Thrombotic Thrombocytopenic Purpura (ADAMTS13 [a Disintegrin and Metalloproteinase With a Thrombospondin Type 1 Motif, Member 13] Deficiency) as Cause of Recurrent Multiterritory Ischemic Strokes.

Abstract

HomeStrokeVol. 53, No. 6Thrombotic Thrombocytopenic Purpura (ADAMTS13 [a Disintegrin and Metalloproteinase With a Thrombospondin Type 1 Motif, Member 13] Deficiency) as Cause of Recurrent Multiterritory Ischemic Strokes Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessCase ReportPDF/EPUBThrombotic Thrombocytopenic Purpura (ADAMTS13 [a Disintegrin and Metalloproteinase With a Thrombospondin Type 1 Motif, Member 13] Deficiency) as Cause of Recurrent Multiterritory Ischemic Strokes Zimbul Albo, MD, PhD, Carol Mathew, MD, Raymond Catton, MD, Brian Silver, MD and Majaz Moonis, MD Zimbul AlboZimbul Albo Correspondence to: Zimbul Albo, MD, PhD, Tufts University Medical School, Department of Neurology, 800 Washington St, Boston, MA 02111. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3690-2140 Department of Neurology (Z.A., R.C., B.S., M.M.), University of Massachusetts Medical School, Worcester. Now with: Department of Neurology, Tufts University Medical School, MA (Z.A.). Search for more papers by this author , Carol MathewCarol Mathew https://orcid.org/0000-0002-9680-960X Hematology and Oncology (C.M.), University of Massachusetts Medical School, Worcester. Now with: Hematology and Oncology, University of Florida, Gainesville (C.M.). Search for more papers by this author , Raymond CattonRaymond Catton https://orcid.org/0000-0002-8878-7308 Department of Neurology (Z.A., R.C., B.S., M.M.), University of Massachusetts Medical School, Worcester. Search for more papers by this author , Brian SilverBrian Silver https://orcid.org/0000-0002-1562-9894 Department of Neurology (Z.A., R.C., B.S., M.M.), University of Massachusetts Medical School, Worcester. Search for more papers by this author and Majaz MoonisMajaz Moonis https://orcid.org/0000-0002-9747-0003 Department of Neurology (Z.A., R.C., B.S., M.M.), University of Massachusetts Medical School, Worcester. Search for more papers by this author Originally published28 Mar 2022https://doi.org/10.1161/STROKEAHA.121.034434Stroke. 2022;53:e237–e240Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 28, 2022: Ahead of Print We present a clinical case of a patient with multifocal acute and subacute strokes due to acquired thrombotic thrombocytopenic purpura (TTP).A 63-year-old right-handed female presented subacutely with dizziness, confusion, right-sided hemiparesis, and sensory deficits. Her past medical history included hypertension, hyperlipidemia, migraines, hypothyroidism, peripheral vascular disease, and vitamin D deficiency. There was no known prior history of arrhythmia, heart failure, valvular abnormality, congenital anomaly, or coagulopathy. National Institutes of Health Stroke Scale was 6 (right hemianopia, right arm drift, right leg drift, right arm ataxia, right sensory loss, and right extinction). No arrhythmia was detected on electrocardiogram or telemetry. Transthoracic echocardiogram showed mild left ventricular wall thickening and mild diastolic dysfunction, but no significant wall motion or valvular abnormalities and no chamber thrombus. Initial platelet count was 15 000/μL. Repeat platelet testing showed a count of 8000/µL. She received 6 units of fresh frozen plasma. A peripheral blood smear showed numerous schistocytes, decreased ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity <5% (normal >61%), elevated ADAMTS13 inhibitor 1.5 Bethesda units (normal <0.4 Bethesda units), decreased haptoglobin of <8 mg/dL (normal, 43–212 mg/dL), and normal fibrinogen of 358 mg/dL (normal, 150–440 mg/dL). Magnetic resonance imaging brain showed an acute infarct in the left posterior cerebral artery territory involving the left medial temporal lobe, left occipital lobe, and left thalamus (Figure 1A). In addition, subacute infarcts were identified in the left cerebellum, left basal ganglia, bilateral occipital lobes, and right corona radiata. Computed tomography angiogram of the head and neck showed a significant stenosis versus occlusion of P2 of left posterior cerebral artery with distal reconstitution (Figure 1B). She was diagnosed with the acquired type of TTP and received 5 days of plasmapheresis and prednisone 80 mg daily. Follow-up peripheral blood smears showed less schistocytes, and her platelet counts improved to 243 000/µL. Her neurological examination slowly improved over the course of hospitalization.Download figureDownload PowerPointFigure 1. Magnetic resonance imaging brain. A, Magnetic resonance imaging brain, axial view showing acute and subacute infarctions in the corona radiata, left thalamus, medial left temporal lobe, left occipital lobe and left cerebellum (not shown). B, Computer tomography angiogram, axial view showing critical stenosis vs occlusion on the left P2 segment of posterior cerebral artery.DiscussionTTP is a rare coagulation disorder with a fascinating pathophysiology clinically characterized by a state of hypercoagulability, acute hemolytic anemia, thrombocytopenia, and end-organ damage- mostly to the kidneys and the brain, requiring therapeutic plasma exchange in the acute setting, with systemic immunosuppression for refractory cases.1 For patients with recurrent multiterritory ischemic strokes, measurement of ADAMTS13, both the enzyme activity level and the presence of inhibitor activity, may prove helpful for determining a potential cause.Environmental factors, such as infections, inflammation, trauma often triggers acute episodes of thrombocytopenia and hemolysis in these patients, as does high shear stress, heavy alcohol intake, and pregnancy. However, acute episodes may have no apparent triggers, and microvascular thrombosis may be silent in some patients.1 In addition, clinical awareness of a more chronic relapsing disease state is also paramount.Stimulation of endothelial cells, shear stress of flow, catecholamine release, cytokines, or histamine, can cause ultralarge VWF (von Willebrand Factor) multimers to be secreted from their endothelial storage site in Weibel-Palade bodies and to either remain attached to the endothelial surface or released into the circulation. These changes aim to finely tune the coagulation response. To this objective ultralarge VWF multimers circulating in plasma have 2 different binding sites: an unexposed prothrombotic platelet-binding site (A1 domain) and a metalloprotease cleavage binding site (A2 domain) for ADAMTS13 leading to an enzymatic conformational activation with subsequent proteolysis of the ultralarge VWF multimers into smaller molecules with less capacity to bind platelets.A Disintegrin and Metalloproteinase With a Thrombospondin Type 1 Motif, Member 13The ADAMTS13 gene contains 29 exons spanning ≈37 kb on chromosome 9q34. In 2001, the protein and its DNA sequence were characterized giving rise to a series of articles supporting its role in TTP. TTP is caused by a deficiency of ADAMTS13, a zinc-containing metalloprotease responsible for cleavage of ultralarge VWF multimers to prevent spontaneous coagulation.2,3 When multimers are not properly cleaved, unprompted platelet aggregation ensues, activating the coagulation cascade and resulting in platelet consumption and end-organ thrombosis.4 The lack of enzymatic activity can be either due to an acquired antibody, or less commonly, to an inherited autosomal recessive disorder, such as in Upshaw-Schulman syndrome. Primary disorders of function in the von Willebrand axis have been associated with athero-thrombosis.5 Decreased ADAMTS13 activity of less than 10% is highly indicative of TTP in the appropriate clinical setting. The presence of ADAMTS13 inhibition (positive inhibitor screen) with a measurable antibody titer is most consistent with an acquired TTP. Of note, antibody titers can appear falsely elevated upon severe hemolysis when hemoglobin >2 gr/dL in peripheral blood.6 Severe ADAMTS13 deficiency (<10% normal values), in the absence of anti-ADAMTS13 antibodies, suggest a diagnosis of hereditary TTP. In this later form, diagnosis is confirmed by molecular analysis revealing a double heterozygous or homozygous mutation in the ADAMTS13 gene.7TTP and StrokeNeurological deficits from minor (confusion, headache, blurred vision, or ataxia) to severe (ischemic stroke, seizures, coma), or transient symptoms occur frequently in TTP.7 Historically, TTP has been associated with small artery infarction but with advances in testing for TTP, it is now clear that infarctions of small and large arteries may occur. A reduced ADAMTS13 activity2,8 in patients with ischemic stroke may help confirm the diagnosis of TTP.Routine investigation for stroke cause includes vascular and cardiac causes. Occasionally, hematologic causes are investigated but usually restricted to evaluations for protein C, protein S, and antithrombin III activity. Testing for homocysteine, factor V Leiden, and prothrombin gene, and lupus anticoagulant activity is also performed. Investigation for other coagulopathies is not a routine part of investigation though at least a quarter of ischemic infarctions remain cryptogenic after testing. When considering recurrent thrombotic strokes, the differential diagnosis encompasses a wide range of disorders from inherited deficiencies of antithrombin III, protein C, and protein S, heparin cofactor II, fibrinolytic system derangements such as disseminated intravascular coagulation, antiphospholipid antibodies and lupus anticoagulants, polycythemia vera, sickle cell anemia, sickle-C disease, essential thrombocythemia, Moyamoya disease, Susac syndrome, deficiency of DADA2 (adenosine deaminase 2), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, Sneddon syndrome, vasculitis, and adenocarcinomas.An evaluation for TTP in the setting of stroke is merited in any patient with low platelet counts and hemolytic anemia. Normal prothrombin time and partial thromboplastin time help distinguish TTP from disseminated intravascular coagulation. However, in hereditary TTP neurological deficits may occur without thrombocytopenia or evidence of hemolysis.1 These patients develop more serious complications only during intermittent episodes of exacerbations3 or exhibit transient symptoms in which small-platelet VWF aggregates occlude the microcirculation without producing sufficient platelet consumption to result in thrombocytopenia.9Patients with hereditary TTP have a high risk of transient ischemic attacks and stroke, beginning at a young age.1 Of note, older patients (>60 years) with acquired TTP may present with atypical neurological symptoms and less prominent cytopenias leading to delays in diagnosis and therapy.10 They also show inferior long-term survival10compared with younger patients.Testing for TTP with ADAMTS13 activity and inhibitor should be considered in patients with recurrent multifocal ischemic strokes and thrombocytopenia (Figure 2). A low ADAMTS13 activity level narrows down the differential diagnosis from a multitude of primary and systemic microangiopathy syndromes, such as complement-mediated, drug-induced, coagulation-mediated, metabolism-mediated thrombotic microangiopathies, toxin-induced hemolytic uremic syndrome, disseminated intravascular coagulation, sepsis, preeclampsia syndromes, systemic rheumatic diseases, liver cirrhosis, HIV infection, malignancy, and transplant.Download figureDownload PowerPointFigure 2. An algorithm from clinical suspicion to diagnosis ofthrombotic thrombocytopenic purpura (TTP) in patients with recurrent strokes. ADAMTS13 indicates a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.There are no established guidelines for managing TTP-related ischemic stroke with thrombolysis or thrombectomy. With no history suggestive of TTP patients can receive treatment for acute stroke assuming normal platelets count above 100 000. If thrombocytopenia appears prompt, investigations with ADAMTS13 activity assays and inhibitors are recommended. Once the diagnosis is confirmed, further steps into the mainstay of treatment for TPP is next. Plasma exchange reduces the chances of thrombotic complications in these patients. A hematology consultation is also valuable in this scenario.In patients with hereditary TTP, plasma infusions are usually sufficient to treat acute episodes, although for severe manifestations therapeutic plasma exchange may be appropriate. Recurrent symptoms can be treated with regular plasma infusions every 2 to 3 weeks. In acquired TTP, corticosteroids should be considered as an adjunct to plasma exchange. The chemotherapeutic agent vincristine and the monoclonal antibody rituximab are often reserved for TTP cases refractory to plasma exchange.Platelet transfusion is controversial but considered contraindicated unless major bleeding is present.Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150 for >48 hours.Further investigation of the prevalence of ADAMTS13 activity and its inhibitor among stroke patients with recurrent strokes seems warranted.Take-Home PointsStrokes caused by both small and large artery etiologies may occur in thrombotic thrombocytopenic purpura.A decreased level of the metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is diagnostic of thrombotic thrombocytopenic purpura.In addition to the enzyme level, obtaining an ADAMTS13 inhibitor level helps provide additional information into the pathophysiology mechanism of thrombotic thrombocytopenic purpura.Evaluation for thrombotic thrombocytopenic purpura should be considered in patients with recurrent multifocal stroke.Article InformationSources of FundingNone.Disclosures Dr Silver disclosed fees from Women’s Health Initiative, Best Doctors, Medicolegal consulting, MedLink, Medscape, and Ebix. The other authors report no conflicts.FootnotesFor Sources of Funding and Disclosures, see page e240.Correspondence to: Zimbul Albo, MD, PhD, Tufts University Medical School, Department of Neurology, 800 Washington St, Boston, MA 02111. Email [email protected]com