The lung pathology seen in patients with coronavirus disease 2019 (COVID-19) shows marked microvascular thrombosis and haemorrhage linked to extensive alveolar and interstitial inflammation that shares features with macrophage activation syndrome (MAS). We have termed the lung-restricted vascular immunopathology associated with COVID-19 as diffuse pulmonary intravascular coagulopathy, which in its early stages is distinct from disseminated intravascular coagulation. Increased circulating D-dimer concentrations (reflecting pulmonary vascular bed thrombosis with fibrinolysis) and elevated cardiac enzyme concentrations (reflecting emergent ventricular stress induced by pulmonary hypertension) in the face of normal fibrinogen and platelet levels are key early features of severe pulmonary intravascular coagulopathy related to COVID-19. Extensive immunothrombosis over a wide pulmonary vascular territory without confirmation of COVID-19 viraemia in early disease best explains the adverse impact of male sex, hypertension, obesity, and diabetes on the prognosis of patients with COVID-19. The immune mechanism underlying diffuse alveolar and pulmonary interstitial inflammation in COVID-19 involves a MAS-like state that triggers extensive immunothrombosis, which might unmask subclinical cardiovascular disease and is distinct from the MAS and disseminated intravascular coagulation that is more familiar to rheumatologists.

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Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges. Objective: These evidence-based guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis. Methods: ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment. Results: The panel agreed on 11 recommendations. Conclusions: Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.

For many years, an association between ABO histo-blood group and risk of thrombosis has been recognized. Blood group non-O (A, B, and AB) individuals have consistently been found to demonstrate increased incidence of both arterial and venous thrombotic disease, compared to group O individuals. This increased risk is attributable to the fact that ABO blood group influences plasma levels of a coagulation glycoprotein named von Willebrand factor (VWF). VWF levels are 25 percent higher in non-O compared to group O individuals. The mechanism by which ABO group determines plasma VWF levels has not been determined. ABO(H) carbohydrate antigenic determinants, however, are expressed on the N-linked glycan chains of circulating plasma VWF. This review will focus on the carbohydrate structures of VWF and recent studies suggesting that subtle variations in these structures (particularly differences in ABO blood group antigen expression) may have clinically significant effects on VWF proteolysis and clearance.

HF and LT contributed equally to this study. SummaryAlthough the pathophysiology underlying severe COVID19 remains poorly understood, accumulating data suggest that a lung-centric coagulopathy may play an important role. Elevated D-dimer levels which correlated inversely with overall survival were recently reported in Chinese cohort studies. Critically however, ethnicity has major effects on thrombotic risk, with a 3-4-fold lower risk in Chinese compared to Caucasians and a significantly higher risk in African-Americans. In this study, we investigated COVID19 coagulopathy in Caucasian patients. Our findings confirm that severe COVID19 infection is associated with a significant coagulopathy that correlates with disease severity. Importantly however, Caucasian COVID19 patients on low molecular weight heparin thromboprophylaxis rarely develop overt disseminated intravascular coagulation (DIC). In rare COVID19 cases where DIC does develop, it tends to be restricted to late-stage disease. Collectively, these data suggest that the diffuse bilateral pulmonary inflammation observed in COVID19 is associated with a novel pulmonary-specific vasculopathy termed pulmonary intravascular coagulopathy (PIC) as distinct to DIC. Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID19 mortality.

ABO histo-blood group is a major determinant of plasma levels of factor VIII (FVIII) and von Willebrand factor (vWF). Blood group O individuals have significantly (approximately 25%) lower plasma levels of both glycoproteins. This association is of clinical significance. Low plasma levels of either FVIII or vWF have long been established as causes of excess bleeding. Conversely, there is accumulating evidence that elevated FVIII-vWF levels may represent an important risk factor for ischaemic heart disease and venous thromboembolic disease. In spite of the well-documented association between ABO blood group and FVIII-vWF levels, the underlying mechanism remains unknown. However, it has been established that the ABO effect is primarily mediated through a direct functional effect of the ABO locus on plasma vWF levels. Theoretically, ABO blood group may alter the rate of vWF synthesis or secretion within endothelial cells. Alternatively, ABO group may affect vWF plasma clearance rates. ABH antigenic determinants have been identified on the N-linked oligosaccharide chains of circulating vWF and FVIII, according to the blood group of the individual. It remains unclear whether these carbohydrate structures are responsible for mediating the effect of ABO blood group on plasma vWF levels.

Critical clinical questions remain unanswered regarding diagnosis and management of patients with low von Willebrand factor (VWF) levels (30-50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with low VWF levels. Despite marginally reduced plasma VWF levels, International Society of Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH BAT) confirmed significant bleeding phenotypes in the majority of LoVIC patients. Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30 to 50 IU/dL range. Furthermore, bleeding phenotypes could not be explained by concurrent hemostatic defects. Plasma factor VIII to VWF antigen (VWF:Ag) ratios were significantly increased in LoVIC patients compared with controls ( < .0001). In contrast, VWF propeptide to VWF:Ag ratios >3 were observed in only 6% of the LoVIC cohort. Furthermore, platelet-VWF collagen binding activity levels were both significantly reduced compared with controls ( < .05). In response to 1-desamino-8-D-arginine vasopressin (DDAVP), peak VWF:Ag levels exceeded 100 IU/dL in 88% of patients and was sustained >100 IU/dL after 4 hours in 72% of subjects. In conclusion, our novel data suggest that low VWF levels can be associated with significant bleeding and are predominantly due to reductions in VWF synthesis and/or constitutive secretion. Although enhanced VWF clearance may contribute to the pathophysiology in some individuals, the absolute reduction in VWF plasma half-life is usually mild and not sufficient to significantly impact upon the duration of DDAVP-induced VWF response. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

The multimeric size and the function of circulating von Willebrand factor are modulated via its proteolytic cleavage by the plasma metalloproteinase, AD-AMTS13. It is unclear how ADAMTS13 activity is regulated within the vascular system. In the absence of a regulatory mechanism, ADAMTS13 activity might compromise platelet adhesion at sites of vascular injury. We hypothesized that at sites of vascular injury, ADAMTS13 activity could be regulated locally by coagulation proteinases. Initiation of coagulation in human plasma resulted in the disappearance of added full-length recombinant ADAMTS13. This loss was inhibited by hirudin. Using purified proteins, we showed that ADAMTS13 is proteolyzed at several cleavage sites by thrombin in a time-and concentration-dependent manner. Furthermore, this proteolysis ablated ADAMTS13 activity against purified von Willebrand factor. Preincubation of thrombin with soluble thrombomodulin, but not heparin, inhibited the proteolysis of AD-AMTS13, suggesting the involvement of IntroductionVon Willebrand factor (VWF) is a large (2050 amino acid/ϳ250 kDa) multidomain glycoprotein whose functions are critical for normal hemostasis. 1 VWF has 2 principal roles that influence the hemostatic process: (1) it acts as a carrier protein for coagulation factor VIII 2 and (2) it mediates rapid adhesion of platelets to sites of vascular perturbation. The latter is one of the first hemostatic events following endothelial disruption and occurs through the specific binding of VWF to exposed subendothelial matrix proteins (principally collagen). 3 Once immobilized, VWF affinity for the glycoprotein (GP) Ib-IX-V receptor complex on the surface of circulating platelets is significantly enhanced. 4 This results in the tethering of platelets at sites of vascular damage and in the formation of a primary platelet plug. Tethered platelets are subsequently activated and expose phosphatidylserine-rich surfaces that are critical for efficient thrombin generation to occur. 5 VWF is constitutively secreted into the blood by endothelial cells as multimers of varying size that differ predominantly in the number of component VWF units. A significant proportion is also stored within Weibel-Palade bodies, predominantly as "ultra-large" multimers (UL-VWF) 6 that may exceed 2 ϫ 10 4 kDa. 1 This pool is released on demand in response to endothelial cell activation. 7 The properties of circulating VWF are, in part, dependent on its molecular size. Larger VWF multimers not only bind circulating platelets more readily than smaller forms, but also undergo marked conformational changes in response to the rheologic forces exerted by the circulating blood. 8 Under normal flowing conditions, VWF multimers circulate in a globular form. However, when VWF is exposed to increased shear forces, these molecules unravel into a "stringlike" conformation. This increases the number of exposed platelet/matrix binding sites and thus enhances the platelet tethering potential of the VWF molecule.Thrombotic thrombocytopenic purpura (TTP) is...