Thrombotic Thrombocytopenic Purpura (TTP): A Rare Presentation in COVID-19

M Pedlakkal Jabir^1*, K Nikitha¹ and N A Ismail^2
*Correspondence: M Pedlakkal Jabir, Department of General Medicine, Aster MIMS Hospital, Kozhikode, Kerala, India, Tel: 919496357213, Email:

Keywords

COVID-19 • Thrombotic thrombocytopenic purpura • Plasma exchange • ADAMTS13

Abbreviations

TTP-Thrombotic Thrombocytopenic Purpura; COVID-19-Coronavirus Disease 2019; ADAMTS13-A Disintegrin Metalloproteinase with Thrombospondin Type 1 Motif, Member 13; vWF-von Willebr and Factor; HUS-Haemolytic Uremic Syndrome; RT-PCR-Real Time Reverse Transcriptase Polymerase Chain Reaction; MAHA-Macroangiopathic Haemolytic Anaemia; LDH-Lactate Dehydrogenase; ANA-Antinuclear Antibody; ELISA-Enzyme Linked Immunosorbent Assay; PLEX-Plasma Exchange; TMA-Thrombotic Microangiopathy; SARS-CoV2-Severe Acute Respiratory Distress Coronavirus 2; HCQ-Hydroxychloroquine

Introduction

TTP is a rare haematological disorder which can be Hereditary or Acquired. Hereditary TTP is a rare autosomal recessive disorder caused by ADAMTS 13 mutations that result in the absence or severe deficiency of the plasma metalloprotease ADAMTS 13. ADAMTS 13 deficiency is most frequently acquired via ADAMTS13 auto antibodies (iTTP). 50% of all iTTP deficiencies are caused by clinical conditions like bacterial infections, SLE, Antiphospholipid syndrome, pregnancy, drugs, pancreatitis, HIV infection, cancers and organ transplantation. COVID-19 related thrombotic microangiopathy both TTP and a HUS has been described in literature. We report a case of TTP in a young female in the setting of COVID-19 infection [1].

Literature Review

A 22-year-old previously healthy obese female presented with sudden weakness and numbness of the right side of her body. She also had slurring of speech and facial deviation which resolved in a few hours. She did not report fever, anosmia, and cardio respiratory or gastrointestinal symptoms. No recent exposure to drugs. Family history was negative. There was no history of any illness during childhood [2]. On evaluation in the emergency room- TEMP 38°C. HR 100/min. BP 120/80 mmHg. RR 12/min. Pallor was noted. No lymph nodes or purpura were seen. Neurological examination showed power of 5/5 in all the limbs. No sensory, cranial nerve or cerebellar deficits. Rest of systems were normal on examination. In view of pandemic scenario, a nasopharyngeal swab was taken which tested positive for COVID-19 by RT-PCR. Laboratory investigations revealed anaemia, thrombocytopenia, unconjugated hyperbilirubinemia, and elevated reticulocyte count (18%) (Table 1).

Peripheral smear showed normocytic anaemia, thrombocytopenia and schistocytes (12%) consistent with Microangiopathic Haemolytic Anaemia (MAHA). Coagulation parameters like fibrinogen, PT-INR and APTT were normal [3]. LDH and D-Dimer were markedly elevated. Direct and indirect coomb’s tests were negative. Serum C3 and C4 were normal. Troponin was normal. ANA by ELISA and antiphospholipid antibody IgM were negative. Automated blood cultures were sterile. Serology testing for HIV, Hep B, Hep C and Dengue viruses were negative. Rapid malarial antigen was negative [4]. Urinalysis revealed trace albuminuria and microhaematuria. Renal function was normal. Liver function showed mild elevation of SGOT. Bone marrow examination was consistent with peripheral platelet destruction. Radiological investigations revealed a normal chest X-ray.

MRI and MRV Brain were normal. ADAMTS 13 testing revealed 36% of normal activity. Inhibitor assay was not available. A diagnosis of TTP was made and she was started on IV Methyl prednisone and Plasma exchange. She received daily plasma exchanges of 2-2.5 litres with replacement by fresh frozen plasma. She had only minimal symptoms of COVID-19.

After 3 sessions of PLEX, her haematological parameters started improving. Her neurological symptoms also improved. Rituximab was not given in view of COVID-19. She showed good response and achieved remission and discharged on Oral prednisone. COVID 19 antigen was negative at Day 10. She has not shown any signs of relapse after discharge [5].

Discussion

TTP-Thrombotic Thrombocytopenic Purpura can be hereditary or acquired, characterised by deficiency of ADAMTS 13, a polymer which degrades the multimers of von Willebrand factor. ADAMTS 13 testing deficiency is the most frequently acquired via ADAMTS13 auto testing antibodies, but rarely inherited via mutations of the ADAMTS 13 gene. Hereditary TTP usually presents in childhood and has a relapsing tendency. The first episode of TTP mostly occurs during adulthood (90% of all TTP cases). In 50% of the cases another clinical condition could trigger the onset of TTP. The well described triggers are bacterial infections, SLE, pregnancy, drugs, HIV Infection and organ transplantation. In 50% cases the trigger remains `idiopathic`. COVID-19 and COVID vaccination has been reported to cause thrombocytopenia and macro thrombosis. Thrombotic microangiopathy involving the lungs and kidneys are also described. The SARS-CoV 2 causes endothelial injury by binding to the ACE-2 receptors expressed in the vascular endothelial cells. Generation of auto antibodies to ADAMTS 13 leads to TTP. The other potential mechanisms suggested are elevated vWF factor and low ADAMTS 13 activity. Both have been reported to predict development of TMA in COVID-19 [6].

As of April 2021, varying presentations ranging from ‘Classical TTP’ to ‘TTP like illness of COVID-19’ numbering less than 20 cases have been reported in literature. Two Case reports with clinical features consistent with TTP in the setting of COVID-19 infection have been reported. ADAMTS 13 levels were not available in both those cases. However, very low ADAMTS 13 activity and positive Inhibitor leading to iTTP has been reported by Albiol-et-al. Law-et-al reported COVID-19 infection triggered autoimmune haemolytic anaemia and iTTP. A case series from Iran reported 4 patients with classical clinical and haematological parameters consistent with classical TTP during COVID-19 infection. COVID-19 infection has also been reported to trigger anti phospholipid antibodies leading to thrombosis and thrombocytopenia. COVID-19 infection has been reported to cause high von Willebrand Factor (vWF) levels with low ADAMTS 13 activity which may lead to the development of thrombotic microangiopathy [7].

In our case female gender, obesity and COVID-19 were the only risk factors for TTP. Clinical and haematological parameters features were classical of TTP. ADAMTS 13 activity, being 36% of normal raises the question whether this is mechanistically more like ‘TTP like illness of COVID-19’ rather than acquired iTTP where ADAMTS 13 activity is <10%. An increased incidence of young stroke in COVID-19 has been reported. Possible mechanisms being hypercoagulable state from systemic inflammation, cytokine storm and direct viral-induced endothelial damage leading to cerebral arterial and venous thrombosis. TTP should be considered in young individual with COVID-19 and neurological symptoms.

Conclusion

COVID-19 infection is emerging as strong risk factor for the development of thrombotic microangiopathy. ‘COVID-19 induced TTP’ is likely a spectrum ranging from Classical iTTP (<10% ADAMTS 13 activities and antibodies to the ADAMTS 13 in plasma) to COVID 19 induced TTP (direct endothelial damage leading to high vWF/ADAMTS 13 ratio). Plasma exchanges and steroids have shown anecdotal benefit in all case series. Role of Rituximab remains unclear. Neurological and haematological parameters have shown sustained improvement with lower reported relapse rate than classical immune TTP suggesting a strong causative role for the COVID-19.

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