Thrombotic events and the profile of hereditary thrombophilia factors in covid-19 patients

ABSTRACT

Background: The leading cause of mortality in more than 2.5 million COVID-19 patients is the development of acute respiratory distress syndrome and multiple organ failure associated with thrombotic events (TE). However, information on the nature of TE and the pathogenetic significance of hereditary thrombophilia factors in patients with COVID- 19 is still not completely understood. Aims: To study possible correlation of TE with the profile of FV 506R/Q, MTHFR 223A/V, F2 20210G/A, and PAI-1 4G/5G mutations in patients with COVID-19. Methods: Autopsy studies of 179 COVID-19 patients were performed from April to July 2020. Median age of the patients was 73 (range 37 to 99).Control healthy group was 71 individuals with median age of 56 (range 25 to 71). DNAs were isolated from formalin-fixed and paraffin-embedded spleen tissues using a QIAamp DNA FFPE Tissue Kit (QIAGEN, USA) according to the manufacturer's instructions. FV 506R/Q, MTHFR 223A/V, F2 20210G/A, and PAI-1 4G/5G alleles were assessed by an allele-specific real-time polymerase chain reaction. Results: According to the results of postmortem examinations, 87 patients with TE were identified (see Figure 1). Pulmonary artery thrombosis was detected in 37.9% (33/87) of cases. Pulmonary embolism (PE) was detected in 27.6% (24/87) of cases, of which 87.5% (21/24) PE was combined with deep vein thrombosis (DVT) of the lower extremities, in two patients - with intracardiac thrombi, and in one case - both with DVT and intracardiac thrombi. The frequency of PE in women was twice as high. The incidence of pulmonary vein thrombosis was 18.4%, with a predominance in men (62.5% vs. 37.5%). Isolated intracardiac thrombi were found in 11.5% (10/87) of patients, with a predominance in women. Hepatic vein thrombosis was 4.6% (4/87) of cases. Cerebral artery, coronary vessels, and mesenteric veins thrombosis was detected in 2.3% (2/87) of cases. FV 506R/Q, MTHFR 223A/V, F2 20210G/A, and PAI-1 4G/5G allele patterns were identified for 122 cases 62 of which had TE (see Figure 1). The group of patients with TE revealed a higher incidence of heterozygous genotypes MTHFR 223A/V compared to those without TE (40.3% versus 25%), but relatively similar to the control healthy group (40.3% vs. 39%), and higher incidence of heterozygous PAI-1 4G/5G compared to both groups (58% vs. 48.3% vs. 39%). On the contrary, the incidence of FV 506R/Q and F2 20210G/A heterozygotes was lower compared to the group without TE, and control healthy group. The incidence of homozygous MTHFR 223V and PAI-I 4G did not differ significantly between COVID-19 patients groups, however the latter genotype incidence was lower compared to control healthy group. Summary/Conclusion: Thrombosis and thromboembolism of arteries and veins of vital organs are detected in about half of patients who died from COVID-19. No significant trends in the distribution of genotypes of predisposition to thrombophilia between groups of COVID- 19 patients with TE and without them, and the control healthy group have been revealed. This is quite unexpected that patients who died from thrombotic complications do not show any signs of hereditary predisposition to thrombophilia. Especially concerning no bias in PAI-4G allele incidence. Probably we do not have enough sample strength to reveal possible differences. Therefore, establishing the role of hereditary thrombophilia factors in the development of COVID-19 associated TE requires further studies with an extended cohort of patients.