key: cord-0822268-erv9oz6r
authors: Bomhof, G.; Mutsaers, P.G.N.J.; Leebeek, F.W.G.; te Boekhorst, P.A.W.; Hofland, J.; Croles, F.N.; Jansen, A.J.G.
title: COVID‐19‐associated immune thrombocytopenia
date: 2020-05-18
journal: Br J Haematol
DOI: 10.1111/bjh.16850
sha: 888f179624a028a9ce7b9325c3570873b51a1925
doc_id: 822268
cord_uid: erv9oz6r

Thrombocytopenia is a risk factor for increased morbidity and mortality in patients with the new severe acute respiratory syndrome corona virus, SARS‐CoV‐2 infection (COVID‐19 infection).(1) Thrombocytopenia in COVID‐19 patients may be caused by disseminated intravascular coagulation (DIC), sepsis or drug‐induced. Recently a single case report suggested immune thrombocytopenia (ITP) may be associated with COVID‐19 infection.(2) ITP is a rare autoimmune disease characterized by a platelet count < 100x10(9)/L, leading to an increased bleeding risk.(3) Several risk factors have been described for ITP including environmental (e.g. infection, malignancy and drugs) and genetic predisposition.(4) We report here the first case series of three patients with ITP associated with COVID‐19 infection.

Thrombocytopenia is a risk factor for increased morbidity and mortality in patients with the new severe acute respiratory syndrome corona virus, SARS-CoV-2 infection (COVID-19 infection). 1 Thrombocytopenia in COVID-19 patients may be caused by disseminated intravascular coagulation (DIC), sepsis or druginduced. Recently a single case report suggested immune thrombocytopenia (ITP) may be associated with COVID-19 infection. 2 ITP is a rare autoimmune disease characterized by a platelet count < 100x10 9 /L, leading to an increased bleeding risk. 3 Several risk factors have been described for ITP including environmental (e.g. infection, malignancy and drugs) and genetic predisposition. 4 We report here the first case series of three patients with ITP associated with COVID-19 infection.

Patient 1 is a 59-year-old man, known for 10 years with a stage IV neuroendocrine tumor (NET) of the small bowel, who presented with oral mucosal petechiae and spontaneous skin hematomas. He also experienced symptoms of coughing and fever 10 days before presentation and his partner had a documented COVID-19 infection. Full blood counts showed an isolated thrombocytopenia (< 3x10 9 /L) without signs of dysplasia in the peripheral blood film and he tested positive for COVID-19 by PCR on nasopharyngeal swab. Additional diagnostic procedures showed no signs of NET progression or other infections ( Table 1 , Supplemental Figures 1A-B) . After excluding other causes of thrombocytopenia, including DIC, bacterial sepsis and medication, he was diagnosed with COVID-19-associated ITP. He was treated with platelet transfusion, without increment, followed by intravenous immunoglobulins (IVIG) 1g/kg for 2 days. Platelet autoantibodies were tested positive. After an increase to 47x10 9 /L platelet count dropped to 19x10 9 /L when dexamethasone was started leading to a platelet count of 51x10 9 /L on day 27 ( Figure 1A ). Patient 2, a 66-year-old woman with hypertension, presented with petechiae, spontaneous epistaxis and increased blood loss from hemorrhoids since three weeks (Supplementary Figure 2) . Four weeks before admission she experienced fever, dyspnea and coughing during a week, followed by diarrhea and vomiting for several days. On admission, oropharyngeal swab PCR confirmed COVID-19 infection. Platelet counts at admission were 2x10 9 /L ( Table 1) . Additional diagnostics showed no signs of other infections, recent medication changes or antiphospholipid antibodies. Autoantibodies to platelets tested negative.

One unit of platelets was administered without increment. She was diagnosed with COVID-19-associated ITP and treated with dexamethasone 40mg daily for 4 days. Without any response on day 6 patient received IVIG resulting in a platelet count of 32x10 9 /L on day 22 ( Figure 1B ).

This article is protected by copyright. All rights reserved Patient 3, a 67-year-old man with a history of hypertension and diabetes mellitus presented with fever, coughing and dyspnea since 9 days. Blood counts were normal at admission and CT scan showed bilateral infiltrates. He was diagnosed with COVID-19 by PCR on oropharyngeal swab. Because of respiratory failure he was transferred to the ICU at day 2 and intubated on day 3. On day 10 a CT scan was repeated due to lack of respiratory improvement, which showed segmental pulmonary embolism for which he was treated with unfractionated heparin. Platelet counts dropped from 112x10 9 /L on day 10 to 3x10 9 /L on day 12 ( Figure 1C ). His clinical condition as well as other coagulation parameters remained stable and heparin-induced thrombocytopenia was excluded (Table 1) The goal of ITP treatment is preventing severe bleeding by providing a safe platelet count. 3 Treatment for COVID-19-associatied ITP may pose several issues. Commonly used treatment include IVIG, glucocorticoids or thrombopoietin receptor agonist (TPO-RAs). 3 IVIG are generally reserved for ITP patients who require rapid increase in platelet counts. Disadvantage of IVIG is that it is not curative and often poorly tolerated. 3 As IVIG inhibits the phagocytic capabilities of macrophages 4 , treatment with IVIG in an early stage of COVID-19 may be successful in treatment of COVID-19 infection. 5 Additionally, some COVID-19 patients who suffered deterioration of clinical symptoms have been salvaged by IVIG treatment. 6 

This article is protected by copyright. All rights reserved with dexamethasone because she had no symptoms of the COVID-19 infection over a week. She received a short course of high-dose dexamethasone rather than a longer period of prednisone which is associated with significant toxicities and a longer time to response. 8 COVID-19 infection may be accompanied by thrombocytopenia as a result of DIC, which is associated with a strongly increased risk of thromboembolism reported in 30% of the patients. 9 As treatment with TPO-RA has shown in selected cases to increase the risk of venous thromboembolism 10 , it should be used with caution in COVID-19 infection.

In conclusion, this is the first case series of 3 patients with a COVID-19-associated ITP. It is important to be aware of this severe complication of a COVID-19 infection and should be diagnosed and treated immediately. Failure of timely recognition may ultimately lead to fatal complications, as shown in one of our patients. Choice of treatment of ITP should be based balancing the risk of bleeding due to ITP versus potential deterioration of COVID-19-infection due to immunosuppressive therapy.

FNC and AJGJ designed the project. GB, FNC, FWGL and AJGJ analyzed the data and wrote the manuscript. GB, PGNJM, FWGL, PAWB and JH interpreted the data, commented, provided essential clinical input and reviewed the manuscript. All authors approved the final version of the manuscript.

The authors declare that there is no conflict of interest in carrying out this study.

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Thrombopoietin-receptor agonists for immune thrombocytopenia

This article is protected by copyright. All rights reserved

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved