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PubMed1992

Measurement of basal levels of factor VIIa in hemophilia A and B patients.

Previous results, presented in abstract form, indicate that replacement of thromboplastin with a mixture of phospholipid and truncated soluble tissue factor apoprotein results in a coagulation assay that can directly measure plasma factor VIIa levels without interference from zymogen factor VII (Atherosclerosis Thromb 11:1544a, 1991 [abstr]). We have exploited the specificity and sensitivity of such a factor VIIa specific coagulation assay to directly assess the in vivo relationship of factor VIII and factor IX on the production of factor VIIa levels under nonthrombotic and nonstimulatory conditions. Normal individuals (n = 20) were found to possess an average circulating factor VIIa level corresponding to 4.34 +/- 1.57 ng/mL, or approximately 1% of their total factor VII antigen. Severe factor VIII deficient patients (n = 13) possessed a slightly lower but statistically significant (P less than .01) decrease in their basal factor VIIa levels (2.69 +/- 1.52 ng/mL), corresponding to approximately 60% of that observed in normal individuals. On the other hand, severe factor IX deficient patients (n = 7) were found to possess even lower levels of factor VIIa corresponding to 0.33 +/- 0.15 ng/mL, or less than 10% of that observed in normal individuals. Measurement of total factor VII antigen levels shows that the variation in basal factor VIIa levels stems from differences in the degree of factor VII activation as opposed to differences in factor VII antigen levels. Our present data are consistent with the hypothesis that factor IXa is the principal in vivo activator of factor VII under basal conditions.

Factor VIIa↗
PubMed1991

A method for measuring activated factor VIII in plasma.

A method is described which enables a quantitative measurement of the concentration of activated factor VIII (VIIIa) in plasma. Based on the ability of factor VIIIa to accelerate the activation of factor X by factor IXa, phospholipid and calcium ions, the course of factor X activation in time is measured using a chromogenic substrate. Free factor Xa is able to activate nonactivated factor VIII present in a plasma sample, which increases the factor X activation velocity, and thus disturbs the measurement of factor VIIIa. Furthermore, factor Xa was found to be inactivated by serine protease inhibitors from the plasma sample. By adding surplus chromogenic substrate these reactions of factor Xa are inhibited and at the same time the rate of substrate conversion is a measure of the amount of factor Xa present. Factor X activation and amidolysis of chromogenic substrate then take place simultaneously. It is shown that under proper conditions the factor X activation velocity is linearly proportional to the factor VIIIa concentration. This causes the optical density to increase as a parabolic function of time. The concentration of factor VIIIa can be obtained from the quadratic coefficient of the equation describing the parabola. The method is specific for factor VIIIa in that the extrinsic factor X activator is shown to have no influence on the measurement of factor VIIIa in thromboplastin activated plasma. We conclude that a sensitive and reliable method for assessing factor VIIIa concentrations in plasma has been developed on the basis of simultaneous inhibition and measurement of factor Xa by a high concentration of chromogenic substrate.

Chromogenic Compounds↗
PubMed1982

Effect of heparin on the inactivation rate of human factor XIa by antithrombin-III.

Factor XIa catalyzes an important reaction in the early phase of blood coagulation by converting factor IX to an active enzyme (factor IXa). Although antithrombin-III, an inhibitor of factor XIa, normally accounts for only one-sixth of the plasma inhibitory activity against factor XIa, its effectiveness has been reported to be enhanced by heparin. We have reinvestigated the ability of heparin to potentiate factor XIa inhibition by both purified antithrombin-III and plasma using synthetic tripeptide amide substrates as well as a coagulant assay. No increase in the inactivation rate of factor XIa amidolytic activity by purified antithrombin-III was observed in the presence of therapeutic heparin concentrations (1 U/ml), although inhibition of the amidolytic activity of thrombin by purified antithrombin-III was enhanced at least 20-fold by the same concentration of heparin. Furthermore, despite the ability of heparin (1 U/ml) to increase the inactivation rate of thrombin by plasma, no acceleration of the rate of inhibition of factor XIa by plasma was observed. Similar results were found when the inhibition of factor XIa was monitored with a coagulant assay after first removing the heparin. Only at heparin concentrations of 5 and 10 U/ml, was a 2- and 4-fold increase in the inactivation rate of factor XIa by purified antithrombin III observed. Therefore, in both purified systems as well as plasma, heparin, at concentrations observed in clinical practice, does not accelerate the inactivation rate of human factor XIa by antithrombin-III.

Amides↗
PubMed1990

Analysis of the generation and inhibition of factor Xa. Area under generation curves is independent of enzyme generation rate.

The activation of factor X in the presence of antithrombin has been studied in order to determine the parameters that control the area under the resulting factor Xa generation curve. Generation curves were analyzed using a model containing three parameters: the total generation of factor Xa, Emax; the rate of factor Xa generation, expressed as a first-order rate constant, kappa 1; and the rate of inhibition, expressed as another first-order rate constant, kappa 2. Using factor IXa-VIIIa to activate factor X, we found the area under the generation curve to be proportional to Emax, which was varied by varying the factor IXa concentration, and inversely proportional to kappa 2, which was varied by varying the antithrombin concentration. With this activator, however, kappa 1 varied in parallel with Emax, resulting in a correlation between integrated area and kappa 1. In order to determine whether Emax or kappa 1, or both, was a controlling parameter, similar activations were done with varying concentrations of the factor X-activating enzyme of Russell's viper venom. With this activator it was possible to vary Emax and kappa 1 independently, again at varying antithrombin concentrations. These results showed the integrated area to be proportional to Emax and inversely proportional to kappa 2, as before, but independent of the activation rate, kappa 1. In this system, therefore, the area under the factor Xa generation curve is controlled by the amount of factor Xa generated and its rate of inhibition but is independent of the rate of factor Xa generation.

Animals↗
PubMed1993

Aprotinin is a competitive inhibitor of the factor VIIa-tissue factor complex.

A highly purified preparation of human plasma factor VIIa was submitted to chromogenic assays with S-2288 factors IXa, Xa, activated protein C and thrombin being absent. Factor VIIa alone or in the presence of calcium, kept its activity even in the presence of high concentrations of aprotinin, inhibition appeared only in the presence of a factor VIIa-tissue factor complex. A two-stage amidolytic assay using activation of purified factor X and hydrolysis of S-2765 chromogenic substrate by the generated Xa was used to show a competitive inhibition with a Ki value of 30 microM. Aprotinin had no effect on factor Xa amidolytic activity per se. The factor VIIa-tissue factor complex could be adsorbed to immobilized aprotinin and removed by a chaotropic ion like KSCN 3 M. The assays with the DFP inactivated VIIa-tissue factor complex proved that the interaction involved the active site of factor VIIa. The inhibition of the VIIa-tissue factor complex was demonstrated in a clotting assay using aprotinin enriched normal or factor VIII deficient plasma.

Aprotinin↗
PubMed1986

Platelets modulate the proteolysis of factor VIII:C protein by plasmin.

Factor VIII coagulant protein (VIII:C) functions as a critical cofactor with factor IXa, calcium ions, and phospholipid during the activation of factor X. In the course of this reaction, the activity of VIII:C is first increased and then is destroyed by one or more serine proteases that are part of the coagulation sequence. In this study, we have investigated the influence of platelets on the inactivation of VIII:C by plasmin. Platelets were separated from plasma proteins in the presence of granule release inhibitors and were incubated with plasmin and isolated VIII:C or the complex of purified VIII:C/von Willebrand factor (vWF); VIII:C activity and antigen levels were assessed over time. In the presence of platelets, the isolated VIII:C showed an initial increase in VIII:C activity that was not present when platelets were absent, and the VIII:C/vWF showed an increase in VIII:C activity over that seen when platelets were absent. In addition, platelets stabilized VIII:C activity over a one-hour time course when compared with buffer. The VIII:C antigen did not increase and decreased slowly whether platelets were present or absent. Preincubating the platelets with ristocetin, collagen, or plasmin did not alter the results, and experiments using platelets from a patient with severe von Willebrand's disease also showed a pattern similar to that seen with normal platelets. Experiments using fixed platelets or phospholipid vesicles showed that they did not support the activation reaction or delay the inactivation reaction. These studies demonstrate that platelets modulate the activation and inactivation of VIII:C by plasmin, apparently by a mechanism that is independent of the platelet release reaction.

Blood Platelets↗
PubMed1994

Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa.

Inherited resistance to activated protein C (APC) is a recently identified major cause of thrombosis. It is associated with a mutation in the factor V gene affecting one of the cleavage sites for APC. APC resistance was recently found to be corrected by factor V, suggesting that factor V may have anticoagulant properties as a cofactor to APC. To elucidate this further, we have studied the effect of factor V and protein S, which is a known cofactor to APC, on APC-mediated degradation of factor VIIIa in a purified system. The APC-mediated degradation of factor VIIIa was monitored by a factor X activation reaction using purified factor IXa, phospholipid, and calcium. In the presence of both factor V and protein S, APC was found to inhibit factor VIIIa activity efficiently. APC alone or together with factor V was ineffective, whereas APC in combination with protein S was less efficient than when factor V was also included in the reaction. Two monoclonal antibodies, one against protein S and the other directed toward factor V, were found to inhibit the APC cofactor activity of the factor V-protein S mixture. Factor Va did not express APC cofactor activity, and addition of excess factor Va over factor V did not inhibit the APC cofactor function of a factor V-protein S mixture. In conclusion, the results suggest that factor V and protein S work in synergy as phospholipid-bound cofactors to APC.

Enzyme Activation↗
PubMed1998

Management of bleeding complications in redo cardiac operations.

Bleeding remains a complication of certain complex surgical procedures, particularly those cardiac operations associated with long bypass times and profound hypothermia. Clinical and novel experimental strategies to reduce bleeding and the need for blood and blood-product transfusions are the focus of this review. Preoperative assessment of the patient will identify drug-induced, acquired, or inherited coagulation defects that may contribute to this problem. The main attention is directed to the perioperative period, and broad areas discussed include the preoperative use of erythropoietin to increase red blood cell mass, autologous donation either preoperatively or before bypass, autotransfusion/hemofiltration, and acceptance of relative anemia both during the operation and into the postoperative period. A further, often overlooked, management strategy in treating major coagulopathies is the consideration of the cost and half-lives of the coagulation factors in individual blood components. Prevention of bleeding has become possible both by manipulation of the control of coagulation and inflammatory processes and by the introduction of pharmacologic agents such as aprotinin. Aprotinin is widely used and has proven efficacy in the management of excess bleeding. It is a serine protease inhibitor and has several possible mechanisms of action, including inhibition of the plasma enzyme systems activated by contact with the foreign surface of the bypass circuit and preservation of platelet function. Safety issues include the possibility of hypersensitivity and anaphylactic reaction on a second exposure. Concerns that aprotinin may induce a prothrombotic or coagulant state have no basis in theory or any good evidence in the current literature. A recent study specifically sought to identify the presence of disseminated microvascular platelet-fibrin thrombi present at autopsy in patients who had received aprotinin therapy. The study concluded that diffuse platelet-fibrin thrombi were not a direct complication of aprotinin therapy. Finally, modern molecular biology has led to the recent development of an inhibitor for factor IXa that competitively replaced IXa in the intrinsic complex and blocked the conversion of factor X to factor Xa. This compound is under investigation in animal studies. These have so far shown efficacy in reducing blood loss after bypass in comparison with standard heparin anticoagulation.

Aprotinin↗
PubMed1987

Molecular pathology and immunology of factor VIII (hemophilia A and factor VIII inhibitors).

Factor VIII is a large procoagulant glycoprotein that circulates in plasma in a noncovalent complex with von Willebrand factor. It is essential for the efficient cleavage of coagulation factor X by factor IXa, and its absence causes a severe bleeding disorder. Plasma factor VIII is reduced from the normal range of approximately 100 to 200 ng/ml in patients with the hereditary coagulation defect, hemophilia A, as well as in patients who develop autoantibodies that inactivate factor VIII. The understanding of factor VIII structure has been enhanced by recent studies that have characterized the X chromosome gene responsible for its synthesis, and preliminary information is now available about specific genetic defects. The basis for antibody formation in approximately 15 per cent of repeatedly transfused hemophilic patients is less clear at this time, however, for these individuals appear to have a variety of genetic defects that are not characteristically different from the patients who do not develop inhibitors. Although the antibodies cause a serious problem for affected individuals, they have been very useful in characterizing normal factor VIII and nonfunctional factor VIII-like protein that is found in the plasmas of 10 per cent of patients with mild hemophilia. Moreover, they are very useful reagents that can be used for immunoassay of factor VIII that has been modified in ways that have destroyed its procoagulant function.

Chemical Phenomena↗
PubMed1998

Hypotension and inflammatory cytokine gene expression triggered by factor Xa-nitric oxide signaling.

The signaling pathway initiated by factor Xa on vascular endothelial cells was investigated. Factor Xa stimulated a 5- to 10-fold increased release of nitric oxide (NO) in a dose-dependent reaction (0.1-2.5 microG/ml) unaffected by the thrombin inhibitor hirudin but abolished by active site inhibitors, tick anticoagulant peptide, or Glu-Gly-Arg-chloromethyl ketone. In contrast, the homologous clotting protease factor IXa or another endothelial cell ligand, fibrinogen, was ineffective. A factor Xa inter-epidermal growth factor synthetic peptide L (83)FTRKL(88) (G) blocking ligand binding to effector cell protease receptor-1 inhibited NO release by factor Xa in a dose-dependent manner, whereas a control scrambled peptide KFTGRLL was ineffective. Catalytically active factor Xa induced hypotension in rats and vasorelaxation in the isolated rat mesentery, which was blocked by the NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) but not by D-NAME. Factor Xa/NO signaling also produced a dose-dependent endothelial cell release of interleukin 6 (range 0.55-3.1 ng/ml) in a reaction inhibited by L-NAME and by the inter-epidermal growth factor peptide Leu(83)-Leu(88) but unaffected by hirudin. Maximal induction of interleukin 6 mRNA required a brief, 30-min stimulation with factor Xa, unaffected by subsequent addition of tissue factor pathway inhibitor. These data suggest that factor Xa-induced NO release modulates endothelial cell-dependent vasorelaxation and cytokine gene expression. This pathway requiring factor Xa binding to effector cell protease receptor-1 and a secondary step of ligand-dependent proteolysis may preserve an anti-thrombotic phenotype of endothelium but also trigger acute phase responses during activation of coagulation in vivo.

Animals↗
PubMed1995

Calreticulin, an antithrombotic agent which binds to vitamin K-dependent coagulation factors, stimulates endothelial nitric oxide production, and limits thrombosis in canine coronary arteries.

Coagulation Factor IX/IXa has been shown to bind to cellular surfaces, and Factor IXa expresses its procoagulant activity by assembling into the intrinsic Factor X activating complex (Factors IXa/VIIIa/X), which also forms on membrane surfaces. This led us to identify cellular proteins which bind Factor IX/IXa; an approximately 55-kDa polypeptide was purified to homogeneity from bovine lung extracts based on its capacity to bind 125I-Factor IX in a dose-dependent and saturable manner. From protein sequence data of the amino terminus and internal peptides, the approximately 55-kDa polypeptide was identified as calreticulin, a previously identified intracellular calcium-binding protein. Recombinant calreticulin bound vitamin K-dependent coagulation factors, 125I-Factor IX, 125I-Factor X, and 125I-prothrombin (Kd values of approximately 2.7, 3.2, and 8.3 nM, respectively), via interaction with its C-domain, although it did not affect the coagulant properties of these proteins. 125I-Calreticulin also bound to endothelial cells in vitro (Kd approximately 7.4 nM), and mouse infusion studies showed an initial rapid phase of clearance in which calreticulin could be localized on the vascular endothelium. Exposure of endothelial cells to calreticulin led to dose-dependent, immediate, and sustained increase in the production of nitric oxide, as measured using a porphyrinic microsensor. In a canine electrically induced thrombosis model, intracoronary infusion of calreticulin (n = 7) prevented occlusion of the left circumflex coronary artery in a dose-dependent manner compared with vehicle-treated controls (n = 5). These results indicate that calreticulin interacts with the endothelium to stimulate release of nitric oxide and inhibit clot formation.

Animals↗
PubMed1996

Determinants of coagulation activation in humans.

To evaluate the mechanism responsible for the generation of factor VIIa in vivo, we measured the levels of this enzyme after administering purified factor IX concentrates to patients with hemophilia B. Their factor VIIa levels were initially very low and gradually increased to normal, but there were no significant changes in the generation of factor Xa or thrombin. The administration of 10 mu g/kg body weight of recombinant factor VIIa to patients with factor VII deficiency increased the circulating levels 35-fold, but this only resulted in normalization of the activation of factor IX and factor X. Our data indicate that factor IXa is primarily responsible for the basal levels of free factor VIIa in vivo, and that changes in free factor VIIa in the blood do not necessarily lead to alterations in factor X activation.

Factor IX↗
PubMed1997

Factor Xa as an interface between coagulation and inflammation. Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo.

Coagulation proteases were tested in a rat model of acute inflammation. Subplantar injection of Factor Xa (10-30 microg) produced a time- and dose-dependent edema in the rat paw, and potentiated carrageenin-induced edema. In contrast, the homologous protease Factor IXa was ineffective. This inflammatory response was recapitulated by the Factor Xa sequence L83FTRKL88(G), which mediates ligand binding to effector cell protease receptor-1 (EPR-1), while a control scrambled peptide did not induce edema in vivo. Conversely, injection of the EPR-1-derived peptide S123PGKPGNQNSKNEPP137 (corresponding to the receptor binding site for Factor Xa) inhibited carrageenin-induced rat paw edema, while the adjacent EPR-1 sequence P136PKKRERERSSHCYP150 was without effect. EPR-1-Factor Xa-induced inflammation was characterized by fast onset and prominent perivascular accumulation of activated and degranulated mast cells, was inhibited by the histamine/serotonin antagonists cyproheptadine and methysergide, but was unaffected by the thrombin-specific inhibitor, Hirulog. These findings suggest that through its interaction with EPR-1, Factor Xa may function as a mediator of acute inflammation in vivo. This pathway may amplify both coagulation and inflammatory cascades, thus contributing to the pathogenesis of tissue injury in vivo.

Amino Acid Sequence↗
PubMed1992

Tissue factor potentiates the factor VIIa-catalyzed hydrolysis of an ester substrate.

We designed a simple and sensitive method to assay the activity of the factor VIIa-tissue factor complex, using as a substrate N alpha-benzyloxycarbonyl-L-arginine p-nitrobenzyl ester (Z-Arg-ONb) (Zur, M., and Nemerson, Y. (1978) J. Biol. Chem. 253, 2203-2209). The principle was to measure the amount of p-nitrobenzyl alcohol released during ester hydrolysis using reversed-phase high performance liquid chromatography. Z-Arg-ONb had a broad specificity for plasma serine proteases and factor IXa. Using this method, we examined the effect of tissue factor on the esterase activity of factor VIIa under various conditions. We found that tissue factor greatly potentiates the factor VIIa-catalyzed hydrolysis of Z-Arg-ONb. Phospholipids were not required for the factor VIIa-catalyzed hydrolysis of Z-Arg-ONb, even in the presence of tissue factor. The Km value of factor VIIa alone toward the ester substrate was six times higher than that of a VIIa-tissue factor complex (3.2 versus 0.54 mM), whereas the kcat value was 12 times lower than that of the VIIa-tissue factor complex (14.3 versus 173 s-1). Thus, tissue factor apparently affects the catalytic site of factor VIIa and enhances hydrolysis of the ester substrate. This enhancing effect of tissue factor disappeared on removal of the gamma-carboxyglutamic acid domain from factor VIIa, whereas the esterase activity in the absence of tissue factor was not affected by this modification. The gamma-carboxyglutamic acid domain is probably required as a potent determinant for interactions with tissue factor, even in the absence of phospholipids in the reaction mixture.

Amino Acid Sequence↗
PubMed2005

New anticoagulants.

The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing.

Animals↗
PubMed1983

Binding of coagulation factors IX and X to the endothelial cell surface.

Bovine coagulation factors IX and X bind to independent sites on bovine aortic endothelial cells. Binding studies with cells maintained serum-free showed that there are at least two classes of binding sites for factor IX and factor X with a dissociation constant of 4.9 x 10(-9) M and 2.1 x 10(-8) M for the respective high affinity sites. Ca+2 was required for specific binding and was reversed by addition of EDTA or EGTA. Competition experiments showed that factor IX and factor IXa bind to the same sites, which are different from the factor X binding sites. Neither binding of factor IX or factor X is inhibited by addition of prothrombin or protein C. Indirect immunofluorescence of factor IX indicated that binding was diffuse on the cell surface.

Animals↗
PubMed1985

Cellular processing of bovine factors X and Xa by cultured bovine aortic endothelial cells.

Previous studies have shown that Factor X and Factor Xa bind specifically to distinct sites on the endothelial cell surface. Since the coagulant activity of a cell-bound clotting protein is dependent on its remaining on the cell surface, endocytosis and degradation studies have been carried out. Cell-bound Factor X was internalized at 0.07 fmol/min/10(6) cells, a rate slower than its dissociation from the cell surface. Endocytosed Factor X was not degraded, but was returned to the cell surface. In contrast, Factor Xa was internalized at an initial rate of 0.38 fmol/min/10(6) cells and subsequently degraded at about the same rate. The degradation of Factor Xa was prevented by chloroquine. These results suggest that Factor Xa is internalized and degraded by a lysosomal-dependent pathway. Studies with Factor X- and Xa-colloidal gold conjugates showed endocytosis proceeding at coated pit regions, and accumulation of Factor Xa-gold particles in lysosome-like structures. Endocytosis was studied as a clearance pathway for cell-bound Factor Xa by activating Factor X with Factors IXa and VIII on the endothelial cell surface. Endocytosis of the Factor Xa formed was significant, as only 44% of the Factor Xa formed was released into the supernatant, whereas the remainder was internalized and degraded. Thus, endocytosis of Factor Xa bound to its specific endothelial cell sites may be an important factor in the balance of vessel wall hemostatic mechanisms.

Animals↗
PubMed1999

Procoagulant expression in platelets and defects leading to clinical disorders.

Hemostasis is a result of interactions between fibrillar structures in the damaged vessel wall, soluble components in plasma, and cellular elements in blood represented mainly by platelets and platelet-derived material. During formation of a platelet plug at the damaged vessel wall, factors IXa and VIIIa form the "tenase" complex, leading to activation of factor X on the surface of activated platelets. Subsequently, factors Xa and Va form the "prothrombinase" complex, which catalyzes the formation of thrombin from prothrombin, leading to fibrin formation. An enhanced expression of negatively charged phosphatidylserine in the outer membrane leaflet resulting from a breakdown of the phospholipid asymmetry is essential for the formation of the procoagulant surface. An ATP-driven and inward-acting aminophospholipid "translocase" and a "floppase" counterbalancing this have been postulated to maintain the dynamic state of phospholipid asymmetry. A phospholipid-nonspecific "scramblase," believed to be responsible for the fast breakdown of the asymmetry during cell activation, has recently been isolated from erythrocytes, cloned, and characterized. An intracellular calcium-binding segment and one or more thioesterified fatty acids are probably of importance for calcium-induced activation of this transporter protein. Cytosolic calcium ions also activate the calcium-dependent protease calpain associated with shedding of microvesicles from the transformed platelet membrane. These are shed with a procoagulant surface and with surface-exposed P-selectin from the alpha-granules. Theoretically, therefore, microvesicles can be involved in both coagulation and inflammation. Scott syndrome is probably caused by a defect in the activation of an otherwise normal scramblase, resulting in a relatively severe bleeding tendency. In Stormorken syndrome, the patients demonstrate a spontaneous surface expression of aminophospholipids. Activated platelets and the presence of procoagulant microvesicles have been demonstrated in several clinical conditions, such as thrombotic and idiopathic thrombocytopenia, disseminated intravascular coagulation, and HIV-1 infection, and have been found to be associated with fibrin in thrombosis. Procoagulant microvesicles may also be formed from other cells as a result of apoptosis.

Blood Coagulation Disorders↗