The ADAMTS13‐von Willebrand factor axis in COVID‐19 patients

Abstract

Background Severe coronavirus disease 2019 (COVID‐19) is characterized by an increased risk of thromboembolic events, with evidence of microthrombosis in the lungs of deceased patients. Objectives To investigate the mechanism of microthrombosis in COVID‐19 progression. Patients/Methods We assessed von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin‐cofactor (VWF:RCo), VWF multimers, VWF propeptide (VWFpp), and ADAMTS13 activity in a cross‐sectional study of 50 patients stratified according to their admission to three different intensity of care units: low (requiring high‐flow nasal cannula oxygenation, n = 14), intermediate (requiring continuous positive airway pressure devices, n = 17), and high (requiring mechanical ventilation, n = 19). Results Median VWF:Ag, VWF:RCo, and VWFpp levels were markedly elevated in COVID‐19 patients and increased with intensity of care, with VWF:Ag being 268, 386, and 476 IU/dL; VWF:RCo 216, 334, and 388 IU/dL; and VWFpp 156, 172, and 192 IU/dL in patients at low, intermediate, and high intensity of care, respectively. Conversely, the high‐to‐low molecular‐weight VWF multimers ratios progressively decreased with increasing intensity of care, as well as median ADAMTS13 activity levels, which ranged from 82 IU/dL for patients at low intensity of care to 62 and 55 IU/dL for those at intermediate and high intensity of care. Conclusions We found a significant alteration of the VWF‐ADAMTS13 axis in COVID‐19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID‐19 patients and their risk of microthrombosis.

Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients

“…This has been evidenced by markedly reduced clot lysis at 30 min via thromboelastography (TEG) in critically-ill patients with COVID-19 18 . Ex vivo evaluation of COVID-19 plasma also noted a prolonged clot lysis time, which was more pronounced among critically-ill COVID-19 patients 19 . Furthermore, a case series demonstrated that 11 of 21 COVID-19 patients who underwent rotational thromboelastometry in an intensive care unit met the criteria for fibrinolytic shutdown; 9 of those 11 patients developed thrombosis during their hospitalization 20 .…”

Role of advanced imaging in COVID-19 cardiovascular complications

“…It has not been fully elucidated yet whether this hypercoagulable state depends on a direct endothelial damage inflicted by the virus or represents a consequence of cytokine storm precipitating the onset of SIRS [ 66 ]. The blood coagulation activation in COVID-19, also substantiated by elevated levels of fibrinogen, Von Willebrand factor activity and factor VIII, seems not meet the criteria for disseminate intravascular coagulation, as platelet count and prothrombin time have been mostly reported within normal ranges, or just slightly increased, in these patients [ 67 , 68 ].…”

Invited commentary to: ADAMTS13 deficiency is associated with abnormal distribution of von Willebrand factor multimers in patients with COVID-19 by Tiffany Pascreau et al. Letter to the Editors-in-Chief, Thrombosis Research

“…Compatible with severe endothelial damage, several authors noted marked elevations of Von Willebrand factor activity (VWF:act), VWF antigen (VWF:Ag) and factor VIII clotting activity (FVIII:C) in COVID-19 patients [ 7 , 8 , 11 , [17] , [18] , [19] , [20] ] and some found low normal or mildly decreased ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 motif, number 13) activity [ 8 , 9 , 11 , [18] , [19] , [20] ]. The VWF:Ag/ADAMTS13 activity ratio was strongly elevated in these studies [ 8 , 11 , 18 , 20 ].…”

“…This imbalance of a markedly increased VWF and moderately decreased ADAMTS13 levels with an elevated VWF/ADAMTS13 ratio is suggested to represent a «consumption» of ADAMTS13 by the massively increased VWF and proposed to contribute to the pulmonary microthrombi formation [ 21 ]. The authors note that in contrast to the disease thrombotic thrombocytopenic purpura (TTP), defined by a very severe autoantibody-mediated or congenital deficiency of the ADAMTS13 [ 22 , 23 ], the hallmarks of severe thrombocytopenia and microangiopathic hemolytic anemia are lacking in almost all COVID-19 patients [ 7 , 8 , 20 ]. Also, the thrombi of the pulmonary microcirculation have mostly been reported as predominantly “fibrinous” [ [14] , [15] , [16] ], even though Fox et al suggested the presence of platelets and VWF in the microthrombi of pulmonary alveolar capillaries by immunostaining [ 24 ].…”

“…Pascreau et al [ 21 ] as well as other investigators [ 9 , 11 , 18 , 20 ] propose that the VWF-ADAMTS13 dysbalance may be causally related to the prothrombotic tendency and the (predominantly pulmonary) microvascular thrombosis. Based on this hypothesis, it is proposed that supplementation of ADAMTS13 [ 21 ] or the use of caplacizumab blocking the VWF A1 domain interaction with platelet glycoprotein Ib-alpha might be useful therapeutically in severe COVID-19 [ 11 ].…”