LAUSR

We are grateful for the comments and the interesting additional novel data presented by von Meijenfeldt et al.1 These findings provide further evidence that sustained endotheliopathy and coagulopathy are both common in patients following acute COVID19.2– 5 The longitudinal data presented provide additional insights into the duration of specific aspects of COVID19– induced hemostatic dysfunction. Previous studies have reported elevated Ddimer levels in 25% of patients in the first few months after SARSCoV2 infection.2,5 Notwithstanding differences in patient cohorts and study design, von Meijenfeldt et al. show that these elevated Ddimer levels after acute COVID appear to normalize by 4 months.1 Given that convalescent COVID19 patients commonly present with respiratory symptoms, this observation has important clinical implications with respect to the utility of Ddimer testing in pulmonary embolism testing algorithms. Dysfunction of the VWFADAMTS13 axis has been consistently reported in patients with acute COVID1968 and postulated to play a role in the pathogenesis of the disseminated pulmonary microvascular thrombosis that constitutes a hallmark of the condition. Interestingly, recent studies have also reported that elevated plasma von Willebrand factor:antigen (VWF:Ag), VWF propeptide, and factor VIII:coagulant (FVIII:C) are also common in convalescent SARSCoV2 patients.3,4 Based upon the data of von Meijenfeldt et al.,1 it appears that increases in circulating VWFFVIII levels persist for longer than elevated Ddimers following COVID19. Nonetheless, VWF and FVIII levels (and thus by inference endothelial cell activation) have returned to normal by 12 months after acute COVID19.1 Consistent with the time course in plasma FVIII:C levels, endogenous thrombin potential remained significantly elevated at 8 months but had normalized by 12 months following hospital discharge. In contrast, however, plasminogen activator inhibitor type 1 levels remained significantly increased even after 12 months. Together with our previous findings,4 the data of von Meijenfeldt et al1 therefore demonstrate that (1) sustained endotheliopathy, coagulopathy and alterations in fibrinolysis are common in convalescent COVID19 patients and (2) the time course for normalization varies between different aspects of hemostatic dysfunction. Further studies will be required to define the biological mechanisms underpinning these observations and their relative clinical importance. Importantly however, the ongoing hemostatic dysfunction seen in these patients occurs independently of any ongoing acute phase response.2 This finding is consistent with the intriguing observation that persistent coagulation abnormalities are not only seen in patients who experienced severe COVID19 (requiring hospital and/or intensive care unit admission), but rather are also present in some individuals who had mild COVID19 managed exclusively as an outpatient.2,4 The key question posed by our collective data is whether persistent hemostatic dysfunction following COVID19 is contributing to postacute sequelae of SARSCoV2 infection (PASC or long COVID syndrome).9 In our study, we observed weak associations between 6min walk test distance and both VWF:Ag and VWF propeptide levels at a median of 68 days after acute COVID19.4 In contrast, using the subjective Sheehan disability scale to assess functional impairment, von Meijenfeldt et al. found no relationship with any hemostatic biomarkers at either 8 or 12 months after discharge.1 The differences in these results may be attributable to a variety of potential confounders. In particular, both studies included a relatively small number of patients (n = 50 and n = 44, respectively), and long COVID symptomatology was assessed using a combination of objective and subjective protocols performed at varying time points following discharge. Moreover, there were also differences between the study cohorts with respect to initial COVID19 severity; patient comorbidities including obesity; and differences in patient management during acute COVID19 (including anticoagulant therapy intensity). Finally, accumulating recent data have highlighted significant phenotypic heterogeneity amongst patients with long COVID syndrome.9,10 In this context, it is clear that much larger stratified prospective studies that include stateoftheart imaging will be essential to defining any relationship and/or any potential causality between PASC and persistent hemostatic dysfunction. Given the huge morbidity associated with long COVID, coupled with the limited understanding of the underlying disease pathogenesis, such studies are required as a matter of urgency.