the case presented here, the clot burden is extensive and the platelet count close to where anticoagulation is reasonable. Risk factors for bleeding in ITP include a prior history of bleeding and age ≥ 60 years, the latter of which is applicable to this patient. I would recommend aggressive treatment of this patient’s ITP, initially using corticosteroids, since agents such as IVIg may potentially predispose to further thrombosis, and I would consider institution of anticoagulation with intravenous heparin or another short-lived anticoagulant once the platelet count increases to ≥45,000/μl. The use of an IVC filter is a matter of preference; it may be more strongly justified if there is evidence of progressive thrombosis, or if the thrombocytopenia does not respond quickly. However, given the association of ITP with thrombosis, I would avoid intravascular devices if possible, and if an IVC filter is used, I would recommend a removable model.
The decision to perform a bone marrow aspirate and biopsy should not be influenced by a thrombotic event. If the peripheral blood smear shows isolated thrombocytopenia and the history and physical examination do not suggest other disorders, bone marrow aspirate would not be required.
- Semple JW, Provan D, Garvey MB, et al. Recent progress in understanding the pathogenesis of immune thrombocytopenia. Curr Opin Hematol 2010;17:590-595.
- Cines DB, Liebman HA. The immune thrombocytopenia syndrome: a disorder of diverse pathogenesis and clinical presentation. Hematol Oncol.Clin North Am 2009;23:1155-1161.
- Fogarty PF. Chronic immune thrombocytopenia in adults: epidemiology and clinical presentation. Hematol Oncol Clin North Am 2009;23:1213-1221.
- Aledort LM, Hayward CP, Chen MG, et al. Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am J Hematol. 2004;76:205-213.
- Sarpatwari A, Bennett D, Logie JW et al. Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database. Haematologica 2010;95:1167-1175.
- Severinsen MT, Engebjerg MC, Farkas DK et al. Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Br J Haematol. 2011;152:360-362.
- Crary SE, Buchanan GR. Vascular complications after splenectomy for hematologic disorders. Blood. 2009;114:2861-2868.
- Diz-Kucukkaya R, Hacehanefioglu A, Yenerel M et al. Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study. Blood. 2001;98:1760-1764.
- Neunert C, Lim W, Crowther M et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190-4207.
- Provan D, Stasi R, Newland AC et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168-186.
- Jy W, Horstman LL, Arce M, Ahn YS. Clinical significance of platelet microparticles in autoimmune thrombocytopenias. J Lab Clin Med. 1992;119:334-345.
- Peerschke EI, Yin W, Ghebrehiwet B. Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol Immunol. 2010;47:2170-2175.
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