Heparin Induced Thrombocytopenia in Patients with COVID-19

Abstract

Background Acute respiratory and renal failure as well as systemic coagulopathy are critical aspects of the morbidity and mortality in patients with COVID-19. Heparin Induced Thrombocytopenia (HIT) occurs when IgG antibodies form against platelet factor 4-Heparin complex, resulting in platelet activation and removal, leading to a prothrombotic state. Studies have shown that only 6% who are investigated serologically for HIT actually have the diagnosis. Methods A retrospective analysis was performed on all COVID-19 positive patients hospitalized between March and June 2020. Patients with suspicion for HIT were tested for HIT antibodies with IgG-specific platelet factor 4(PF4)-dependent enzyme immunoassay (EIA). Confirmatory testing with serotonin release assay (SRA) and heparin-induced platelet aggregation were used in cases with intermediate or low optical density (OD) with EIA positivity (EIA+). Due to rarity of disease, a through literature review on HIT in COVID-19 patients was also analyzed. Results Incidence of EIA + in COVID-19 patients was 0.6%, significantly higher than in the general population 0.2% (p < 0.0001). The incidence of thromboembolic events in EIA + patients was 87.5%, significantly higher than the rate of 10.90% in all COVID-19 patients (p < 0.0001). The mortality rate in EIA + patients was 50%, significantly greater than the mortality rate of 12% in all hospitalized COVID-19 patients (p = 0.0011). Serological confirmation of HIT diagnosis was 37.5% which is significantly higher than confirmation of HIT in nonCOVID-19 patients 6% (p < 0.0001). Of 39 HIT antibody positive patients in the literature, 23.07% had positive confirmatory testing (6 SRA, 3 HIPAA) which is significantly higher than 5.6% in the general population (p = 0.00001). The incidence of thrombosis in EIA + COVID-19 patients in the literature was 56.4% which is significantly higher than reported rates of thrombotic events in in all COVID-19 patients in the literature at 4.8%1 (p = 0.00001). Conclusion Our study indicates incidence of HIT is higher in the COVID-19 population. This can be attributed to the cytokine storm and severe sepsis seen in critically ill COVID-19 patients. Our study also suggests that development of HIT can contribute to increased risk for thromboembolic events as well as mortality of COVID-19 patients, however, our study is limited due to small sample size.

COVID‐19 vaccine‐associated immune thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a new syndrome

“…In addition, PF4 binds directly to bacteria thus creating a neoantigen which is targeted by anti‐PF4/heparin or anti‐PF4/polyanion antibodies to form immune complexes that play a key role in antibacterial host defense 26 . A similar mechanism could also be implicated in the antiviral response to SARS‐CoV‐2 infection, considering that non‐platelet‐activating and platelet‐activating anti‐PF4/heparin antibodies have been detected by several investigators in COVID‐19 patients 28‐30 …”

Trombocitopenia como efecto secundario por la administración de heparinas en los pacientes de COVID-19. Una revisión sistemática

“…De los 12 estudios seleccionados, 4 eran estudios de cohorte y 8 casos clínicos o series de casos (Cuadro 1), el tamaño de las cohortes presentadas osciló de 86 y de 1265. 14,15 De las cuatro cohortes se contaba con un total de 21 pacientes confirmados con pruebas de SRA o HIPA, las cuales tenían un resultado confirmatorio positivo y negativo, dentro de los casos clínicos y series de caso se reportaron 12 pacientes cuyos estudios de laboratorio confirmaban HIT son SRA o HIPA con resultados eran positivos y solo uno confirmó HIT con SRA negativo y dos casos clínicos que no reportaban pruebas serológicas confirmatorias para HIT sino que se hizo el diagnóstico solo con…”

“…16,22 De los inmunoensayos en un caso usaron anti-IgG, 20 el resto de los casos clínicos reportaron inmunoensayos utilizado la prueba ELISA con resultados positivos y pruebas confirmatorias positivas a excepción de uno que reportaba pruebas serológicas negativas. 22 Por otro lado, en los estudios de cohorte no reportaron un historial clínico por lo que se optó por informar el IMC dado que dos estudios tenían información disponible de este dato, 14,15 en ambos estudios sus pacientes tenían sobrepeso, obesidad y solo uno tenía obesidad mórbida con un IMC de 47. 14 En todas las cohortes tenían infor-mación suficiente para caracterizar y agrupar los datos de tipo de heparina en donde al 43% se le administró HNF, al 19% HBPM y en 38% utilizaron ambas heparinas, en una cohorte evaluaron únicamente casos bajo terapia de HNF y que en promedio tuvieron una exposición a la heparina de 11.7 días (RIC 7, 15).…”

“…En las pruebas confirmatorias para HIT dos de los estudios contaban con resultados positivos y dos reportaban pruebas con pruebas confirmatorias negativas. 15,25 dIscusIón En esta revisión sistemática se analizaron 12 estudios que cumplían con los criterios de elegibilidad. Se separaron las cohortes de los casos y series de casos clínicos para obtener promedios y porcentajes de los datos en común de los pacientes que se confirmaron con HIT (Cuadro 4).…”

Lessons learnt from COVID‐19 coagulopathy

“…Another immune problem which was observed in the COVID-19 coagulopathy setting is the well-known therapeutic complication of heparininduced thrombocytopenia (HIT). Although this adverse effect with the use of heparin can occur in COVID-19 patients as much as in the pre-COVID-19 era with the widespread use of heparin, HIT incidence has been suggested to be much higher than in the critically ill non-COVID-19 patients [55,56]. Nazy et al recently described findings in 10 critically ill COVID-19 patients who developed thrombocytopenia while receiving heparin and thus a clinical suspicion for HIT was raised [57].…”