Coagulopathy in Acute Puumala Hantavirus Infection

Abstract

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections between coagulation pathways and inflammatory mediators, as well as complement and kallikrein-kinin systems, have been reported. The bleeding symptoms are usually mild. PUUV-infected patients also have an increased risk for disseminated intravascular coagulation (DIC) and thrombosis.

Keywords: DIC; Puumala hantavirus; acute kidney injury; coagulation; complement system; endothelium; fibrinolysis; platelet.

Figure 1

Vasculopathy in HFRS. Hantaviruses infect endothelial cells (EC) lining the vasculature. The infected ECs express viral Gn/Gc glycoproteins and upregulate ICAM-1 adhesion molecules, to which circulating platelets and neutrophils adhere. The interactions activate platelets and neutrophils (through neutrophil extracellular traps, NETs), which promote coagulation through thrombus and fibrin clot formation. At the same time, the infected ECs induce the local production of bradykinin that is released into the bloodstream, which, together with complement membrane attack complex, compromises the EC barrier function, resulting in increased blood flow into tissues. Another factor produced by infected ECs, tissue plasminogen activator (tPA) solubilizes blood clots and thereby contributes to EC permeability. The activity of tPA is inhibited by plasminogen activator inhibitor (PAI)-1 that is upregulated in the more severe HFRS cases (caused by DOBV hantavirus). This image was created with BioRender.com.