Embolic stroke of undetermined source with low ADAMTS13 level without evidence of microangiopathic hemolytic anemia- case series from single center experience

Abstract Background Low ADAMTS13 activity has been associated with ischemic stroke in a large cohort study (Michelle S, Blood, 2015). In patients with a history of thrombotic thrombocytopenic purpura (TTP), persistently low ADAMTS13 levels during remission are linked to an increased risk of stroke (Upreti H, Blood, 2019). Case reports (Matthews A, J Stroke Cerebrovasc Dis, 2022) suggest that low ADAMTS13 may be associated with embolic stroke of undetermined source (ESUS) even in the absence of overt microangiopathy. However, association of low ADAMTS13 activity and stroke remains poorly characterized with no treatment consensus. Therefore, we report a single center observational study of patients with or without history of TTP with ESUS and had ADAMTS13 level without evidence of microangiopathic hemolytic anemia (MAHA). Methods TTP ICD-10 code was used to extract data from electronic medical records. ADAMTS13 activity <20% was used to define relapse, per International TTP Working Group Consensus (Cuker A, Blood, 2021). Absence of MAHA was defined by normal haptoglobin, lactate dehydrogenase (LDH), reticulocyte and absence or occasional schistocytes on the peripheral smear reviewed by hematologist. Patients with other potential etiologies of stroke were excluded, particularly antiphospholipid syndrome. Patients with history of TTP who had ADAMTS13 relapse without clinical relapse or stroke were selected as control group. Data were compared between patients with stroke and low ADAMTS13 levels and control group. Categorical variables were analyzed by Chi-Squared test and continuous variable using Mann-Whitney U test for small samples. Results Of 63 patients identified by ICD 10 code. 9 met the inclusion criteria for the USUS group. 6 had a prior history of TTP (one with 2 stroke episodes), while 3 patients had no known TTP history. All patients had low ADAMTS13 level as part of ESUS workup, none of the case had evidence of MAHA. The control group included 9 patients with 14 episodes of isolated ADAMTS13 relapse. In stroke group, 78% were female (7/9), all from minority backgrounds (3 Hispanic, 6 African American); Most patients had preexisting conditions including hypertension (HTN) (7/9), diabetes (3/9), hyperlipidemia (3/9), prior stroke (6/9). Stroke group had a significantly higher proportion of African American patients (70% vs 7.1%, p=0.002), more HTN (70% vs 7.1%, p=0.002) and prior stroke (70% vs 7.1%, p=0.002) compared to control. Among the 10 stroke episodes, 9 had middle cerebral artery stroke, one had cerebellar stroke. ADAMTS13 activity was less than 3% in 8 out of 10 episodes and 14% and 17% in other two episodes. Stroke group had higher absolute neutrophil counts [5.6 (3.8-6.4) vs 3.7 k/uL (3.1-4.0), p=0.034], lower absolute platelet counts [179 (130-245) vs 289 k/uL (215-342), p=0.015] and delta percentage of platelet fall [31.1% (7.3-44.1) vs 3.8% (-19.4-16.8), p=0.042], higher LDH [270 (215-330) vs 204 U/L (174-225), p=0.015], blood urea nitrogen (BUN) [18 (13-21) vs 12 mg/dL (11-13), p=0.021] and creatinine level [0.95 (0.88-1.31) vs 0.81 mg/dL (0.79-0.86), p=0.009]. There was no difference in ADAMTS13 level, ADAMTS13 inhibitor titer, indirect bilirubin, haptoglobin, liver enzyme levels, reticulocyte and lymphocyte count between groups. Plasmapheresis was used in 6 episodes, 5 received steroids, 9 received rituximab and 1 received caplacizumab. 1 patient deceased within 30 days likely from cardiac arrythmia, 2 patients remained on caplacizumab after 6 months due to lack of ADAMTS13 response, 6/9 patients had residual neurologic deficits. No recurrent strokes in neither group during follow up. Conclusion This study represents the largest reported cohort of ESUS associated with low ADAMTS13 activity in the absence of MAHA. Compared to patients with low ADAMTS13 level without stroke, stroke risk was higher among Black patients and those with HTN or prior stroke. Although there was no overt evidence of MAHA, stroke group carries higher LDH, BUN and creatine levels and lower platelet count, suggestive of subclinical endothelial injury or low grade MAHA. In addition to conventional antiplatelet therapy all the patients received TTP directed therapy. Early recognition of high-risk patients during ADAMTS13 relapse without hematologic relapse is crucial as preemptive therapy such as caplacizumab in addition to ADAMTS13 inhibitor eradication might be warranted in this group of patients.