key: cord-1017930-hq519xef
authors: Jacobs, Jeremy W.; Adkins, Brian D.; Walker, Shannon C.; Booth, Garrett S.; Wheeler, Allison P.
title: Coagulation factor inhibitors in COVID‐19: From SARS‐CoV‐2 vaccination to infection
date: 2022-04-14
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12700
sha: e9300e916ebaeb2ca857a10aa09f60e9e3bce39a
doc_id: 1017930
cord_uid: hq519xef

BACKGROUND: Recent reports have highlighted patients with COVID‐19 and vaccine recipients diagnosed with coagulation factor inhibitors. This is challenging. as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has been identified as a prothrombotic risk factor, with heparin treatment decreasing mortality. However, both infection and vaccination have been associated with immune‐mediated hematologic abnormalities, including thrombocytopenia, further rendering these groups at risk for both hemorrhagic and thrombotic events. OBJECTIVES: We sought to characterize the incidence and clinical findings of coagulation factor inhibitors in patients with COVID‐19 and vaccine recipients. METHODS: We queried the US Centers for Disease Control and Prevention’s Vaccine Adverse Event Reporting System (VAERS), a publicly accessible database, for reports of potential bleeding episodes or coagulation disturbances associated with SARS‐CoV‐2 vaccination. We performed an additional comprehensive literature review to identify reports of SARS‐CoV‐2 infection or vaccination‐associated coagulation factor inhibitors. RESULTS: VAERS data showed 58 cases of coagulation factor inhibitors, suggesting a rate of 1.2 cases per 10 million doses. A total of 775 articles were screened and 15 were suitable for inclusion, with six reports of inhibitors after vaccination and nine reports of inhibitors after infection. Inhibitor specificity for factor VIII was most common. Among reported cases, two patients expired due to hemorrhage, one following infection and one following vaccination. CONCLUSION: The incidence of coagulation factor inhibitors in patients with SARS‐CoV‐2 vaccination and infection appears similar to the general population. Nonetheless, given the importance of heparin therapy in treating hospital patients, recognition of inhibitors is important.

• Coagulation factor inhibitors are rare in the general population at 1.5 per million annually.

• We queried the Centers for Disease Control and Prevention's Vaccine Adverse Event (VAERS) database of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination through December 27, 2021.

• There were 58 factor inhibitor reports in VAERS and rare literature case reports with COVID-19.

• The rate of factor inhibitors in SARS-CoV-2 vaccination is 1.2 per 10 million doses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, is capable of potentiating numerous hematologic derangements in those infected. Much research has focused on mechanisms by which this virus contributes to a prothrombotic state; however, there is mounting evidence that other hematologic anomalies, such as immune thrombocytopenia, 1 autoimmune hemolytic anemia, 2 and vaccine-induced thrombosis and thrombocytopenia 3 may also be associated with SARS-CoV-2 infection and/or vaccination. Hypotheses for development of these immune dyscrasias include immune hyperstimulation, molecular mimicry, and antibody cross reactivity with antigens on platelets and red blood cells. 4, 5 Despite significant research and insight gained into the mechanisms of these presumptive autoimmune cytopenic phenomena, little is known about the potential for SARS-CoV-2 to elicit a severe bleeding phenotype secondary to autoreactivity. [6] [7] [8] [9] Several case reports have recently described acquired coagulation factor inhibitors in the setting of SARS-CoV-2 infection 7-9 or following SARS-CoV-2 vaccination. [10] [11] [12] [13] While few cases have been reported, determining whether these hematologic abnormalities are related to SARS-CoV-2 infection or vaccination, or are simply temporal associations, is important as a recent randomized controlled trial demonstrated decreased mortality with therapeutic-dose heparin for patients admitted with COVID-19 and elevated D-dimers. 14 Therefore, to provide insight into this potential relationship between acquired immune-mediated mechanisms underlying bleeding phenotypes and COVID-19, we reviewed all documented cases of patients with autoantibodies specifically directed against blood coagulation factors in the setting of SARS-CoV-2 infection or vaccination. The epidemiology, coagulation parameters, and patient outcomes were documented. Furthermore, we assessed the US Centers for Disease

to ascertain an estimate of potential cases not published in the medical literature and estimate the risk per vaccine dose.

The CDC's VAERS database was queried to assess for reports of potential bleeding episodes or coagulation laboratory abnormalities associated with receipt of a COVID- 19 Figure 1 ). Journal titles and abstracts were screened by two authors according to specific inclusion criteria, and all included publications were coded into relevant categories.

All cases describing the development of a blood coagulation factor inhibitor following a SARS-CoV-2 vaccine dose reported to the CDC's VAERS database were included, regardless of time interval from vaccination to confirmation of coagulation abnormality. We also included all case reports, case series, letters and correspondence, and case-control and cohort studies with available and relevant clinical data in the published literature. For cases that met inclusion criteria, we abstracted demographic, laboratory, treatment, and outcomes data.

To analyze outcomes, a binary parameter of either alive or deceased at the time of the report was used. If the suspected cause of death was reported by the original authors, we included the data for those patients reported to be deceased. The outcome of cases reported in the CDC's VAERS database was either "deceased" or "not deceased" at the time of the submitted report.

All statistical analyses were conducted using PRISM version 9.2.0 (GraphPad Software, San Diego, CA, USA). Distribution was nonnormal using a D'Agostino-Pearson test, and groups were compared using Mann-Whitney tests. Contingency tables were assessed using Fisher exact test. P <.05 was considered significant. 

Thirty-five articles fulfilled criteria for comprehensive screening to assess relevance for inclusion in the analysis (Figure 1) . A total of 15 articles were included in the study, 6 of which described coagulation factor inhibitors associated with SARS-CoV-2 vaccination (Table 2) . 

Immune thrombocytopenia secondary to COVID-19: a systematic review

COVID-19 and immune-mediated RBC

COVID-19 vaccination and immune thrombocytopenia

Clinical characteristics, management and outcome of COVID-19-associated immune thrombocytopenia: a French multicentre series

The SARS-CoV-2 as an instrumental trigger of autoimmunity

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection

The first case of acquired hemophilia A associated with SARS-CoV-2 infection

De novo acquired hemophilia as an immune dysregulation phenomenon following SARS-CoV-2 infection

A case of acquired hemophilia A following SARS-CoV-2 infection

A case report of acquired hemophilia following COVID-19 vaccine

First and fatal case of autoimmune acquired factor XIII/13 deficiency after COVID-19/SARS-CoV-2 vaccination

A case of acquired haemophilia A in a 70-year-old post COVID-19 vaccine

Autoimmunity after coronavirus disease 2019 (COVID-19)vaccine: a case of acquired hemophilia A

Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediatedose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial

Autoimmune-and complement-mediated hematologic condition recrudescence following SARS-CoV-2 vaccination

Dark skin"-acquired hemophilia A after Pfizer-BIONTECH COVID-19 vaccine

An 89-year-old man with COVID-19-associated coagulopathy presenting with a prolonged partial thromboplastin time, lupus anticoagulant, and a high titer of factor VIII Inhibitor

Severe acquired haemophilia associated with asymptomatic SARS-CoV-2 infection

Acquired factor V inhibitor in the setting of coronavirus disease 2019 infection

Acquired factor V inhibitor after coronavirus disease 2019 (COVID-19)

Transient acquired factor XII deficiency associated with moderately severe Covid-19 pneumonia

Acquired factor XI deficiency during SARS-CoV-2 infection: not only thrombosis

Acquired inhibitors of clotting factors: AICE recommendations for diagnosis and management

Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

Acquired haemophilia A in association with influenza A and urinary tract infection

An acquired factor VIII inhibitor in a patient with HIV and HCV: a case presentation and literature review

Acquired factor VIII haemophilia following influenza vaccination

Hadid T, Kafri Z, Al-Katib A. Coagulation and anticoagulation in COVID-19

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial

Coagulation factor inhibitors in COVID-19: From SARS-CoV-2 vaccination to infection

of available data from currently published medical literature and the VAERS database system, and is the first study assessing acquired coagulation factor inhibitors in patients with SARS-CoV-2 infection and in SARS-CoV-2-vaccinated individuals.Monitoring hemostasis in patients with COVID-19 remains complex, with the standard-of-care continually evolving. The incidence of coagulation factor inhibitors in patients with SARS-CoV-2 infection appears to be similar to the cumulative incidence in the general population. Nonetheless, given the thromboembolic risk and importance of heparin therapy, careful assessment and monitoring of coagulation status is a necessity in this high-risk population. Though the development of these inhibitors is rare in individuals with SARS-CoV-2 infection and following SARS-CoV-2 vaccination, clinicians and laboratories should be aware of this potential adverse event and be familiar with testing and management of patients with these inhibitors.

The authors declare no conflicts of interest. Allison P. Wheeler @allisonp1979