Case Report
 
Refractory Thrombotic Thrombocytopenic Purpura
 
Dawlat Sany1, Wadah Ahmed Osman2, Walaa Abdelmaaboud3, Heba Mohamed Abdelfattah4 
1Departments of Internal Medicine and Nephrology, Kalba Hospital, Sharjah, EHS; 2Department of Internal Medicine, Kalba Hospital, EHS; 3Department of Anesthesia and Critical Care, Khor Fakan Hospital, Sharjah, EHS; 4Department of Pathology, Pure Health Group Company, Sharjah, UAE.


Corresponding Author:
Dr Dawlat Sany
Email: Dawlat.hussein@ehs.gov.ae

Abstract

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic hemolytic anemia, and severe ADAMTS13 deficiency, often due to inhibitory autoantibodies. If left untreated, the mortality rate can exceed 90%. Case Report: A 44-year-old male presented with fever, confusion, agitation, and pallor. Laboratory evaluation revealed DAT-negative hemolytic anemia, thrombocytopenia, schistocytes on peripheral smear, elevated LDH and creatinine, and neurologic symptoms. His PLASMIC score was high, suggesting severe ADAMTS13 deficiency, later confirmed by a markedly reduced ADAMTS13 activity level (<0.03 IU/mL) and the presence of anti-ADAMTS13 antibodies. The patient was promptly treated with daily therapeutic plasma exchange (TPE) and high-dose methylprednisolone. Due to delayed platelet recovery, rituximab was added, resulting in sustained hematologic improvement. Conclusion: This case highlights the importance of early recognition and prompt initiation of plasma exchange and immunosuppressive therapy in suspected TTP. The addition of rituximab in refractory cases may hasten recovery and reduce the risk of relapse. Timely diagnosis and aggressive treatment are critical to improving outcomes in patients with acquired TTP.

Introduction 

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) characterized by a severe deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. The condition has an estimated incidence of 3.7 cases per 1,000,000 population [1] and predominantly affects individuals in their third decade of life, with a female-to-male ratio of approximately 3:2 [2]. TTP may be acquired, most often immune-mediated through autoantibodies against ADAMTS13 or hereditary, due to mutations in the ADAMTS13 gene [3]. The underlying mechanism involves the formation of small-vessel platelet-rich thrombi, which result in thrombocytopenia, microangiopathic hemolytic anemia, and ischemia of various organs [4]. Neurological involvement is common in adults and may include confusion, visual disturbances, motor or sensory deficits, seizures, and altered consciousness [2]. Renal abnormalities such as proteinuria, microscopic hematuria, and acute kidney injury are also frequently observed [2,4].
The PLASMIC score is a useful clinical tool to estimate the probability of severe ADAMTS13 deficiency (=10%) in adults presenting with features of TMA, particularly in the presence of thrombocytopenia and schistocytes on peripheral smear [5].

Case Report 

A 44-year-old male presented to the emergency department with a five-day history of fever, confusion, headache and irritability. He reported a recent mosquito bite but had no significant drug exposures or family history of similar illness. On admission, his vital signs were notable for a temperature of 38°C, heart rate of 102 bpm, blood pressure of 105/83 mmHg, respiratory rate of 20 breaths per minute, and oxygen saturation of 100% on room air. On physical examination, he appeared pale and icteric, and although he was agitated, his Glasgow Coma Scale (GCS) score was 13/15 with no focal neurological deficits. The remainder of the systemic examination was unremarkable.
Initial laboratory investigations revealed severe anemia with hemoglobin at 6.6 g/dL (normal: 13.5-17.5 g/dL), profound thrombocytopenia with a platelet count of 9,000/µL (normal: 150,000-450,000/µL), and an elevated reticulocyte count of 10.3% (normal: 0.5-2.5%). Hemolysis was evident by markedly raised lactate dehydrogenase (LDH) at 1603 U/L (normal: 140-280 U/L), elevated indirect bilirubin at 80 µmol/L (normal: <20 µmol/L), and low haptoglobin <0.1 g/L (normal: 0.3-2.0 g/L). Renal function was deranged with blood urea nitrogen (BUN) of 9 mmol/L (normal: 2.5-7.1 mmol/L) and serum creatinine at 156 µmol/L (normal: 60-110 µmol/L), suggestive of acute kidney injury. Peripheral blood smear demonstrated fragmented red blood cells (schistocytes), consistent with microangiopathic hemolytic anemia. Direct antiglobulin test (DAT) was negative, excluding autoimmune hemolytic anemia. Coagulation parameters were within normal limits: prothrombin time (PT) was 12.9 seconds (normal: 11-14 sec), activated partial thromboplastin time (aPTT) was 37.2 seconds (normal: 25-35 sec), and international normalized ratio (INR) was 1.0 (normal: 0.9-1.1), thus making disseminated intravascular coagulation (DIC) less likely. Neuroimaging (non-contrast CT and MRI of the brain) was unremarkable.
Based on the clinical presentation and laboratory findings, a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP) was made. The patient had received an initial transfusion of 600 mL of fresh frozen plasma (FFP) and one unit of packed red blood cells at the referring facility. On admission to the intensive care unit, his PLASMIC score was calculated as 6, indicating a 72% probability of ADAMTS13 activity less than 10%. Therapeutic plasma exchange (TPE) was initiated immediately along with intravenous methylprednisolone at a dose of 1 gram daily for 3 days. The estimated plasma volume (EPV) was calculated using the formula: EPV = (0.065 × body weight in kg) × (1 - hematocrit). Daily TPE was administered using frozen plasma as the replacement fluid, with a target of 1-1.5 EPV per session. Treatment was planned to continue daily until the platelet count exceeded 150,000/µL and LDH levels approached normal for at least two to three consecutive days. By the following day, the patient's neurological status improved, with normalization of GCS to 15/15 and resolution of agitation. Renal function also began to improve. ADAMTS13 testing confirmed a severely deficient activity level of <0.03 IU/mL (normal: 0.4-1.4 IU/mL), and anti-ADAMTS13 antibodies were detected, confirming the diagnosis of acquired immune-mediated TTP. Serologic tests for dengue, hepatitis B and C, and HIV were negative. Complement factor H levels were normal, and autoimmune markers for systemic lupus erythematosus, Sjögren’s syndrome, and antiphospholipid syndrome were all negative. Despite continued daily TPE and oral prednisone, the patient experienced a decline in platelet count after an initial partial response (platelets >50×109/L), raising concern for refractory TTP. On day 10 of ICU stay, rituximab was initiated at a dose of 375 mg/m² weekly, in conjunction with ongoing TPE and corticosteroids. By the third week of hospitalization, the patient's platelet count normalized to 151,000/µL, and renal function returned to baseline. He received two additional TPE sessions and completed three doses of rituximab, with plans for a fourth dose to be administered in follow-up. After 23 days of hospitalization, the patient remained clinically stable and was discharged. In total, he had received 16 sessions of TPE, 320 mL of FFP, two units of packed red blood cells, and three doses of rituximab.
At discharge, he was advised to continue oral prednisolone at 40 mg/day with a tapering schedule over eight weeks, along with vitamin D supplementation and cotrimoxazole 960 mg three times a week for six months for Pneumocystis jirovecii pneumonia prophylaxis. He was counselled on the importance of hematology follow-up for monitoring of ADAMTS13 activity, complete blood count, and hemolysis markers. Laboratory trends of hemoglobin, platelet count, LDH, and serum creatinine throughout the hospital stay are depicted in Figures 1-4.



Discussion 

Microangiopathic hemolytic anemias (MAHA), such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), are rare but potentially fatal conditions if not recognized and treated promptly [6]. Early diagnosis and immediate initiation of life-saving therapy are critical to improving outcomes [7]. In immune-mediated TTP, therapeutic plasma exchange (TPE) remains the cornerstone of treatment. It works by both removing circulating anti-ADAMTS13 autoantibodies and replenishing functional ADAMTS13 from donor plasma [8]. Without treatment, TTP may follow a progressive course, leading to worsening neurological impairment, myocardial ischemia, end-stage renal disease, and ultimately, high mortality [9]. In the present case, the diagnosis of TTP was strongly supported by the presence of diagnostic features including DAT-negative microangiopathic hemolytic anemia, severe thrombocytopenia, neurological symptoms, fever, and acute kidney injury. Treatment with daily TPE and immunosuppressive therapy using corticosteroids (prednisolone) was initiated promptly upon admission.
Steroid therapy plays a supportive role in accelerating recovery by reducing the release of ADAMTS13 inhibitors, suppressing cytokine production, and potentially lowering the rate of ADAMTS13 clearance by autoantibodies. This approach aligns with the 2020 International Society on Thrombosis and Haemostasis (ISTH) guidelines, which strongly recommend steroid use in acute TTP [8]. The addition of rituximab, a monoclonal anti-CD20 antibody, has been shown to enhance therapeutic outcomes by depleting B cells responsible for producing the ADAMTS13 autoantibodies. Incorporating rituximab early in the course of treatment can reduce the number of required TPE sessions and lower the risk of relapse [10]. In this case, rituximab was added after 10 days due to inadequate platelet response despite ongoing TPE and steroids, indicating a refractory disease course. The timing of rituximab infusion was spaced at least 24 hours apart from plasma exchange to avoid drug removal. Caplacizumab, another therapeutic option targeting von Willebrand factor, offers rapid inhibition of platelet aggregation and may be beneficial if used early. However, its high cost, bleeding risk, and need for concurrent immunosuppression limit its routine use.
According to current recommendations, TPE is typically discontinued once the platelet count remains =150,000/µL for at least two consecutive days. In this case, LDH and hemoglobin levels improved significantly by day 7 (hemoglobin from 6.6 to 9.4 g/dL; LDH from 1603 to 219 U/L), while the platelet count normalized only after 21 days of therapy, following the addition of rituximab. The patient was discharged in stable condition with improving laboratory parameters and maintained remission on oral steroids with a gradual taper. Continued outpatient follow-up showed sustained remission.

Conclusion

This case reinforces the importance of considering TTP in the differential diagnosis of patients presenting with thrombocytopenia and microangiopathic hemolytic anemia. Immune-mediated TTP should be suspected when laboratory findings include thrombocytopenia, hemolysis (elevated LDH, indirect hyperbilirubinemia, low haptoglobin), presence of schistocytes on peripheral smear, and a negative direct antiglobulin test. The PLASMIC score serves as a valuable tool in assessing the likelihood of severe ADAMTS13 deficiency and supports early treatment decisions. Definitive diagnosis is confirmed by demonstrating reduced ADAMTS13 activity along with the presence of anti-ADAMTS13 antibodies. TTP constitutes a hematologic emergency requiring urgent initiation of therapeutic plasma exchange and immunosuppressive therapy. Prompt recognition and aggressive management remain vital in reducing mortality and preventing long-term complications.

Contributors: DS: manuscript writing, patient management; WAO, WA: manuscript editing, patient management; HMA: critical inputs into the manuscript. DS will act as a study guarantor. All authors approved the final version of this manuscript and are responsible for all aspects of this study.
Funding: None; Competing interests: None stated.
Acknowledgement: I am grateful to EHS for offering facilities and resources for case diagnosis and treatment.   

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