Antithrombin III Levels Research Articles

Hemostatic and fibrinolytic status in patients with ovarian cancer and benign ovarian cysts: could D-dimer and antithrombin III levels be included as prognostic markers for survival outcome?

We determined the hemostatic and fibrinolytic status in 60 patients with ovarian cancer and benign ovarian cysts. Hypercoagulation, increased platelets, and enhanced fibrinolysis were seen in patients with preoperative ovarian cancer compared to patients with benign ovarian cysts. Enhanced thrombin generation, evidenced by increased F1+2 and decreased antithrombin III (ATIII) levels with further enhanced fibrinolysis by elevated D-dimer, was seen in advanced cancer. Ten ovarian cancer patients died within 13 months after diagnosis and another died at 24 months, all from advanced stage of cancer, except one from stage IC cancer who died at 11 months. The survival rates from the disease at 13 months and 24 months were 66.7% and 45%, respectively. Most of the patients had gone through the complete course of chemotherapy, and those patients still alive have been disease free between 13 and 42 months. No statistical relationships for the hemostatic parameters studied in ovarian cancer patients could be found between those who died and those still living 13 and 24 months after diagnosis, except for ATIII and D-dimer levels. Elevated D-dimer levels were associated with those who died within 13 and 24 months from the disease, and the decreased ATIII levels only reached statistical significance by 24 months. It could be suggested that these two parameters might be useful as systemic prognostic markers in survival outcome from the disease for the first 24 months in advanced ovarian cancer, in addition to the known correlation with the International Federation of Gynecology and Obstetrics stage.

The Effects of Triiodothyronine Augmentation on Antithrombin III Levels in Sepsis

Sepsis and multisystem organ failure are often associated with disseminated intravascular coagulation and consumption of coagulation inhibitors such as antithrombin III (ATIII). The "sick euthyroid syndrome" is also seen in association with significant illnesses and consists of decreased levels of circulating triiodothyronine (T3). We evaluated whether T3 supplementation would affect ATIII levels in septic rats. Thirty Sprague-Dawley rats were divided into three groups: sham laparotomy (S) plus saline, cecal ligation and puncture (CLP) plus saline, and CLP plus T3 (3 ng/hour) via an osmotic minipump. Twenty-four hours after laparotomy blood was drawn, and T3 and ATIII levels were then compared with baseline values. T3 supplementation partially negated the sepsis-induced decrease in circulating T3 levels. The levels are expressed as percentage change from the levels before surgery (S, -12.9 +/- 3.1; CLP, -60.0 +/- 5.3; CLP + T3, -34.9 +/- 4.3; mean +/- standard error; P < 0.05). T3 supplementation also statistically changed the percentage difference in ATIII levels toward the control (S, 9.6 +/- 2.8; CLP, -37.9 +/- 5.4; CLP + T3, -16.0 +/- 4.5; mean +/- standard error; P < 0.01). T3 supplementation reduced the sepsis-induced decrease in ATIII levels. Whether this was accomplished by decreased consumption or increased production of ATIII via the direct anabolic effect of T3 on acute-phase protein synthesis in the liver is unknown and warrants further investigation.

Quantitative analysis of transcription and translation in gene amplified Chinese hamster ovary cells on the basis of a kinetic model.

The elevation of expression levels for secreted glycoproteins by gene amplification in mammalian cells shows a saturation behavior at high levels of gene amplification. At high expression levels a drop in the secretion efficiency for the recombinant protein occurs (Schröder and Friedl, 1997), coinciding with the appearance of misfolded protein in the cell. In this communication we investigated whether additional limitations exist at the levels of transcription and translation. Four Chinese hamster ovary (CHO) cell lines expressing different amounts of human antithrombin III (ATIII) were used as a model system. A tenfold increase in the ATIII cDNA copy number from the lowest to the highest producing cell line coincided with a 38-fold increase in ATIII mRNA levels, and an 80-fold increase in the amount of intracellular ATIII levels. The data was analyzed using a simple kinetic model. The following conclusions were derived: I. The transcriptional activity for the recombinant protein is not saturated. II. Translation itself is not saturated either, but may be downregulated as secretion efficiency drops. III. Two explanations for the previously reported drop in secretion efficiency for the recombinant protein with increasing expression level are possible: A. Protein degradation is an alternative fate for translated ATIII and the fraction of ATIII degraded after translation increases as expression level is increased. B. Translation is downregulated as the secretory apparatus becomes exhausted to maintain cell viability.

The Effect of Danaparoid Sodium (Danaparoid) on Endotoxin-induced Experimental Disseminated Intravascular Coagulation (DIC) in Rats

Danaparoid sodium (danaparoid) is a low molecular weight heparinoid with anticoagulation properties, which mainly consists of heparan sulfate. Compared with heparin sodium (heparin), danaparoid has a much higher anti-Xa/anti-thrombin ratio. We compared the effect of danaparoid on endotoxin-induced experimental disseminated intravascular coagulation (DIC) in rats with heparin. A bolus injection of endotoxin (10 mg/kg) induced gradual decreases in the platelet count, and the plasma fibrinogen, antithrombin III (AT-III) and heparin cofactor II levels, as well as an increase in the fibrinogen/fibrin degradation products level from 1 to 6 hours after the injection, indicating that both coagulation and fibrinolysis were activated. The intravenous administration of danaparoid or heparin 3 hours after the endotoxin injection inhibited the endotoxin-induced decreases in the platelet count and plasma fibrinogen level and also inhibited the endotoxin-induced increase in glomerular fibrin deposition in the kidney. Differences between danaparoid and heparin were observed in their effects on the plasma AT-III level and clotting time. Danaparoid significantly inhibited both the decrease in the plasma AT-III level and the prolongation of the prothrombin time induced by endotoxin, where as heparin showed no effect on those responses. Moreover, danaparoid enhanced the prolongation of the activated partial thromboplast in time induced by endotoxin to a lesser degree than heparin. These findings suggest that the effects of danaparoid on the endotoxin-induced decrease of the plasma AT-III level and the prolongation of the clotting time are more advantageous than those of heparin. The results may have been due to a higher anti-Xa/anti-thrombin ratio of danaparoid than that of heparin, indicating that danaparoid may be useful in the treatment of DIC.

A CASE OF EARLY GASTRIC CANCER ASSOCIATED WITH CONGENITAL ANTITHROMBIN III DEFICIENCY

A 37-year-old woman was admitted to the hospital for an early gastric cancer. She was a member of a family who have venous thromboembolic episodes in a high incidence, and had been diagnosed as having hereditary antithrombin III (ATIII) deficiency, with the ATIII activity of 56.8%. This time a distal gastrectomy was performed with a diagnosis of IIc cancer of the angular notch. For perioperative management antithrombin III concentrates were administered and the plasma ATIII level (ATIII activity) was maintained at values in excess of 80% for postoperative one week. No thrombotic complications occurred as judged by clinical examination. It has been confirmed that any operation can increase a risk of association of thrombosis in this congenital disorder. When ATIII consumption is enhanced (for example, during sugical procedures), usual antithrombotic therapies such as administration of heparin are not enough and replacement therapy may be necessary in order to normalize ATIII level.

The Association of Anticoagulant Protein Concentrations with Acute Myocardial Infarction in the Thromholysis in Myocardial Infarction Phase II (TIMI II) Trial.

Background: Little is known about the relationship between myocardial infarction and the coagulation inhibitors protein C, protein S, and antithrombin III (ATIII). Methods: We explored the hypothesis. that partial deficiencies in protein C, protein S, and ATIII may be associated with acute myocardial infarction by comparing the baseline levels of these anti coagulants in a sample of participants in the Thrombolysis in Myocardial Infarction Phase II Trial (TIMI II) to the levels in a sample of Red Cross donors. We also examined the changes in concentrations of hemostatic and inhibitory factors during thrombolytic therapy, the correlations between the inhibitors and plasminogen and fibrinogen, and the association of baseline inhibitor levels with the degree of plasmin generation during treatment. Levels of protein C, free and total protein S, ATIII, fibrinogen, tissue-type plasminogen activator, (t-PA), plasminogen, and alpha-2 antiplasmin were measured in plasma samples obtained at baseline before treatment with thrombolytic therapy and at 50 minutes, 5 hours, and 8 hours after the start of therapy (n=92). Protein C, free and total protein S, and ATIII were also measured in plasma samples from comparable Red Cross donors (n=92). Results: Baseline protein C and ATIII levels were higher in the TIMI II subjects than in controls (3.7 µ/ml vs 3.3 for protein C, P=0.002; 118% vs 111% for ATIII, P=0.006). Free and total protein S levels were lower in the TIMI II subjects than in controls (4.3 µ/ml vs 5.2 for free protein S, and 15.3 µ/ml vs 17.2 for total protein S, P=0.001). There were no major changes in protein C or protein S levels after initiation of thrombolytic therapy, but there was a 13% decrease in ATIII. Significant correlations were found between baseline protein C, Protein S, ATIII, and plasminogen; none of these factors were correlated with baseline fibrinogen concentration. The pretreatment levels of the inhibitors were correlated with markers of the amount of plasmin generated during therapy. Conclusions: It is not likely that partial protein C or ATIII deficiency is commonly associated with myocardial infarction. It is more likely that at the time of infarction, these inhibitors are somewhat higher possibly due to a homeostatic response to previous plaque rupture and thrombosis. Partial protein S deficiency may play a role in coronary thrombosis. The levels of these inhibitors at the time of infarction may be important in the efficacy of thrombolytic therapy.

Survival in Acute Myocardial Infarction Induced by Coronary Ligation: Prognostic Relevance of Certain Hemostatic Factors During the Occlusion Phase.

Alterations in various hemostatic factor have been identified as risk factors for survival after acute myocardial infarction (AMI). However, these clinical data are primarily limited to observations made during the postinfarct stage. We assessed the effects of 50 minutes of left anterior descending artery occlusion on several hemostatic factors and analyzed their changes with outcome in 18 Yorkshire swine. Blood samples were obtained from the systemic circulation at base-line and at 25 and 50 minutes of occlusion. Platelet aggregability and plasma antithrombin-III protein C, protein S, fibronectin, endothelin-1, as well as the metabolites of thromboxane and prostacyclin were measured. Of the 18 swine, 7 survived the infarct and 11 animals developed fatal ventricular fibrillation. Both groups demonstrated significant decreases in platelet aggregation, and a decline in plasma protein S when compared with baseline. Thromboxane, prostacyclin, and ondothelin-1 plasma concentrations were also markedly reduced at the end of occlusion. There were significant changes in antithrombin-III, protein C, and fibronectin levels between surviving animals and those that died of ventricular fibrillation. Acute coronary artery occlusion is associated with substantial changes in the hemostatic factors in swine. Plasma levels of fibronectin, antithrombin-111, and protein C differed between survivors and nonsurvivors and thus might serve as predictors of mortality due to fatal ventricular fibrillation during AMI. The mechanisms of these changes during the acute phase of AMI are unclear. Immediately AMI prognosis may be related to hemostatic changes not only after thrombolysis or spontaneous reperfusion, but also during the occlusion phase as well.

Activated protein C resistance, thrombophilia, and inflammatory bowel disease.

Thromboembolic events frequently complicate the clinical course of patients with inflammatory bowel disease (IBD). Hereditary thrombophilia may contribute to this tendency. Resistance to activated protein C is the most recently described thrombophilic state and may account for up to 40% of patients with thrombophilia. Thirty-seven patients with IBD were studied (mean age 44 years, range 18-82 years). Three patients had a history of thrombotic episodes. The 37 controls included 23 men and 17 women (mean age 48 years, range 16-89 years). Disease activity was assessed using the Harvey Bradshaw index for patients with Crohn's disease and the Truelove and Witts grading system for patients with ulcerative colitis. Levels of fibrinogen, antithrombin III (ATIII), protein C, protein S, activated protein C resistance (APCR), and the presence of a lupus anticoagulant (LA) were determined. Median ATIII levels in patients with IBD were significantly lower than controls (98% vs 106%, P = 0.007), while fibrinogen was elevated (4.2 vs 3.3 g/liter, P = 0.026) despite quiescent disease activity. LA was detected in 7/37 patients in the IBD group compared to 0/37 controls. (chi2 = 5.68, P = 0.017). No significant difference was observed in levels of inherited thrombophilic factors and in particular APCR between IBD patients and controls. In conclusion, the presence of inherited thrombophilic defects, in particular APCR, is uncommon in patients with IBD and does not merit routine screening.

Use of antithrombin III in cancer patients with sepsis complicated with disseminated intravascular coagulopathy

Mortality rate from sepsis is estimated to be 20% to 60% with disseminated intravascular coagulation (DIC) often accompanying sepsis. Replacement therapy with antithrombin III (ATIII) concentrate has been hypothesized to be a means for attenuating DIC, since ATIII is rapidly consumed during DIC. A reliable index of poor prognosis is an initial decrease of serum ATIII level. The purpose of this pilot study was to evaluate the effects of the administration of ATIII in patients sepsis complicated by DIC.

Coagulation protein function V: diminution of antithrombin III function by acetaldehyde.

The anticoagulant activity of antithrombin III (ATIII), as observed in a plasma-free system consisting of thrombin and fibrinogen, is readily reduced by acetaldehyde (AcH) at concentrations of 447, 89.4, and 17.9 mM. Whereas control thrombin-fibrinogen mixtures clotted in 17.7+/-0.75 sec, ATIII prolonged clotting time to 55.0+/-1.75 sec on preincubation with thrombin for 30 min at room temperature. On subsequent preincubation of ATIII with the AcH for 30 min at room temperature and passage of the mixture through Sephadex G-25 minicolumns to remove excess AcH, the eluates were tested for anticoagulant activity. Clotting times of 20.9+/-1.0, 32.3+/-1.0, and 45.3+/-1.6 sec were obtained with 447, 89.4, and 17.9 mM AcH-ATIII mixtures, respectively. These data suggest that functional groups on ATIII, such as guanidiniums, aminos, and others are susceptible to adduct formation with AcH, thereby altering the shape and charge of the anticoagulant. As a consequence of this type of reaction, an altered molecule of reduced biological activity may be produced. These experimental results may explain, in part, the reduction in ATIII levels reported by others in patients with alcoholic liver disease.

Antithrombin-III for the treatment of chemotherapy-induced organ dysfunction following bone marrow transplantation.

A hypercoaguable state has been shown to follow high-dose chemotherapy for bone marrow transplantation (BMT). Deficiency of the natural anticoagulants, antithrombin III (AT-III), protein C and protein S correlate with organ dysfunction following BMT. We treated 10 patients with severe post-BMT organ dysfunction with AT-III concentrate. Indications for treatment included AT-III anticoagulant level less than 88% and life-threatening single or multiorgan dysfunction. All patients were loaded with 50 units/kg AT-III every 8 h for three doses followed by 50 units/kg/day each day for 3-12 days. Clinical improvement was seen within 1-5 days of start of therapy in all patients. Patients with veno-occlusive disease (VOD) showed a decrease in platelet consumption in nine of nine patients, resolution of hepatic tenderness in six of eight patients, and reduction of severe ascites and weight gain in four of five patients. The probability of death due to VOD and life-threatening organ dysfunction was significantly less in the AT-III-treated group when compared to a historical control group receiving the same preparative regimen (P = 0.047 and P = 0.034, respectively). Significant improvements in organ dysfunction following AT-III treatment in this small study supports a causal relationship between AT-III deficiency and post-BMT chemotherapy-induced organ dysfunction.

Coagulation patterns of disseminated intravascular coagulation in acute promyelocytic leukemia

Coagulation patterns of 19 newly-diagnosed acute promyelocytic leukemia (APL) patients with disseminated intravascular coagulation (DIC) at presentation were studied. Seventeen patients had hemorrhagic complications, of which four were fatal. Fatal hemorrhages were related with lower fibrinogen level and lower platelet count. DIC of the APL patients without infection was characterized by low fibrinogen and normal antithrombin III (ATIII) level. Thrombin–ATIII complex level was elevated in all patients examined. Patients with infection had higher fibrinogen levels than those without infection and some patients had reduced ATIII level. Ten remission inductions were tried with multidrug chemotherapy and seven with all-trans retinoic acid (ATRA). Complete remission was achieved in seven of ten inductions with chemotherapy and in all seven inductions with ATRA. Two patients treated with chemotherapy had fatal hemorrhage after starting therapy but none treated with ATRA. © 1997 John Wiley & Sons, Ltd.

Coagulation patterns of disseminated intravascular coagulation in acute promyelocytic leukemia.

Coagulation patterns of 19 newly-diagnosed acute promyelocytic leukemia (APL) patients with disseminated intravascular coagulation (DIC) at presentation were studied. Seventeen patients had hemorrhagic complications, of which four were fatal. Fatal hemorrhages were related with lower fibrinogen level and lower platelet count. DIC of the APL patients without infection was characterized by low fibrinogen and normal antithrombin III (ATIII) level. Thrombin-ATIII complex level was elevated in all patients examined. Patients with infection had higher fibrinogen levels than those without infection and some patients had reduced ATIII level. Ten remission inductions were tried with multidrug chemotherapy and seven with all-trans retinoic acid (ATRA). Complete remission was achieved in seven of ten inductions with chemotherapy and in all seven inductions with ATRA. Two patients treated with chemotherapy had fatal hemorrhage after starting therapy but none treated with ATRA.

Antithrombin III concentrate use in patients with cirrhosis with coagulation disorders

Patients with severe hepatic failure present acquired deficiency of antithrombin III (ATIII) owing to reduced synthesis associated with intravascular activation of blood coagulation, which may be corrected by ATIII infusion. The aim of this uncontrolled trial was to verify the effect of a standard dose of ATIII concentrate (Kybernin), that is, 50 U/kg of body weight per day, every 2 days, on ATIII levels in patients with severe hepatic failure and hemostatic imbalance. Six cirrhotic patients were studied: mean age of 44 years (14 to 63 years), who presented at least 2 abnormal coagulation tests (PT > 1.40, APTT > 1.25, Fibrinogen < 1.5 g/dL, Platelet count < 80,000/mm3). Mean serum albumin was 2.6 g/dL (1.9 to 3.8 g/dL). Blood was drawn before infusion, 4 h after the first infusion, and just before the next infusion. ATIII levels were measured by amidolytic method. Mean ATIII levels were: initial = 35.8%, 4th h = 56.2%*, 2nd d = 48.7%*, 4th d = 45.7%*, and 8th d = 42.3%. ATIII levels increased significantly after infusion of this standard dose in all patients, although they have not been fully corrected (Friedman test, * p < 0.02), which has been sustained till the 4th day. There was no improvement on the clinical outcome. These findings suggest that doses of ATIII concentrate higher than 50 U/kg/infusion must be administered to patients with severe hepatic failure, to guarantee normal levels of the inhibitor, in order to verify its influence on the hemostatic mechanism.

Veränderungen hämostaseologischer Parameter unter Hormonsubstitutionstherapie in Abhängigkeit von der Gestagendosis

Bei 54 postmenopausalen Frauen unter Langzeithormonsubstitution wurden klinisch relevante hämostaseologische Parameter untersucht. Ziel der Studie war, Unterschiede im Gerinnungs- und Fibrinolyseverhalten unter Estrogenmonotherapie (0,6 mg konjugierte Estrogene) und Sequentialtherapie mit 3 oder 5 mg Medrogeston herauszustellen. Quick, PTT, Thrombinzeit, Fibrinogen und Thrombozytenzahlen zeigten keine signifikanten Veränderungen unter den 3 untersuchten Substitutionsformen. Die Antithrombin III-Spiegel fielen unter Estrogenmonotherapie am stärksten ab. lm Untersuchungszeitraum wurden keine klinisch relevanten Antithrombin III-Abfälle unter 80% registriert. Der Gestagenzusatz zur Hormonsubstitutionstherapie hat keinen Einfluß auf die untersuchten hämostaseologischen Parameter: Quick, PTT, Thrombinzeit, Fibrinogen, Thrombozytenzahlen und Antithrombin III.

Is there a need for antithrombin III substitution early after burn injury?

The changes in antithrombin III (AT-III) levels in the blood and restitution in congulation parameters between patients receiving and not receiving AT-III substitution were examined early after burn injury. The study was divided into two parts with a total of 14 consecutive patients (per cent total body surface area (TBSA) ≥20 per cent). The first six patients were given AT-III substitution when AT-III levels fell below 50 per cent. The second part examined the restitution of the coagulation parameters when the patients ( n = 8) obtained AT-III substitution only at extremely low values of AT-III. The decline in AT-III observed occurred in parallet to the permeability changes and the haemodilution normally seen secondarily to the initial fluid rescucitation. The observed changes in the coagulation parameters were modest and no hepatic dysfunction was noted. In addition, no differences of the restitution in these coagulation parameters were noted between the substituted and non-substituted groups. These results suggest that changes in AT-III early after burn injury depend mainly on factors other than an ongoing disseminated coagulation process. Probable causes are increased capillary leak and haemodilution. Our results suggest that substitution of AT-III in the early postburn period, on the assumption that low levels alone indicate ongoing coagulation, is not warranted.

The effect of immunodepletion of antithrombin III on the response of rabbits to Russell's viper venom-induced activation of factor X.

Many years ago it was shown that an infusion of tissue factor (TF) into rabbits causing only limited consumption of factor X and prothrombin resulted in extensive consumption of fibrinogen. More recently it was shown that an injection of a concentration of the factor X-activating fraction of Russell's viper venom (RVV-X) depleting rabbits of factor X resulted in only minimal consumption of both plasma prothrombin and fibrinogen. We report here experiments in which rabbits depleted of antithrombin III (ATIII) to different degrees were infused over 4 hours with a concentration of RVV-X, causing consumption of about 60% of plasma factor X. Similar minimal mean falls in plasma prothrombin and fibrinogen levels were observed in control rabbits given nonimmune goat IgG and in rabbits immunodepleted with goat anti-rabbit ATIII IgG to about 40% of normal plasma ATIII activity. However, if rabbits were immunodepleted to about 10% to 20% of normal plasma ATIII, then mean consumption of prothrombin was increased modestly and, more impressively, mean consumption of plasma fibrinogen was increased markedly. Whereas limited amounts of thrombin generated on the surface of phospholipid vesicles by factor VIIa/ TF can trigger extensive intravascular coagulation in rabbits with normal plasma ATIII levels, limited amounts of thrombin generated by reactions triggered by factor Xa formed in fluid phase did so only after plasma ATIII levels were markedly depleted. A possible reason for this difference is discussed.

Regulation of Tissue Factor Initiated Thrombin Generation by the Stoichiometric Inhibitors Tissue Factor Pathway Inhibitor, Antithrombin-III, and Heparin Cofactor-II

The effects of the stoichiometric inhibitors tissue factor pathway inhibitor (TFPI), antithrombin-III (AT-III) and heparin cofactor-II (HC-II) on thrombin generation were evaluated in a reaction system composed of coagulation factors VIIa, X, IX, VIII, and V and prothrombin initiated by tissue factor (TF) and phospholipids. Initiation of the reaction in the absence of inhibitors resulted in explosive thrombin generation for factor VIIa.TF concentrations varying from 100 to 0.25 pM with the lag time or initiation phase of thrombin generation increasing from 0 to 180 s with decreasing factor VIIa.TF concentrations. During the propagation phase, prothrombin is quantitatively activated to 1.4 micro;M alpha-thrombin. At normal plasma concentration (2.5 nM) full-length recombinant TFPI prolonged the initiation phase of thrombin generation 2-fold, and the rate of thrombin generation in the propagation phase of the reaction was 25-50% that of the uninhibited reaction when the reaction was initiated with 1.25-20 pM factor VIIa.TF. Inhibition of the reaction by TFPI is associated with a delay in factor V activation. In the presence of TFPI no explosive thrombin generation was observed when factor VIII was omitted from reactions initiated by factor VIIa.TF concentrations </=20 pM. This indicates that in the presence of TFPI the factor IXa.factor VIIIa pathway becomes essential at low factor VIIa.TF concentrations. In the reconstituted system, AT-III (3.4 micro;M) did not prolong the initiation phase of thrombin generation when the reaction was initiated with 1.25 pM factor VIIa.TF, nor did AT-III delay factor V activation. The rate of thrombin formation in the presence of AT-III was reduced to 30% that of the uninhibited reaction, and the alpha-thrombin formed was rapidly inhibited subsequent to its generation. The addition of HC-II alone at its physiological concentration (1.38 micro;M) to the procoagulant mixture did not alter the rate or extent of thrombin generation. Subsequently, the thrombin formed was slowly inhibited by HC-II. The slow inactivation of thrombin by HC-II does not contribute to thrombin inhibition in the presence of AT-III. In contrast, the combination of physiological levels of AT-III and TFPI inhibited explosive thrombin generation initiated by 1.25 pM factor VIIa.TF completely. The absence of prothrombin consumption indicated that the combination of TFPI and AT-III is able to prevent the formation of prothrombinase activity at low factor VIIa.TF concentrations. The data indicate that TFPI potentiates the action of AT-III by decreasing the rate of formation and thus the amount of catalyst formed in the reaction, enabling AT-III to effectively scavenge the limited traces of factor IXa and factor Xa formed in the presence of TFPI. The initiation of thrombin generation by increasing factor VIIa.TF concentrations in the presence of physiological concentrations of TFPI and AT-III showed dramatic changes in the maximal rates of thrombin generation over small changes in initiator concentration. These data demonstrate that significant thrombin generation becomes a "threshold-limited" event with regard to the initiating factor VIIa.TF concentration in the presence of TFPI and AT-III.

Thrombophilia in Patients with Hypertriglyceridemia.

Objectives: To investigate a possible relationship between hypertriglyceridemia and the coagulation system, a Cardiovascular Risk Factor Two-township Study was conducted in Taiwan. Design: A case-control study. This longitudinal, prospective study focused on the evolution of cardiovascular disease risk factors with emphasis on haemostatic factors. Subjects: Hypertriglyceridemic subjects (triglyceride <2.26 mmoll+1, n = 327) and age-matched normal controls from a population screening program. Main outcome measures: Haemostatic parameters measured in this study included prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors VIIc and VIIIc, and antithrombin-III and plasminogen levels. Results: In our male hypertriglyceridemic subjects, aPTT was not significantly reduced, while significant elevations of factor VIIIc, factor VIIc, and plasminogen and antithrombin-III levels were noted. In the female hypertriglyceridemic subjects, the elevation of factor VIIc, factor VIIIc, and plasminogen and antithrombin-III levels was highly-significant, whereas aPTT was not significantly reduced. Unexpectedly, the levels of the established coronary risk factor, fibrinogen, did not show a statistically different change. Similar to previous data, our hypertriglyceridemic subjects also presented with hyperinsulinemia, glucose intolerance, upper body obesity, and elevated blood pressure. Conclusions: Despite the fact that in population studies, triglycerides do not consistently appear to be an independent risk factor for coronary heart disease, our data suggest that a pronounced increase in triglycerides warrants aggressive therapy, because this increase may be associated with a hypercoagulable state. This phenomenon contributes another perspective to the study of higher cardiovascular mortality in hypertriglyceridemic subjects.

Fibrinolysis, inhibitors of blood coagulation, and monocyte derived coagulant activity in acute malaria.

Different parameters of fibrinolytic systems like t-PA, PAI, D-dimer, and inhibitors of blood coagulation, i.e., protein C (PC), protein S(PS), and antithrombin III (AT-III), have been studied in cases of acute malaria due to Plasmodium falciparum and plasmodium vivax infection, and these patients were followed up. It was observed that the plasma PAI-1 was very high in cases of P. falciparum malaria infection as compared to normal controls and P. vivax infection. The changes in complicated cases of P. falciparum were remarkable as compared to uncomplicated ones. The PC, PS, and AT-III levels were also low in P. falciparum, particularly so in complicated cases, and were normal in P. vivax infection. The factor VIII R:Ag levels were invariably high in acute malaria. On follow-up of some of these cases the values came back to normal after the antiparasite treatment. The monocyte procoagulant activity was found to be significantly higher in P. falciparum infection as compared to that of P. vivax infection. All these findings therefore contribute towards the production of a hypercoagulable state in P. falciparum infection and partly explain the complications of P. falciparum infection like cerebral malaria.