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Induced Thrombocytopenia: a Rare Manifestation of COVID-19 Katherine Julian ‍ ‍ ,1 Donald Bucher,2 Rohit Jain2

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Induced Thrombocytopenia: a Rare Manifestation of COVID-19 Katherine Julian ‍ ‍ ,1 Donald Bucher,2 Rohit Jain2 Case report BMJ Case Rep: first published as 10.1136/bcr-2021-243315 on 24 May 2021. Downloaded from Autoimmune heparin- induced thrombocytopenia: a rare manifestation of COVID-19 Katherine Julian ,1 Donald Bucher,2 Rohit Jain2 1Penn State College of Medicine, SUMMARY antibody seroconversion. In addition, other causes Hershey, Pennsylvania, USA We describe the case of a 65- year- old male who of thrombocytopenia must be excluded.5 2 Department of Internal presented to an outside hospital for shortness of breath, Although rare, spontaneous HIT is character- Medicine, Penn State Health nausea and vomiting 8 days after testing positive for ised as an autoimmune HIT that develops in the Milton S Hershey Medical absence of heparin exposure.7 The pathogenesis Center, Hershey, Pennsylvania, COVID-19. Initial workup revealed massive bilateral USA pulmonary emboli and thrombocytopenia. The patient of this condition is incompletely understood, but was then admitted to our hospital, received an inferior several proposed mechanisms exist. First, auto- Correspondence to vena cava filter and initially started on argatroban for immune HIT antibodies may activate platelets Katherine Julian; autoimmune heparin- induced thrombocytopenia (HIT) through recognition of non- heparin glycosamino- kjulian1@ pennstatehealth. prophylaxis. On hospital stay day 6, labs revealed a glycans and PF4 on platelet surfaces. Second, acti- psu. edu diagnosis of HIT in the setting of COVID-19. This case vated platelets release polyphosphates that are able highlights the rare occurrence of a patient developing to bind to PF4 and autoimmune HIT antibodies. Accepted 7 May 2021 HIT without heparin exposure and in the setting of a Third, autoimmune HIT antibodies are able to novel infectious agent, COVID-19. strongly bind to PF4, and the resulting PF4–IgG complexes result in larger platelet-activating immune complexes.8 HIT is a potentially life- threatening complica- BACKGROUND tion of heparin therapy due to its association with The COVID-19 pandemic has manifested as a venous thromboemboli, such as pulmonary embo- major public health crisis in the USA by infecting lism or deep vein thrombosis. The mortality rate more than 30 million patients and resulting in 9 of HIT is approximately 20%–30%, and compli- over 500 000 deaths.1 Infection with SARS- CoV-2 cations include deep vein thrombosis, pulmo- continues to challenge healthcare providers due nary embolism, myocardial infarction, end- organ to its wide variety of clinical manifestations and damage and death. complications. In addition to the respiratory symp- toms displayed by most patients with COVID-19, http://casereports.bmj.com/ haematological manifestations remain a significant CASE PRESENTATION clinical concern. In the setting of COVID-19, a A- 65- year old male with medical history significant recent meta- analysis found that thrombocytopenia for psoriatic arthritis, hypertension, urinary reten- is associated with increased risk of severe disease tion and recent COVID-19 infection presented to 2 and mortality. In addition, many other haemato- an outside hospital 8 days after testing positive for logical abnormalities can be observed with COVID- COVID-19 with dyspnoea, nausea and vomiting. 19. One such rare complication is the development Initial workup revealed massive bilateral pulmo- 3 of heparin- induced thrombocytopenia (HIT). nary emboli with D- dimer of 15.39 (normal<0.54) HIT is a prothrombotic type II hypersensitivity and thrombocytopenia with platelet count of 6 k/μL on September 24, 2021 by guest. Protected copyright. reaction characterised by the development of anti- (normal 150–450 k/μL). The patient was referred to bodies against complexes of platelet factor 4 (PF4) our institution for platelet transfusion, which was and heparin.4 The resulting heparin–PF4–IgG not available at the outside hospital, and consid- complex activates platelets and results in the release eration for advanced interventions for pulmonary of prothrombotic platelet-derived microparticles, embolism. Imaging showed right ventricular strain platelet consumption and subsequent thrombocy- on transthoracic echocardiogram and deep vein topenia. Additionally, the immune complex causes thromboses in the left lower extremities visual- antibody- mediated endothelial injury and leads to ised via Doppler ultrasound. The patient initially further activation of the coagulation cascade.5 received cefepime, vancomycin, dexamethasone, The incidence of HIT in patients exposed to intravenous immunoglobulin (IVIG), 2 L normal heparin is between 0.2% and 5%, and occurs saline, platelet transfusion and 3 L nasal cannula more commonly with exposure to unfractionated supplemental oxygen. On presentation to our © BMJ Publishing Group heparin (UFH) than low molecular weight heparin hospital, the patient was deemed to be a poor Limited 2021. No commercial 6 re-use . See rights and (LMWH). The diagnosis is made clinically by taking surgical candidate due to his severe thrombocyto- permissions. Published by BMJ. several factors into account. These include baseline penia. In order for an inferior vena cava filter to be platelet count, drop to platelet count to <100 k/ placed, the patient’s platelets needed to be >50 k/ To cite: Julian K, Bucher D, Jain R. BMJ Case Rep μL or >50% from baseline, onset of thrombocyto- μL, and therefore, the decision to transfuse platelets 2021;14:e243315. penia within 5–10 days after initiation of heparin, was made. The aetiology of the thrombocytopenia doi:10.1136/bcr-2021- acute thrombotic event, resolution of thrombo- was unclear at this time. His platelets rose from 6 243315 cytopenia after cessation of heparin and (+) HIT to 77 k/μL after the transfusion but subsequently Julian K, et al. BMJ Case Rep 2021;14:e243315. doi:10.1136/bcr-2021-243315 1 Case report BMJ Case Rep: first published as 10.1136/bcr-2021-243315 on 24 May 2021. Downloaded from to the novelty of COVID-19 and unknown infection sequelae, the initial workup revealing thrombocytopenia and presenta- tion of multiple pulmonary emboli, HIT antibody screening was ordered to rule out this diagnosis. Two key diagnostic tests used to confirm a HIT diagnosis are the HIT antibody assay and SRA. The HIT antibody assay has a specificity of >95% and measures IgG antibodies generated against the PF4–heparin complex; however, many patients develop these antibodies but do not develop HIT.10 The SRA test is much more sensitive (88%– 100%) for a HIT diagnosis by measuring the amount of radio- active serotonin released by platelets that have been activated by heparin. A positive SRA test shows >20% release of serotonin when low-dose heparin is mixed with the patient’s serum and greater than 50% decrease when the patient’s serum is exposed 10 Figure 1 Platelet count throughout hospital admission labelled with to high- dose heparin. A positive test therefore indicates that relevant interventions. IVIG, intravenous immunoglobulin. the platelet activation is heparin dependent. In this patient’s case, both the HIT antibody and SRA yielded positive results. dropped back to 30 k/μL. Platelet counts for the patient’s entire hospital stay are depicted in figure 1. DIFFERENTIAL DIAGNOSIS We considered several diagnoses for this patient’s thrombo- Anticoagulation for pulmonary embolism was initially held cytopenia. First, we considered thrombotic thrombocyto- due to thrombocytopenia, but the patient then received arga- penic purpura (TTP), a disorder characterised by deficiency troban 50 mg for prophylaxis of HIT. Labs revealed elevated of ADAMTS13 and small vessel thrombosis. Because acquired haptoglobin at 294 mg/dL (normal 30–200 mg/dL), elevated TTP is more common in patients with a history of autoimmune lactate dehydrogenase at 480 units/L (normal 135–250 units/L), disease, we thought this may be likely due to the patient’s history normal reticulocyte count at 56.1 k/μL (normal 16.7–96.7 k/ of psoriatic arthritis. However, the peripheral blood smear did μL), normal ADAMTS13 at >100% (normal≥70%) and normal not reveal any morphological evidence of microangiopathic bone marrow biopsy. Pertinent labs are outlined in table 1. The haemolytic anaemia; his haptoglobin level was elevated; and patient did not start remdesivir for COVID-19 due to dyspnoea his ADAMTS13 level was normal (>100, normal≥70). We explained by pulmonary emboli. This patient continued intrave- also considered a myelodysplastic syndrome, but bone marrow nous dexamethasone 40 mg/day for 7 days and received six inter- biopsy revealed no abnormalities. Third, immune thrombo- mittent doses of IVIG throughout his hospital stay. cytopenic purpura (ITP) was considered due to the patient’s On hospital stay day 7, labs revealed (+) HIT antibody severe thrombocytopenia. While the clinical suspicion for ITP and (+) serotonin reactive assay (SRA) with >20% positivity was initially very high due to the patient’s severe thrombocyto- http://casereports.bmj.com/ at low heparin exposure and <20% (6%) positivity at high penia, the patient experienced only a modest improvement in heparin exposure. Both findings are consistent with a diagnosis platelet count after starting dexamethasone treatment, making of HIT. The patient was still taking intravenous argatroban at this diagnosis less likely. Disseminated intravascular coagulop- this time but needed to transition to an oral anticoagulant and athy (DIVC) was also considered, given this patient’s presenta- was discharged on apixaban 5 mg two times per day. He was tion of thrombocytopenia
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