Increased elastase-alpha 1-antitrypsin complex in fulminant hepatic failure: relationship to bacterial infection and activation of coagulation.

To study the effect of infection, a frequent complication of fulminant hepatic failure (FHF), on the release of elastase from polymorphonuclear leucocytes and its inhibition in circulation we have measured the concentrations of alpha 1-antitrypsin, which binds and inhibits elastase in the circulation, and of elastase-alpha 1-antitrypsin complex, in 30 patients with FHF. Elastase-alpha 1-antitrypsin complex was significantly increased in FHF as compared to controls (303 +/- 51 micrograms/l compared to 37 +/- 5 micrograms/l; n = 10; P less than 0.001) demonstrating activation of leucocytes in FHF. Infection caused greater release of leucocyte elastase, complex levels were significantly greater in patients who were infected when compared to those who were not (463 +/- 84 micrograms/l; n = 13 compared to 180 +/- 46 micrograms/l; n = 17; P less than 0.01). Also patients who survived had significantly lower complex levels than those who did not (212 +/- 49 micrograms/l; n = 18 compared to 440 +/- 94 micrograms/l; n = 12; P less than 0.02). alpha 1-Antitrypsin activity was not significantly different from control subjects (0.99 +/- 0.06 U/ml compared to 0.97 +/- 0.05 U/ml). However alpha 1-antitrypsin activity was significantly higher in patients who survived (1.17 +/- 0.05 U/ml; n = 18) compared to those who did not (0.71 +/- 0.03 U/ml; n = 12; P less than 0.001) and patients who died had significantly lower levels than control subjects (P less than 0.01) indicating the importance of maintenance of normal inhibitor levels in patients with FHF. The leucocyte activation and release of elastase in FHF was linked to activation of the coagulation system; elastase--alpha 1-antitrypsin complex levels correlated significantly with thrombin-antithrombin III complex levels (r = 0.68; P less than 0.001) and inversely with fibrinogen (r = -0.71; P less than 0.001).     

Laboratory and clinical evaluation of an assay of thrombin-antithrombin III complexes in plasma

We evaluated a recently developed commercial assay for quantifying thrombin-antithrombin III (TAT) complexes in human plasma. The assay is precise (within-assay CV less than 10%, between-assay CV less than 13%), and sensitive (detection limit 0.7 micrograms of TAT per liter of plasma). Measurements for healthy volunteers yielded a normal reference (95 percentile) interval of 0.8 to 5.0 micrograms/L (n = 50, mean 2.1 micrograms/L, range 1.1 to 7.5 micrograms/L). TAT concentrations were increased in 25 of the 41 patients who fulfilled the clinical criteria of disseminated intravascular coagulation (DIC, overall mean 15.8 micrograms/L) and in 30 of the 35 patients with deep-vein thrombosis of the leg (overall mean 9.4 micrograms/L). We assessed the accuracy of the TAT assay by comparison with established criteria for the laboratory diagnosis of DIC involving various cutoff values for antithrombin III, factor V, fibrinogen, platelet count, fibrin/fibrinogen degradation products, and activated partial thromboplastin time. The low specificity of the TAT assay with regard to some of these criteria indicates that the latter are probably insensitive.     

Anticoagulation with a synthetic thrombin inhibitor after cardiovascular surgery and for treatment of disseminated intravascular coagulation

A synthetic thrombin inhibitor, MD-805, was used to anticoagulate 15 patients after cardiovascular surgery (CVS). A mean infusion rate of 0.71 +/- 0.1 (SD) microgram/kg . min maintained an activated coagulation time of about 150 sec in all patients, and significantly prolonged both activated partial thromboplastin time and prothrombin time. MD-805 was also administered to ten patients with disseminated intravascular coagulation (DIC), eight of whom had not responded to either heparin or gabexate mesilate (FOY), and eight of whom had circulating antithrombin III levels below 20 mg/dl. MD-805 therapy was successful in nine DIC patients. These results recommend MD-805 anticoagulant therapy after CVS and for treatment of DIC, especially when circulating levels of antithrombin III are low.     

The control of anti-coagulation in acute dialyses with sensitive laboratory parameters.

In seven patients who had to be dialysed between four and 13 times due to acute renal failure, low molecular weight heparin (LMWH) Fragmin was used for anticoagulation. According to dose-finding studies, 80-90 U kg-1 body weight of LMWH as a single bolus were administered initially, producing dose-related levels of 0.3-1.5 anti-factor Xa U ml-1 in plasma. Apart from the anti-Xa activity in the plasma, the thrombin anti-thrombin III complex (TAT complex) and a fibrin degradation product (D-dimer) were measured as parameters of a coagulation activation. A sufficient anti-coagulation during dialysis was supposed to exist at a normal range (5.0 micrograms l-1 or below) of TAT complex. Pathological TAT concentrations at the end of dialysis indicated the requirement of an increased dose for the next dialysis. These concentrations reflected a need for more heparin if, for example, inflammation, indicated by increasing C-reactive protein levels (CRP), occurred. The increase of TAT complex and D-dimer during dialysis showed a good agreement (p less than 0.001). Due to a single bolus application before dialysis, one measurement of TAT at the end of the dialysis was sufficient. The determination of the TAT complex concentration enabled a heparinization better adapted to the clinical situation of intensive-care patients undergoing acute dialyses, so that the coagulation system was not additionally activated by the extracorporeal circulation.     

Role of endothelial dysfunction and coagulation disorders in the development of pulmonary fibrosis in patients with interstitial lung diseases

Thirty-two patients with different forms of interstitial lung diseases (ILD), such as idiopathic fibrosing alveolitis (IFA) (n = 17) and fibrosing alveolitis concurrent with diffuse connective tissue diseases (FA-DCTD), were examined. Clinical, echocardiographic, computed tomographic, coagulative, and immunological studies were performed. Enzyme immunoassay was used to determine the levels of a complex of thrombin and antithrombin III (TAT) and platelet factor IV (PF-IV). There were significant increases in the levels of PF-IV (4.36 +/- 0.25 mg/l) and TAT (10.87 +/- 3.8 mg/l) in patients with ILD as compared to the control (2.75 +/- 0.47 and 1.8 +/- 0.2 mg/l, respectively; p < 0.05). In patients with early FA-DCTD with the predominance of the milk glass syndrome during high-resolution CT (HRCT), the level of PF-IV was greater than the normal levels (p < 0.05) and decreased with the progression of the disease and with the formation of the honeycomb lung. If there were HRCT signs of active inflammation, the level of TAT was higher than that in the control; this was also in the development of irreversible fibrous changes.     

脑梗死患者血浆中血栓标志物及凝血指标联合检测的临床意义

目的探讨凝血分子标志物和常规凝血指标的检测在脑梗死患者中的临床意义,为脑梗死的诊断和治疗监测提供依据。方法测定90例脑梗死患者血浆中凝血酶原片段1 2(F1 2)、凝血酶-抗凝血酶复合物(TAT)、二聚体(D-D)、抗凝血酶(AT)、蛋白C(PC)、血管性血友病因子(vWF)、凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血酶时间(TT),并与健康正常对照组进行比较。结果脑梗死患者F1 2、TAT、D-D、vWF和健康对照组相比均有显著增高,而PT、APTT、TT、PC和AT与健康对照组相比差异无统计学意义。结论脑梗死患者体内呈高凝状态,凝血酶原活性增强,凝血酶生成增多,纤溶活性增强,抗凝系统活化不足,同时内皮细胞损伤在脑梗死患者的凝血系统激活和发病过程中可能起主要作用,F1 2、TAT、D-D、vWF等凝血分子标志物可以作为脑梗死的诊断指标,而常规的凝血指标不能反映脑梗死患者的高凝状态。     

Clinical usefulness of serum tartrate-resistant acid phosphatase activity determination to evaluate bone turnover.

The study was carried out to evaluate the clinical validity and usefulness of serum tartrate-resistant acid phosphatase (TRAP) activity determined using an improved spectrophotometric assay. Enzyme activity was measured in 84 normal subjects and in 109 patients with common metabolic bone diseases. Mean values of serum TRAP activity in male subjects (n = 19; 10.4 +/- 2.15 U l-1) were not significantly different from those found in female subjects (n = 65; 10.8 +/- 1.8 U l-1). In the latter group mean values were significantly raised in post-menopausal subjects (10.5 +/- 2.0 U l-1; p less than 0.01) compared with mean values in pre-menopausal women (8.45 +/- 1.8 U l-1). We found a significant inverse correlation between serum TRAP activity values and bone mineral density (BMD) measured both at an ultradistal radial point (n = 33, r = -0.506; p less than 0.01), and at the lumbar spine (n = 57, r = -0.261; p less than 0.05). Mean serum TRAP activity values in patients with metabolic bone diseases were: primary hyperparathyroidism, n = 30: 14.2 +/- 4.89 U l-1, p less than 0.001 vs normal subjects; chronic maintenance haemodialysis, n = 19: 17.4 +/- 6.7, p less than 0.001; metastatic cancer, n = 13: 21.2 +/- 6.3, p less than 0.001; post-surgical hypoparathyroidism, n = 10: 9.9 +/- 1.8, NS; involutional osteoporosis, n = 20: 12.5 +/- 2.3 p less than 0.001; Paget's disease, n = 10: 16.8 +/- 3.5, p less than 0.001; osteomalacia, n = 7: 19.5 +/- 3.31, p less than 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)     

The response of antithrombin III activity after supplementation decreases in proportion to the severity of sepsis and liver dysfunction

The decrease in the antithrombin III activity is thought to result from consumption by ongoing coagulation, degradation by neutrophil elastase, capillary leak syndrome, and impaired synthesis. A retrospective data analysis of patients with sepsis was conducted to investigate the response of antithrombin III activity after supplementation in patients with sepsis, and to determine what factors affect the response of antithrombin III activity. The study included 42 patients with sepsis, 75 patients with severe sepsis, and 65 patients with septic shock, who were administered antithrombin III. Antithrombin III activity, platelet counts, coagulation, and fibrinolytic markers were collected before administration and 24 h after the supplementation. In the patients with septic shock, the response of antithrombin III activity after supplementation was 0.37% +/- 1.21%/IU per kg body weight, which was significantly lower in comparison with those in the patients with sepsis (1.81 +/- 1.75; P < 0.001) or severe sepsis (1.36 +/- 1.65; P < 0.001). The patients with liver dysfunction had significantly lower response to antithrombin III activity than that of the patients without liver dysfunction (P < 0.0001). A stepwise multiple linear regression analysis revealed that the severity of sepsis and liver function were independent predictors for the response to antithrombin III activity. These results suggest that the response to antithrombin III supplementation may be affected by both a systemic inflammation and impaired synthesis in patients with sepsis.     

Serum albumin levels anticipate antithrombin III activities before and after antithrombin III agent in critical patients with disseminated intravascular coagulation

Elevated thrombin-antithrombin complex (TAT) or decreased serum albumin levels suggest heightened vascular permeability in disseminated intravascular coagulation (DIC). In such a situation, plasma antithrombin III (AT-III) may decrease because of the leakage. We thus examined whether AT-III activity before and after administration of an AT-III agent changed depending on plasma TAT and/or serum albumin levels in 20 consecutive patients with DIC. We also analyzed the pharmacokinetics for AT-III using a two-compartment model. Serum albumin levels before AT-III administration correlated with preadministered and postadministered AT-III activity, but TAT levels did not. Regardless of TAT levels, AT-III trough activity on the third day increased significantly. In patients with albumin levels of 2.5 g/dL or less, AT-III trough levels on the third day were significantly lower than those with higher levels of albumin. The half-life of the distribution phase for AT-III agent in the patients was shortened to less than one third the value reported in congenital AT-III deficiency, suggesting increased vascular permeability in the acute state patients here. The distribution volume of the agent increased remarkably compared with the previous control. We report here for the first time that in critical patients with DIC, plasma AT-III levels before and after AT-III administration could be predicted by preadministered serum albumin levels, but not by TAT. These findings could be explained by the pharmacokinetic profile, increased vascular permeability and distribution volume, observed in critical patients.     

Heparin treatment in thrombin-induced disseminated intravascular coagulation in the baboon

BACKGROUND AND METHODS: We postulated that low-dose heparin (10 IU/kg.hr) administered as a continuous iv infusion may prevent or ameliorate the induction of thrombin-induced disseminated intravascular coagulation in baboons under general anesthesia. In a nonrandomized experiment lasting 8 hrs, animals were divided into three groups: 11 received thrombin only (group A); ten were pretreated with heparin before thrombin administration (group B); and 15 received heparin 2 hrs after disseminated intravascular coagulation was induced with thrombin (group C). All animals were monitored hemodynamically and coagulation tests were performed hourly. Tests included the following: one-stage prothrombin ratio; activated partial thromboplastin time; fibrinogen and fibrin degradation products; thrombin time; plasma fibrinogen level; antithrombin III and activated clotting time. After the acute phase of the experiment, the animals were observed for 6 days and a postmortem examination was performed on a survivor of each group. RESULTS: Six (55%) group A animals died within 6 days, while there were no deaths in group B and one animal (7%) died in group C. In group C, the administration of heparin could not normalize the clotting profile, but the mortality rate was significantly less than in group A. The prophylactic administration of heparin in group B prevented the induction of disseminated intravascular coagulation. The postmortem findings were of interest, but no statistically valid conclusions could be made, as only one autopsy was done for each group. However, the results suggest that heparin pretreatment may protect against lung edema and liver necrosis. CONCLUSIONS: The results suggest that heparin, in a dose of 10 IU/kg.hr iv, could possibly be safely used in patients at high risk of developing disseminated intravascular coagulation and in those patients with established disseminated intravascular coagulation.     

Exercise-induced changes in insulin-like growth factors and their low molecular weight binding protein in healthy subjects and patients with growth hormone deficiency

Serum concentrations of insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), the low molecular weight form of IGF binding protein (IGFBP-1), insulin, C-peptide and GH were determined in six healthy subjects and four patients with GH deficiency during 30 min of moderate physical exercise on the cycle ergometer. The load corresponded to 60% of individual maximal oxygen uptake. IGF-1 and IGF-2 were determined by radioimmunoassays developed with antibodies isolated from immunized hens eggyolk after separation by automated acid gel filtration of serum samples prior to assay. Significant increases in the serum concentrations (mean +/- SEM) of IGF-1 (157 +/- 24 to 196 +/- 29 micrograms l-1, P less than 0.05) and IGF-2 (451 +/- 37 to 678 +/- 85 micrograms l-1, P less than 0.01) were seen in the healthy subjects after 10 min of exercise. The mean percentage increase was 26 +/- 5% for IGF-1 and 50 +/- 11% for IGF-2. No relation to the GH release was found. In GH-deficient patients the mean IGF-2 concentration rose 48 +/- 17% from basal 216 +/- 63 micrograms l-1 to a peak concentration of 324 +/- 115 micrograms l-1 (P less than 0.01) after 30 min, while the 38 +/- 20% rise of IGF-1 from basal 36 +/- 13 micrograms l-1 to a peak concentration of 55 +/- 27 micrograms l-1 was not significant. The serum IGFBP-1 concentration did not change during exercise, while insulin and C-peptide concentrations, as well as blood glucose, decreased in both healthy subjects and GH-deficient patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

凝血酶原片段F1+2、凝血酶-抗凝血酶复合物和D-二聚体定量测定在 DIC早期诊断中的价值

目的:探讨、比较三种血栓前态分了樗物珲量浊定在DIC早期诊断中的价值。方法收集了30倒正常对照(NC)血浆和62临床已诊DIC的病人血浆,,根据DIC病程分为DIC早期、中期和晚期,分别有ELISA法测定了血栓前状态分为子标志物凝血酶原片段F_(1 2)、酶-抗凝血酶复合物(TAT)和D-二聚体(D-dimer,D-D)含量。结果:早期DIC病人中D-D含量为1.621.46/L,NC组为0.510.12mg/L;F_(1 2)含量为33.1120.59/L,NC组为1.643.14/L加期DIC中D-D含量为6.858.37mg/LF_(1 2)含量为4.362.44nmol/L,TAT含量为22.5320.98/L;晚期DID中D-D含量为10.325.85/LF_(1 2)的含量为6.443.51/L,TAT含量为36.6420.09/L。经统计学分析,各DIC组D-D含量与NC组相比均有极显著性差异(P<0.01),各组之间也有极显著性差异(P<0.01);各DIC组1 2和TAT的含量较NC组均有极显著性差异(P<0.01),而各DIC组之间却无明显的差异(P>0.05)。F_(1 2)和TAT在所有DIC病人中有显著性相关(r=0.679,P<0.0001),而F_(1 2)与D-D、TAT与D-D无相关性。结论:综合应用不同的血栓前状态分子标志物的定量测定,不但有助于早期诊断DIC,并且可用于判断DIC的发展情况。     

Disseminated intravascular coagulation following Echis carinatus venom in dogs: effects of a synthetic thrombin inhibitor

Disseminated intravascular coagulation (DIC) was produced by an infusion of a prothrombin activator (Echis carinatus venom; 30 minutes; 0.5 NIH thrombin equivalent U/kg) in mongrel dogs (Echis group, n = 7). Fibrinogen declined to below measurable levels (less than 25 mg/dl), and fibrin-fibrinogen degradation products appeared (53 +/- 8 micrograms/ml) at end venom infusion in the Echis group. These alterations were not seen when an irreversible thrombin inhibitor, D-phenylalanyl-L-prolyl-L-arginine-L-chloromethyl ketone (PPACK) (57 nmol/kg/min for 120 minutes), was given alone (PPACK group, n = 5) or in association with venom (Echis + PPACK group, n = 5). Factor II activity (1% +/- 1%) in the Echis and Echis + PPACK groups was significantly below the PPACK (55% +/- 9%) and the control (79% +/- 2%) levels at 120 minutes. In contrast, factor VIII coagulant (factor VIII:C) activity in the Echis group (1% +/- 1%) remained significantly below that in the Echis + PPACK (68% +/- 8%), PPACK (78% +/- 10%), and control (91% +/- 9%) groups at this interval. No change in factors X (91% +/- 7% to 81% +/- 7%, P not significant) and VII (64% +/- 10% to 48% +/- 11%, P not significant) activities were observed. Hemolysis was observed only in the Echis group, whereas thrombocytopenia and leukopenia were noted in both the Echis and the Echis + PPACK groups. These data show that large amounts of E. carinatus venom produce rapid DIC in vivo, because of the activation of prothrombin. In contrast, the decline in factor VIII:C activity appeared to be the result of the liberated thrombin. PPACK antagonized all of the venom-released thrombin without any major deleterious clotting abnormalities. This inhibitor appears to prevent thrombin-mediated DIC in vivo. In contrast, heparin was found to be an unreliable antagonist of the venom-released thrombin in vitro. PPACK also inhibited the marked hemolysis usually observed after venom. In addition, we found that the esterolytic (N-benzoyl-L-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide HCL) activity of E. carinatus venom degrades fibrinogen in vitro.     

Reduction of blood coagulation and monocyte-platelet interaction following the use of a minimal extracorporeal circulation system (Synergy) in coronary artery bypass grafting (CABG)

Cardiovascular surgery with cardiopulmonary bypass (CPB) induces activation of blood coagulation and systemic inflammation involved in post-operative complications. Our study evaluated the impact of the minimal extracorporeal circulation (mini-CPB) system (Synergy, Sorin Group) on these functional aspects. Twenty patients were randomly assigned to standard CPB (n = 10) or to Synergy (n = 10). Platelet expression of PAC-1, and monocyte/granulocyte-platelet conjugates were evaluated by flow cytometry. A leukocyte-platelet adhesion index was calculated after cell number normalization. ELISAs were performed to measure IL-6 and TNF-alpha, thrombin-antithrombin III complexes (TAT), prothrombin fragments (F1+2), beta-thromboglobulin (beta-TG) and sP-selectin (sCD62P). Blood samples were drawn at the time of anesthesia (T1), at the end of CPB (T2), and at 4 (T3) and 24 hours (T4) after weaning from CPB. All patients were similar for clinical characteristics. When compared to standard CPB, the Synergy showed lower levels of the monocyte-platelet adhesion index at T2 (0.023 +/- 0.005 vs 0.063 +/- 0.013, P = 0.0092) and T4 (0.031 +/- 0.003 vs 0.055 +/- 0.005, P = 0.0017), TAT complexes at T2 (27.175 +/- 5.967 vs 86.592 +/- 5.415, P = 0.0005) and T3 (26.977 +/- 2.468 vs 45.146 +/- 4.365, P = 0.0041), F1+2 fragments at T2 (2.222 +/- 0.226 vs 4.249 +/- 0.292, P = 0.0009), and sP-selectin at T3 (115.17 +/- 19.623 vs 169.554 +/- 19.709, P = 0.0703) and T4 (108.542 +/- 6.429 vs 140.799 +/- 14.771, P = 0.0833). In summary, the Synergy exhibited a lower post-operative activation of blood coagulation, together with a reduced interaction between circulating monocytes and platelets.     

Serum octopamine, coma, and charcoal haemoperfusion in fulminant hepatic failure

Serum octopamine levels were significantly higher in twenty patients with fulminant hepatic failure (FHF) during the first 48 h of grade IV coma than in health control subjects (3.38 +/- 0.20 ng/ml and 1.75 +/- 0.19 ng/ml respectively, P less than 0.001). Serial measurements in five patients who died without regaining consciousness showed serum octopamine to remain raised, and concentrations in the cerebrospinal fluid at death reflected serum levels. In five patients who regained consciousness, improvement in encephalopathy was associated with a significant reduction in serum octopamine. Renal failure in patients with FHF was found to contribute to raised serum octopamine but could not alone account for the observed levels. Patients given neomycin therapy did not have significantly lower serum octopamine levels than an untreated group. There was, however, a significant correlation between elevated serum octopamine and the occurrence of gestrointestinal bleeding during the previous 24 h. Charcoal haemoperfusion did not appreciably reduce serum octopamine levels.     

Thrombin generation: phenotypic quantitation

Summary.  An individual's ability to generate thrombin following tissue factor stimulus was evaluated in 13 healthy male donors in a 6-month study. Thrombin generation in whole blood collected by phlebotomy, contact pathway suppressed by the presence of 100 µg mL⁻¹ corn trypsin inhibitor, was initiated by the addition of 5 p m tissue factor/10 n m phospholipid. Reactions were quenched at 20 min by the addition of an ethylenediaminetetraacetic acid (EDTA), benzamidine, FPRck cocktail. Thrombin generation was determined by an ELISA for thrombin–antithrombin III (TAT) complex formation. Results showed that the levels of TAT observed varied from 245 to 775 n m . Thrombin production was consistent within each individual, CVi = 11.6%, but varied significantly within the group, CVg = 25.2%, and correlated inversely with an individual's clotting time ( r  = − 0.54, P  = 0.07). No correlations were individually observed between TAT and C-reactive protein, antithrombin III, factors II, V, VII, VIII, IX and X, fibrinogen and prothrombin time. However, computer simulations, which integrated each individual's coagulation factor levels using the Speed Rx method (Hockin et al. , J Biol Chem 2002; 277: 18322), predicted maximum active thrombin levels (ranging from calculated values of 220–500 n m ) consistent with the empirically determined values. Overall, these data suggest that thrombin generated in whole blood exclusively by tissue factor stimulation can be used as an integrative phenotypic marker to determine an individual's response to a tissue factor challenge.     

Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways

Summary. Background: Activation of coagulation and fibrinolysis play a role in the pathophysiology of experimental arthritis. Objective: To determine the extent of activation of the coagulation and fibrinolytic pathways in different joint diseases in humans and to ascertain the factors that may influence fibrin deposition within the joint. Methods: Plasma from normal subjects (controls, n= 21) and plasma and synovial fluid samples from patients with rheumatoid arthritis (RA; n = 64), osteoarthritis (OA; n = 29), spondyloarthropathy (SpA; n = 22) and crystal arthritis (CA; n = 25) were analyzed for the levels of TF (tissue factor) and tissue factor pathway inhibitor (TFPI) activities, thrombin–antithrombin III (TAT) complexes, and F1 + 2 (thrombin fragment), fibrin d ‐dimer and thrombin‐activated fibrinolysis inhibitor (TAFI) antigenic levels. The measurements were analyzed by pairwise correlation with each other as well as with standard parameters of inflammation [C‐reactive protein (CRP), joint leukocyte count]. Inter‐group comparisons were performed to look for disease‐specific differences. Results: Compared with healthy controls, patients with joint diseases had higher levels of TAT, F1 + 2 and d ‐dimers in their plasma. In the synovial fluid, TF activity, TAT, d ‐dimers, and TAFI were significantly higher in inflammatory arthritides than in OA. The levels were highest in RA patients. In the plasma, TF activity was correlated with TAT and d ‐dimer levels with CRP, TFPI, and TAT. In the synovial fluid, TF activity correlated with plasma CRP levels, synovial fluid leukocyte count, and synovial TAT and TAFI levels. In addition, synovial d ‐dimers correlated with CRP, and synovial TAFI levels were correlated with synovial F1 + 2 and TAT. Conclusions: Activation of the coagulation and fibrinolytic cascades in the joint and in the circulation is evident in both inflammatory and degenerative joint diseases. Within the joint, inflammatory mechanisms leading to TF‐mediated activation of the coagulation pathway and subsequent fibrin deposition is the most likely explanation for the observed findings. In the plasma, the link between inflammation (CRP increase) and TF activation is weak, and a non‐TF‐mediated mechanism of coagulation activation could explain these findings. RA is characterized by significantly higher levels of TAT in the synovial fluid and plasma than other arthritides. Although fibrinolytic activity is linked to inflammation, the increased amounts of TAFI in the joint, particularly in RA, may explain why fibrin formation is so prominent in this condition compared with other joint diseases.     

Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration

The metabolism of human antithrombin III (heparin cofactor) was studied in four control subjects, in four subjects with peripheral obliterative arterial disease, in six patients with recent venous thrombosis and in one patient with clinically severe haemophilia A. The labelled antithrombin III has a high specific activity (5.75 units/mg) and displayed a single band on SDS-polyacrylamide gel electrophoresis. On Sephadex G-100 gel filtration the labelled material eluted in the same position as the antithrombin III activity in plasma. Crossed immunoelectrophoresis of a mixture of fresh plasma and labelled antithrombin III against a specific antiserum, revealed a single precipitin line in which radioactivity was concentrated. The changes in electrophoretic mobility of both the plasma antithrombin III and the labelled material following the addition of heparin to the mixture or following coagulation were identical. The purified antithrombin III behaved as a homogeneous protein in the turnover experiments. The plasma radioactivity data were approximated by a sum of two exponential terms and the metabolism of antithrombin III represented by a two compartment mammillary model. Results in the control subjects were as follows: plasma antithrombin III concentration 19.6 +/- 2.3 mg/100 ml; intravascular fraction 0.45 +/- 0.05; fractional catabolic rate 0.55 +/- 0.02 of the plasma pool per day; half-life of the plasma radioactivity 2.83 +/- 0.26 days. Circulating large molecular weight degradation products of labelled antithrombin III could not be detected by Sephadex G-100 gel filtration. No significant differences in these parameters were found in the patients with peripheral arterial insufficiency. The turnover rate of antithrombin III was normal in the patient with haemophilia A. In three patients with venous thrombosis not treated with heparin, the turnover of labelled antithrombin III was in the normal range. In three patients with venous thrombosis, treated with heparin, the plasma radioactivity half-life was significantly shortened (2.13 +/- 0.08 days) and the fractional catabolic rate increased (0.75 +/- 0.05) of the plasma pool per day). In one of these patients, the labelled antithrombin III had been incubated with an equimolar amount of heparin prior to injection. In this patient the plasma radioactivity half-life was in the same range as in the other two patients (2.15 days).     

Biochemical and clinical response of fulminant viral hepatitis to administration of prostaglandin E. A preliminary report.

The effect of PG on patients with fulminant and subfulminant viral hepatitis (FHF) was studied. 17 patients presented with FHF secondary to hepatitis A (n = 3), hepatitis B (n = 6), and non-A, non-B (NANB) hepatitis (n = 8). 14 of the 17 patients had stage III or IV hepatic encephalopathy (HE). At presentation the mean aspartate transaminase (AST) was 1,844 +/- 1,246 U/liter, bilirubin 232 +/- 135 mumol/liter, prothrombin time (PT) 34 +/- 18, partial thromboplastin time (PTT) 73 +/- 26 s, and coagulation Factors V and VII 8 +/- 4 and 9 +/- 5%, respectively. Intravenous PGE1 was initiated 24-48 h later after a rise in AST (2,195 +/- 1,810), bilirubin (341 +/- 148), PT (36 +/- 15), and PTT (75 +/- 18). 12 of 17 responded rapidly with a decrease in AST from 1,540 +/- 833 to 188 +/- 324 U/liter. Improvement in hepatic synthetic function was indicated by a decrease in PT from 27 +/- 7 to 12 +/- 1 s and PTT from 61 +/- 10 to 31 +/- 2 s, and an increase in Factor V from 9 +/- 4 to 69 +/- 18% and Factor VII from 11 +/- 5 to 71 +/- 20%. Five responders with NANB hepatitis relapsed upon discontinuation of therapy, with recurrence of HE and increases in AST and PT, and improvement was observed upon retreatment. After 4 wk of intravenous therapy oral PGE2 was substituted. Two patients with NANB hepatitis recovered completely and remained in remission 6 and 12 mo after cessation of therapy. Two additional patients continued in remission after 2 and 6 mo of PGE2. No relapses were seen in the patients with hepatitis A virus and hepatitis B virus infection. Liver biopsies in all 12 surviving patients returned to normal. In the five nonresponders an improvement in hepatic function was indicated by a fall in AST (3,767 +/- 2,611 to 2,142 +/- 2,040 U/liter), PT (52 +/- 25 to 33 +/- 18 s), and PTT (103 +/- 29 to 77 +/- 44 s), but all deteriorated and died of cerebral edema (n = 3) or underwent liver transplantation (n = 2). These results suggest efficacy of PGE for FHF, and further investigation is warranted.     

Immunoassay for the determination of surfactant apoprotein (SP-A) in human amniotic fluid: comparison with other indices of assessing foetal lung maturity.

The concentration of the major surfactant-associated protein SP-A (28-36 kDa) was determined in 73 amniotic fluid samples obtained from normal (n = 40) and complicated (n = 33) pregnancies. Lecithin/sphingomyelin (L/S) ratio and phosphatidylglycerol (PG) levels were also determined in all the samples by one-dimensional step-wise thin-layer chromatography. An enzyme-linked immunosorbent assay was used to determine human lung surfactant apoprotein SP-A. The amount of SP-A in human amniotic fluid increased as a function of gestational age from 8 mg l-1 at 36 weeks to 11.75 mg l-1 at 40-41 weeks of gestation. There was a significant difference (p less than 0.01) in amniotic fluid SP-A concentration from female (9.93 +/- 0.60 micrograms ml-1) compared to male (9.10 +/- 0.52 micrograms ml-1) foetuses. In amniotic fluid samples obtained from a group of complicated pregnancies, SP-A levels were significantly lower than in the normal group when adjusted for gestational age and sex of the foetus (p less than 0.05).