von Willebrand Factor: The Canary in the Hemostasis Coal Mine of Extracorporeal Membrane Oxygenation?*

An imbalance of hemostasis, manifest as hemorrhage, thrombosis or both, is commonly noted in critically ill adults and children with up to one-third of patients in ICUs experiencing bleeding or thrombosis of varied clinical significance during admission (1). An increased risk of bleeding or thrombosis is of particular relevance for patients undergoing extracorporeal membrane oxygenation (ECMO) support owing to the prothrombotic effects of extracorporeal circulation and the resulting use of anticoagulation therapy. Recent studies of the effects of ECMO on hemostasis have demonstrated altered platelet function (2,3), whereas others show activation of coagulation and in vivo cleavage of von Willebrand factor (VWF) (4,5). Many of the commonly obtained in vitro measures of hemostasis which are often noted to be abnormal during critical illness and anticoagulation therapy rely on fibrin clot formation as their endpoint. However, these tests of hemostasis (i.e., prothrombin time [PT], the PT-derived international normalized ratio, activated partial thromboplastin time [aPTT, also abbreviated as “PTT”], activated clotting time [ACT]) along with fibrinogen, anti-Xa assay, and viscoelastic assays (e.g., rotational thromboelastometry, thromboelastogram) have been shown to be poor predictors of thrombosis or hemorrhage during ECMO support when utilized separately or in combinations (6,7). Consequently, efforts to better identify those patients most at risk for clinically relevant sequelae of ECMO-associated alterations in hemostasis continue.

In this issue of Pediatric Critical Care Medicine, Van Den Helm et al (8) present an analysis of changes in plasma-VWF measurements during ECMO support. In a prospective observational study of 25 neonates and children (< 18 yr) undergoing ECMO support at a single academic institution from April 2017 to May 2019, blood for assessment of VWF multimer pattern, VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), and VWF collagen binding (VWF:CB) was obtained at the time of PICU admission and then serially until 24 hours post-decannulation. The authors found that following initiation of ECMO, patients exhibited a loss of high molecular weight VWF multimers (HMWM) accompanied by an increase in intermediate VWF multimers (IMWM), and decrease in VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios with a return toward normal of all parameters after decannulation. The authors hypothesize that the loss of HMWM with a concomitant increase in IMWM may reflect increased degradation of VWF induced by the ECMO process. In addition, based on the decrease in VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag, they further hypothesize a decrease in VWF function. However, this decrease in function may be more artifactual than actual as both VWF:CB and VWF:RCo are highly dependent on the larger(est) VWF multimers while the smaller multimers found in VWF variants characterized by aberrant VWF multimerization or increased VWF cleavage still contain the antigenic sites identified in typical VWF:Ag assays (9). Consequently, while the data do support a conclusion that VWF activity is reduced during ECMO, it may be an overstatement to conclude that ECMO induces an intrinsic alteration (reduction) in the ability of VWF multimers (irrespective of size) to affect hemostasis, or at a minimum, this conclusion must be interpreted in the context of test limitations. Regarding the noted changes in VWF during ECMO, the authors characterize the overall laboratory profile as being consistent with Acquired von Willebrand Syndrome (AVWS). However, bleeding that is generally noted in the clinical presentation of AVWS was not associated with any of the identified changes in VWF multimeric pattern or “function” identified while on ECMO. Consequently, application of the term AVWS to these patients is more a reflection of an altered VWF multimeric pattern rather than descriptive of a clinical entity. Based on their findings, the authors conclude that routine monitoring of VWF parameters in addition to currently employed coagulation assays (e.g., aPTT, ACT) is not sufficient to identify those patients at highest risk for bleeding while on ECMO. They further suggest that measurement of A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) levels may be informative in understanding the mechanism by which VWF HMWM undergo degradation during ECMO, as a major function of this proteinase is to degrade HMWM VWF to smaller, less hemostatically active, forms (10). Consequently, this suggestion to include ADAMTS13 in an algorithm to assess hemostasis balance flows logically from the reported data.

VWF plays many important roles in regulating hemostasis including the promotion of clot formation through its interactions with specific receptors found on platelets, endothelial cells (ECs), and erythrocytes as well as interacting with complement in the process of immunothrombosis (11). With this understanding supporting the underlying basis for the study by Van Den Helm et al (8), it is somewhat surprising that the authors found neither bleeding nor thrombosis to be associated with the noted changes in VWF. While the inability to identify an association of VWF parameters with hemostatic outcomes may be the result of the small sample size in this clinical study, it also raises the possibility that the focus on plasma-VWF may be misdirected. VWF, synthesized in megakaryocytes and ECs, is found in plasma, ECs and platelets but while VWF in EC Weibel-Palade bodies rapidly translocate to EC cell membrane and to plasma upon activation of ECs, platelet-VWF largely remains in, and on, platelets. Indeed, studies focused specifically on platelet-VWF have identified important differences in how VWF comes to be expressed on the surface of activated platelets. While the primary platelet receptor for plasma-VWF is the glycoprotein Ib (GPIb) receptor, that for platelet-VWF is GPIIb/IIIa. Additionally, platelet-VWF is able to increase platelet surface expression following platelet activation by both alpha-granule secretion-dependent and secretion-independent mechanisms (12). Platelet-VWF exhibits differences in glycosylation from that of plasma-VWF that renders platelet-VWF less susceptible to cleavage by ADAMTS13 (13). Platelet-VWF has also been shown to modulate bleeding risk in von Willebrand disease (12). Indeed, platelet-VWF has been shown, in a mouse model, to exacerbate thromboinflammatory disorders such as stroke via a GPIb-mediated mechanism while not playing a significant role in normal hemostasis (14). A similar reliance on GPIb-mediated VWF binding to RBCs with consequent thrombi formation is noted to be enhanced in the presence of free hemoglobin that occurs with hemolysis (15). In aggregate, these reports paint a picture of ECMO-induced shear stress promoting a VWF-mediated prothrombotic milieu, which is subsequently down-regulated by ADAMTS13-mediated VWF cleavage, a modulation that may not be apparent when platelet-derived VWF is a prominent component owing to its different glycosylation pattern (13).

While the overall effect on hemostatic balance the ECMO-induced alterations in plasma-VWF reported by Van Den Helm et al (8) play may only be speculative at this time, these findings, along with those from other investigators, do point to VWF as a potentially important target for the identification of “at risk” patients undergoing ECMO support. Whether plasma- or platelet-VWF (or both) represent the most appropriate target is not addressed in this study, but Van Den Helm and colleagues (8) have identified a path for further investigation. If, indeed, VWF is shown to be a “canary in the coal mine” (i.e., an early predictor of bleeding or thrombosis risk), then VWF could also become a potential target for therapeutic intervention. Further investigations involving broader in vitro assessments of changes in both plasma- and platelet-VWF and their interactions with platelets, ECs, and RBCs under shear-stress conditions followed by clinical studies including a larger number of patients may be fruitful paths to pursue.

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