The world is amid a pandemic caused by severe acute respiratory syndrome-coronavirus 2. Severe acute respiratory syndrome-coronavirus causes serious respiratory tract infections that can lead to ...viral pneumonia, acute respiratory distress syndrome, and death. Some patients with coronavirus disease 2019 (COVID-19) have an activated coagulation system characterized by elevated plasma levels of d-dimer-a biomarker of fibrin degradation. Importantly, high levels of D-dimer on hospital admission are associated with increased risk of mortality. Venous thromboembolism is more common than arterial thromboembolism in hospitalized COVID-19 patients. Pulmonary thrombosis and microvascular thrombosis are observed in autopsy studies, and this may contribute to the severe hypoxia observed in COVID-19 patients. It is likely that multiple systems contribute to thrombosis in COVID-19 patients, such as activation of coagulation, platelet activation, hypofibrinolysis, endothelial cell dysfunction, inflammation, neutrophil extracellular traps, and complement. Targeting these different pathways may reduce thrombosis and improve lung function in COVID-19 patients.
Currently available evidence supports the contention that elevated levels of factor XI (fXI) are associated with a greater risk of venous thromboembolism and ischemic stroke, but, less convincingly, ...with myocardial infarction. Conversely, reduced plasma levels of fXI seem to offer some protection from venous thromboembolism and stroke, but not myocardial infarction. Factor XI-deficient patients are at risk for certain types of bleeding, particularly posttraumatic hemorrhage on mucosal surfaces where there is a high endogenous fibrinolytic activity. In contrast, the situation with fXII in human thrombosis remains enigmatic. Deficiency of fXII is clearly not associated with any bleeding risk, but neither does it seem to be protective against thrombosis. The longstanding debate as to whether partial fXII deficiency represents a risk factor for thrombosis remains unresolved, with seemingly conflicting results depending on study design, type of assay used, and analyte evaluated. The possibility that elevated fXII levels represent a risk factor for thrombosis is not borne out in the literature.
It has long been recognised that pancreatic cancer induces a hypercoagulable state that may lead to clinically apparent thrombosis. Although the relationship between pancreatic cancer and ...hypercoagulability is well described, the underlying pathological mechanism(s) and the interplay between these pathways remain a matter of intensive study. This review summarises existing data on epidemiology and pathogenesis of thrombotic complications in pancreatic cancer with a particular emphasis on novel pathophysiological pathways. Pancreatic cancer is characterised by high tumoural expression of tissue factor, activation of leukocytes with the release of neutrophil extracellular traps, the dissemination of tumour-derived microvesicles that promote hypercoagulability and increased platelet activation. Furthermore, other coagulation pathways probably contribute to these processes, such as those that involve heparanase, podoplanin and hypofibrinolysis. In the era in which heparin and its derivatives-the currently recommended therapy for cancer-associated thrombosis-might be superseded by direct oral anticoagulants, novel data from mouse models of cancer-associated thrombosis suggest the possibility of future personalised therapeutic approaches. In this dynamic era for cancer-associated thrombosis, the discovery of novel prothrombotic and proinflammatory mechanisms will potentially uncover pharmacological targets to prevent and treat thrombosis without adversely affecting haemostasis.
Situations that ordinarily necessitate consideration of anticoagulation, such as arterial and venous thrombotic events and prevention of stroke in atrial fibrillation, become challenging in patients ...with inherited bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease. There are no evidence-based guidelines to direct therapy in these patients, and management strategies that incorporate anticoagulation must weigh a treatment that carries a risk of hemorrhage in a patient who is already at heightened risk against the potential consequences of not treating the thrombotic event. In this paper, we review atherothrombotic disease, venous thrombotic disease, and atrial fibrillation in patients with inherited bleeding disorders, and discuss strategies for using anticoagulants in this population using cases to illustrate these considerations.
Reactive and clonal neutrophil expansion has been associated with thrombosis, suggesting that neutrophils play a role in this process. However, although there is no doubt that activated monocytes ...trigger coagulation in a tissue factor-dependent manner, it remains uncertain whether stimulated neutrophils can also directly activate coagulation. After more than a decade of debate, it is now largely accepted that normal human neutrophils do not synthetize tissue factor, the initiator of the extrinsic pathway of coagulation. However, neutrophils may passively acquire tissue factor from monocytes. Recently, the contact system, which initiates coagulation via the intrinsic pathway, has been implicated in the pathogenesis of thrombosis. After the recent description of neutrophil extracellular trap (NET) release by activated neutrophils, some animal models of thrombosis have demonstrated that coagulation may be enhanced by direct NET-dependent activation of the contact system. However, there is currently no consensus on how to assess or quantify NETosis in vivo, and other experimental animal models have failed to demonstrate a role for neutrophils in thrombogenesis. Nevertheless, it is likely that NETs can serve to localize other circulating coagulation components and can also promote vessel occlusion independent of fibrin formation. This article provides a critical appraisal of the possible roles of neutrophils in thrombosis and highlights some existing knowledge gaps regarding the procoagulant activities of neutrophil-derived extracellular chromatin and its molecular components. A better understanding of these mechanisms could guide future approaches to prevent and/or treat thrombosis.
Hemostasis requires both platelets and the coagulation system. At sites of vessel injury, bleeding is minimized by the formation of a hemostatic plug consisting of platelets and fibrin. The ...traditional view of the regulation of blood coagulation is that the initiation phase is triggered by the extrinsic pathway, whereas amplification requires the intrinsic pathway. The extrinsic pathway consists of the transmembrane receptor tissue factor (TF) and plasma factor VII/VIIa (FVII/FVIIa), and the intrinsic pathway consists of plasma FXI, FIX, and FVIII. Under physiological conditions, TF is constitutively expressed by adventitial cells surrounding blood vessels and initiates clotting. In addition so-called blood-borne TF in the form of cell-derived microparticles (MPs) and TF expression within platelets suggests that TF may play a role in the amplification phase of the coagulation cascade. Under pathologic conditions, TF is expressed by monocytes, neutrophils, endothelial cells, and platelets, which results in an elevation of the levels of circulating TF-positive MPs. TF expression within the vasculature likely contributes to thrombosis in a variety of diseases. Understanding how the extrinsic pathway of blood coagulation contributes to hemostasis and thrombosis may lead to the development of safe and effective hemostatic agents and antithrombotic drugs.
The D-dimer antigen is a unique marker of fibrin degradation that is formed by the sequential action of 3 enzymes: thrombin, factor XIIIa, and plasmin. First, thrombin cleaves fibrinogen producing ...fibrin monomers, which polymerize and serve as a template for factor XIIIa and plasmin formation. Second, thrombin activates plasma factor XIII bound to fibrin polymers to produce the active transglutaminase, factor XIIIa. Factor XIIIa catalyzes the formation of covalent bonds between D-domains in the polymerized fibrin. Finally, plasmin degrades the crosslinked fibrin to release fibrin degradation products and expose the D-dimer antigen. D-dimer antigen can exist on fibrin degradation products derived from soluble fibrin before its incorporation into a fibrin gel, or after the fibrin clot has been degraded by plasmin. The clinical utility of D-dimer measurement has been established in some scenarios, most notably for the exclusion of VTE. This article consists of 2 sections: in the first, the dynamics of D-dimer antigen formation is discussed and an overview of commercially available D-dimer assays is provided. The second section reviews available evidence for the clinical utilization of D-dimer antigen measurement in VTE, as well as emerging areas of D-dimer utilization as a marker of coagulation activation in other clinical settings.
Summary
Sickle cell trait (SCT) is the carrier state for sickle cell disease that results from the HBB rs334 missense mutation (p.Glu6Val) in the β‐globin chain of haemoglobin. While not associated ...with any impact on life expectancy, it has been established that SCT is associated with an increased risk of both venous thromboembolism (and in particular, pulmonary embolism) and chronic kidney disease. It is largely unknown what short‐ or long‐term effect, if any, pregnancy has upon the risk or outcomes of these disorders. In addition, SCT has been linked with various adverse outcomes in pregnancy, ranging from maternal complications such as elevated risk of bacteriuria to potentially life‐threatening entities such as pre‐eclampsia and prematurity. In these scenarios also, no clear association with SCT has been established. Given the high worldwide prevalence of SCT, further studies addressing these issues are warranted.
Here we critically evaluate the role of elevated hematocrit as the principal determinant of thrombotic risk in polycythemia and erythrocytosis, defined by an expansion of red cell mass. Since red ...cell volume determination is no longer readily available, in clinical practice, polycythemia and erythrocytosis are defined by elevated hemoglobin and hematocrit. Thrombosis is common in Chuvash erythrocytosis and polycythemia vera. Although the increased thrombotic risk is assumed to be due to the elevated hematocrit and an associated increase in blood viscosity, thrombosis does not accompany most types of erythrocytosis. We review studies indicating that the occurrence of thrombosis in Chuvash erythrocytosis is independent of hematocrit, that the thrombotic risk is paradoxically increased by phlebotomy in Chuvash erythrocytosis, and that, when compared to chemotherapy, phlebotomy is associated with increased thrombotic risk in polycythemia vera. Inherited and environmental causes that lead to polycythemia and erythrocytosis are accompanied by diverse cellular changes that could directly affect thrombotic risk, irrespective of the elevated hematocrit. The pressing issue in these disorders is to define factors other than elevated hematocrit that determine thrombotic risk. Defining these predisposing factors in polycythemia and erythrocytosis should then lead to rational therapies and facilitate development of targeted interventions.
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