Embolic stroke of undetermined source in a young woman
Authors: Calin I. Prodan, Pooja Vijayvargiya, James K. Feisal, Mohamad O. Khawandanah, Yang Jiang, James N. George
Journal: American Journal of Hematology (2019)

2018: A 42 year-old right-handed woman presented to our hospital with right facial droop, numbness and tingling beginning that afternoon. Earlier in the day she had noticed petechiae. On arrival, the facial numbness and tingling had resolved; later that evening the facial droop also resolved. She previously had 4 episodes of thrombotic thrombocytopenic purpura (TTP), between 2001-2008. In 2016 she had a stroke with residual right arm and leg weakness; she was on warfarin prophylaxis. On examination, petechiae were present on her face and legs. She had a mild right spastic hemiparesis with flexion contractures of her right arm. Initial laboratory data: platelet count 67 000/μL, hematocrit 42%, MCV 85 fL, reticulocytes 3.2%, haptoglobin 107 mg/dL, serum creatinine 0.9 mg/dL, LDH 338 U/L, INR 4.1. Review of the peripheral blood smear revealed only rare schistocytes. Brain magnetic resonance imaging (MRI) demonstrated severe atrophy of her left cerebral cortex with evidence for multiple chronic infarctions in both hemispheres, primarily in the left hemisphere (Figure 1). TTP was initially not suspected because of her normal hematocrit, mild thrombocytopenia, normal haptoglobin, and rare schistocytes. However we felt that a diagnosis of TTP was appropriate in spite of these data because of her history of TTP with multiple relapses and because she had not always had severe anemia and thrombocytopenia with her previous episodes (Table 1). In spite of the platelet count of 67 000/μL, our diagnosis of TTP was supported by a PLASMIC score of 5/6 (excluding the INR variable): reticulocyte count >2.5%, MCV <90 fL, creatinine <2.0 mg/dL, no history of stem cell or organ transplantation, no active cancer.1 Subsequently, the diagnosis of TTP was confirmed by ADAMTS13 activity of 5%. Treatment was begun with corticosteroids and rituximab. Plasma exchange (PEX) was not performed because the INR of 4.1 created risk for hemorrhage with central venous catheter insertion. This experience illustrates the occurrence of atypical presentations of TTP, which may be more common with relapse episodes. 2001-2008: During these 8 years, when our patient was 25-32 years old, she had 4 episodes of TTP. Each of the episodes responded to PEX and corticosteroids; she also received rituximab for her 4th episode. With her first 2 episodes, she presented with severe thrombocytopenia. Her 3rd episode was diagnosed during evaluation for acute pharyngitis, when her platelet count was 38 000/μL, decreased from 302 000/μL 1 month previously. Her 4th episode was diagnosed by steadily decreasing platelet counts, from 429 000/μL 1 month previously to 50 000/μL. She had no neurologic abnormalities during these 4 episodes. Although severe thrombocytopenia (platelet count <30 000/μL, a criterion for the PLASMIC score1) is typical for TTP, platelet counts may be higher, especially with relapse episodes when patients are followed closely. Higher platelet counts at presentation with TTP may also occur when the patient's normal platelet count is in the high-normal range. Each person has their unique individual normal platelet count.2 Our patient's normal range is near the upper limit of normal. She has had 22 platelet counts during remission, 2001-2019; the mean value was 344 000/μL, the range was 251 000/μL-455 000/μL. 2009. Following recovery from her 4th episode of TTP, we evaluated her during remission only once, in 2009. At that time, she appeared healthy, her platelet count was 324 000/μL, ADAMTS13 activity was 51%. She did not attend other remission evaluations in spite of our encouragement. The importance of this ADAMTS13 activity measurement is that it excluded the diagnosis of hereditary TTP. Patients with hereditary TTP can have clinical features distinct from acquired autoimmune TTP, such as the occurrence of neurologic symptoms, including stroke, without thrombocytopenia.3 Our patient continued to have annual evaluations with her primary care physician through 2014, with platelet counts of 310 000/μL-365 000/μL. After 2014 we had no contact with her until the 2018 episode described above. 2016. Prior to 2016, our patient had remained healthy and active with no neurologic symptoms. Then, during a weekend vacation, she had the sudden onset of left facial numbness and slurred speech that resolved within 10 minutes. MRI performed 8 days later showed multiple small foci of diffusion restriction in the right frontal and bilateral parietal lobes consistent with acute and subacute infarcts. This distribution of infarctions occurring at different times suggested an embolic etiology. This is an alarming observation. The suspected sources of embolic strokes are critical disorders: cardiovascular abnormalities and systemic cancer.4 Although stroke is known to occur in patients with TTP, the occurrence of embolic strokes has not been previously described. The imaging pattern of embolic strokes is consistent with the pathogenesis of stroke in patients with TTP: microvascular occlusion caused by systemic platelet-von Willebrand factor (VWF) emboli.3 The occurrence of subacute infarcts suggests that she may have had silent brain infarcts.5 One previous report has documented the occurrence of silent brain infarcts in 9 (39%) of 23 asymptomatic patients in remission from acquired TTP.6 2016: Three days after the MRI she was admitted to another hospital with persistent right facial droop, right arm and leg weakness, and aphasia. She was taking no regular medicines. At that time, her height was 66 in., weight 332 pounds (body mass index, 54 kg/m2) and blood pressure 168/99. She had never smoked cigarettes. Laboratory data: platelet count 224 000/μL, hematocrit 41%, creatinine 1.1 mg/dL, total bilirubin 0.4 mg/dL. Her history of TTP was noted but ADAMTS13 activity was not measured and we were not contacted. Cardiac rhythm was normal. Echocardiogram demonstrated no interatrial shunt. She had no extracranial or intracranial large artery stenosis. On her first hospital day right-sided weakness progressed to severe hemiplegia. Repeat MRI demonstrated extension of her left parietal ischemic stroke with involvement of the left frontal lobe. Because of a previous report of heterozygous Factor V Leiden mutation by her primary care physician, she was treated initially with heparin and then switched to warfarin. During her hospitalization her platelet count steadily decreased to 128 000/μL on day 7, recovering to 180 000/μL at hospital discharge. Although her decreasing platelet count may have been caused by heparin-induced thrombocytopenia, we also suspected that she could have had an acute TTP episode. Her multiple previous episodes of TTP increased her risk for relapse and the diagnosis of TTP cannot be excluded without measurement of ADAMTS13 activity. In addition to her previous episodes of TTP, our patient also had other risk factors for stroke: extreme obesity and hypertension. In the absence of any other arterial or venous thrombotic events, we think it is unlikely that a heterozygous Factor V Leiden mutation was responsible for her stroke.7 2018-2019: Following her 2016 hospitalization, she had no recurrent neurologic symptoms until she came to our hospital in 2018. Following her 2018 hospitalization, her platelet count recovered to normal with corticosteroids and rituximab. At the time of her last follow-up in 2019 she remained well, her blood pressure was 124/77 and ADAMTS13 activity was normal (68%). We will continue to follow her ADAMTS13 activity and will treat her with rituximab if her ADAMTS13 activity is <20%, to attempt to prevent another TTP relapse.8 She is currently treated with aspirin, rivaroxaban and lisinopril. There are many lessons to be learned from our patient. Relapse episodes of TTP, confirmed by ADAMTS13 activity <10%, may occur without overt hemolysis or severe thrombocytopenia. The typical occurrence of severe thrombocytopenia may not occur in patients whose normal platelet counts are in the high-normal range. Stroke may occur many years following an initial TTP episode, even if neurologic symptoms did not occur with previous episodes. The microvascular thrombosis that occurs in TTP may increase risk for subsequent thrombosis in vulnerable blood vessels. Our patient's initial MRI in 2016 documented multiple infarcts in both hemispheres that had occurred at different times, suggesting that she had preceding silent brain infarcts.5 Silent brain infarcts may be common in patients who have recovered from an acute episode of acquired TTP.6 Our patient's story suggests that when stroke occurs in a patient with a history of TTP, relapse of TTP should be considered and ADAMTS13 activity should be measured, even if the patient does not have overt hemolysis and severe thrombocytopenia. Stroke can occur without overt hemolysis or severe thrombocytopenia in patients with hereditary TTP.3 This suggests that stroke could also occur without overt hemolysis or severe thrombocytopenia in patients with acquired TTP. In a patient who presents with a stroke without a history of TTP and without hemolysis or thrombocytopenia, MRI may document infarcts in multiple regions, consistent with an embolic etiology. Following normal results of evaluation for cardiovascular and other etiologies, the patient's stroke would be classified as embolic stroke of undetermined source.4 Patients with TTP could initially present with embolic stroke of undetermined source because TIA/stroke symptoms may occur before hemolysis and thrombocytopenia occur.9-13 Therefore the occurrence of embolic stroke of undetermined source requires measurement of ADAMTS13 activity to support or exclude the diagnosis of TTP, especially in younger patients who have no strong risk factors for stroke. We are currently treating our patient with aspirin, because it is the conventional treatment for prevention of atherosclerotic strokes,14 and rivaroxaban, because it has been used for prevention of recurrent embolic strokes and was recommended by her treating neurologist, although it is not superior to aspirin.15 Antiplatelet drugs prevent activation of the membrane receptor, glycoprotein IIb-IIIa, which is required for platelet adhesion to fibrinogen or fibrin. However microvascular thrombosis in TTP is caused by adhesion of platelet membrane glycoprotein Ib to VWF, which does not require platelet activation.16 Anticoagulants prevent the conversion of fibrinogen to fibrin, however the thrombosis caused by platelet adhesion to VWF does not require coagulation. Therefore our treatment may not be effective for preventing recurrent stroke in our patient. The occurrence of strokes in patients with TTP has similarities to patients with sickle cell anemia. Patients with sickle cell anemia have a high risk for stroke at a young age,17 similar to patients with hereditary TTP.3 In patients with sickle cell anemia, stroke prevention focuses on treatment of the sickle cell anemia; antiplatelet therapy and anticoagulation are not considered.18 For patients with hereditary TTP, strokes can be prevented by plasma prophylaxis. For patients with acquired TTP, prevention of relapse may be the only effective way to prevent strokes.8, 19 Figure 2 presents data from the Oklahoma TTP Registry,20 1995-2018. We use the phrase “TIA/stroke” because TIA and stroke can only be accurately distinguished by documentation of infarction with MRI, and only 13 (38%) of the 34 patients with TIA/stroke symptoms presented in this figure were evaluated by MRI. Ten (13%) of the 79 patients who survived their initial episode had subsequent TIA/stroke symptoms; they are described in the Table S1. The median age of these 10 patients (40 years) was the same as the median age of all Registry patients (40 years21). In 5 of these 10 patients (Patients 1, 2, 4, 8, and 10, Table S1), subsequent TIA/stroke symptoms only occurred at the time of a TTP relapse. Patients 3 and 5 had normal platelet counts at the time of recurrent TIA/stroke symptoms; ADAMTS13 activity was not measured, TTP was not diagnosed. Patient 6 had a normal platelet count and ADAMTS13 activity of 21% at the time of a stroke; TTP was not diagnosed. Patient 7 had multiple cardiovascular-cerebrovascular events, including TIA/stroke; ADAMTS13 activity was not measured, TTP was not diagnosed. Patient 9 is our patient, described above; ADAMTS13 was not measured and TTP was not diagnosed at the time of her stroke. None of our patients have been documented to have normal ADAMTS13 activity at the time of their recurrent TIA/stroke symptoms. We have measured ADAMTS13 activity during remission in 62 patients at the time of 12 annual evaluations, 2004-2017.22 In some patients, ADAMTS13 activity was extremely variable across time. For example, Patient 8 (Table S1) had ADAMTS13 activity of 83% that decreased to 7% and then increased to 96% in 3 consecutive years, all during continuous clinical remission. ADAMTS13 activity during remission may have clinical importance in addition to the anticipation of relapse.8, 19 Table 2 compares the lowest remission ADAMTS13 activity in these 62 TTP patients to the levels of ADAMTS13 activity reported in the Rotterdam populational study that documented a significantly increased risk for incident stroke in individuals with low-normal ADAMTS13 activity.23 In 12 (19%) of our 62 patients, ADAMTS13 activity was always ≥100% on 1-9 (mean, 5) remission measurements; none have relapsed or have had TIA/stroke symptoms after beginning remission evaluations. Among the 10 patients with recurrent TIA/stroke symptoms, 9 had 1-10 (mean, 5) remission ADAMTS13 activity measurements (Patient 3, Table S1, had no remission evaluations). Although 7 of the 9 patients had at least 1 year with ADAMTS13 activity ≥83%, 8 of the 9 patients also had at least one low value (≤42%). Our patient had only one remission ADAMTS13 activity measurement, which was 51%. These data suggest an association of TIA/stroke with remission ADAMTS13 activity, comparable to the report of the Rotterdam populational study.23 With improved treatment providing increased survival from initial episodes of TTP and decreased occurrence of overt relapse episodes, identification and management of long-term complications in survivors become more important.21 The occurrence of stroke in our patient, 15 years after her initial TTP episode, demonstrates the critical importance of careful and continuous long-term follow-up for all patients following recovery from acquired TTP. The occurrence of stroke in our patient also illustrates the need for a multidisciplinary approach, involving both hematologists and neurologists. The authors have no conflict with this topic or these data. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.