Thrombotic Thrombocytopenic Purpura Without Schistocytes

Case

A 43-year-old woman was admitted for acute unusual headache, vertigo, and left upper limb weakness. She had been complaining of asthenia for the past few weeks. Her medical history included uterine cervix cancer treated with conisation and 2 pregnancies without serious complications. No allergy or recent drug introduction was noted. After ruling out current pregnancy, magnetic resonance imaging (MRI) was immediately performed and showed recent ischemic strokes in multiple territories. Doppler ultrasound imaging showed no carotid or vertebral arteries lesion. Electrocardiogram showed no ST elevation or atrial fibrillation, and echocardiography did not reveal embolic lesion or patent foramen ovale. Blood cell count showed thrombocytopenia at 17 × 10⁹/L (confirmed in citrate tube) and hyperleukocytosis at 18 × 10⁹/L without anemia (hemoglobin at 12.9 g/dL). Basic metabolic profile, kidney, and liver function tests were normal. Hemolysis signs were present: reticulocytes, total bilirubin, lactate dehydrogenase (LDH), and haptoglobin levels were at 147 × 10⁹/L, 27.2 μmol/L, 454 U/L, and bellow 0.08 g/L, respectively. Repeated blood smears showed no schistocytes. A disseminated intravascular coagulation was ruled out (normal activated partial thromboplastin time and prothrombin time, fibrinogen at 3.6 g/L), and autoimmune cytopenia (Coombs test was negative), hyperhomocysteinemia, vitamin deficiencies (B9, B12), and paroxysmal nocturnal hemoglobinuria. Bone marrow examination showed increased megakaryocytes with normal morphology excluding a central origin. Lupus anticoagulant, anticardiolipin, and anti- β2gp1 antibodies were negative. A thoraco-abdominopelvic scan with contrast showed small renal and splenic infarcts; no suspect tumor was observed.

Thrombotic thrombocytopenic purpura (TTP) was suspected after elimination of thrombocytopenia and hemolytic anemia differential diagnoses, despite the persistent absence of schistocytes. A specific treatment was started immediately (before obtaining the ADAMTS13 activity results). ADAMTS13 activity was low (<5%), and anti-ADAMTS13 antibodies were positive at 60 U/mL (normal values <25 U/mL). Diminution of ADAMTS13 below 10% and quick plasmapheresis efficacy led to acquired TTP diagnosis. No TTP-associated disorders such as autoimmune disorders, systemic infections, or cancers were identified. Daily plasma exchanges and corticosteroid therapy at 1 mg/kg per day led to a dramatic improvement of platelet counts, and hemolytic signs occurred in 5 days. Clinical and biological recovering allowed progressive plasmapheresis spacing (a total of 10 plasma exchanges were administrated) and corticosteroids tapering. ADAMTS13 activity was 84% at 3 months and 110% at 6 months.

Discussion

TTP is a thrombotic microangiopathy characterized by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeat motif 13, a von Willebrand factor-cleaving protease) activity deficiency, caused by autoantibodies inhibition in acquired forms, and resulting in large von Willebrand factor multimers and platelet thrombi.¹

We identified 10 cases of TTP without schistocytes in the literature (table). Seven of 10 patients (70%) suffered relapsing TTP. Among 3 relapsing patients presenting with cerebrovascular accidents, no thrombocytopenia or hemolytic anemia was observed, and TTP diagnosis was suspected because of ADAMTS13 deficiency. In these cases, the absence of thrombocytopenia and hemolytic anemia can be explained by an early stage of TTP when platelet aggregation and thrombosis are not yet diffuse. Indeed, schistocytes are initially absent in up to 30% of patients, and blood smear examination should be regularly repeated.² Asynchronous development of TTP signs is consistent with pathophysiology. Microvascular thrombi consist mainly of inactivated platelets and von Willebrand factor with very little fibrin leading to platelet sequestration and thrombocytopenia. On the 1 hand, hemolysis and the production of schistocytes are a consequence of blood flow partial occlusion by microthrombi in high shear regions³; on the other hand, ultra large von Willebrand factor multimers secreted by endothelial cells can bind tightly to platelets and induce their sequestration in the microvasculature, even in low shear conditions. Clinical signs are because of tissue ischemia, which depends on the location of thrombi and collateral circulation. Neurologic manifestations such as strokes or seizures can be caused by small thrombi in focal regions without hemolysis or thrombocytopenia.

Table.

Literature Review of TTP Cases Without Schistocytes

Without appropriate treatment, overall survival is poor (below 10%), and 80% of patients with TTP die within 3 months.⁴ Plasma exchanges changed TTP prognosis: survival at 6 months is almost 80%.^5,6 Absence of schistocytes can delay TTP diagnosis and plasma exchanges initiation, which could lead to a higher mortality risk. Schistocytes absence should not postpone plasma exchange initiation in case of clinically and biologically suggestive presentation.

Appendix. Authors

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