Pan-Pseudothrombocytopenia in COVID-19: A Harbinger for Lethal Arterial Thrombosis?
Pseudothrombocytopenia in the setting of COVID-19-associated coagulopathy prompts the question whether it is representative of increased platelet aggregation activity in vivo.
Patrick Kuhlman is a PGY-6 Resident, and Michael Goodman is an Assistant Professor, both in the Hematology- Oncology Fellowship Program; Julio Nasim is a PGY-5 Resident in the Infectious Disease Fellowship Program; all at Wake Forest University School of Medicine in Salem, North Carolina, and the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina. Correspondence: Patrick Kuhlman (pkuhlman@wakehealth.edu)
Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
In late 2019 a new pandemic started in Wuhan, China, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its similarities with the virus responsible for the SARS outbreak of 2003. The disease manifestations are named coronavirus disease 2019 (COVID-19).1
Pseudothrombocytopenia, or platelet clumping, visualized on the peripheral blood smear, is a common cause for artificial thrombocytopenia laboratory reporting and is frequently attributed to laboratory artifact. In this case presentation, a critically ill patient with COVID-19 developed pan-pseudothrombocytopenia (ethylenediaminetetraacetic acid [EDTA], sodium citrate, and heparin tubes) just prior to his death from a ST-segment elevation myocardial infarction (STEMI) in the setting of therapeutic anticoagulation during a prolonged hospitalization. This case raises the possibility that pseudothrombocytopenia in the setting of COVID-19 critical illness may represent an ominous feature of COVID-19-associated coagulopathy (CAC). Furthermore, it prompts the question whether pseudothrombocytopenia in this setting is representative of increased platelet aggregation activity in vivo.
Case Presentation
A 50-year-old African American man who was diagnosed with COVID-19 3 days prior to admission presented to the emergency department of the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina, with worsening dyspnea and fever. His primary chronic medical problems included obesity (body mass index, 33), type 2 diabetes mellitus (hemoglobin A1c 2 months prior of 6.6%), migraine headaches, and obstructive sleep apnea. Shortly after presentation, his respiratory status declined, requiring intubation. He was admitted to the medical intensive care unit for further management.
Notable findings at admission included > 20 mcg/mL FEU D-dimer (normal range, 0-0.56 mcg/mL FEU), 20.4 mg/dL C-reactive protein (normal range, < 1 mg/dL), 30 mm/h erythrocyte sedimentation rate (normal range, 0-25 mm/h), and 3.56 ng/mL procalcitonin (normal range, 0.05-1.99 ng/mL). Patient’s hemoglobin and platelet counts were normal. Empiric antimicrobial therapy was initiated with ceftriaxone (2 g IV daily) and doxycycline (100 mg IV twice daily) due to concern of superimposed infection in the setting of an elevated procalcitonin.
A heparin infusion was initiated (5,000 U IV bolus followed by continuous infusion with goal partial thromboplastin time [PTT] of 1.5x the upper limit of normal) on admission to treat CAC. Renal function worsened requiring intermittent renal replacement therapy on day 3. His lactate dehydrogenase was elevated to 1,188 U/L (normal range: 100-240 U/L) and ferritin was elevated to 2,603 ng/mL (normal range: 25-350 ng/mL) (Table). Initial neuromuscular blockade and prone positioning maneuvers were instituted to optimize oxygenation based on the latest literature for respiratory distress in the COVID-19 management.2
Intermittent norepinephrine infusion (5 mcg/min with a 2 mcg/min titration every 5 minutes as needed to maintain mean arterial pressure of > 65 mm Hg) was required for hemodynamic support throughout the patient’s course. Several therapies for COVID-19 were considered and were a reflection of the rapidly evolving literature during the care of patients with this disease. The patient originally received hydroxychloroquine (200 mg by mouth twice daily) in accordance with the US Department of Veterans Affairs (VA) institutional protocol between day 2 and day 4; however, hydroxychloroquine was stopped due to concerns of QTc prolongation. The patient also received 1 unit of convalescent plasma on day 6 after being enrolled in the expanded access program.3 The patient was not a candidate for remdesivir due to his unstable renal function and need for vasopressors. Finally, interleukin-6 inhibitors also were considered; however, the risk of superimposed infection precluded its use.
On day 7 antimicrobial therapy was transitioned to linezolid (600 mg IV twice daily) due to the persistence of fever and a portable chest radiograph revealing diffuse infiltrates throughout the bilateral lungs, worse compared with prior radiograph on day 5,suggesting a worsening of pneumonia. On day 12, the patient was transitioned to cefepime (1 gram IV daily) to broaden antimicrobial coverage and was continued thereafter. Blood cultures were negative throughout his hospitalization.
Given his worsening clinical scenario there was a question about whether or not the patient was still shedding virus for prognostic and therapeutic implications. Therefore, his SARS-CoV-2 test by polymerase chain reaction nasopharyngeal was positive again on day 18. On day 20, the patient developed leukocytosis, his fever persisted, and a portable chest radiograph revealed extensive bilateral pulmonary opacities with focal worsening in left lower base. Due to this constellation of findings, a vancomycin IV (1,500 mg once) was started for empirical treatment of hospital-acquired pneumonia. Sputum samples obtained on day 20 revealed Staphylococcus aureus on subsequent days.
From a hematologic perspective, on day 9 due to challenges to maintain a therapeutic level of anticoagulation with heparin infusion thought to be related to antithrombin deficiency, anticoagulation was changed to argatroban infusion (0.5 mcg/kg/min targeting a PTT of 70-105 seconds) for ongoing management of CAC. Although D-dimer was > 20 mcg/mL FEU on admission and on days 4 and 5, D-dimer trended down to 12.5 mcg/mL FEU on day 16.
Throughout the patient’s hospital stay, no significant bleeding was seen. Hemoglobin was 15.2 g/dL on admission, but anemia developed with a nadir of 6.5 g/dL, warranting transfusion of red blood cells on day 22. Platelet count was 165,000 per microliter on admission and remained within normal limits until platelet clumping was noted on day 15 laboratory collection.
Hematology was consulted on day 20 to obtain an accurate platelet count. A peripheral blood smear from a sodium citrate containing tube was remarkable for prominent platelet clumping, particularly at the periphery of the slide (Figure 1). Platelet clumping was reproduced in samples containing EDTA and heparin. Other features of the peripheral blood smear included the presence of echinocytes with rare schistocytes. To investigate for presence of disseminated intravascular coagulation on day 22, fibrinogen was found to be mildly elevated at 538 mg/dL (normal range: 243-517 mg/dL) and a D-dimer value of 11.96 mcg/mL FEU.
On day 22, the patient’s ventilator requirements escalated to requiring 100% FiO2 and 10 cm H20 of positive end-expiratory pressure with mean arterial pressures in the 50 to 60 mm Hg range. Within 30 minutes an electrocardiogram (EKG) obtained revealed a STEMI (Figure 2). Troponin was measured at 0.65 ng/mL (normal range: 0.02-0.06 ng/mL). Just after an EKG was performed, the patient developed a ventricular fibrillation arrest and was unable to obtain return of spontaneous circulation. The patient was pronounced dead. The family declined an autopsy.
