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.
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Pseudothrombocytopenia, or platelet clumping (agglutination), is estimated to be present in up to 2% of hospitalized patients.4 Pseudothrombocytopenia was found to be the root cause of thrombocytopenia hematology consultations in up to 4% of hospitalized patients.5 The etiology is commonly ascribed to EDTA inducing a conformational change in the GpIIb-IIIa platelet complex, rendering it susceptible to binding of autoantibodies, which cause subsequent platelet agglutination.6 In most cases (83%), the use of a non-EDTA anticoagulant, such as sodium citrate, resolves the platelet agglutination and allows for accurate platelet count reporting.4 Pseudothrombocytopenia in most cases is considered an in vitro finding without clinical relevance.7 However, in this patient’s case, his pan-pseudothrombocytopenia was temporally associated with an arterial occlusive event (STEMI) leading to his demise despite therapeutic anticoagulation in the setting of CAC. This temporal association raises the possibility that pseudothrombocytopenia seen on the peripheral blood smear is an accurate representation of in vivo activity.
Pseudothrombocytopenia has been associated with sepsis from bacterial and viral causes as well as autoimmune and medication effect.4,8-10 Li and colleagues reported transient EDTA-dependent pseudothrombocytopenia in a patient with COVID-19 infection; however, platelet clumping resolved with use of a citrate tube, and the EDTA-dependent pseudothrombocytopenia phenomenon resolved with patient recovery.11 The frequency of COVID-19-related pseudothrombocytopenia is currently unknown.
Although the understanding of COVID-19-associated CAC continues to evolve, it seems that initial reports support the idea that hemostatic dysfunction tends to more thrombosis than to bleeding.12 Rather than overt disseminated intravascular coagulation with reduced fibrinogen and bleeding, CAC is more closely associated with blood clotting, as demonstrated by autopsy studies revealing microvascular thrombosis in the lungs.13 The D-dimer test has been identified as the most useful biomarker by the International Society of Thrombosis and Hemostasis to screen for CAC and stratify patients who warrant admission or closer monitoring.12 Other identified features of CAC include prolonged prothrombin time and thrombocytopenia.12
There have been varying clinical approaches to CAC management. A retrospective review found that prophylactic heparin doses were associated with improved mortality in those with elevated D-dimer > 3.0 mg/L.14 There continues to be a diversity of varying clinical approaches with many medical centers advocating for an intensified prophylactic twice daily low molecular-weight heparin compared with others advocating for full therapeutic dose anticoagulation for patients with elevated D-dimer.15 This patient was treated aggressively with full-dose anticoagulation, and despite his having a down-trend in D-dimer, he suffered a lethal arterial thrombosis in the form of a STEMI.
Varatharajah and Rajah believe that CAC is more closely aligned with endotheliopathy-associated vascular microthrombotic disease (EA-VMTD).16 EA-VMTD involves a disequilibrium state between insufficient ADAMTS13 enzyme and excessive exocytosis of ultralarge von Willebrand factor (ULvWF) multimers from endothelial cells affected by COVID-19. This theory endorses that ULvWF multimers cause platelet adhesion and subsequent rapid platelet activation, causing platelet aggregation and formation of microthrombi.17 As these platelet aggregates grow to a certain point, they can no longer remain adhered to ULvWF, causing these platelet aggregates to be released into the circulation and causing thrombotic sequelae.16 Therefore, a plausible explanation for the patient’s pan-pseudothrombocytopenia may be the detection of these circulating platelet aggregates, which, in turn, was the same process leading to his STEMI. Interestingly, this patient’s fatal arterial event occurred in the presence of therapeutic anticoagulation, raising the question of whether other therapeutic interventions to treat CAC, such as further antithrombotic therapy (eg, aspirin, clopidogrel) or novel strategies would be of benefit.
