Unusual presentation of more common disease/injury Case report Large vessel stroke as initial presentation of thrombotic thrombocytopenic purpura Ryan Sugarman,1,2 Andrea M Tufano,2,3 Johnson M Liu1,2 1 Hematology-Oncology, Monter Cancer Center, Northwell Health, Lake Success, New York, USA 2 Donald and Barbara Zucker School of Medicine, Hofstra/ Northwell, Hempstead, New York, USA 3 Internal Medicine, North Shore University Hospital, Northwell Health, Manhasset, New York, USA Correspondence to Dr. Ryan Sugarman, ​Rsugarman@​northwell.​edu Accepted 17 January 2018 Summary A 67-year-old right-handed woman presented with dysarthria, left upper extremity weakness and rightsided neglect of 3 hours duration. Imaging of the brain revealed acute right middle cerebral artery stroke; however, tissue plasminogen activator could not be administered due to severe thrombocytopenia. A peripheral smear revealed schistocytes and the patient was treated empirically for thrombotic thrombocytopenic purpura (TTP) with therapeutic plasma exchange. An extensive workup revealed no embolic source or other cause for stroke, and a diagnosis of large vessel infarct secondary to TTP was made. After a prolonged hospital course, the patient had partial neurological recovery and was discharged to a rehabilitation facility. Although transient neurologic deficits due to small vessel occlusions are well described in TTP, large vessel infarct can occur as well. This diagnosis should be considered in patients presenting with concomitant stroke and thrombocytopenia, as untreated TTP is nearly always fatal. Background To cite: Sugarman R, Tufano AM, Liu JM. BMJ Case Rep Published Online First: [please include Day Month Year]. doi:10.1136/bcr-2017221857 Thrombotic thrombocytopenic purpura (TTP) is an uncommon disease with an incidence of approximately four cases per million adults per year.1 It is characterised by the classic pentad of thrombocytopenia, microangiopathic haemolytic anaemia, acute kidney injury, fever and neurological symptoms. TTP results from inherited deficiency or acquired inhibition of the enzyme ADAMTS13, which is responsible for cleaving von Willebrand factor (vWF) into smaller multimers. Diminished ADAMTS13 activity results in larger multimers of vWF, which cause increased platelet adhesion at sites of endothelial injury, resulting in thrombi formation. The mortality of untreated TTP is approximately 90%; however, prognosis is markedly improved when diagnosed early and treated with therapeutic plasma exchange (TPE).1 2 Approximately, 50% of acquired TTP cases have neurological involvement at the time of presentation. This is believed to be secondary to thrombi development in the small vessels of the brain. Neurological symptoms include fluctuating or persistent alterations of level of consciousness, confusion, aphasia, visual disturbances, paresthesias, motor deficits and seizure.3 These can be attributed to ischaemia of the cerebral cortex and/or subcortical white matter causing transient occlusions or microinfarcts. However, these symptoms tend to be reversible in most patients who survive the acute presentation.4 In contrast, large cerebral artery occlusion (LCAO) in TTP is very rare, with only nine prior reports identified after extensive literature review.5–12 Here, we report a patient with TTP who presented with right middle cerebral artery (MCA) occlusion that caused permanent neurologic deficit. Case presentation A 67-year-old right-handed female with prediabetes presented to the Emergency Department with a chief complaint of sudden onset slurred speech. Physical examination revealed a partial right gaze palsy, asymmetric smile, left arm motor drift, dysarthria and right-sided neglect, consistent with National Institute of Health Stroke Score of 7. Investigations A stroke workup was performed with several imaging studies. Non-contrast head CT revealed no ischaemia or haemorrhage (figure 1). CT angiography showed normal carotid and vertebral arteries but revealed an occlusion of the right MCA at the level of the right MCA bifurcation (figure 2). Blood work revealed severe thrombocytopenia, acute kidney injury, an elevated lactate dehydrogenase and diminished haptoglobin (table 1). Schistocytes were identified on microscopic evaluation of a peripheral smear. Treatment The patient was transferred to the intensive care unit where TPE and high-dose corticosteroid therapy was initiated; tissue plasminogen activator (tPA) was held due to thrombocytopenia. Outcome and follow-up Diagnosis of TTP was confirmed when the ADAMTS13 assay resulted (figure 1). While the platelet count and kidney function recovered with TPE, the patient had a functional decline from the time of admission with the development of leftsided hemiparesis and dysphagia. Brain MRI revealed the known right MCA occlusion, as well as scattered infarcts in the cerebellum, left frontal and occipital regions (figure 3), suggestive of an embolic source of stroke. The patient tested negative for antiphospholipid syndrome; however, other causes of hypercoagulable state such as antithrombin III deficiency, protein C and S deficiencies were not tested for at the time of presentation because their Sugarman R, et al. BMJ Case Rep 2018. doi:10.1136/bcr-2017-221857 1 Unusual presentation of more common disease/injury Table 1 Initial laboratory findings Laboratory studies Patient values (reference range) Haemoglobin 14.1 (11.5–15.5 g/dL) Platelet count 19 (150–400 109/L) Creatinine 1.63 (0.5–1.3 mg/dL) Lactate dehydrogenase 1250 (122–222 U/L) Haptoglobin <3 (34–200 mg/dL) ADAMTS13 Activity 5% (>70%) ADAMTS13 Inhibitor 7.4 (<0.4) Total bilirubin 1.5 (0.2–1.2 mg/dL) Discussion Figure 1 infarct. CT brain on admission showed no acute haemorrhage or levels may be diminished in the setting of acute clot. Extensive workup with 3-month loop recorder, transoesophageal echocardiogram and CT angiography of the neck revealed no other cause of stroke and the patient was discharged to a subacute rehabilitation facility with a diagnosis of cerebrovascular accident secondary to TTP. At the time of discharge, the patient was using wheelchair and received nutrition through a percutaneous gastrostomy tube. Nearly 3 years later, the patient has had significant neurological recovery and no longer suffers from dysphagia. While her strength has improved, residual left upper extremity weakness persists. Figure 2 CT angiography of the brain on admission revealed occlusion of the right middle cerebral artery at the M1 segment (red arrow). 2 Central nervous system involvement causing headache, confusion, seizures and focal deficits are common in TTP. The mechanism is believed to be occlusion by the platelet–fibrin complex. However, it is very rare to have permanent neurologic deficit secondary to large cerebral artery occlusion.3 In a 2009 retrospective study by Burrus et al, brain MRI in 33 patients newly diagnosed with TTP revealed acute change in 83% of cases, with no instances of large ischaemic infarct.13 Our patient suffered LCAO stroke and was left with permanent neurologic deficit. We believe that the MCA occlusion was thrombotic in origin, as extensive workup for embolic source was negative. On review of the literature, we could only identify nine cases that reported LCAO in the context of TTP (table 2). Of these, only four cases reported cerebrovascular accident occurring as initial presentation of TTP.5–8 Notably, one case report described two siblings with TTP with stroke, suggesting the role of inherited ADAMTS13 deficiency in this rare presentation. However, since none of the other case studies reported testing for the presence of the ADAMTS13 inhibitor, we are unable to establish an association between the type of TTP (primary vs secondary) and large vessel stroke presentation. Figure 3 Brain MRI showed acute infarcts in the right basal ganglia, corona radiata and right frontal parietal regions, as well as scattered infarcts in the cerebellar hemispheres, occipital lobes and left frontal lobe suggestive of embolic stroke. Sugarman R, et al. BMJ Case Rep 2018. doi:10.1136/bcr-2017-221857 Unusual presentation of more common disease/injury Table 2 Literature reported cases of large vessel cerebrovascular occlusion in TTP Publication Country of year reported case Age Stroke Gender location Schistocytes present on Platelet count ADAMTS13 activity blood smear (109 u/L) Treatment Outcome Reference 1991 USA 44 F L parietal Yes 30 Not reported TPE Permanent L eye blindness Rinkel et al5 1994 USA 38 M R thalamic Yes 24 Not reported Heparin Permanent aphasia Wijdicks6 1998 Switzerland 46 F L MCA Yes 57 Not reported TPE+splenectomy Permanent aphasia Kelly et al7 and R upper extremity weakness 1998 Switzerland 27* F R MCA Yes 19 Not reported TPE+steroids Expired during hospital course 2004 Germany 46* M R PCA Yes <20 <5% TPE+steroids Permanent neurologic Scheid et al8 deficit 2005 Spain 36 M Bilateral cerebral large arteries Yes 52 Not reported TPE Expired during hospital course Ibernon et al9 2011 France 30 F R MCA Yes 252 <5% tPA+heparin Permanent L upper extremity weakness Sevy et al10 2013 Portugal 39 M L MCA Unknown 27 Not reported tPA then TPE Full neurological recovery Boattini and Procaccianti11 2015 Hong Kong 58 F L MCA Yes 8 Not reported TPE Permanent R-sided paralysis Yu et al12 2017 USA 67 F R MCA Yes 67 <5% TPE+steroids Permanent L upper extremity weakness Current case report Kelly et al7 *Siblings. F, female; L, left; M, male; MCA, middle cerebral artery; PCA, posterior cerebral artery; R, right; tPA, tissue plasminogen activator; TPE, total plasma exchange; TTP, thrombotic thrombocytopenic purpura. Management of TTP varied. Seven patients received TPE, two received corticosteroids, two received heparin, one received cryoreduced plasma and one underwent splenectomy. Additionally, two patients received thrombolytic therapy with Alteplase. In one case, the patient had a normal platelet count at the time of tPA administration and developed thrombocytopenia later in the course. Ultimately, this patient had residual left arm weakness. In the other case, documented by Boattini et al, administration of tPA was done in the setting of a platelet count of 27 000, as well as TPE and resulted in restored cerebral blood flow as well as full neurological recovery.11 While successful in that case, it is difficult to recommend tPA in this setting as TPE alone may have caused reversal of the neurological symptoms, and thrombolysis in the setting of severe thrombocytopenia could lead to a life-threatening haemorrhage. Although there is limited follow-up data on patients with TTP and stroke, the outcome tends to be poor. Only one patient achieved complete recovery and two patients expired. This case illustrates that TTP can cause large vessel infarct, and plasma exchange should not be delayed for embolic workup or ADAMTS13 assay result. Thrombolytic therapy should only be considered in select cases where the benefit of treating a large vessel stroke outweighs the risk of a life-threatening bleeding event. Learning points ►► To recognise the incidence of large cerebral artery occlusion (LCAO) as a rare but possible presentation of thrombotic thrombocytopenic purpura (TTP). ►► To manage LCAO secondary to TTP with plasma exchange. ►► To consider the use of thrombolytic therapy in cases of LCAO as previously described in literature. Sugarman R, et al. BMJ Case Rep 2018. doi:10.1136/bcr-2017-221857 Acknowledgements Dr Rebecca Nejat and Dr Kyle Katona were instrumental in providing care for the patient and expertise facilitated the research process. Contributors RS contributed to the planning, drafting of the manuscript, data review and literature review. AMT contributed to the literature review, data review and made significant edits to the manuscript. JML contributed to edits as well as mentorship for the planning of this manuscript. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. References 1 Tsai HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol 2010;91:1–19. 2 Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis study group. N Engl J Med 1991;325:393–7. 3 Sadler JE. What’s new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program 2015;2015:631–6. 4 Meloni G, Proia A, Antonini G, et al. Thrombotic thrombocytopenic purpura: prospective neurologic, neuroimaging and neurophysiologic evaluation. Haematologica 2001;86:1194–9. 5 Rinkel GJ, Wijdicks EF, Hené RJ. 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Stroke due to typical thrombotic thrombocytopenic purpura treated successfully with intravenous thrombolysis and therapeutic plasma exchange. BMJ Case Rep 2013;2013:bcr2012008426. 12 Yu WL, Leung T, Soo Y, et al. Thrombotic thrombocytopenic purpura with concomitant small- and large-vessel thrombosis, atypical posterior reversible encephalopathy syndrome and cerebral microbleeds. Oxf Med Case Reports 2015;2015:179–82. 13 Burrus TM, Wijdicks EF, Rabinstein AA. Brain lesions are most often reversible in acute thrombotic thrombocytopenic purpura. Neurology 2009;73:66–70. Copyright 2018 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit http://group.bmj.com/group/rights-licensing/permissions. BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission. 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