Role of complement factor H-related protein 5 in venous thromboembolism and COVID-19

A recent article posted to the medRxiv* preprint server discussed the role of complement factor H-related protein 5 (CFHR5) in venous thromboembolism (VTE) patients and hospitalized coronavirus disease 2019 (COVID-19) patients.

Study: Elevated plasma Complement Factor H Regulating Protein 5 is associated with venous thromboembolism and COVID-19 severity. Image Credit: Nhemz/Shutterstock
Study: Elevated plasma Complement Factor H Regulating Protein 5 is associated with venous thromboembolism and COVID-19 severity. Image Credit: Nhemz/Shutterstock

Background

VTE, which includes both pulmonary embolism (PE) and deep vein thrombosis (DVT), is a multi-cause illness with devastating long- and short-term consequences. VTE has a significant death rate in the initial year, particularly in the first 30 days, and a strong probability of recurrence, with a 10-year cumulative incidence rate of 25%.

VTE diagnosis is difficult since the underlying common risk factors and clinical manifestations, specifically in the case of PE, can be confused with a variety of other illnesses. Improved techniques based on plasma biomarkers are needed in clinical practice for VTE risk prediction and diagnosis. Furthermore, thrombotic effects are a characteristic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hospitalized patients during the ongoing COVID-19 pandemic.

About the study

In the present study, the scientists tried to find new biomarkers linked with acute VTE that might be associated with the etiology of the disease.

The authors screened plasma from patients with suspected acute VTE from venous thromboembolism biomarker study (VEBIOS) and VEBIOS emergency room (ER) study via multiplex proteomics profiling. The scientists further performed a case-control evaluation of individuals monitored after stopping anticoagulant therapy for a first VTE. 

The team replicated the findings in five independent investigations: 1) Swedish Karolinska Age-Adjusted D-Dimer study (DFW-VTE study), 2) French FARIVE study, 3) Riesgo de Enfermedad Tromboembólica Venosa (RETROVE) study, 4) Marseille Thrombosis Association study (MARTHA), and 5) COVID-19 biomarker and Immunity (COMMUNITY) study, comprising 1,272 controls and 1,137 patients. Further, among 2,967 subjects, the team conducted a genome-wide association study (GWAS).

Findings

The study results revealed that a regulator of the alternative complement activation route, CFHR5, was an acute VTE-associated biomarker, which was also linked to VTE etiology. Three additional case-control or cohort studies confirmed the link between CFHR5 and present or prior VTE. The scientists also discovered a link with the likelihood of unprovoked VTE recurrence. Additionally, the researchers identified a substantial signal connected with CFHR5 levels in the CFHR1-5 gene cluster locations across the genome.

The results further showed that CFHR5 has a direct role in pro-thrombotic phenotype induction by affecting platelet activation. The researchers demonstrated that in acute COVID-19, elevated CFHR5 was linked to the extent of prognosis and respiratory insufficiency. The findings suggested that CFHR5 might be used as a clinical biomarker for VTE risk prediction and diagnosis, bolstering the theory that complement regulation plays a role in VTE pathogenesis.

In the acute VTE scenario, the researchers detected no connection between D-dimer and CFHR5, indicating that higher D-dimer concentration upon diagnosis was not due to thrombus development. Nevertheless, investigators discovered a significant association between CFHR5 and D-dimer levels in patients followed up after finishing therapy for a first VTE, yet not in controls. Since D-dimer has been linked to an elevated risk of first and recurrent VTE, these findings support a relationship between subclinical coagulability and CFHR5 in these individuals at follow-up, presumably because of persisting risk factors.

In the VEBIOS coagulation investigation, complement 3 (C3) was linked to past VTE, yet not with acute VTE in the VEBIOS ER trial. When corrected for C3 in the VEBIOS coagulation investigation, the link between CFHR5 and prior VTE remained substantial. At one end of chromosome 1q31.3 (chr1q31.3), the CFHR5 locus was part of a 350-kb gene cluster that also contains the CFHR4, CFHR2, CFHR3, CFH, and CFHR1 loci. 

The scientists discovered rs10737681, which maps between the CFHR1 and CFHR4 genes and has a genome-wide correlation with CFHR5 levels. Unfortunately, neither MARTHA nor RETROVE imputed rs143410348, and therefore, the researchers were unable to investigate its connection with CFHR5 plasma levels in the current meta-analysis. Nonetheless, in FARIVE, where rs143410348 was imputed, its correlation with CFHR5 levels was less apparent than rs10737681.

Conclusions

The study findings discovered a modulator of the alternative pathway of complement stimulation, CFHR5, to be a new VTE-related plasma biomarker. The authors found a genome-wide drastic protein quantitative trait loci (pQTL) signal on chr1q31.3 correlated with CFHR5 levels. Higher CFHR5 concentrations were linked to enhanced thrombin production in patient plasma, and recombinant CFHR5 improved platelet activation in vitro. Moreover, the investigators discovered that baseline CFHR5 values were linked to a short-term prognosis of acute SARS-CoV-2 severity, characterized as the highest respiratory assistance level required throughout the hospital stay.

Collectively, the present data suggest that the alternate route of complement activation has a clinically significant role in the etiology of VTE and pulmonary consequences in acute COVID-19. As a result, CFHR5 might be a diagnostic or risk-predicting plasma biomarker for VTE and acute SARS-CoV-2 infection. Of note, the authors emphasize the requirement of additional investigations to understand the mechanism of the functional role of CFHR5 in VTE development.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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