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The dynamic haemostatic balance between blood coagulation and fibrinolysis and its influence on the development of disseminated intravascular coagulation are described. The effects of heparin and antithrombin-III are illustrated by clinical cases.
A model was experimentally made with 2 hours serial infusion of thromboplastin (Tp) into rabbits to examine the drug's effect on a hemorrhagic tendency and to elucidate the coagulation and fibrinolytic system in acute DIC encountered in obstetrics, and the system was periodically observed. Groups given the drug, given it during pregnancy, those which bled massively, and those with accelerated fibrinolysis were prepared. The results are as follows. 1) Fibrinogen, PT, APTT, TEG, ELT, AT-III, antiplasmin activity, and platelet count varied markedly from the initiation of Tp injection, and returned to normal following termination. 2) Blood from the heparin dose group showed non-coagulation but decreases in the platelet count and fibrinogen were inhibited. 3) In the aprotinin dose group, serial 2 hour administration induced inhibition of fibrinolysis despite the relatively delayed appearance of anti-fibrinolytic activity. 4) No fibrinolytic effects were seen in anti-plasmin activity or ELT in the tranexamic acid dose group. 5) Lowering of parameters examined was marked in the Tp dose group during pregnancy. 6) The mortality rate up to 6 hours after Tp infusion was 54.5% with solely given, and 10% with group given drug. 7) Death within one hour of Tp infusion in the mass bleeding group, being rated for 50%, was improved to 16.7% by the pre-administration of urokinase.
An analysis was made of 41 cases of disseminated intravascular coagulation in dogs, with the objective of evaluating routine and nonroutine laboratory tests used in making the diagnosis. The dogs were grouped on the basis of underlying disease, which included neoplasia (39%), pancreatitis (30%), chronic active hepatitis (15%), heat stroke (12%), and sepsis (4%). Of the diagnostic tests evaluated, those for determination of activated partial thromboplastin time, antithrombin III activity, prothrombin time, and the platelet count were the most valuable. Of the clotting factors, factor V activity was decreased more frequently than the activity of factor VIII:C (factor VIII: procoagulant). The factor VIII:C activity was in conflict with prevailing dogma that reflects depression of this factor in disseminated intravascular coagulation. Factor VIII:C activity was decreased in only 29% of dogs studied. Activation of the fibrinolytic system was manifested by decreased plasminogen activity in 49% of the dogs studied. Sixty-one percent of the dogs had increased amounts of fibrin (ogen) degradation products.
A case of disseminated intravascular coagulation occurred with midtrimester dilation and evacuation. The case was treated successfully but required substantial volumes of blood products. The use of a coagulation analyzer facilitated the diagnosis and treatment.
BACKGROUND: Interstitial laser coagulation (ILC) is a method of local tissue destruction for solid tumors such as irresectable hepatic metastases from colorectal cancer. With the availability of new magnetic resonance (MR) techniques, which allow real time tissue temperature mapping, it is essential to know the critical temperature and exposure times leading to cell death. MATERIALS AND METHODS/STUDY DESIGN: Samples (8 mm(3)) of solid rat tumor (CC-531, syngenic to the WAG/Rij rat strain), were warmed in tubes for four different temperatures (40, 50, 60 or 80 degrees C) and four different exposure times (3, 6, 12, or 24 minutes). Combinations were replicated in five-fold. Cell viability was assessed with three methods: Trypan blue exclusion test in collagenase/dispase dissociated samples, NADH activity in snap frozen samples and outgrowth for 2 weeks under the renal capsule of WAG/Rij rats. RESULTS: Results of the three methods revealed that viability was not affected with heating at 40 and 50 degrees C except for 24 minutes at 50 degrees C. At higher temperatures cell death occurred at all exposure times. CONCLUSION: The temperature range resulting in sufficient tissue coagulation for cell death is between 50 degrees C and 60 degrees C for a short duration (<3 minutes). These data can be used to achieve complete tumor destruction and minimal surrounding tissue damage during real-time MR-controlled ILC.
More efficacious anticoagulant and antiplatelet agents have been introduced in vascular medicine and in the prevention of perioperative venous thromboembolisms. Patient management should be guided by familiarity with the pharmacology of coagulation-altering drugs and by consensus statements. The present paper reviews recommendations from the Austrian Task Force for Perioperative Coagulation which are based on thorough evaluation of the available pharmacological information and case reports. The consensus statement focuses on neuraxial and peripheral techniques and is designed to encourage safe and quality patient care.
Factor VII coagulant activity (VIIc) is considerably higher in rabbits fed a 1% cholesterol-supplemented diet than in rabbits fed a standard diet. This increase was statistically significant 4-6 days from the beginning of treatment and rose to about 300% during the 100 days of treatment. Treatment is also associated with a 20-fold increase in plasma cholesterol concentration with the major fraction of excess cholesterol associated with the very low and intermediate density lipoprotein fractions. In both groups of rabbits, the direction and extent of variation in VIIc generally coincided with variation in cholesterol, so that over time there were significant and positive correlations between plasma cholesterol concentration in both the rabbits fed the standard diet and the rabbits fed the cholesterol-supplemented diet. The increase in VIIc was due to a higher proportion of the more active alpha VIIa in the plasma of hypercholesterolaemic rabbits rather than to an increase in the concentration of the single-chain protein. The plasma concentration of factor X and prothrombin had increased in the hypercholesterolaemic rabbits by 10 days from the beginning of treatment and both proteins were maintained at 150-200% of the concentrations in the plasma of rabbits fed the standard diet. However, these differences were only seen when the factor X and prothrombin were assayed using synthetic substrates. The specific coagulation assays for these two factors revealed no differences between the groups of animals up to 100 days.
Previous studies demonstrated proteolytic activation of human blood coagulation factor VII by an unidentified protease following complex formation with tissue factor expressed on the surface of a human bladder carcinoma cell line (J82). In the present study, an active-site mutant human factor VII cDNA (Ser344----Ala) has been constructed, subcloned, and expressed in baby hamster kidney cells. Mutant factor VII was purified to homogeneity in a single step from serum-free culture supernatants by immunoaffinity column chromatography. Mutant factor VII was fully carboxylated, possessed no apparent clotting activity, and was indistinguishable from plasma factor VII by SDS-PAGE. Cell binding studies indicated that mutant factor VII bound to J82 tissue factor with essentially the same affinity as plasma factor VII and was cleaved by factor Xa at the same rate as plasma factor VII. In contrast to radiolabeled single-chain plasma factor VII that was progressively converted to two-chain factor VIIa on J82 monolayers, mutant factor VII was not cleaved following complex formation with J82 tissue factor. Incubation of radiolabeled mutant factor VII with J82 cells in the presence of recombinant factor VIIa resulted in the time-dependent and tissue factor dependent conversion of single-chain mutant factor VII to two-chain mutant factor VIIa. Plasma levels of antithrombin III had no discernible effect on the factor VIIa catalyzed activation of factor VII on J82 cell-surface tissue factor but completely blocked this reaction catalyzed by factor Xa. These results are consistent with an autocatalytic mechanism of factor VII activation following complex formation with cell-surface tissue factor, which may play an important role in the initiation of extrinsic coagulation in normal hemostasis.
A decrease in light transmittance before clot formation, manifesting as a biphasic waveform (BPW) pattern in coagulation assays, was previously correlated with the onset of disseminated intravascular coagulation (DIC). In this study of 1187 consecutive admissions to the intensive care unit, the degree of this change on admission predicts DIC better than D-dimer measurements. Additionally, the BPW preceded the time of DIC diagnosis by 18 hours, on average, in 56% (203 of 362) of DIC patients. The BPW is due to the rapid formation of a precipitate and coincident turbidity change on recalcification of plasma. The isolated precipitate contains very-low-density lipoprotein (VLDL) and C-reactive protein (CRP). The addition of CRP and Ca(++) to normal plasma also causes the precipitation of VLDL and IDL, but not LDL or HDL. The K(d) of the CRP/VLDL interaction is 340 nM, and the IC(50) for Ca(++) is 5.0 mM. In 15 plasmas with the BPW, CRP was highly elevated (77-398 microg/mL), and the concentration of isolated VLDL ranged from 0.082 to 1.32 mM (cholesterol). The turbidity change on recalcification correlates well with the calculated level of the CRP-VLDL complex. Clinically, the BPW better predicts for DIC than either CRP or triglyceride alone. The complex may have pathophysiological implications because CRP can be detected in the VLDL fraction from sera of patients with the BPW, and the VLDL fraction has enhanced prothrombinase surface activity. The complex has been designated lipoprotein complexed C-reactive protein.
Tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor with three tandem inhibitory domains (K1, K2 and K3), inhibits the initial reactions of the extrinsic blood coagulation pathway through its K1 and K2 domains. We prepared and characterized a monoclonal antibody (Mab8-1) against TFPI-factor Xa (TFPI-Xa) complex. The reactivities of Mab8-1 toward TFPI-Xa complex, TFPI without C-terminal (TFPI-C)-Xa complex, K1K2-Xa complex and K2K3-Xa complex were examined using a surface plasmon resonance analysis (Biacore). The Biacore system allowed a quantitative analysis of antibody-antigen interaction, in real time, from which the association and dissociation rate constants could readily be obtained. The bindings of Mab8-1 to TFPI-Xa complex, TFPI-C-Xa complex and K2K3-Xa complex were each concentration-dependent. However, no binding of Mab8-1 to the K1K2-Xa complex was observed. The binding of Mab8-1 to TFPI or Xa was also not observed. These results suggested that the epitope for Mab8-1 was exposed in the K3 domain of TFPI, which was generated by the conformational change after the formation of TFPI-Xa complex. We then developed an enzyme-linked immunosorbent assay method specific for TFPI-Xa complex using Mab8-1, and we used this assay to measure plasma levels of TFPI-Xa. The normal range assessed from analyses of plasma from 30 normal healthy volunteers was 17.7-66.7 with a mean of 35.5 +/- 11.7 pmol/l. In order to asses the clinical implication of TFPI-Xa complex in the plasma of patients with thrombotic disorders, plasma concentrations were measured in 37 patients with disseminated intravascular coagulation (DIC) caused by a variety of underlying diseases. The TFPI-Xa antigen levels were significantly higher in the patients with DIC (51.9 +/- 21.6 pmol/l) and the 36 patients with pre-DIC (55.1 +/- 20.2 pmol/l) than in the 137 non-DIC patients (37.9 +/- 13.1 pmol/l). In the patients with DIC or pre-DIC, there was no significant correlation between TFPI-Xa complex and the elevated levels of thrombin-antithrombin complex, plasmin-alpha2 plasmin inhibitor complex, D-dimer, soluble fibrin monomer, soluble thrombomodulin or tissue factor. These data indicate that the plasma level of TFPI-Xa seems to be a novel independent molecular marker of DIC and pre-DIC.
Blood coagulation factor XIII (FXIII) promotes cross-linking of fibrin during blood coagulation; impaired clot stabilization in human genetic deficiency is associated with marked pathologies of major clinical impact, including bleeding symptoms and deficient wound healing. To investigate the role of FXIII we employed homologous recombination to generate a targeted deletion of the inferred exon 7 of the FXIII-A gene. FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice. Plasma fibrin gamma-dimerization was also indetectable in the homozygous deficient animals, confirming the absence of activatable FXIII. Homozygous mutant mice were fertile, although reproduction was impaired. Bleeding episodes, hematothorax, hematoperitoneum and subcutaneous hemorrhage in mutant mice were associated with reduced survival. Arrest of tail-tip bleeding in FXIII-A deficient mice was markedly and significantly delayed; replacement of mutant mice with human plasma FXIII (Fibrogammin P) restored bleeding time to within the normal range. Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization. The mutant mice thus reiterate some key features of the human genetic disorder: they will be valuable in assessing the role of FXIII in other associated pathologies and the development of new therapies.
The postoperative behavior of different parameters of coagulation and fibrinolysis have been studied in three groups of 20 patients each. Group A got only 4-hydroxycumarin, group B 500 ml Dextran 60 intraoperatively in addition to that, group C 500 ml Dextran 60 during surgery and on the 1., 2., 4., 7. and 10. postoperative day. The results show that the hypercoagulability which occurs immediately after surgery can be prevented by infusion of Dextran 60. On the other hand there is no evidence that Dextran 60 may cause a consumptive coagulability. There is only little influence on fibrinolysis, so that no defect of haemostasis can be expected. So it is possible to use Dextran 60 both for bridging over the phase of early embolism after surgery until the change to other anticoagulants and as a substance which can be applicated for a longer period of time in prophylaxis of thromboembolism. It is referred to the additional properties of Dextran 60 in prevention of thrombosis due to reduction of blood viscosity and improvement of microcirculation.
The hemostatic mechanism has evolved to provide efficient protection from traumatic blood loss and yet maintain the blood in a fluid state in the circulation as a whole. Recent advances in biochemistry have provided both detailed understanding of hemostasis and clinically useful coagulation assays to exploit this understanding. Clinicians now have the means to delineate most of the hemostatic problems of clinical significance.
Protein C was measured by means of enzyme-linked immunosorbent assay (ELISA) in plasmas from 58 normal subjects, 39 patients with disseminated intravascular coagulation (DIC) and 5 patients with thrombotic thrombocytopenic purpura (TTP). Protein C levels ranged from 69.7 to 163.6% (95% confidence limits) in normal subjects. In patients with DIC, protein C concentrations were significantly decreased, with a geometric mean value of 42.1%. Protein C concentration was positively correlated with plasma prothrombin, antithrombin III and serum pseudocholinesterase, and was negatively correlated with von Willebrand factor antigen (vWF:Ag) and vWF:Ag/factor VIII ratio. These findings suggest that low protein C concentrations in DIC mean a consumption of protein C probably due to its activation by thrombin and/or impaired liver synthetic function. In patients with TTP, protein C levels were normal with a geometric mean value of 116.7%, indicating that the pathophysiology of TTP is quite different from that of DIC.
A polyaluminum chloride (PAC) coagulant was prepared from AlCl3 x 6H2O and Na2CO3. The Al13 species in PAC was separated and purified by the SO4(2-)/Ba2+ deposition-replacement method, and characterized by 27Al-NMR and XRD. From 27Al-NMR spectroscopy, it was found that PAC obtained after separation and purification contained more Al13 (PAC-Al13, for short) than original PAC before separation and purification. In XRD spectra, a strong Al13 signal appeared in the range of 2theta from 5 to 25 degrees. Jar tests were performed to test the coagulation efficiency of AlCl3, PAC and PAC-Al13 in treating synthetic or actual water samples. Compared with PAC and AlCl3, PAC-Al13 gives the best results for turbidity, humic acid and color removal, and achieves the highest charge-neutralizing ability. Under the study conditions, PAC-Al13 gave about 90% humic acid removal and almost 100% reactive blue dye removal when its dosages were 4.0 and 15 mg/L as Al, respectively. The Al13 species has a higher positive charge and is the most effective polymeric Al species in water and wastewater treatment.
Blood coagulation can be initiated when factor VII(a) binds to its cofactor tissue factor. This factor VIIa/tissue factor complex proteolytically activates factors IX and X, which eventually leads to the formation of a fibrin clot. Plasma contains a lipoprotein-associated coagulation inhibitor (LACI) which inhibits factor Xa directly and, in a Xa-dependent manner, also inhibits the factor VIIa/tissue factor complex. Here we report the cloning of the human LACI gene and the elucidation of its intron-exon organization. The LACI gene, which spans about 70 kb, consists of nine exons separated by eight introns. As has been found for other Kunitz-type protease inhibitors, the domain structure of human LACI is reflected in the intron-exon organization of the gene. The 5' terminus of the LACI mRNA has been determined by primer extension and S1 nuclease mapping. The putative promoter was examined and found to contain two consensus sequences for AP-1 binding and one for NF-1 binding, but no TATA consensus promoter element.
Optimally adjusted anticoagulation under LDL apheresis is essential for successful treatment: Excessive anticoagulation exposes the outpatient to the risk of uncontrolled hemorrhage, insufficient anticoagulation may shorten the duration of utilization of the immune-adsorption columns. A new device (coagulation monitor 512, Ciba Corning) allows individual adaptation of dosage and timing of heparin application by modifying the standard schedule (5,000 IU intravenously before treatment, 2,000 IU/h continuously). APTT was measured before and after application of heparin and then at 30-min intervals both by the coagulation monitor and by conventional laboratory methods; the respective heparin concentration was determined in addition. The correlation coefficient between the heparin concentration and both the monitor-derived and the laboratory-derived aPTT was 0.811 and 0.590, respectively. An explanation for this finding might be that the monitor avoids the influences induced by subsequent collection and testing of samples associated with laboratory procedures.
We describe the peculiar and concomitant presence of a severe coagulation defect predisposing to bleeding and a mutation associated with inherited thrombophilia. A 6-year-old boy had a severe deficiency in factor V procoagulant activity and antigen and yet remained asymptomatic. This paradox might be explained by the hypothesis of the simultaneous presence of a thrombophilic disorder that might have restored hemostatic balance. The boy was a homozygous carrier of the Arg506Gln mutation of coagulation factor V, that renders this factor resistant to inactivation by its naturally occurring inhibitor, activated protein C. The family members, none of whom had bleeding or thrombotic symptoms, were heterozygotes for either the bleeding or the thrombophilic defect. Despite the severity of the bleeding defect, the absence of bleeding symptoms in the boy can be explained by the hypothesis that any residual amount of factor V present in his plasma is resistant to inactivation by activated protein C.