key: cord-322007-xy66t0ls
authors: Humbert, S; Razanamahery, J; Payet-Revest, C; Bouiller, K; Chirouze, C
title: COVID-19 as a cause of immune thrombocytopenia
date: 2020-05-20
journal: Med Mal Infect
DOI: 10.1016/j.medmal.2020.05.003
sha: 
doc_id: 322007
cord_uid: xy66t0ls

nan

Immune thrombocytopenia (ITP) is a rare autoimmune disease characterized by isolated thrombocytopenia below 100,000/µL and no other cause of thrombocytopenia [1] . Clinical presentation is heterogeneous from absence of symptoms to mild mucocutaneous bleeding or even life-threatening hemorrhage. ITP can be a primary condition or secondary to other diseases especially viral infections. ITP has been described during the course of several viral infections: HIV, EBV, CMV, HCV but only once during severe acute respiratory distress coronavirus 2 (SARS-CoV-2) [2] .

On April 2020, an 84-year-old man was admitted to hospital for a 10-day history of cough and progressively worsening dyspnea. He had medical history of polymyalgia rheumatica and essential tremor. His medications were prednisone 5 mg/day and propranolol. On arrival, the patient required oxygenation therapy with a flow rate of 4 L/min. Physical examination showed bilateral crackles on auscultation. Platelet count was 330,000/µL. CT scan showed diffuse ground-glass opacities and J o u r n a l P r e -p r o o f condensations involving more than 50% of pulmonary parenchyma highly suggestive of SARS-CoV-2 infection and sub-segmental pulmonary embolism. SARS-CoV-2 diagnosis was confirmed using RT-PCR on nasopharyngeal swabs. The patient received an antibiotic therapy with ceftriaxone, therapeutic anticoagulation with rivaroxaban, and prednisone was replaced by hydrocortisone. The patient remained febrile, with oxygenation therapy dependence during the first five days. On day 6, sudden onset of spontaneous macroscopic hematuria and bilateral epistaxis was observed. Platelet count was then at 4,000/µL with no schistocytes on blood smear, hemoglobin level was at 12.7 g/dL, WBC at 9,200/µL, lymphocyte counts at 330/µL. Fibrinogen was at 7.3 g/L and INR was at 1.52. Vitamin B9 and B12 were normal. Autoimmune workup did not reveal any ENA, ANCA, and platelet antibodies. The search for antiphospholipid antibodies showed a lupus anticoagulant antibody.

As immune thrombocytopenia was the most relevant diagnosis and due to severe bleeding, we started prednisone (1 mg/kg/day) and one course of intravenous immunoglobulins 1 g/kg. The day after, platelet count was at 57,000/µL, and at one week it was at 155.000/µL. Due to the patient's altered condition and the rapid rise in platelet count, we did not perform bone marrow aspiration.

Acute ITP can be triggered by many viruses. An ITP flare has recently been described during Zika virus infection [3] ; and once during non-symptomatic infection with SARS-CoV-1 [4] . We describe here the second case of SARS-CoV-2-induced ITP.

COVID-19 is an emerging pandemic that appeared in December 2019. COVID-19 is caused by SARS-CoV-2, responsible for severe pneumonia in less than 20% of cases. Thrombocytopenia is considered a poor prognostic factor during SARS-CoV-2 infection [5] . However, even if platelet counts are significantly lower in severe patients, it rarely decreases below 100,000/µL. COVID-19 thrombocytopenia could be secondary to direct platelet-virus interaction via pathogen recognition receptors (PRR). This interaction leads to platelet activation and subsequent clearance by the reticuloendothelial system [6] . It could also be secondary to sepsis.

In our case, thrombocytopenia is lower than what is usually observed during COVID-19 and may be secondary to an immune-related mechanism. Indeed, an autoimmune process can be induced by many viruses by several mechanisms. The most relevant mechanism is molecular mimicry between the virus component and platelet glycoproteins [7] .Interestingly, Zhang et al. demonstrated that several HCV core-envelope peptides shared molecular mimicry with glycoprotein IIIa, a part of an integrin complex found on platelets. Those peptides could induce the production of antibodies which acquire the ability for platelet fragmentation [8] . To date, no sequence homology between SARS-CoV-2 and platelet components has been described. Moreover, the recognition of SARS-CoV-2 by PRR (mostly TLR7) could stimulate autoreactive B cells and then induce the production of autoantibody directly against platelet glycoprotein. Median time for seroconversion after onset of SARS-CoV-2 infection is approximately 12 days; then RNA detectability decreases from the second week of the infection [9] .

In our case, ITP occurred on day 16 after the first symptom of COVID-19. The suddenness and severity of thrombocytopenia could be explained by the patient's advanced age as coronavirus induced higher antibodies production in older people [10] . Polymyalgia rheumatica is usually not associated with ITP and as cases of drug-induced ITP, i.e. rivaroxaban and ceftriaxone, have very rarely been reported, the best explanation for thrombocytopenia was virus-induced ITP. The clinical and biological remission with steroids and intravenous immunoglobulins confirmed this hypothesis. SARS-CoV-2 is an infectious agent to be listed as an ITP-inducing virus. Urgent treatment of ITP, including corticosteroid therapy, should not be delayed.

The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia

Immune Thrombocytopenic Purpura in a Patient with Covid-19

Zika virus (ZIKV) infection related with immune thrombocytopenic purpura (ITP) exacerbation and antinuclear antibody positivity

Severe Immune Thrombocytopenia Complicated by Intracerebral Haemorrhage Associated with Coronavirus Infection: A Case Report and Literature Review

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Exploring possible mechanisms for COVID-19 induced thrombocytopenia: Unanswered Questions

Pathogenesis of immune thrombocytopenia

Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia

Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019

Antibodies to coronaviruses are higher in older compared with younger adults and binding antibodies are more sensitive than neutralizing antibodies in identifying coronavirus-associated illnesses