Abstract 350: Influence of HIV-1 Infection and Antiretroviral Therapy on the Coagulation System

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Kevin Fasing ◽  
Brian R Weil ◽  
Kyle J Diehl ◽  
Jared J Greiner ◽  
Brian L Stauffer ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Factor Viii ◽  
Tissue Factor ◽  
Plasma Concentrations ◽  
Tissue Type ◽  
Factor Vii ◽  
Coagulation System ◽  
Factor X ◽  
Thrombotic Risk ◽  
Hiv 1

HIV-1-infected individuals have a two- to four-fold greater incidence of cardiovascular disease and atherothrombotic events compared with the general population. The mechanisms responsible for this heightened cardiovascular risk are not fully understood. We have previously reported that the capacity of the endothelium to release tissue-type plasminogen activator (t-PA), the primary activator of fibrinolysis and a key endogenous defense mechanism against intravascular fibrin deposition and thrombosis, is impaired in HIV-1-seropositive adults. Whether diminished fibrinolytic activity is coupled with a hypercoagulative state in this population is unknown. Elevations in specific coagulation markers such as tissue factor and Factor VII are associated with increased thrombotic risk. The experimental aim of this study was to determine the influence of HIV-1 infection and antiretroviral therapy (ART) on markers of coagulation. To address this aim we studied 33 men: 16 HIV-1-seronegative (age: 41±3 yr); 7 HIV-1-seropositive treatment-naïve (34±2 yr); and 10 HIV-1-seropositive receiving ART (42±3 yr; efavirenz-based regimen). All subjects were non-obese, normotensive and free of overt cardiometabolic disease. Circulating concentrations of tissue factor, Factor VII, Factor VIII and Factor X were determined by immunoassay. There were no significant differences in plasma concentrations of tissue factor (32+3 vs 40+3 pg/mL), Factor VII (103+9 vs 100+5 %), Factor VIII (111+13 vs 117+8 %) and Factor X (89+5 vs 91+2 %) between HIV-1-seropositive treatment-naïve and healthy men. Moreover, there was no influence of ART on these circulating markers. Plasma tissue factor (41+5 pg/mL), Factor VII (107+6 %), Factor VIII (103+7 %) and Factor X (90+3%) were similar in the HIV-1-seropositive receiving ART compared with HIV-1-seropositive treatment-naïve and seronegative groups. These data suggest that neither HIV-1 infection per se nor ART are associated with unfavorable changes in specific coagulation markers. Thus, changes in the coagulation system that have been linked to increased thrombotic burden are not apparent in HIV-1-seropositive adults.

scholarly journals Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 2039-2047 ◽  
Author(s):  
KA Bauer ◽  
PM Mannucci ◽  
A Gringeri ◽  
F Tradati ◽  
S Barzegar ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Plasma Concentrations ◽  
Factor Ix ◽  
Factor Vii ◽  
Coagulation System ◽  
Activate Factor ◽  
Factor X ◽  
Factor Ixa ◽  
Tissue Factor Pathway ◽  
Activation Peptide

Abstract We have infused recombinant factor VIIa into patients with hereditary factor VII deficiency with marked reductions in plasma concentrations of factor IX activation peptide (FIXP), factor X activation peptide (FXP), and prothrombin activation fragment F1+2. These investigations show substantial elevations in these markers of coagulation activation and thereby demonstrate that the factor VII-tissue factor pathway is largely responsible for the activation of factor IX as well as factor X in the basal state (ie, the absence of thrombosis or provocative stimuli). We have administered a monoclonal antibody purified factor IX concentrate to individuals with hemophilia B. These studies show an increase in the plasma levels of FIXP that were initially greatly decreased, but no change in FXP or F1+2. We have also infused highly purified factor VIII concentrate into patients with hemophilia A. The data demonstrate no significant changes in the plasma concentrations of FXP and F1+2. The above observations indicate that factor IXa generated by the factor VII-tissue factor pathway is unable to activate factor X under basal conditions. Based upon the above findings, we outline a model of blood coagulation system function under basal conditions, and suggest a process by which the generation of factor Xa and thrombin might be accelerated during normal hemostasis and in the setting of thrombotic disorders.

scholarly journals Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 2039-2047
Author(s):  
KA Bauer ◽  
PM Mannucci ◽  
A Gringeri ◽  
F Tradati ◽  
S Barzegar ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Plasma Concentrations ◽  
Factor Ix ◽  
Factor Vii ◽  
Coagulation System ◽  
Activate Factor ◽  
Factor X ◽  
Factor Ixa ◽  
Tissue Factor Pathway ◽  
Activation Peptide

We have infused recombinant factor VIIa into patients with hereditary factor VII deficiency with marked reductions in plasma concentrations of factor IX activation peptide (FIXP), factor X activation peptide (FXP), and prothrombin activation fragment F1+2. These investigations show substantial elevations in these markers of coagulation activation and thereby demonstrate that the factor VII-tissue factor pathway is largely responsible for the activation of factor IX as well as factor X in the basal state (ie, the absence of thrombosis or provocative stimuli). We have administered a monoclonal antibody purified factor IX concentrate to individuals with hemophilia B. These studies show an increase in the plasma levels of FIXP that were initially greatly decreased, but no change in FXP or F1+2. We have also infused highly purified factor VIII concentrate into patients with hemophilia A. The data demonstrate no significant changes in the plasma concentrations of FXP and F1+2. The above observations indicate that factor IXa generated by the factor VII-tissue factor pathway is unable to activate factor X under basal conditions. Based upon the above findings, we outline a model of blood coagulation system function under basal conditions, and suggest a process by which the generation of factor Xa and thrombin might be accelerated during normal hemostasis and in the setting of thrombotic disorders.

Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1330-1335 ◽  
Author(s):  
Cornelis van 't Veer ◽  
Neal J. Golden ◽  
Kenneth G. Mann
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Factor Viia ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Factor Vii ◽  
Lag Phase ◽  
Single Chain

Factor VII circulates as a single chain inactive zymogen (10 nmol/L) and a trace (∼10-100 pmol/L) circulates as the 2-chain form, factor VIIa. Factor VII and factor VIIa were studied in a coagulation model using plasma concentrations of purified coagulation factors with reactions initiated with relipidated tissue factor (TF). Factor VII (10 nmol/L) extended the lag phase of thrombin generation initiated by 100 pmol/L factor VIIa and low TF. With the coagulation inhibitors TFPI and AT-III present, factor VII both extended the lag phase of the reaction and depressed the rate of thrombin generation. The inhibition of factor Xa generation by factor VII is consistent with its competition with factor VIIa for TF. Thrombin generation with TF concentrations >100 pmol/L was not inhibited by factor VII. At low tissue factor concentrations (<25 pmol/L) thrombin generation becomes sensitive to the absence of factor VIII. In the absence of factor VIII, factor VII significantly inhibits TF-initiated thrombin generation by 100 pmol/L factor VIIa. In this hemophilia A model, approximately 2 nmol/L factor VIIa is needed to overcome the inhibition of physiologic (10 nmol/L) factor VII. At 10 nmol/L, factor VIIa provided a thrombin generation response in the hemophilia model (0% factor VIII, 10 nmol/L factor VII) equivalent to that observed with normal plasma, (100% factor VIII, 10 nmol/L factor VII, 100 pmol/L factor VIIa). These results suggest that the therapeutic efficacy of factor VIIa in the medical treatment of hemophiliacs with inhibitors is, in part, based on overcoming the factor VII inhibitory effect.

scholarly journals Evidence for tissue factor-dependent activation of the classic extrinsic coagulation mechanism in blood obtained from bleeding time wounds

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 629-635 ◽  
Author(s):  
HJ Weiss ◽  
B Lages
Keyword(s):  
Tissue Factor ◽  
Platelet Activation ◽  
Bleeding Time ◽  
Plasma Concentrations ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Platelet Factor ◽  
Heparin Administration ◽  
Coagulation Mechanism

Abstract The activation of platelets and the coagulation mechanism was studied by collecting blood from a standard bleeding time incision at 30-second intervals and measuring the plasma concentrations of fibrinopeptide A (FPA), platelet factor 4 (PF4), and thromboxane B2 (TxB2). FPA was observed in the first samples (30 to 60 seconds) obtained, increased progressively until cessation of bleeding, and was markedly diminished after heparin administration, thus indicating that thrombin formation occurs early in incisional blood. PF4 increased monotonically throughout blood sampling, whereas the major increase in TxB2 appeared near the cessation of bleeding. The initial increase in FPA content occurred normally in patients with deficiencies of either factor IX or VIII, was markedly diminished in patients with factor X or V deficiency, and was delayed in patients with factor VII deficiency. These studies suggest that tissue factor activation of the classic (activation of factor X) extrinsic coagulation mechanism occurs as an early event during the arrest of bleeding from bleeding time incisions. The relation of the aforementioned to platelet activation is less clear because there was no consistent correlation between decreased FPA formation and impaired PF4 secretion or TxB2 production. In fact, the latter were normal in some subjects with the most impaired FPA formation, which suggests that both collagen and thrombin, perhaps synergistically, may contribute to platelet activation during the primary arrest of bleeding.

Effect of Plasmatic Procoagulant Factors in Thrombin Generation Parameters in a Platelet-Poor Plasma Model System.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4021-4021
Author(s):  
Jogin R. Wu ◽  
Bing Bai
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Lag Time ◽  
Model System ◽  
Factor Vii ◽  
Factor X ◽  
Plasma Model ◽  
Cat Assay ◽  
Viii And Ix

Abstract The evolution of the thrombin generation (TG) concept and the recent technical advances in automated TG measurement have made its clinical utility practical but the clinical relevance of all parameters thrombin generation provided still remain unclear. In the current study we investigated effects of various procoagulant plasmatic factors in the TG parameters, such as rate, peak, lag time and area under the curve (AUC), in a platelet poor plasma model system using the calibrated automated thrombography (CAT). The plasma model system was made by mixing well-characterized commercial normal pooled human plasma with plasmas that are deficient in various procoagulant factors (factor VIII, IX, II, X, V and VII) to reach factor levels between <1 % to 100% normal. Initially 5 pM of tissue factor and 4 μM of phospholipid were used and all TG parameters (lag time, peak, rate, and AUC) were compared with various levels of all procoagulant factors. Our result showed that the AUC is proportional to concentrations of factor II and X but not sensitive to factor VIII, IX and VII levels under such experimental conditions. Factor VII affects only the lag time and factor X affects both the lag time and the rate of thrombin generation. Factor II and X affect the peak as well. Factor VIII and IX affect both the rate and peak but not the AUC. Factor V plays very little role on affecting these parameters. Furthermore different concentrations of tissue factor (0.5 to 5 pM) were used to explore the sensitivity of TG for screening hemophiliac factor deficiencies. When ≤ 2pM of tissue factor and 4 μM of phospholipid were used the AUC showed three fold difference for factor VIII deficient plasma versus the normal plasma pool as compared with the less than 20% of difference in AUC (SD=15% for normal population) under the 5 pM concentration of tissue factor. Using the AUC and the rate of TG factor VIII and IX levels were well differentiated under such further diluted tissue factor concentrations (≤ 2 pM). Our study indicated that, under the standard CAT assay condition, 1) the lag time is mainly an indicator of extrinsic tenase reaction (factor VII, X); 2) the peak and rate reflect the intrinsic tenase reaction (factor X, IX, and VIII); and 3) the AUC and peak are largely affected by the prothrombinase factors (II, X) indicating the total free thrombin available for its overall plasmatic procoagulant activity. When proper concentration of triggering agent is used (≤ 2pM of tissue factor and 4 μM of phospholipid) TG becomes sensitive to all plasmatic procoagulant factors and CAT can be used for screening factor deficiencies in hemophiliac patients. A combination of these TG parameters can be used in an in-vitro screening assay to indicate the overall hemostasis balance in plasma under physiological conditions and an individual factor deficiency in related to hemostasis unbalance. Such further diluted triggering agent needs to be optimized for the CAT assay and a standardized large scale clinical retrospective study is needed to prove the utility of these parameters.

scholarly journals Evidence for tissue factor-dependent activation of the classic extrinsic coagulation mechanism in blood obtained from bleeding time wounds

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 629-635 ◽  
Author(s):  
HJ Weiss ◽  
B Lages
Keyword(s):  
Tissue Factor ◽  
Platelet Activation ◽  
Bleeding Time ◽  
Plasma Concentrations ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Platelet Factor ◽  
Heparin Administration ◽  
Coagulation Mechanism

The activation of platelets and the coagulation mechanism was studied by collecting blood from a standard bleeding time incision at 30-second intervals and measuring the plasma concentrations of fibrinopeptide A (FPA), platelet factor 4 (PF4), and thromboxane B2 (TxB2). FPA was observed in the first samples (30 to 60 seconds) obtained, increased progressively until cessation of bleeding, and was markedly diminished after heparin administration, thus indicating that thrombin formation occurs early in incisional blood. PF4 increased monotonically throughout blood sampling, whereas the major increase in TxB2 appeared near the cessation of bleeding. The initial increase in FPA content occurred normally in patients with deficiencies of either factor IX or VIII, was markedly diminished in patients with factor X or V deficiency, and was delayed in patients with factor VII deficiency. These studies suggest that tissue factor activation of the classic (activation of factor X) extrinsic coagulation mechanism occurs as an early event during the arrest of bleeding from bleeding time incisions. The relation of the aforementioned to platelet activation is less clear because there was no consistent correlation between decreased FPA formation and impaired PF4 secretion or TxB2 production. In fact, the latter were normal in some subjects with the most impaired FPA formation, which suggests that both collagen and thrombin, perhaps synergistically, may contribute to platelet activation during the primary arrest of bleeding.

Very Low Activated Factor VII and Reduced Factor VII Antigen in Familial Abetalipoproteinaemia

1998 ◽  
Vol 80 (08) ◽  
pp. 233-238 ◽  
Author(s):  
K. A. Mitropoulos ◽  
M. N. Nanjee ◽  
D. J. Howarth ◽  
J. C. Martin ◽  
M. P. Esnouf ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Positive Association ◽  
Factor Ix ◽  
Factor Vii ◽  
Unesterified Fatty Acid ◽  
Factor Xii ◽  
Factor X ◽  
Factor Xi ◽  
Activated Factor Vii ◽  
Normal Mean

SummaryAbetalipoproteinaemia is a rare disorder of apolipoprotein B metabolism associated with extremely low plasma concentrations of triglyce-ride. To discover whether the general positive association between factor VII and triglyceride levels extends to this condition, 5 patients were compared with 18 controls. All patients had a triglyceride below 100 μmol/l. Plasma unesterified fatty acid concentration was normal. Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B. The patients’ mean factor VII activity and factor VII antigen were also significantly reduced to 54% and 63% of those in controls, respectively. Mean factor XI activity and tissue factor pathway inhibitor activity were reduced in patients to 70% and 75% of control values respectively, while factor XII, factor XI antigen, factor X, prothrombin and protein C were normal.

Self-Damping Mechanism in Blood Coagulation

1974 ◽  
Vol 32 (01) ◽  
pp. 057-064 ◽  
Author(s):  
Y Nemerson ◽  
S.A Silverberg ◽  
J Jesty
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Calcium Ions ◽  
Control Mechanism ◽  
Factor Vii ◽  
Damping Factor ◽  
Factor V ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Two Systems

SummaryTwo reactions of the extrinsic pathway of coagulation, the activations of Factor X and prothrombin, have been studied in purified systems and shown to be self-damping. Factor X was activated by the tissue factor - Factor VII complex, and prothrombin by two systems: the coagulant protein of Taipan venom, and the physiological complex of activated Factor X, Factor V, lipid, and calcium ions. In each case the yield of enzyme, activated Factor X or thrombin, is a function of the concentration of activator. These and other observations are considered as a basis for a control mechanism in coagulation.

Factors Affecting the lnteraction of Tissue Factor/Factor Vll with Factor X in a Heterogeneous Tubular Reactor

1991 ◽  
Vol 65 (02) ◽  
pp. 139-143 ◽  
Author(s):  
Cynthia H Gemmell ◽  
Vincet T Turitto ◽  
Yale Nemerson
Keyword(s):  
Steady State ◽  
Tissue Factor ◽  
Factor Viia ◽  
Transmembrane Protein ◽  
Strong Association ◽  
Tubular Reactor ◽  
Factor Xa ◽  
Phospholipid Bilayer ◽  
Factor Vii ◽  
Factor X

SummaryA novel reactor recently described for studying phospholipiddependent blood coagulation reactions under flow conditions similar to those occurring in the vasculature has been further charactenzed. The reactor is a capitlary whose inner wall is coated with a stable phospholipid bilayer (or two bilayers) containing tissue factor, a transmembrane protein that is required for the enzymatic activation of factor X by factor VIIa. Perfusion of the capillary at wall shear rates ranging from 25 s−1 to 1,200 s−1 with purified bovine factors X and VIIa led to steady state factor Xa levels at the outlet. Assay were performed using a chromogenic substrate, SpectrozymeTMFXa, or by using a radiometric technique. In the absence of Ca2+ or factor VIIa there was no product formation. No difference was noted in the levels of factor Xa achieved when non-activated factor VII was perfused. Once steady state was achieved further factor Xa production continued in the absence of factor VIIa implying a very strong association of factor VIIa with the tissue factor in the phospholipid membrane. In agreement with static vesicle-type studies the reactor was sensitive to wall tissue factor concentration, temperature and the presence of phosphatidylserine in the bilayer.

scholarly journals Epinephrine Exerts Anticoagulant Effects during Human Endotoxemia

1997 ◽  
Vol 185 (6) ◽  
pp. 1143-1148 ◽  
Author(s):  
Tom van der Poll ◽  
Marcel Levi ◽  
Mieke Dentener ◽  
Patty M. Jansen ◽  
Susette M. Coyle ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasma Concentrations ◽  
Systemic Infection ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Coagulation System ◽  
Type I ◽  
Maximal Activation ◽  
Antithrombotic Effects ◽  
Activator Inhibitor Type

To determine the effect of a physiologically relevant elevation in the plasma concentrations of epinephrine on the activation of the hemostatic mechanism during endotoxemia, 17 healthy men were studied after intravenous injection of lipopolysaccharide (LPS, 2 ng/kg), while receiving a continuous infusion of epinephrine (30 ng/kg/min) started either 3 h (n = 5) or 24 h (n = 6) before LPS injection, or an infusion of normal saline (n = 6). Activation of the coagulation system (plasma concentrations of thrombin–antithrombin III complexes and prothrombin fragment F1+2) was significantly attenuated in the groups treated with epinephrine when compared with subjects injected with LPS only (P <0.05). Epinephrine enhanced LPS-induced activation of fibrinolysis (plasma levels of tissue-type plasminogen activator and plasmin-α2–antiplasmin complexes; P <0.05), but did not influence inhibition of fibrinolysis (plasminogen activator inhibitor type I). In subjects infused with epinephrine, the ratio of maximal activation of coagulation and maximal activation of fibrinolysis was reduced by >50%. Hence, epinephrine exerts antithrombotic effects during endotoxemia by concurrent inhibition of coagulation, and stimulation of fibrinolysis. Epinephrine, whether endogenously produced or administered as a component of treatment, may limit the development of disseminated intravascular coagulation during systemic infection.

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