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Thromboembolic events are not uncommon in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is an immune-mediated disorder where patients are usually asymptomatic or present with minimal bruising. Although the most serious, wellrecognized complication of ITP is life-threatening bleeding, there have been recent reports of thromboembolic (TE) events associated with this condition. We report two patients with ITP who developed cerebral infarcts and raise postulates for the pathophysiology of TE events in ITP. A 56-year-old female presented in June 2009 with left-sided arm and facial weakness, and expressive dysphasia. Computerized Tomography (CT) scan and carotid Dopplers were normal although Magnetic Resonance Imaging demonstrated infarcts in her parietal and temporal lobes. She had been under haematological follow-up for ITP, which had been diagnosed 7 years previously with an initial platelet count of 5 · 10/l. Although she had initially made an excellent response to steroids at the time of diagnosis, this was discontinued based on patient preference to avoid steroid-related side effects. Similar treatment was not initiated during this episode in case a sudden increase in platelet count worsened the thrombotic event. She has recovered reasonably with physiotherapy although her platelet count has remained <10 · 10/l for the last 9 months. Antiphospholipid and anticardiolipin antibody tests to identify a common cause for thrombocytopenia and thrombosis were negative. An 81-year-old female was admitted in February 2010 with light-headedness and fluctuating disturbance of consciousness. She had a history of diabetes, hypertension and ischaemic heart disease and a permanent pacemaker fitted for bradycardia. She had been investigated a week previously for thrombocytopenia (platelet count 15 · 10/l), found on a routine blood count. Bone marrow examination was normal with no dysplasia or malignant features but increased number of megakaryocytes suggestive of a diagnosis of ITP. She was kept under close monitoring until the present episode when her platelet count dropped to 8 · 10/l. CT scan confirmed a large frontal lobe infarct. Antiplatelet agents were discontinued and she was started on oral prednisolone (1 mg/kg/d) in addition to a platelet transfusion to prevent haemorrhagic transformation of the infarct. Her count started improving gradually and at the last follow-up, 2 months after the stroke, her platelet count is 74 · 10/l on 15 mg of prednisolone. Once again, tests for anticardiolipin antibodies and antiphospholipid syndrome were negative. These cases illustrate that TE are not uncommon in patients with ITP. Although both arterial embolic disease and ITP are more common in older individuals, and a coincidental finding can be argued, there are increasing reports of the association of both venous and arterial clots in patients with ITP. A recent survey of the UK General Practice Research Database, including 1070 adults with primary ITP over 15 years, demonstrated an increased risk for venous TE in patients with primary ITP (Sarpatwari et al, 2010). Aledort et al (2004) reported 18 thrombotic episodes in 10 out of 186 patients with ITP, including five arterial events. The authors concluded that the incidence of 5% thrombotic risk with ITP was comparable to those with malignancy, a well-known high-risk state for thrombosis. Another comparative study of ITP patients with and without transient ischaemia-like syndrome found recurring dizzy spells, recent memory loss, and cognitive impairment progressing to dementia relatively more common in those treated with splenectomy and who had relatively higher platelet counts (Ahn et al, 2002). These correlated radiologically with ischemic small vessel disease and in the laboratory with increased platelet microparticles and CD62, a platelet activation marker. Several mechanisms have been proposed to explain the thrombotic tendency observed with ITP. These include circulating platelet-leucocyte-monocyte aggregates, endotheliumactivating antibodies, larger proportion of young activated platelets, and platelet microparticles released during immune platelet destruction (Ahn et al, 2002; Aledort et al, 2004, Rhee et al, 2009). The platelet microparticles, while serving the physiological purpose of protecting against bleeding in thrombocytopenia, may also promote thrombosis. Activation of the complement system was shown to contribute to the thrombocytopenia of ITP by enhancing clearance of opsonized platelets, or by direct damage (Peerschke et al, 2010). Although not studied in patients with ITP and thrombosis, complement activation may contribute to the thrombocytopenia-thrombosis paradox, especially as it is well recognized in the pathophysiology of thrombosis with infections and autoimmune disorders. Nitric oxide depletion due to continuous immune activation has been suggested to be platelet-aggregatory and prothrombotic in addition to contributing to excessive tiredness, a common complaint in patients with ITP. Therapeutic modalities, such as intravenous immunoglobulin and splenectomy, are other risk factors for thrombosis with ITP (Paran et al, 2005). Immunoglobulin infusions promote clot formation often (not always) in the infused limb suggesting local increased viscosity as a possible factor (Paran et al, 2005). Activated factor XI in the pooled concentrate can be another reason, in addition to vasospasm triggered by these infusions when used in the treatment of neurological disorders (Paran et al, 2005). Correspondence