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PubMed1989

Sepsis model with reproducible manifestations of multiple organ failure (MOF) and disseminated intravascular coagulation (DIC).

A new reproducible animal model of sepsis was established to investigate interrelationship between disseminated intravascular coagulation (DIC) and multiple organ failure (MOF). Sepsis was induced by injecting fecal suspension into bile duct of rabbits, in which the amount of endotoxin in circulating blood was gradually increased and manifestations of sepsis were confirmed. During 9 hours' observation period, an occurrence of hypercoagulable state leading to DIC was evidenced by the abnormal hemostaseological parameters. Simultaneously the elevation of plasma bilirubin and creatinine levels was observed, indicating the presence of liver and kidney failure, which was confirmed by the histological examination. Thereby, the present sepsis model complicates DIC and MOF with high reproducibility, which is relevant to sepsis seen in clinical patients.

Animals↗
PubMed1990

A sensitive, accurate assay for extrinsic pathway inhibitor (EPI) activity in rabbit plasma: paradoxical effect of excess exogenous factor X.

A sensitive assay is described for the measurement of rabbit plasma EPI activity in experimental studies of induced hypercoagulable states in this species. It is based upon the ability of a dilution of rabbit plasma to inhibit human factor VIIa/rabbit brain tissue factor (TF) catalyzed activation of human factor IX (tritiated activation peptide release assay). Addition of 3H-factor IX to the reaction mixture is delayed for 45 minutes to allow full inhibition by EPI/factor Xa complex before the residual catalytic activity of factor VIIa/TF is measured. Although the diluted rabbit plasma test sample contains both EPI and factor X, supplemental factor X is added to the reaction mixture to assure that only EPI content of the test sample affects the assay result. However, the final concentration of factor X in the reaction mixture is critical. Too high a concentration of factor X diminishes the sensitivity of the assay. The reason for this phenomenon, which was observed with both human and rabbit factor X preparations, is unknown.

Animals↗
PubMed1990

The effect of heparin on multiple organ failure and disseminated intravascular coagulation in a sepsis model.

In order to elucidate a possible role of hypercoagulability leading to disseminated intravascular coagulation (DIC) in the pathogenesis of multiple organ failure (MOF), unfractionated heparin and the related agents were administered to septic rabbits which manifest DIC and MOF. Administration of heparin resulted in prevention of thrombocytopenia, leukopenia and elevation of plasma bilirubin and creatinine. The morphological hepatic damage was also ameliorated by heparin. Similar favorable effects were obtained by the administration of low molecular weight heparin. Dextran sulfate prevented the hepatic damage to some extent without improvement on other parameters. No significant effect was observed by the administration of a synthetic thrombin inhibitor (MD805). These results indicate that the favorable effect of heparin is due to its anticoagulant property, especially anti-Xa activity. Thereby, it is concluded that the hypercoagulable state leading to DIC is a prerequisite for the occurrence of MOF in sepsis.

Animals↗
PubMed1990

L-asparaginase treatment reduces the anticoagulant potential of the protein C system without affecting vitamin K-dependent carboxylation.

The changes in plasma levels of the vitamin K-dependent natural anticoagulants protein C (PC) and protein S (PS) and procoagulant factors II, IX and X were evaluated in 8 adult patients during treatment with L-asparaginase (L-ase i.v. 120,000 U/m2 over 10 days). PC anticoagulant activity and factor IX, X and II coagulant activity decreased proportionally to their half-lives to a nadir of 50-60% of pretreatment values after 2-5 L-ase infusions, suggesting that inhibition of protein synthesis rather than consumption is the main mechanism responsible for the observed changes. Free PS antigen levels declined at a rate similar to total PS antigen, reaching a nadir of 56% of pretreatment values after 3 L-ase infusions; however due to C4b-binding protein levels higher than total PS levels (p less than 0.05), they were constantly lower than the corresponding total PS antigen levels (0.05 less than p less than 0.001). This implicates that total PS antigen levels cannot be taken as an indicator of PS activity. No differences between the antigenic levels and the anticoagulant activities of PC and free PS could be observed suggesting that L-ase does not affect the mechanisms of vitamin K-dependent carboxylation of Gla-residues. The faster rate of decline of PC and PS activities relative to that of factor II may be responsible for the onset of an hypercoagulable state during the early phase of L-ase treatment.

Adult↗
PubMed1990

A modified quantitative whole blood clot lysis method for general laboratory analysis of fibrinolysis.

Because fibrinolysis is now recognized as an important factor in hypercoagulable states, we have developed and characterized an easily performed, rapid, and quantitative screening test that assesses a patient's fibrinolytic activity. This modification of the dilute whole blood clotting time (DWBCT) counts the number of intact erythrocytes released from the clot formed in samples obtained before and after the application of a venous occlusion cuff. Samples were corrected for the plasma volume changes that occurred during venous occlusion. This test was performed on nine healthy volunteers. Specimens were diluted 1:1 with PBS, rapidly clotted with thrombin and incubated at 37 C. Starting thirty minutes after the thrombin was added and then at twenty minute intervals until 110 minutes, the number of RBCs released from the clot were counted using a Coulter S Plus counter. There were consistently more RBCs released at each time period after venous occlusion (p less than 0.001). Aliquots were also obtained for measuring PAI activity and TPA levels. PAI activity was lower post-cuff at every point (p less than 0.001). TPA level was higher at every point (p less than 0.001) post-cuff. The addition of exogenous TPA, activated protein C, or anti-PAI antibodies increased the amount of clot lysis; while the addition of anti-TPA antibodies and EACA each prevented the post-cuff increase. Unlike the euglobulin lysis time (ELT) this modified DWBCT (mDWBCT) measures the patients intact fibrinolytic system, including PAI and erythrocytes, in a quantitative fashion. Unlike either the ELT or the DWBCT the mDWBCT can be performed within two hours, so results are rapidly available for clinical decisions. These studies have demonstrated an easily performed, inexpensive, quantitative screening test of a patient's overall fibrinolytic system that reacts appropriately to pharmacologic manipulations.

Aminocaproic Acid↗
PubMed1990

Activation of coagulation and fibrinolysis during surgery, analyzed by molecular markers.

Activation of hemostasis during surgery was investigated in 30 elective cases, who underwent either gastric (group G) or hepatic (group H) resection by a serial determination of various molecular markers such as fibrinopeptide A (FPA), fibrinopeptide B beta 15-42 (B beta 15-42) D-dimer, thrombin-antithrombin III complex (TAT) and plasmin-alpha 2 plasmin inhibitor complex (PIC). In both groups, the values of FPA and TAT were significantly elevated intraoperatively, indicating an occurrence of hypercoagulable state. The degree of the elevation was more marked in group H, probably due to greater tissue damage during hepatic resection. Also in both groups, the values B beta 15-42 and PIC were significantly increased during surgery, while the amount of D-dimer was within normal range in most cases, indicating the occurrence of the primary fibrinolysis. These findings are compatible with our previous observations on the postoperative changes in hemostasis. There were statistically significant but variable correlations between the values of fibrinopeptides and the enzyme-inhibitor complexes. The absolute values of the molecular markers of fibrinolysis were always higher than those of coagulation, suggesting that a considerable amount of plasmin, rather than thrombin, is released by surgical tissue damages.

Antithrombin III↗
PubMed1990

Increased fibrin/fibrinogen degradation products without increase of plasmin-alpha 2-plasmin inhibitor complex after hepatectomy for hepatocellular carcinoma.

To clarify the meaning of increased serum fibrin/fibrinogen degradation products (FDP) in the postoperative period of hepatectomy, blood coagulation and fibrinolysis were studied using recently devised laboratory assays of a group of 30 patients with hepatocellular carcinoma. Twenty of these cases were associated with liver cirrhosis. As a control group, 15 patients with colorectal carcinoma without liver diseases were also selected. In the early postoperative period following hepatectomy, a hypercoagulable state designated as intravascular thrombin generation was confirmed from the finding of increased plasma levels of fibrinopeptide A (FPA). Fibrinopeptide B beta 15-42 (B beta 15-42) in the plasma also increased immediately after the peak of FPA, followed by a gradual decline in B beta 15-42 levels. On the other hand, FDP in the serum increased significantly rather late in the postoperative period following hepatectomy without increased levels of plasmin-alpha 2-plasmin inhibitor complex. However, postoperative increase of fibrin/fibrinogen degradation products-D (FDP-D) was modest and not different from the colectomy group. Therefore, the relevance of intravascular coagulation in the hepatectomy for the patients with liver cirrhosis seems not to be significant, and then such an increase of FDP in the serum seems to be related to other mechanisms.

Adult↗
PubMed1990

Comparison of different prothrombin complex concentrates--in vitro and in vivo studies.

The potency and tests for thrombogenicity were studied prospectively in 7 different (two lots of each brand, A-G) prothrombin complex concentrates (PCC). Human albumine (H) and a factor IX concentrate (I), served as controls. The potency of coagulation factors and inhibitors varied considerably. Two brands (E, F) contained no protein S, additionally one brand contained no protein C. Two preparations exhibited high amidolytic activities, especially towards the thrombin-sensitive chromogenic substrate S-2238, in vitro. These activities could be quenched in part by the addition of hirudin or antithrombin III. The heparin and antithrombin III content of the PCCs was significantly different, and, after addition of antithrombin III an increase of thrombin-antithrombin III complexes in 2 preparations (B, D) was observed in vitro. Additionally, three brands (B, D, F) caused more severe cardio-pulmonary reactions in rabbits, associated with an increase of fibrin split products for brands B and D. We conclude that the use of these preparations in patients, in whom an acquired protein C or S defect, or a hypercoagulable state, can be suspected, cannot be recommended.

Animals↗
PubMed1990

Hypercoagulability in acute ischemic stroke: analysis of the extrinsic coagulation reactions in plasma by a highly sensitive automated method.

The coagulability of plasmas from 63 patients with acute ischemic stroke (cerebral thrombosis and cerebral embolism) was analyzed by an automated method for prothrombin time using a fluorogenic peptide substrate. The fluorogenic prothrombin time (FPT) of patients' plasmas collected within 48 hr after onset, as expressed as percent of control plasma, was significantly higher in cerebral thrombosis than in an age-matched control group (p less than 0.01). The high values of FPT in cerebral thrombosis patients were observed until the 30th day after onset. On the other hand, FPT values in cerebral embolism patients were not significantly different than that of the control group. Factor VII activity levels in cerebral thrombosis patients were significantly higher than those of the control group and cerebral embolism patients, while levels of factor X activity were not significantly different among these groups. Although FPT and factor VII activity in these stroke patients did not significantly correlate, factor VII activity did correlate well with factor VII antigen. Decreased levels of antithrombin III and elevated levels of FDP and alpha 2-antiplasmin-plasmin complexes were observed only in cerebral embolism patients. Our findings strongly suggest that patients with cerebral thrombosis have been in a hypercoagulable state before the onset of symptoms, which was caused in part by an increase of factor VII activity/antigen, and in part by other unknown mechanisms. In contrast, patients with cerebral embolism were in a low grade consumptive coagulopathy.

Adult↗
PubMed1992

Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus.

Selected coagulation and fibrinolytic parameters were assessed in 40 insulin dependent diabetes mellitus patients with varying degrees of metabolic control; 30 healthy subjects matched for age and sex formed the control group. Activated Partial Thromboplastin Time, Prothrombin Time, Fibrinogen, Factor VII, Antithrombin III, Protein C, Plasminogen, alpha 2-Plasmin Inhibitor, Plasminogen Activator Inhibitor-1, tissue-Plasminogen Activator were functionally evaluated. Antigenic levels of tissue-Plasminogen Activator, Thrombin-Antithrombin complexes and fibrinolytic specific product B beta 15-42 were also determined. Compared to the control group diabetic patients displayed significantly higher levels of Fibrinogen (p < 0.01), Factor VII (p < 0.01), Thrombin-Antithrombin complexes (p < 0.01) and Plasminogen Activator Inhibitor-1 activity (p < 0.01). Regardless of the normal level of the tissue-Plasminogen Activator-related antigen, diabetic patients had tissue-Plasminogen Activator activity lower than the control group (p < 0.05). Coagulation Factor VII and Thrombin-Antithrombin complexes were increased only in the patients with poor metabolic control (p < 0.01). Activated Partial Thromboplastin Time, Prothrombin Time, Antithrombin III, Protein C, Plasminogen, alpha 2-Plasmin Inhibitor, B beta 15-42 fibrin peptide were found to be in the normal range. Fibrinogen correlated positively with fasting blood glucose (p < 0.05) and Thrombin-Antithrombin complexes with glycosylated haemoglobin (p < 0.05), whereas Factor VII was positively correlated with glycemia (p < 0.01) and glycosylated haemoglobin (p < 0.05). Higher levels of Fibrinogen were found in patients affected by nephropathy (p < 0.005) or neuropathy (p < 0.05). These results demonstrate an impairment of the haemostatic balance in diabetic patients, that is a possible hypercoagulable state, which represents an important factor in the pathogenesis of atherosclerotic complications.

Adult↗
PubMed1994

High plasma levels of plasminogen activator inhibitor 1 (PAI-1) in polycythemia vera and essential thrombocythemia are associated with thrombosis.

We attempted to determine if a hypercoagulability state exists in patients with polycythemia vera (PV) and essential thrombocythemia (ET). We studied the hematocrit level, platelet count, use of any antiaggregant drugs, thrombotic or bleeding accidents and plasma levels of antithrombin III, protein C, total protein S, free protein S, vWF:Ag (Von Willebrand's factor related antigen), thrombin-antithrombin complexes, D-dimer, fibrinolytic activity, tissue plasminogen activator, plasminogen and PAI-1 in 33 patients (19 with ET and 14 with PV). PAI-1 plasma concentration was significantly higher in, both ET and PV patients than in the control group, and were higher in those patients with previous thrombotic episodes than in asymptomatic patients or with previous bleeding episodes. Increasing age was associated to more thrombotic episodes while younger patients presented with more hemorrhagic complications. A linear correlation between platelet count and PAI-1 levels in PV patients (r = 0.44, p < 0.05) and ET patients (r = 0.30, p < 0.05) was found. Fibrinolytic activity in patients with ET was significantly decreased when compared to the control group. A hypofibrinolytic state could be an additional factor which could be used as a predictive index of the thrombotic or bleeding tendency in each patient.

Adult↗
PubMed1994

Do smoking and diabetes change the hemostatic parameters?--a study in the Chinese people.

Plasma plasminogen activator inhibitor-1 (PAI) antigen, fibrinogen, antithrombin III (ATIII), protein C, beta-thromboglobulin (BTG), platelet count, fibrinogen degradation product (FDP) D-dimer, factors VII and XII, as well as cholesterol, triglyceride (TG) and glucose were determined in 163 subjects. First we compared the difference of these parameters between 50 diabetics (Group D, mean age 64.9 years) and 50 age-matched healthy controls (Group C, mean age 63.1 years). Nineteen of the diabetics and 19 of the healthy controls were smokers. Plasma glucose, cholesterol, TG and protein C were significantly higher in Group D than in Group C (p = 0.0010, 0.0308, 0.0083 and 0.0068, respectively), whereas ATIII and factor XII were significantly lower in Group D (p = 0.0213 and 0.0061). Secondly, we divided 113 healthy controls (Group C, including Group C plus 63 subjects at various ages) into smokers (mean age 56.7 years) and non-smokers (mean age 40.0 years) and compared the difference between them. Fibrinogen and glucose were higher in the smokers than in the non-smokers (p = 0.0139 and 0.0402, respectively). Other parameters were not different. In conclusion, our study did not find any important hypercoagulation state in the diabetics. Smoking can only increase fibrinogen and glucose without the change of other hemostatic parameters.

Adult↗
PubMed1995

Plasma concentration of tissue factor and factor VII in patients after abdominal surgery.

Tissue injury following trauma and surgery may induce alterations in blood coagulation and fibrinolysis. Hypercoagulable state after surgery can be associated with the risk of postoperative thromboembolic complications. The contact of coagulation factors with TF after injury of vessel wall and organ tissues may contribute to the development of thrombosis after surgery (1). TF, the cell surface receptor and cofactor of factor VII/VIIa is normally not expressed by cells within the vasculature. Only monocytes and endothelial cells can be stimulated to express TF transiently by a variety of inflammatory and immunological reactions (for review see 2,3). Also surgical treatment was reported to induce TF synthesis in monocytes (4,5,6). TF is present in many extravascular tissues as vascular adventitia, organ capsules, epidermis, colonic mucosal epithelium, liver stroma, pancreas stroma and also on tumor cells (7-12). In this study, we investigated, whether we can detect the release of TF from the traumatized tissues and from activated monocytes into the circulation following abdominal surgery. To test the dependence of the extension of tissue injury during surgery we segregated the patients into group A with major abdominal operations and group B consisting of patients with appendectomy and cholecystectomy. No relationship could be established between changes of TF and postoperative thromboembolic complications.

Abdomen↗
PubMed1996

Blood clotting activation during normal pregnancy.

Pregnancy is considered as a hypercoagulable state and an increased incidence of thromboembolic phenomena has been reported in pregnant women. Relevant changes in the hemostatic mechanism have been reported during physiological pregnancy: briefly, increased levels of coagulation factors, enhanced thrombin generation and suppression of fibrinolysis are commonly found in women with uncomplicated pregnancy. We recently described progressive increases in fibrinogen and D-dimer plasma levels during normal pregnancy. The increase in D-dimer levels makes difficult their interpretation for the exclusion of thromboembolic phenomena in pregnancy. The behavior of prothrombin fragment 1+2 (F1+2) levels during physiological pregnancy is scarcely known. The aim of this preliminary study was to establish range values of F1+2 plasma levels for different periods of normal pregnancy.

Adult↗
PubMed1990

Coagulopathy and warfarin-associated breast necrosis in a patient with a primary brain tumor.

Although the association of coagulopathy and neoplastic disease is well documented, there have been few reports of patients with primary central nervous system tumors who exhibited hypercoagulable states. We report the case of a 58-year-old woman with a recurrent falcine meningioma and repeated episodes of venous thrombosis who developed warfarin-associated breast necrosis on the fifth day of coumadin therapy. Laboratory evaluation at that time demonstrated an elevated prothrombin time and normal activated partial thromboplastin time. Of the 24 cases of warfarin-associated massive necrosis of the breast described in the literature, only one other case was associated with a neoplasm, a resected craniopharyngioma.

Blood Coagulation Disorders↗
PubMed1988

Inferior vena cava thrombosis. Unusual presentation of testicular tumor.

We report an unusual case of testicular tumor presenting as thrombosis of the inferior vena cava. However, in contrast to a previous report, thrombosis in this patient was not caused by compression of the vena cava by neoplasm metastases. In our patient, we postulate that tumor invaded the vena cava and that thrombosis was exacerbated by a hypercoagulable state induced by the tumor.

Adult↗
PubMed1986

Defective release of vascular plasminogen activator in patients with gynecologic malignancies.

Vascular plasminogen activator release was measured in 176 women with gynecologic malignancies and 92 normal women. Releasable plasminogen activator was considerably decreased in the patients (P less than 0.00001 by Wilcoxon's rank sum test) with 59.1% releasing less than 0.04 Committee on Thrombolytic Agents units per milliliter of plasma after a standard venous occlusion procedure. The data were also stratified by tumor location, demonstrating that this decrease in releasable vascular plasminogen activator was seen for ovarian (P = 0.0001), endometrial (P = 0.0017), and cervical (P = 0.0063) cancers. Postoperative deep vein thrombosis, with or without pulmonary emboli, occurred in 28 patients (15.9% incidence). These patients also demonstrated markedly lower levels of releasable vascular plasminogen activator compared to control subjects (P less than 0.0001). It is suggested that defective release of vascular plasminogen activator contributes to a hypercoagulable state in patients with gynecologic malignancies and predisposes to postoperative thromboembolic complications.

Colorimetry↗