2 cases surviving acute fatty liver of pregnancy are reported. Both cases had signs of disseminated intravascular coagulation, and extremely low plasma concentration of antithrombin III. One of the women received antithrombin III concentrate. The rationale of this therapy is discussed.

Disseminated intravascular coagulation (DIC) is a major complication of meningococcal sepsis and closely associated with the development of multiple organ failure and death [ 1 Brandtzaeg P. Pathogenesis of meningococcal infections. in: Cartwright K. Meningococcal disease. Chichester, Wiley1995: 71-114 Google Scholar , 2 van Deuren M. Brandtzaeg P. van der Meer J.W.M. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin. Microbiol. Rev. 2000; 13: 144-166 Crossref PubMed Scopus (485) Google Scholar ]. Fulminant meningococcal sepsis is characterized by exceptionally high plasma levels of endotoxin, i.e., bacterial lipopolysaccharides, which upregulate tissue factor (TF) on the surface of circulating blood monocytes and possibly on the surface of endothelial cells [ 1 Brandtzaeg P. Pathogenesis of meningococcal infections. in: Cartwright K. Meningococcal disease. Chichester, Wiley1995: 71-114 Google Scholar , 2 van Deuren M. Brandtzaeg P. van der Meer J.W.M. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin. Microbiol. Rev. 2000; 13: 144-166 Crossref PubMed Scopus (485) Google Scholar , 3 Brandtzaeg P. Bjerre A. Øvstebø R. Brusletto B. Joø G.B. Kierulf P. Neisseria meningitides lipopolysaccharides in human pathology. J. Endotoxin. Res. 2001; 7: 401-420 PubMed Google Scholar ]. Fragments of disintegrated monocytes with documented procoagulant activity are present in plasma collected from patients with meningococcal sepsis [ [4] Nieuwland R. Berckmans R.J. McGregor S. et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood. 2000; 95: 930-935 Crossref PubMed Google Scholar ]. TF forms complex with factor VII (FVII), which activates factors IX and X. TF induced coagulation is modulated by tissue factor pathway inhibitor (TFPI), which inhibits coagulation in a two-step fashion. It the first step, TFPI builds an inhibitory complex with activated factor X (FXa). In the second step, the FXa/TFPI complex builds a quaternary inhibitory complex with FVIIa/TF. Numerous experimental studies including gene knock-out [ [5] Broze Jr., G.J. Tissue factor pathway inhibitor gene disruption. Blood Coagul. Fibrinolysis. 1998; 9: 89-92 Google Scholar ], immunodepletion of TFPI [ [6] Sandset P.M. Warn-Cramer B.J. Rao L.V. Maki S.L. Rapaport S.I. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc. Natl. Acad. Sci. U. S. A. 1991 Feb.; 88: 708-712 Crossref PubMed Scopus (185) Google Scholar ], and supplementation of exogenous TFPI [ [7] Bajaj M.S. Bajaj S.P. Tissue factor pathway inhibitor: potential therapeutic applications. Thromb. Haemost. 1997; 78: 471-477 PubMed Google Scholar ] have demonstrated the key role of TFPI in the regulation of TF induced coagulation.

Tissue factor pathway inhibitor (TFPI) fractions and coagulation markers were determined in 26 patients with disseminated intravascular coagulation (DIC). Thrombin-antithrombin complex and fibrin monomer values were markedly elevated in all patients (P < 0.01). The median TFPI activity level (2.1 nmol/l) was lower than in normal controls (2.6 nmol/l; P < 0.01). The median free TFPI level was within the normal reference range, but seven patients had levels above and nine patients had levels below normal range. The median activated factor X (FXa)-TFPI complex level in patients (0.13 nmol/l) was lower than in controls (0.18 nmol/l; P < 0.01). Only one patient had a FXa-TFPI complex level above the normal range, while eight patients had levels below. In conclusion, TFPI activity, free TFPI antigen and FXa-TFPI complex levels vary considerably in DIC. Activation of coagulation may increase TFPI levels, as reported by other workers and supported by a positive correlation between tissue factor and free TFPI in the present material. A negative correlation between fibrin monomer and free TFPI (r = -0.46, P = 0.019) might indicate that hyperactive coagulation leads to consumption of TFPI. Subnormal FXa-TFPI levels in DIC, possibly caused by consumption, may imply a reduced capacity to inactivate the triggering factor VIIa-tissue factor complex.

Lipoprotein and hemostatic profiles including coagulation inhibitors were determined in 136 patients with acute ischemic stroke. Based on clinical examination, cerebral computed tomography, Doppler ultrasonography of precerebral arteries and transthoracic echocardiography, the strokes were classified as cardioembolic (n = 38), non-cardioembolic (n = 92), and mixed cardioembolic/hypertensive (n = 6). Patients with cardioembolic stroke were older than patients with non-cardioembolic stroke. Lipoprotein(a) was higher in the cardioembolic than in the non-cardioembolic group. Lipoprotein(a) was not significantly correlated to the other lipid levels and may represent an independent lipid risk factor. The non-cardioembolic group had higher levels of total cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol ratio, low-density lipoprotein cholesterol, apolipoprotein A1, and apolipoprotein B. The cardioembolic group had higher concentrations of fibrinogen and D-dimer, and lower levels of antithrombin, protein C, protein S and heparin cofactor 2 than the non-cardioembolic group. The differences in the hemostatic profile are consistent with thrombosis due to activated coagulation being more involved in the pathogenesis of cardioembolic than of non-cardioembolic stroke. Lipoprotein(a) seems to be more associated with coagulation markers of thrombosis than with atherosclerosis, whereas the other lipids mainly seem to be risk factors for atherosclerosis.

Over a period of three years, 378 patients with objectively verified venous thromboembolism were treated at Aker University Hospital. Below the age of 60, men and women had about the same incidence of venous thromboembolism, but that age the incidence was significantly higher among men than among women. Incidence increased exponentially with age, from about 1:10,000 at age 20 to about 1:1,000 at age 50. The incidence found here is lower than in earlier Nordic studies. The great majority of the patients (93%) had deep venous thrombosis in the lower extremities, 11% had symptomatic and verified pulmonary embolism, and 1% had their thrombus in an inner organ vein. 23% of patients were previously treated for venous thromboembolism, and 22% had cancer. Seven women were on oral contraception, and 22 used postmenopausal hormone substitution. An obvious temporary precipitating factor was present in 42% of the patients, while 36% had a spontaneous venous thromboembolism. Hereditary thrombophilic disorder was found in 32% of patients below the age of 60.

We have previously reported high levels of the coagulation inhibitor TFPI in the blood of patients with gastrointestinal cancer. TFPI is not an acute-phase reactant, but high levels have also been reported in patients with septicaemia and disseminated intravascular coagulation (DIC). To study its relationship with other types of malignancy, TFPI activity was first determined in plasma samples from 214 patients with various malignancies. In a second cohort of 83 patients, total and free TFPI antigen, protein C, antithrombin, fibrin monomer and D-dimer were also measured. Elevated TFPI activity and antigens were found in about half of the patients with solid tumours. In contrast, elevated TFPI was rare in haematological malignancies (12%). In the 18 patients with acute nonlymphocytic leukaemia (ANLL), elevated free TFPI was found only in patients who also had DIC. No correlation was found between TFPI levels and fibrin monomer or D-dimer levels. Only four out of 20 patients with solid tumours had normal levels of fibrin monomer and D-dimer, yet three out of these four had elevated TFPI. In conclusion, elevated TFPI in ANLL is related to the coexistence of DIC. In solid tumour disease increased TFPI may reduce protective fibrin formation, but the pathogenic mechanism is as yet unknown.

Objectives. The present trial investigated the efficacy and safety of dalteparin in the prevention of arterial thromboembolism after an acute anterior myocardial infarction (MI).Background. Left ventricular (LV) thrombus formation is associated,vith increased risk of arterial embolism in patients with an acute MI. Thrombolytic and antiplatelet therapy do not prevent thrombus formation.Methods. A total of 776 patients were enrolled in a multicenter, randomized, double blind, placebo-controlled trial of subcutaneous dalteparin (150 IU/kg body weight every 12 h during the hospital period). Thrombolytic therapy and aspirin were administered in 91.5% and 97.6% of patients, respectively. The primary study end point was the composite of thrombus formation diagnosed by echocardiography and arterial embolism on day 9 +/- 2.Results. Of 517 patients with echocardiographic recordings available for end point analysis, thrombus formation or embolism, or both, was found in 59 (21.9%) of 270 patients (59 with thrombus, none with embolism) in the placebo group and 35 (14.2%) of 247 patients (33 with thrombus, 1 with embolism) in the dalteparin group (p = 0.03). The risk reduction of thrombus formation associated with dalteparin treatment was 0.63 (95% confidence interval 0.43 to 0.92, p = 0.02). Analyses of all randomized patients (388 in each group) revealed no significant difference between the placebo and dalteparin groups with respect to arterial embolism (6 vs. 5 patients), reinfarction (8 vs. 6 patients) and mortality rates (23 vs. 23 patients, p = NS for all). Dalteparin was associated with an increased risk of hemorrhage: major in 11 dalteparin group patients (2.9%) versus 1 placebo group patient (0.3%, p = 0.006); minor in 52 dalteparin group patients (14.8%) versus 8 placebo group patients (1.8%, p < 0.001).Conclusions. Dalteparin treatment significantly reduces LV thrombus formation in acute anterior MI but is associated with increased hemorrhagic risk. (C) 1997 by the American College of Cardiology.

Plasma samples from 10 healthy persons and 10 patients with acute-phase reaction were heparinized in vitro to obtain 0.00-0.70 U/ml. The activated partial thromboplastin time (aPTT) was then determined, using an optical method (Automated Coagulation Laboratory) and four reagents (actin, Cephotest, Platelin, and Throm bosil). The heparin sensitivity showed variation between individuals and was lower in acute-phase plasma than in normal plasma. There was also a marked difference in heparin sensitivity among the different reagents; actin was the least sensitive reagent, while Platelin was the most sensitive reagent in normal plasma and Thrombosil the most heparin-sensitive reagent in acute-phase plasma. Delay in testing prolonged the aPTT values in both acute- phase and normal heparinized plasma. With actin and Ce photest, a delay of 90 min at 22°C resulted in 30-50% prolongation of the aPTT. A delay of 150 min caused a prolongation of 75-110% with actin. Cephotest, Platelin, and Thrombosil were less prolonged. Ex vivo samples from heparinized plasma showed similar degrees of pro longation. Storage at 4°C resulted in less prolongation. Assuming a therapeutic range of 0.35-0.70 U/ml of hep arin, the therapeutic aPTT ratio ranges in heparinized, acute-phase plasma were 1.5-3.0 for actin and 2.5-4.5 for Cephotest, Platelin, and Thrombosil. These results un derscore certain limitations in monitoring heparin therapy with the aPTT system. Unless the assay is performed within 30 min after sampling, unduly prolonged aPTT val ues will be recorded. This may lead to underdosing of the patient.

Tissue factor pathway inhibitor (TFPI) is mainly bound to the vessel wall and is released to circulating blood after injections of heparin. It has been suggested that the highly positively charged carboxy terminal end of heparin releasable TFPI is bound to negatively charged binding molecule(s), presumably glycosaminoglycans (GAGs), on the luminal surface of endothelial cells. The aim of the present study was to characterize this binding. Confluent monolayers of human umbilical vein endothelial cells (HUVECs) and Ea·hy926 cells were incubated with 125I-labelled recombinant TFPI (rTFPI). Two different rTFPI preparations were used in the experiments; one preparation was full-length rTFPI and one preparation was truncated at the C-terminal end (rTFPI1–161). Binding of 125I-rTFPI reached equilibrium conditions after 2 hours incubation at room temperature. Scatchard plots indicated a single class of binding sites with a mean Kd value of 164±16 nmol/L for HUVECs and a Kd value of 296±10 nmol/L for Ea·hy926 cells. The number of rTFPI binding sites per cell were approximately 1.107. Binding of 125I-rTFPI1–161 was non-specific. GAGs reduced binding of 125I-rTFPI in a dose-dependent manner by 50–75%. The potency of different GAGs to displace bound rTFPI was in the following order: Unfractionated heparin (UF) > low-molecular weight (LMW) heparin > hexadecasaccharides/octasaccharides/dodecasaccharides > heparan sulfate > dermatan sulfate. Treatment of the cells with heparinase III, with chondroitinase ABC lyase, or with sodium chlorate (to prevent sulfation) did not influence the binding of TFPI. We conclude that the C-terminal end is necessary for binding of TFPI to endothelial cells, but the binding is weak and does not involve GAGs. Copyright © 1996 Elsevier Science Ltd

Activation of coagulation leads to generation of thrombin which in turn is inactivated by the formation of thrombin-antithrombin (TAT) complexes, and thrombin-heparin cofactor complexes (T-HCII). These complexes were measured in plasma by ELISA methods. During normal delivery, the median TAT level in ten women increased from 4.1 to 7.8 times the median normal reference level. There was great individual variation, and levels 42 and 56 times normal median were found in two women shortly after normal delivery. The median T-HCII levels increased only moderately from 2.3 to 3.1 times median normal reference. D-dimer values were elevated in 28 out of the 30 samples. In blood sampled 1-2 days after delivery, the median TAT level was 2.5 times the median normal reference. The median T-HCII level was now 5.6 times the median normal reference value. The values were stable during the first 4 days post partum, and there was little difference between those delivered vaginally or by Caesarean section (C-section). D-dimer values were above normal reference in all women, and higher in women delivered by C-section. In conclusion, increasing TAT levels during labour and delivery indicated generation of thrombin which was mainly inactivated by antithrombin. The T-HCII levels increased less during delivery. In the early post partum period, the T-HCII levels were relatively more increased than the TAT levels. These results suggest that intravascularly generated thrombin is preferably inactivated by antithrombin, even in parturient women. In the post partum period, formation of T-HCII complexes was more evident, possibly reflecting extravascular inactivation of thrombin.

Tissue factor pathway inhibitor (TFPI) controls activation of blood coagulation while antithrombin (AT) regulates the final stage. Both inhibitors inhibit the intermediate stage of activation. Subnormal levels of TFPI increase the risk of disseminated intravascular coagulation (DIC) in septic conditions, and the risk of occlusive thrombi over damaged vascular intima or fissured arteriosclerotic plaques. The risk of venous thrombosis is increased by subnormal AT or subnormal activity of the protein C system. In contrast, TFPI may be little involved in the control of deep venous thrombosis. Heparin strongly accelerates AT and releases TFPI to the blood. Both these effects may contribute to the antithrombotic effect of heparin. In septic DIC, heparin may contribute little to quench activation of coagulation. Once hereditary deficiency of TFPI is described, its biological role will be better understood.

The aim of this study was to measure plasminogen in the cerebrospinal fluid (CSF) of control neonates with no infection or haemorrhage and in infants who had suffered intraventricular haemorrhage (IVH). A chromogenic substrate method was used. The 16 reference infants had a median CSF plasminogen level of 0.74% of that of normal adult plasma (range 0.17-1.1%). The 11 infants with IVH had a median CSF plasminogen level of 0.55% of normal adult plasma (range 0-4.4%). Six of the IVH infants went on to develop permanent hydrocephalus despite the use of intraventricular plasminogen activators. Endogenous fibrinolysis and the potential for fibrinolytic treatment in the CSF may be limited by low concentrations of plasminogen, and administration of recombinant plasminogen may assist attempts to clear intraventricular blood clots.

Microheterogeneity of antithrombin III (AT-III) was investigated by crossed immunoelectrofocusing (CIEF) on eleven molecular variants. A normal pattern was found in five variants while two different abnormal CIEF patterns were found in the other four and two variants, respectively. Point mutations causing a major pI change (exceeding 4.0) of the amino acid substituted lead to alterations in the overall microheterogeneity. The variants thus substituted share a first type of abnormal CIEF pattern with alterations throughout the pH range, regardless of the location of the mutation (reactive site and adjacent regions or heparin binding region). Minor amino acid pi changes in these regions do not alter the AT-III overall microheterogeneity, whatever the resulting functional defect. However, if the mutation is placed in the region around positions 404 or 429, then even minor changes of the amino acid pI seem able to alter the overall charge, leading to a second type of abnormal CIEF pattern with the main alteration at pH 4.8-4.6. Neuraminidase treatment leads to disappearance of microheterogeneity except for the variants with the Arg393 to Cys substitution. Addition of thrombin induces CIEF modifications specifically related to the functional defect. A normal formation of thrombin-antithrombin complexes induces a shift towards the more acid pH range, whereas in the variants substituted at the reactive site the CIEF pattern is substantially unaffected by thrombin; variants substituted at positions 382-384 show a maximal thrombin-induced increase of the isoforms at pI 4.8-4.6. Therefore mutant antithrombins with different functional abnormalities but sharing a common CIEF pattern were well distinguished. Thus CIEF can be a useful tool to investigate congenital AT-III pathological variants as well as different functional roles of physiological isoantithrombins.