Pathophysiology of Antiphospholipid Syndrome.
Thrombosis and haemostasis
The antiphospholipid syndrome is characterized by antibodies directed against phospholipid-binding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidized lipoproteins, and activated complement components. When antibodies bind to these complex antigens, cells are activated and the coagulation and complement cascades are triggered, culminating in thrombotic events and pregnancy morbidity that further define the syndrome. The phospholipid-binding proteins most often involved are annexins II and V, β-glycoprotein I, prothrombin, and cardiolipin. A distinguishing feature of the antiphospholipid syndrome is the "lupus anticoagulant." This is not a single entity but rather a family of antibodies directed against complex antigens consisting of β-glycoprotein I and/or prothrombin bound to an anionic phospholipid. Although these antibodies prolong in vitro clotting times by competing with clotting factors for phospholipid binding sites, they are not associated with clinical bleeding. Rather, they are thrombogenic because they augment thrombin production in vivo by concentrating prothrombin on phospholipid surfaces. Other antiphospholipid antibodies decrease the clot-inhibitory properties of the endothelium and enhance platelet adherence and aggregation. Some are atherogenic because they increase lipid peroxidation by reducing paraoxonase activity, and others impair fetal nutrition by diminishing placental antithrombotic and fibrinolytic activity. This plethora of destructive autoantibodies is currently managed with immunomodulatory agents, but new approaches to treatment might include vaccines against specific autoantigens, blocking the antibodies generated by exposure to cytoplasmic DNA, and selective targeting of aberrant B-cells to reduce or eliminate autoantibody production.
10.1055/a-1701-2809
Cellular Components Contributing to the Development of Venous Thrombosis in Patients with Pancreatic Cancer.
Seminars in thrombosis and hemostasis
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer and has a poor prognosis. Patients with PDAC are at high risk of developing thromboembolic events, which is a leading cause of morbidity and mortality following cancer progression. Plasma-derived coagulation is the most studied process in cancer-associated thrombosis. Other blood components, such as platelets, red blood cells, and white blood cells, have been gaining less attention. This narrative review addresses the literature on the role of cellular components in the development of venous thromboembolism (VTE) in patients with PDAC. Blood cells seem to play an important role in the development of VTE. Altered blood cell counts, i.e., leukocytosis, thrombocytosis, and anemia, have been found to associate with VTE risk. Tumor-related activation of leukocytes leads to the release of tissue factor-expressing microvesicles and the formation of neutrophil extracellular traps, initiating coagulation and forming a scaffold for thrombi. Tissue factor-expressing microvesicles are also thought to be released by PDAC cells. PDAC cells have been shown to stimulate platelet activation and aggregation, proposedly via the secretion of podoplanin and mucins. Hypofibrinolysis, partially explained by increased plasminogen activator inhibitor-1 activity, is observed in PDAC. In short, PDAC-associated hypercoagulability is a complex and multifactorial process. A better understanding of cellular contributions to hypercoagulability might lead to the improvement of diagnostic tests to identify PDAC patients at highest risk of VTE.
10.1055/s-0043-1777304
Red blood cells: the forgotten player in hemostasis and thrombosis.
Journal of thrombosis and haemostasis : JTH
New evidence has stirred up a long-standing but undeservedly forgotten interest in the role of erythrocytes, or red blood cells (RBCs), in blood clotting and its disorders. This review summarizes the most recent research that describes the involvement of RBCs in hemostasis and thrombosis. There are both quantitative and qualitative changes in RBCs that affect bleeding and thrombosis, as well as interactions of RBCs with cellular and molecular components of the hemostatic system. The changes in RBCs that affect hemostasis and thrombosis include RBC counts or hematocrit (modulating blood rheology through viscosity) and qualitative changes, such as deformability, aggregation, expression of adhesive proteins and phosphatidylserine, release of extracellular microvesicles, and hemolysis. The pathogenic mechanisms implicated in thrombotic and hemorrhagic risk include variable adherence of RBCs to the vessel wall, which depends on the functional state of RBCs and/or endothelium, modulation of platelet reactivity and platelet margination, alterations of fibrin structure and reduced susceptibility to fibrinolysis, modulation of nitric oxide availability, and the levels of von Willebrand factor and factor VIII in blood related to the ABO blood group system. RBCs are involved in platelet-driven contraction of clots and thrombi that results in formation of a tightly packed array of polyhedral erythrocytes, or polyhedrocytes, which comprises a nearly impermeable barrier that is important for hemostasis and wound healing. The revisited notion of the importance of RBCs is largely based on clinical and experimental associations between RBCs and thrombosis or bleeding, implying that RBCs are a prospective therapeutic target in hemostatic and thrombotic disorders.
10.1111/jth.14360
Thrombus Structural Composition in Cardiovascular Disease.
Alkarithi Ghadir,Duval Cédric,Shi Yu,Macrae Fraser L,Ariëns Robert A S
Arteriosclerosis, thrombosis, and vascular biology
Thrombosis is a major complication of cardiovascular disease, leading to myocardial infarction, acute ischemic stroke, or venous thromboembolism. Thrombosis occurs when a thrombus forms inside blood vessels disrupting blood flow. Developments in thrombectomy to remove thrombi from vessels have provided new opportunities to study thrombus composition which may help to understand mechanisms of disease and underpin improvements in treatments. We aimed to review thrombus compositions, roles of components in thrombus formation and stability, and methods to investigate thrombi. Also, we summarize studies on thrombus structure obtained from cardiovascular patients and animal models. Thrombi are composed of fibrin, red blood cells, platelets, leukocytes, and neutrophil extracellular traps. These components have been analyzed by several techniques, including scanning electron microscopy, laser scanning confocal microscopy, histochemistry, and immunohistochemistry; however, each technique has advantages and limitations. Thrombi are heterogenous in composition, but overall, thrombi obtained from myocardial infarction are composed of mainly fibrin and other components, including platelets, red blood cells, leukocytes, and cholesterol crystals. Thrombi from patients with acute ischemic stroke are characterized by red blood cell- and platelet-rich regions. Thrombi from patients with venous thromboembolism contain mainly red blood cells and fibrin with some platelets and leukocytes. Thrombus composition from patients with myocardial infarction is influenced by ischemic time. Animal thrombosis models are crucial to gain further mechanistic information about thrombosis and thrombus structure, with thrombi being similar in composition compared with those from patients. Further studies on thrombus composition and function are key to improve treatment and clinical outcome of thrombosis.
10.1161/ATVBAHA.120.315754