Microparticles (MPs), membrane fragments of 0.1–1.0 μm, are derived from many cell types in response to systemic inflammation. Acute liver failure (ALF) is a prototypical syndrome of systemic inflammatory response syndrome (SIRS) associated with a procoagulant state. We hypothesized that patients with ALF develop increased procoagulant MPs in proportion to the severity of systemic complications and adverse outcome. Fifty patients with acute liver injury (ALI), 78% of whom also had hepatic encephalopathy (HE; ALF), were followed until day 21 after admission. MPs were characterized by Invitrox Sizing, Antigen Detection and Enumeration, a light-scattering technology that can enumerate MPs as small as 0.15 μm, and by flow cytometry. Procoagulant activity was assessed by a functional MP-tissue factor (MP-TF) assay. Sixteen patients (32%) died and 27 (54%) recovered without liver transplantation (LT). Total MPs (0.15–1.0 μm) were present in nearly 19-fold higher concentrations in ALI/ALF patients, compared to healthy controls (P < 0.0001). MP-TF assays revealed high procoagulant activity (9.05 ± 8.82 versus 0.24 ± 0.14 pg/mL in controls; P = 0.0008). MP concentrations (0.28–0.64 μm) were higher in patients with the SIRS and high-grade HE, and MPs in the 0.36–0.64-μm size range increased in direct proportion to SIRS severity (P < 0.001) and grade of HE (P < 0.002). Day 1 MPs (0.28–0.64 μm) correlated with laboratory predictors of death/LT (higher phosphate and creatinine; lower bicarbonate), and day 1 and 3 MPs were higher in patients who died or underwent LT, compared to spontaneous survivors (P ≤ 0.01). By flow cytometry, 87% of patients had circulating CD41+ MPs, indicating platelet origin. Conclusion: Highly procoagulant MPs of specific size ranges are associated with the SIRS, systemic complications, and adverse outcome of ALI/ALF. MPs may contribute to the multiorgan system failure and high mortality of ALF.
Heparin-induced thrombocytopenia (HIT) is IntroductionHeparin-induced thrombocytopenia (HIT) is a well-recognized complication of heparin therapy and is one of the most common and potentially devastating causes of drug-induced thrombocytopenia. 1 Millions of Americans are exposed to heparin each year, resulting in thousands of cases of HIT annually. 2 Platelet factor 4 (PF4), a strongly cationic chemokine expressed by megakaryocytes and packaged into the ␣ granules of platelets, is released on platelet activation. 3 PF4 binds with high affinity to highly anionic molecules, such as heparin and endogenous heparin-like glycosaminoglycans (GAGs). 4 The precise physiologic role of PF4 in the regulation of coagulation is not known. 5 A subset of patients exposed to heparin develop autoantibodies (so called HIT Abs) against PF4/heparin complexes. 6,7 These Abs bind to specific epitopes on PF4, leading to the formation of trimeric complexes of PF4/heparin-IgG, which are referred to as HIT Ab complexes. 8,9 These complexes bind to platelets, resulting in platelet activation and the development of thrombocytopenia. 10 Immune complexes exert their effects on cells via engagement of specific Fc receptors. IgG Abs bind to Fc␥ receptors. In humans, 3 different classes of Fc␥Rs have been identified: Fc␥Rs I, II, and III. Fc␥RI is a high-affinity receptor and as such can also bind monomeric IgG as opposed to the low-affinity Fc␥Rs, Fc␥RII and Fc␥RIII, that only bind aggregated immunoglobulins or Ag-Ab complexes. 11 Fc␥RI is expressed on monocytes/macrophages, neutrophils, eosinophils, and dendritic cells. Fc␥RII is further subclassified into Fc␥RIIa and Fc␥RIIb. Fc␥RIIa is an activating receptor and is expressed on monocytes/macrophages, neutrophils, eosinophils, platelets, and Langerhans cells, whereas Fc␥RIIb is expressed on B lymphocytes and mast cells. In terms of function, Fc␥RIIb is the only inhibitory Fc␥R, and all the other Fc␥Rs result in activation of cells. 12 Fc␥RIII is subdivided into Fc␥RIIIa, which is expressed on natural killer cells and macrophages, and Fc␥RIIIb, which is expressed on eosinophils, neutrophils, macrophages, mast cells, and follicular dendritic cells. Binding of immune complexes to the activating Fc␥Rs leads to phosphorylation of the cytoplasmic immunoreceptor tyrosine-based activation motif by src-kinases, leading to activation of downstream signaling. 12 It has been found that platelet activation by HIT Ab complexes is mediated by engagement of the Fc␥RIIa receptor. 10 Most thrombocytopenias are associated with an increased risk of bleeding. However, the most-feared complication in HIT is the development of arterial and venous thrombosis. 13,14 The precise mechanism leading to thrombosis in HIT is unknown. It has been proposed that platelet activation and the release of platelet-derived microparticles (PMPs) may be responsible for thrombosis. 15,16 Microparticles (MPs) are sub-micron-sized membrane vesicles released on cell activation or apoptosis. 17 PMPs generally express phosphatidylserine a...
The tissue factor (TF)/factor (F)VIIa complex is the primary initiator of coagulation in vivo. Tissue factor pathway inhibitor (TFPI) is the physiological inhibitor of the TF/FVIIa complex. Deficiencies of either TF or TFPI have not been reported in humans, and a complete absence of either of these two proteins in mice is embryonically lethal. To maintain normal hemostasis, levels of TF and TFPI need to be balanced. Increased levels of TF can overwhelm the inhibitory capacity of TFPI, resulting in thrombosis. Decreased levels of TF are associated with bleeding. Global assays of coagulation are defined as tests capable of evaluating all components of the clotting cascade that are present in plasma. In these tests the thrombogenic surface is either provided by platelets or exogenous phospholipids. Clotting assays currently used in clinical practice are not designed to measure endogenous levels of TF and TFPI. Therefore, there is a need to develop sensitive and specific assays for measuring levels of functional TF and TFPI in whole blood and plasma. These assays could be useful in patient management in many scenarios. KeywordsTissue factor; tissue factor pathway inhibitor; thrombosis; thromboelastography Significant progress has been made over the last decade in understanding the many complex interactions involved in the process of blood coagulation. The care ofpatientswithdisordersofthrombosisisalsoentering a new era with many new treatment modalities in varying stages of development, including new oral anticoagulants, aptamers targeted against coagulation factors and the use of natural anticoagulants. 1,2 In addition, hemophilia patients with inhibitors can be treated with recombinant factor (F)VIIa, and possibly in the future with drugs that interfere with the activity of anticoagulant proteins, such as tissue factor pathway inhibitor (TFPI). In keeping with these advances, ongoing efforts are aimed at improving our ability to identify at-risk patients, such as those at risk for bleeding or those at risk for venous thromboembolism (VTE). Successful risk stratification has the advantage of both improving outcomes and decreasing the number of patients exposed to unnecessary interventions. This review briefly discusses the role of tissue factor (TF) and TFPI in hemostasis and the measurement of endogenous levels of these proteins in whole blood and plasma. TF is constitutively expressed by perivascular cells, which ensures rapid activation of coagulation at sites of vascular damage. TF is also constitutively expressed in the brain, heart, lung, kidney, and placenta, where it provides additional tissue-specific hemostatic protection to these vital organs. The importance of TF in these organs is underscored by the development of hemorrhages in the brain, lung, and heart in mice expressing low levels of TF or FVIIa. A genetic deficiency of TF has not been described in humans, and a complete absence of TF is embryonically lethal in mice. 4 TF expression can also be induced in a variety of cells, such as monocyt...
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