Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome are classified under microangiopathic hemolytic anemias (MAHAs). MAHA is characterized by hemolytic anemia with schistocytes (fragmented red blood cells [RBCs]) in the peripheral blood smears. TTP is a clinical syndrome associated with classical pentad which includes thrombocytopenia, hemolytic anemia, fever, neurological symptoms, and renal dysfunction. Majority of (90%) cases do not have all the five clinical features. MAHA and thrombocytopenia are sufficient to suspect the diagnosis of TTP.
The pathogenesis of TTP is related to autoantibodies to a von Willebrand factor (VWF) cleaving protease (ADAMTS13). Currently, plasma exchange (PEX) and corticosteroids are the first line of treatment in most of the patients with TTP. Rituximab, an anti-CD20 chimeric monoclonal antibody, has been proposed for the treatment of refractory TTP patients. Here, we describe a case of refractory TTP treated successfully with the addition of rituximab after initial poor response to multiple PEXs.
A 43-year-old female was brought to the emergency department with complaints of fever, generalized weakness, mild headache, rash over forearms and upper chest for 7 days, and one episode of generalized tonic-clonic seizures, followed by altered sensorium a day before. On examination, she was drowsy, obeying simple commands, febrile with a temperature of 101°F, pulse rate was 120/min regular, and blood pressure was 130/60 mm of Hg. Multiple ecchymotic patches were noticed over her forearms, chest, and abdomen. Fundus examination was normal and no focal neurological deficits or neck stiffness were observed. Following 1500 mg of intravenous levetiracetam infusion in the emergency room, she was shifted to the intensive care unit. Initial laboratory evaluation revealed severe thrombocytopenia (platelets 8000/mm3), anemia (hemoglobin 4.8 g/dL), and peripheral blood smear showed helmet-shaped schistocytes (fragmented RBCs) and few triangular forms of RBCs [Figure 1]. Reticulocytosis was present with a reticulocyte percentage of 50%.
Biochemical parameters showed indirect hyperbilirubinemia (4.3 mg/dl) and increased lactate dehydrogenase (LDH) levels (860 u/l). Random blood sugar was 86 mg/dl and serum creatinine was 0.9 mg/dl. Blood coagulation parameters including prothrombin time, activated partial thromboplastin time, and fibrinogen levels were normal. Direct Coombs test was negative. Workup for infective etiologies such as malaria, dengue, leptospirosis, and scrub typhus was negative. Serological tests for HBV, HCV, HIV 1 and 2, and syphilis were negative. Thyroid profile, antinuclear antibody profile, and antiphospholipid antibody profile were normal. Chest X-ray and computed tomography of the chest revealed bilateral mild pleural effusion with no parenchymal changes. Ultrasound of the abdomen was unremarkable. In view of persistent mild drowsiness, magnetic resonance imaging of the brain and venogram were done, which showed mild diffuse cerebral edema with no other significant changes. Based on peripheral smear findings of fragmented RBCs, anemia, thrombocytopenia, fever, and seizure, the possibility of MAHA was considered and ADAMTS13 enzyme activity was found to be 5% (normal 68%–163%), supporting the diagnosis of TTP.
In the intensive care unit, she was started on daily cryo-poor PEXs equal to an estimated one plasma volume. She was also administered pulse dose steroid therapy comprising methylprednisolone, 1 g intravenous daily for the first 3 days followed by oral prednisolone 1 mg/kg/day. Injection levetiracetam 500 mg twice a day and supportive therapy was continued. The patient’s clinical condition including drowsiness improved, but platelet count did not improve despite 7 days of daily PEXs, suggesting refractory TTP. On day 11 of admission, the first dose of rituximab was administered at 375 mg/m2 body surface area intravenously and the second equal dose was given on day 18. She also received 5 units of packed RBCs during her hospital stay. After the initiation of rituximab, platelet count improved to 135,000/mm3 by day 15 and to 185,000/mm3 by day 20 of admission. In addition to close clinical monitoring, laboratory parameters were also monitored periodically during the hospital stay, details of which are as summarized in Table 1.
Following sustained clinical and laboratory parameters improvement, she was discharged on oral prednisolone of 50 mg/day with gradual tapering and tablet levetiracetam 500 mg twice a day. She maintained consistent improvement over the next 6 months and did not have any relapse.
The entity TTP was first labeled as an “acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries” by Eli Moscowitz in 1925. The illness is principally caused by acquired deficiency of ADAMTS13, which habitually cleaves VWF multimers, forfeiture of which results in large circulating multimers of VWF. The VWF multimers cause platelets to adhere to the endothelium with resultant thrombosis, thrombocytopenia, and shearing of red cells as they pass the thrombi leading to MAHA. The very well-known diagnostic pentad of TTP is MAHA, thrombocytopenia, renal failure, fever, and altered mental status.
The hallmark of MAHA is the development of schistocytes (helmet and triangular form of RBCs) seen in peripheral blood smear. The International Council for Standardization in Haematolgy (ICSH) Schistocyte Working Group agreed that schistocyte percentage above 1% in a peripheral blood smear in adults is a robust cytomorphological indication in favor of a diagnosis of thrombotic microangiopathies when additional features suggesting an alternative diagnosis are absent. Intravascular hemolysis results in elevation of the markers such as LDH, bilirubin, reticulocyte count, and drop in haptoglobin levels.
The most common diagnostic differentials of the TTP are hemolytic uremic syndrome, disseminated intravascular coagulation syndromes, systemic lupus erythematosus (SLE) with other vasculitis syndromes, and pregnancy syndromes. In acquired TTP, one should rule out associated secondary diseases such as SLE (most common), antiphospholipid antibody syndrome, adult-onset still’s diseases, rheumatoid arthritis, systemic sclerosis, Sjogren’s syndrome, polymyositis, and dermatomyositis. The possible pathogenesis is a higher prevalence of anti-endothelial cell antibodies in sera of mixed connective tissue disease cases and decreased plasma fibrinolytic activity.
PEX is the treatment of choice in MAHA. As the prognosis of TTP is improved by prompt recognition and treatment, emergency apheresis should be conducted in any patient diagnosed with MAHA. Common adjuvant treatment includes the addition of 1 mg/kg/day of prednisolone. PEX with fresh frozen plasma or cryo-poor plasma, that too a pooled plasma (human), that has been treated with a solvent detergent process is preferred. Octaplas is a pooled plasma, with a reduced risk of viral transmissions. When immediate PEX is not available, simple plasma infusion can be performed till the patient can be referred to a tertiary care center for PEX. PEX is well tolerated in general, but some patients may have catheter access problems, electrolyte imbalance, hypotension, and reactions to plasma. PEX should preferably be performed daily until the evidence indicates that the disease is in remission. The patient should have a normal end-organ function, including normal sensorium and renal functions. The most sensitive indicator of response is a rising platelet count, which should be normal (>150,000/mL) for several days (at least 3–5) before PEX is discontinued. The LDH level is also a sensitive indicator of tissue hypoxia and can be used to monitor the response to therapy. The peripheral smear morphology, reticulocyte response, should be monitored along with LDH and serum ionized calcium levels.
In refractory or relapsing TTP cases, alternative pharmacological therapeutic options include rituximab, vincristine, cyclophosphamide, and surgical management in the form of splenectomy. Other recent developments include capalcizumab, a nanobody directed against domain A1 of VWF that prevents the formation of VWF-platelet aggregates, plasma cell inhibitor (bortezomib), recombinant ADAMTS13, N-acetyl cysteine, and Anfibatide which inhibits VWF-glycoprotein Ib/IX interaction. Our patient had a poor response to the combination of corticosteroids and multiple PEXs. However, timely initiation of rituximab with close clinical and laboratory parameters monitoring helped in better outcomes.
TTP is a rare hematological emergency associated with diverse clinical presentations and significant mortality. The prognosis of TTP is improved by prompt recognition and early initiation of plasma exchange along with corticosteroid therapy. Assessing the refractoriness to ongoing first-line treatment and timely initiation of novel therapeutic options such as rituximab helps in better outcomes in selected patients.
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