Hypocoagulable state of human preovulatory ovarian follicular fluid: role of sulfated proteoglycan and tissue factor pathway inhibitor in the fluid.
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Ovulation accompanied by tissue damage can cause an increase in the level of tissue factor (TF) in the follicular fluid, triggering the extrinsic coagulation pathway. However, follicular fluid must block fibrin formation and maintain fluidity until the release of the oocyte at ovulation. The combination of sulfated proteoglycan, antithrombin, and TF pathway inhibitor (TFPI) appears to play a critical role in the hypocoagulability of human follicular fluid. When compared with plasma, folicular fluid differs markedly in the levels of a number of important coagulation proteins. Principal among these are 15-fold, 13-fold, and 3.7-fold increases in free TFPI, thrombin-antithrombin complex, and TF, respectively. The excessively prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT) of human ovarian follicular fluid appear to be primarily due to high concentrations of sulfated proteoglycans, which accelerate the inactivation of thrombin and the anti-Xa activity of TFPI. Thus, heparitinase treatment shortened the clotting times of follicular fluid and reduced the inhibition of thrombin by the proteoglycan fraction combined with a fraction containing antithrombin. The remaining prolongation of APTT and PT may be caused by high levels of free TFPI in follicular fluid, which were confirmed by Northern blotting analysis, demonstrating TFPI mRNA expression by granulosa cells. (+info)
Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects.
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BACKGROUND: In view of the central role of the tissue factor-factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor-factor VIIa complex, in a double-blind randomized crossover study. METHODS AND RESULTS: Administration of nematode anticoagulant protein c2 (3.5 microgram/kg) caused a prolongation of the prothrombin time from 13.7+/-0.6 to 16.9+/-1.2 seconds. The subsequent injection of rVIIa (90 microgram/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75+/-0.64 to 3.29+/-6.3 nmol/L and from 2.4+/-0.6 to 10.7+/-3.9 microgram/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2. CONCLUSIONS: During treatment with an inhibitor of the tissue factor-factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor. (+info)
A family is described in which a syndrome resembling moderately severe classic hemophilia was apparently inherited as an X chromosome-linked trait. In two affected individuals, the titer of functional antihemophilic factor varied dramatically from time to time, while the conversion of prothrombin to thrombin was impaired in no apparent relationship to AHF functional activity. A transfusion of 200 ml of fresh-frozen plasma did not correct the serum prothrombin times in either patient. In vitro, the additions of 10% of normal plasma or serum or washed plain or frozen platelets also did not normalize the serum prothrombin times. No inhibitor could be demonstrated in the blood of either patient. In one patient, RH, dissipation of infused cryoprecipitated AHF was abnormally slow, and, after an intensive course of transfusion of cryoprecipitate and whole blood, the titer of functional AHF remained at normal levels for at least 1 wk. The plasma of RH inhibited a human antibody against AHF in proportion to its titer of functional AHF (i.e., the defect was CRM-) despite the presence of relatively greater amounts of antigenic material recognized by heterologous antiserum. No qualitative abnormality of the AHF-like material in RH's plasma was identified. Inheritance of the abnormality appears superficially to be X chromosome-linked; on this assumption, three of four obligate carriers of the disorder were recognized by the presence of excess amounts of AHF-like antigens relative to AHF functional activity. This coagulation disorder has been designated Heckathorn's disease and may presage the discovery of other examples of hemophilia-related syndromes. (+info)
Coagulation and fibrinolysis in the dog.
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A range of tests of coagulation and fibrinolysis was measured in "normal" dogs and compared with values obtained in "normal" humans by the same methods. The hematocrit platelet count, fibrinogen and plasminogen were similar in dogs and in humans. The prothrombin and partial thromboplastin times were considerably shorter in the dog than in man but the thrombin clotting time was comparable. Fibrinolysis was more active in dogs but the levels of fibrin degradation products were low, suggesting that there was no significant fibrin deposition and lysis occurring in vivo. (+info)
Prognostic significance of blood coagulation tests in lung cancer.
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Previous studies have shown that activation of coagulation has an impact on the clinical course of lung cancer. This study was carried out to assess the potential prognostic significance of platelet count (P), prothrombin time (PT), partial thromboplastin time (PTT), anti-thrombin III (AT-III), fibrinogen (F), D-dimer (DD), factor II (F-II), factor VII (F-VII), factor X (F-X), protein C clotting (PCC), plasminogen (PL), and antiplasmin (AP) in 343 consecutive new lung cancer patients. A set of 32 anthropometric, clinical, physical, laboratory, radiological, and pathological variables was recorded prospectively for all patients. Patients were carefully followed-up, and their subsequent clinical course recorded. The most frequent abnormalities were of DD, F, and AT-III followed by F-VII, F-X, and F-II. Among the 12 clotting variables, the strongest relationships were those of F-II and F-X (Spearman rank (rs)=0.565), PT and F-VII (rs=0.562), F-VII and F-X (rs=0.514), PL and AP (rs=0.515), F and P (rs=0.490), AT-III and PCC (rs=0.476). Univariate analyses of survival showed that prolonged PT (p<0.043), and abnormally elevated DD (p<0.003), F (p<0.031), and P (p<0.047) were all associated with a poor prognosis. The multivariate model, however, did not confirm the prognostic significance of the coagulation factors. The results show subclinical activation of blood coagulation in lung cancer patients with early disease. In addition, clotting activation is confirmed as a predictor of survival, although not independently of other prognostic factors. (+info)
Normal tension glaucoma and primary open angle glaucoma associated with increased platelet aggregation.
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On purpose of the present study was to evaluate platelet aggregation and fibrinolytic systems in patients with normal tension glaucoma (NTG) or primary open angle glaucoma (POAG). For platelet aggregation, we photoelectrophotometrically investigated adenosine diphosphate (ADP) or collagen-induced platelet aggregation in consecutively selected patients with glaucoma (22 patients with NTG and 13 patients with POAG) and 42 glaucoma free control subjects with normal ocular findings. The aggregation patterns of the patients' platelets reacted abnormally to ADP 1 microM or collagen 0.5 microg/ml as evidenced by secondary aggregation were compared with those of control subjects. For blood coagulative and fibrinolytic systems, we measured prothrombin time, activated partial thromboplastin time, fibrinogen, thrombin-antithrombin III complex (TAT), alpha2 plasmin inhibitor-plasmin complex. Seventeen of 22 patients (77%) with NTG and 5 of 13 patients (38%) with POAG showed abnormal secondary aggregation. A significant difference was observed between the two groups. No control subjects showed abnormal secondary aggregation. In the fibrinolytic test, all the parameters examined showed within normal ranges, although the log10(TAT) value was higher in NTG than in POAG. Results of the present study suggested that increased platelet aggregation as defined by ADP or collagen induced abnormal secondary aggregation in vitro is frequently associated with glaucoma patients and this tendency is more apparent in NTG than that in POAG. (+info)
Quality assessment of oral anticoagulant treatment in the Beer-Sheba district.
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OBJECTIVE: To evaluate the adequacy of oral anticoagulation therapy in patients with either prosthetic heart valves or atrial fibrillation. DESIGN: Adequacy of anticoagulation therapy of patients treated with warfarin was determined before and after implementation of an improvement programme. SETTING: The central haematology laboratory of the Soroka Medical Center, Beer-Sheba Israel. STUDY PARTICIPANTS: One hundred and ten patients treated with chronic anticoagulation therapy were evaluated by measuring the international normalized ratio of the prothrombin time before and after implementation of an improvement plan aimed at improving anticoagulation control. INTERVENTION: A programme that included physician and patient education and procedural changes covering all aspects of anticoagulation therapy was implemented. MAIN OUTCOME MEASURE: The percent of international normalized ratio tests below, within and above the therapeutic range was determined. RESULTS: Prior to implementation of an improvement plan, only 32% of the measured international normalized ratio values were within the therapeutic range. 16% were above and 52% were below therapeutic range. Improvement intervention led to an increase in the proportion of international normalized ratio tests that fell within the therapeutic range from 32% to 43.2%. CONCLUSIONS: Improvement in the control of anticoagulation therapy of patients receiving long-term warfarin treatment is possible. A combined effort involving the community, physician and patient is required. (+info)
Disseminated intravascular clotting in kwashiorkor.
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The role of disseminated intravascular clotting (DIC) in the pathogenesis of the bleeding diathesis kwashiorkor was investigated in 22 patients. According to the severity of the clinical and haematological findings, two grades of DIC were observed. A severe grade of DIC was shown in 6 cases (5 fatal) presenting with thrombocytopenia, hypofibinogenaemia, and multiple coagulation defects, and with abnormally prolonged partial thromboplastin,prothombin, and thrombin times]. A second goups of 16 patients (7 fatal) showed a less severe grade of DIC manifested by thrombocytopenia, low fibringoen level, and a clotting factor defect shown by rpolonged prothrombin and thrombin times. (+info)