Vaccine-induced immune thrombotic thrombocytopenia: Updates in pathobiology and diagnosis.

Coronavirus disease 2019 (COVID-19) is a viral respiratory infection caused by the severe acute respiratory syndrome virus (SARS-CoV-2). Vaccines that protect against SARS-CoV-2 infection have been widely employed to reduce the incidence of symptomatic and severe disease. However, adenovirus-based SARS-CoV-2 vaccines can cause a rare, thrombotic disorder termed vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT often develops in the first 5 to 30 days following vaccination and is characterized by thrombocytopenia and thrombosis in unusual locations (e.g., cerebral venous sinus thrombosis). The diagnosis is confirmed by testing for anti-PF4 antibodies, as these antibodies are capable of platelet activation without any cofactor. It can be clinically challenging to differentiate VITT from a similar disorder called heparin-induced thrombocytopenia (HIT), since heparin is commonly used in hospitalized patients. VITT and HIT have similar pathobiology and clinical manifestations but important differences in testing including the need for PF4-enhanced functional assays and the poor reliability of rapid immunoassays for the detection of anti-platelet factor 4 (PF4) antibodies. In this review we summarize the epidemiology of VITT; highlight similarities and differences between HIT and VITT; and provide an update on the clinical diagnosis of VITT.

The COVID Complex: A Review of Platelet Activation and Immune Complexes in COVID-19.

Coronavirus disease 2019 (COVID-19) is a highly prothrombotic viral infection that primarily manifests as an acute respiratory syndrome. However, critically ill COVID-19 patients will often develop venous thromboembolism with associated increases in morbidity and mortality. The cause for this prothrombotic state is unclear but is likely related to platelet hyperactivation. In this review, we summarize the current evidence surrounding COVID-19 thrombosis and platelet hyperactivation. We highlight the fact that several studies have identified a soluble factor in COVID-19 patient plasma that is capable of altering platelet phenotype in vitro. Furthermore, this soluble factor appears to be an immune complex, which may be composed of COVID-19 Spike protein and related antibodies. We suggest that these Spike-specific immune complexes contribute to COVID-19 platelet activation and thrombosis in a manner similar to heparin-induced thrombocytopenia. Understanding this underlying pathobiology will be critical for advancement of future research and therapeutic options.

Physician experiences in management of COVID-19-associated coagulopathy in pregnancy: Communication from the ISTH SSC Subcommittee on Women's Health Issues in Thrombosis and Haemostasis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) occurs following infection with the potentially fatal, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Infection can be complicated by coagulopathy, at times featuring thrombocytopenia and thrombosis alongside other coagulation abnormalities, also termed COVID-19-associated coagulopathy (CAC). Data concerning CAC in pregnancy are limited. Better understanding of physician experiences is essential to identify current practice patterns and knowledge gaps. OBJECTIVES: To determine physician experiences and practice patterns regarding CAC in pregnancy. METHODS: Self-administered survey using the RedCap online platform; supported by the ISTH Subcommittee on Women's Health Issues in Thrombosis and Hemostasis. RESULTS: Seventy-five respondents fully or partially completed the survey. Of 1546 reported cases, disease severity was specified in 1298. Sixty-four percent of COVID-19 infections were mild, whereas 4% were severe. Of all cases, 1% developed CAC, with 65% classified as severe. The most frequent abnormalities included thrombocytopenia, elevated C-reactive protein, D-dimer, and lymphopenia. Low molecular weight heparin was the anticoagulant of choice in CAC and was provided by 77% of respondents, with 60% using standard prophylactic dosing. Thrombosis occurred in seven anticoagulated patients who were receiving standard prophylactic (four) or weight-based (three) dosing. Disease severity and additional thrombosis risk factors dictated anticoagulation duration. CONCLUSION: In the select population reported by our survey, CAC appears to be uncommon in pregnancy. Anticoagulation practices vary and may not reflect current guidelines. Venous thromboembolism was observed in some CAC patients despite prophylactic anticoagulation (including standard and weight-adjusted dosing). Urgent research is required to determine appropriate anticoagulant dosing and duration in pregnant women with COVID-19 infection.

Platelet-activating immune complexes identified in critically ill COVID-19 patients suspected of heparin-induced thrombocytopenia.

BACKGROUND: Thrombocytopenia and thrombosis are prominent in coronavirus disease 2019 (COVID-19), particularly among critically ill patients; however, the mechanism is unclear. Such critically ill COVID-19 patients may be suspected of heparin-induced thrombocytopenia (HIT), given similar clinical features. OBJECTIVES: We investigated the presence of platelet-activating anti-platelet-factor 4 (PF4)/heparin antibodies in critically ill COVID-19 patients suspected of HIT. PATIENTS/METHODS: We tested 10 critically ill COVID-19 patients suspected of HIT for anti-PF4/heparin antibodies and functional platelet activation in the serotonin release assay (SRA). Anti-human CD32 antibody (IV.3) was added to the SRA to confirm FcγRIIA involvement. Additionally, SARS-CoV-2 antibodies were measured using an in-house ELISA. Finally, von Willebrand factor (VWF) antigen and activity were measured along with A Disintegrin And Metalloprotease with ThromboSpondin-13 Domain (ADAMTS13) activity and the presence of anti-ADAMTS13 antibodies. RESULTS: Heparin-induced thrombocytopenia was excluded in all samples based on anti-PF4/heparin antibody and SRA results. Notably, six COVID-19 patients demonstrated platelet activation by the SRA that was inhibited by FcγRIIA receptor blockade, confirming an immune complex (IC)-mediated reaction. Platelet activation was independent of heparin but inhibited by both therapeutic and high dose heparin. All six samples were positive for antibodies targeting the receptor binding domain (RBD) or the spike protein of the SARS-CoV-2 virus. These samples also featured significantly increased VWF antigen and activity, which was not statistically different from the four COVID-19 samples without platelet activation. ADAMTS13 activity was not severely reduced, and ADAMTS13 inhibitors were not present, thus ruling out a primary thrombotic microangiopathy. CONCLUSIONS: Our study identifies platelet-activating ICs as a novel mechanism that contributes to critically ill COVID-19.