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Biomedical subjects

C Kluft

Publications and source records attributed to C Kluft.

At least 235 records · Page 13Linked to original sources
PubMed1986

Advances in clinical fibrinolysis.

The discovery of a fast-acting plasminogen activator inhibitor has resulted in the notion that the balance between tissue-type plasminogen activator and its inhibitor determines the net fibrinolytic activity of blood. The inhibitor shows a rapidly fluctuating acute-phase pattern, which may be important in relation to thrombosis in acute disease. Other newly discovered modulators of the fibrinolytic system include histidine-rich glycoprotein, tetranectin and thrombospondin. The role of fibrin as a cofactor in its own dissolution is further elucidated with emphasis on local aspects. Therapeutic inhibition of overactive fibrinolysis by various drugs needs careful monitoring. Prophylactic stimulation of fibrinolysis is possible, e.g. by stanozolol or other drugs that lower inhibitor levels, but its proven value is as yet limited. Results of clinical trials with activators of the fibrinolytic system as thrombolytic agents are discussed in relation to the physiology of the fibrinolytic system.

Coronary Disease↗
PubMed1986

The effect of increasing fibrinolysis in patients with rheumatoid arthritis: a double blind study of stanozolol.

Fibrin deposition in rheumatoid arthritis may be responsible for some of the clinical manifestations of the disease. It has been shown that in severe rheumatoid arthritis fibrinolysis is decreased but can be stimulated using the fibrinolytic enhancing agent stanozolol. A prolonged increase in fibrinolysis may decrease joint fibrin deposition and lead to clinical improvement and we have therefore investigated stanozolol as a therapeutic agent. Forty patients were enrolled. Twenty patients received stanozolol 5 mg twice daily for six months and 20 received a matching placebo. Assessment of disease activity was made in the conventional way. Results show that the two groups were comparable. After six months nine of the control patients had withdrawn because of drug ineffectiveness compared with two stanozolol patients, and five control patients felt they had improved compared with 15 stanozolol patients. Disease activity had significantly decreased by the end of the study in the treated group, and detailed analysis showed improvement in ESR, articular index, duration of morning stiffness and visual analogue pain scale. We suggest that stanozolol may be of value in rheumatoid arthritis although this pilot study has looked at only small numbers of patients over a short period.

Arthritis, Rheumatoid↗
PubMed1985

Protein C antigen levels in major abdominal surgery: relationships to deep vein thrombosis, malignancy and treatment with stanozolol.

Activated protein C is a potent inhibitor of coagulation, and familial protein C deficiency has been associated with recurrent venous thrombosis. We have investigated protein C antigen levels in patients undergoing major elective abdominal surgery, to determine their relationships to postoperative deep vein thrombosis (DVT), malignancy, and preoperative treatment with intramuscular or oral stanozolol. Preoperative and postoperative protein C levels were not significantly different in patients with and without DVT (detected by 125I-fibrinogen leg scans), nor in patients with and without malignancy. In a placebo group (n = 26), a significant fall in protein C was maximal on the first postoperative day and persisted for 7 days. In a group given intramuscular stanozolol, 50 mg on the preoperative day (n = 23) stanozolol shortened the duration of the postoperative fall in protein C, but did not prevent DVT. In a group given oral stanozolol, 10 mg/day for 2 weeks before and 1 week after operation (n = 11), stanozolol significantly increased protein C levels prior to surgery, hence maintaining protein C at pretreatment levels after surgery. The effect of this regimen on the incidence of DVT is under study.

Adult↗
PubMed1985

Identification of a reversible inhibitor of plasminogen activators in blood plasma.

Inhibition of tissue-type plasminogen activator (t-PA) by pooled plasma could be ascribed for only 60% to the endothelial cell type PA inhibitor. The residual inhibition is ascribed to a so-far undescribed plasma component present at 0.2 nmol/l. This component shows reversible binding to t-PA with an apparent Ki of 10 pmol/l (does not hinder t-PA binding to fibrin); also reacts with urokinase, but not with DIP-t-PA; is stable at 37 degrees C and does not occur in media of endothelial cells, hepatocytes and fibroblasts. This PA binding component in plasma adds to the regulation of plasminogen activator activities.

Glycoproteins↗
PubMed1985

Increased euglobulin fibrinolytic potential in women on oral contraceptives low in oestrogen--levels of extrinsic and intrinsic plasminogen activators, prekallikrein, factor XII, and C1-inactivator.

Components of the fibrinolytic system were studied in samples of plasma from 15 normal, young women and from 11 women taking oral contraceptives containing 30 micrograms ethinyl oestradiol and 150 micrograms levo-norgestrel. Fibrinolytic activity of euglobulins precipitated at pH 5.9 was higher than normal in the hormone group, with significant fluctuations related to the cycle. Normal women showed only minor fluctuations. The concentration of C1-inactivator was lower in euglobulins of the hormone group. However, the difference in fibrinolytic activity was retained, when C1-inactivator was inactivated with sodium flufenamate. Fluctuations of the extrinsic (tissue-type) plasminogen activator (t-PA) activity parallelled those of the euglobulin activity. The intrinsic plasminogen activator activity (dextran sulphate precipitated euglobulin) was significantly increased in the hormone group and the cyclic pattern differed from that of the normal group. The increased activity was factor XII-dependent. Plasma prekallikrein did not differ. The factor XII level was increased in the hormone group but this could not explain the increased intrinsic fibrinolytic activity, suggesting an increase in the quantity of an additional factor XII-dependent proactivator.

Adult↗
PubMed1985

Effects of oral stanozolol used in the prevention of postoperative deep vein thrombosis on fibrinolytic activity.

Plasminogen, fibrinogen, antithrombin III, euglobulin lysis time, tissue plasminogen activator (t-PA) and fast-acting t-PA inhibitor were measured in 21 patients receiving either stanozolol (10 mg orally given for 14 days preoperatively) or subcutaneous heparin, during a continuing comparative trial in the prevention of postoperative deep vein thrombosis. Stanozolol treatment resulted in significant (p less than 0.01) increases between the 14th and 1st preoperative days in the plasma concentrations of plasminogen (3.4 to 4.9 Cu/ml) and antithrombin III (107% to 132%); t-PA levels did not increase significantly (6.0 to 16.0 mU/ml; p greater than 0.1). There were significant (p less than 0.02) falls in fast-acting t-PA inhibitor (132% to 75%) and fibrinogen (2.4 to 1.8 g/l). Surgery reversed the changes in fibrinolytic activity seen preoperatively in the stanozolol-treated patients, and similar changes were seen in the heparin-treated group. In this dosage, stanozolol does not appear to prevent the fibrinolytic shutdown which occurs after elective major surgery.

Fibrinolysis↗
PubMed1985

Protection against venous thrombosis in an antithrombin-III deficient patient suffering from episodes of arterial thrombosis requiring major surgery. Effects of oral stanozolol in combination with subcutaneous heparin and intravenous AT-III.

In an antithrombin-III (AT-III) deficient patient suffering from recurrent episodes of venous and arterial thrombosis requiring major surgery an attempt was made to institute antithrombotic protection by long-term stanozolol treatment supplemented during periods of thrombogenic exposure with subcutaneous heparin and, when needed, infusion of AT-III as plasma or concentrate. Stanozolol raised the plasma levels of AT-III, demonstrating a sparing effect on the AT-III needed. Despite the repeated exposures to major surgery, protection against venous thrombosis was complete, but the arterial disease progressed and led to the demise of the patient.

Administration, Oral↗
PubMed1985

Fibrinolytic shut-down after surgery: impairment of the balance between tissue-type plasminogen activator and its specific inhibitor.

In nine patients with non-malignant diseases undergoing major upper abdominal surgery, the mechanism of the postoperative fibrinolytic shut-down was investigated because of its potential significance for postoperative deep vein thrombosis by employing new and specific methods for assessing and stimulating the fibrinolytic system. The shut-down was found to result from an impairment of the balance between tissue-type plasminogen activator, t-PA, and its recently discovered fast-acting inhibitor. In this balance, the t-PA antigen concentrations both in resting conditions and after stimulation evoked by desamino-D-arginine vasopressin (DDAVP) were found to be unchanged by surgery. However, there was a significant postoperative increase in t-PA inhibitor levels. The release of t-PA under the stimulus of DDAVP infusion overcame the postoperative shut-down of t-PA activity. However, DDAVP infusion was associated with potentially unfavourable increases in the Factor VIII/von Willebrand factor complex. The discovery of increased t-PA inhibitor in the postoperative period opens new possibilities for a rational approach to reduce or abolish the postoperative fibrinolytic shut-down.

Adult↗
PubMed1985

Evaluation of euglobulin methods for the study of blood fibrinolytic activity: results for patients with rheumatoid arthritis and in the postoperative period.

Euglobulin fractionation is a frequently employed pretreatment of plasma for the determination of fibrinolytic activity. The fractionation procedure suffers from possible in vitro artifacts, e.g., variable precipitation of C1-inactivator. This is illustrated by the following two situations. It is shown that increased amounts of C1-inactivator not related to an increased plasma concentration are present in euglobulin fractions in cases of classic rheumatoid arthritis. Similarly, postoperatively, a disproportional increase in C1-inactivator in euglobulin fractions occurs. In both cases, an artificially reduced fibrinolytic activity is recorded due to increased inhibition by C1-inactivator. This is circumvented and recognized by adding sodium flufenamate or C1s-esterase to euglobulin fractions to uniformly eliminate C1-inactivator. Two specific assays for tissue-type plasminogen activator activity in euglobulin fractions (as C1-inactivator-resistant activator activity and a parabolic rate assay on a synthetic substrate) correlate excellently (r = 0.8728; p less than 0.001; n = 108). The first mentioned is corrected for variable endogenous C1-inactivator; the latter assay is found to be insensitive to inhibition by C1-inactivator. It is concluded that with euglobulin methods a misinterpretation of blood fibrinolytic activity is possible in rheumatoid arthritis patients. In the postoperative period, the fibrinolytic shutdown concerns tissue-type plasminogen activator activity; the pattern of the shutdown can be misjudged in using traditional euglobulin methods.

Abdomen↗
PubMed1985

Appropriate milieu for the assay of alpha-2-antiplasmin activity with chromogenic substrates.

Inhibition reference curves for alpha 2-antiplasmin showed a deviation from linearity at low inhibitor concentrations using the chromogenic substrate S-2251. Extrapolation of these curves to zero inhibition gave higher amidolytic activities than actually recorded with the free enzyme plasmin. It was further found that comparison of purified alpha 2-antiplasmin and that in plasma was prevented by the deviation. The difference between calculated and measured plasmin activity could not be attributed to instability of plasmin. It was established that the observations (1) were specific for high concentrations of S-2251, (2) were not the same with another plasmin substrate, chromozym PL, and (3) were related to the addition of plasma proteins. Apparently, the problem was related to the solubility state of S-2251. A solution to this problem is the addition of nonionic detergents, notably Tween 80 (0.01%) or Triton X-100 (0.03%), which prevent all deviations.

Chromogenic Compounds↗
PubMed1985

The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma.

The plasma activity level of the recently discovered fast-acting inhibitor of tissue-type plasminogen activator (t-PA) was found to be temporarily increased after surgery, myocardial infarction and severe trauma. Detailed analysis of the postoperative period revealed simultaneously increased t-PA antigen and inhibition and decreased t-PA activity only on the first postoperative day. These changes were more rapid than those in fibrinogen and C-reactive protein. It is concluded that t-PA inhibition shows the most rapidly changing pattern observed so far in response to trauma. The postoperative fibrinolytic shutdown in blood fibrinolytic activity can be ascribed to a primary increase in t-PA inhibitor levels.

Antigens↗
PubMed1985

PAF-acether-induced release of tissue-type plasminogen activator from vessel walls.

Platelet-activating factor (PAF-acether; 1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) induced the release of plasminogen activator in rat, both in vivo and in perfused hind legs. The released plasminogen activator was shown by immunologic and functional criteria to be tissue-type plasminogen activator (t-PA). Release of t-PA by PAF-acether could be inhibited by phospholipase inhibitors and by lipoxygenase inhibitors, but not by cyclooxygenase inhibitors. It is suggested that PAF-acether induces the release of t-PA from vascular endothelial cells by the (calcium-dependent) activation of a phospholipase-lipoxygenase pathway.

Animals↗
PubMed1984

Improved assay conditions for automated antithrombin III determinations with the chromogenic substrate S-2238.

Assays for antithrombin III activity using the chromogenic substrate S-2238 were automated in various modifications on various instruments. Standard curves for the assay showed a deviating "0% point" in several but not all modifications. Addition of polyethylene glycol 6000/8000 (0.40-1.0%) minimizes this deviation. However, the deviation of the 0% point was not completely abolished in every modification of the test. Examination of Lineweaver-Burk plots showed nonlinearity at high concentrations of S-2238 as used in the antithrombin III assays. Addition of Tween-80 (0.01%) restores the Lineweaver-Burk plot and, at the same time, the standard curve in the assays is found to be linear. Therefore, we recommend the use of PEG 6000/8000 as well as Tween-80 in automated assay systems.

Antithrombin III↗
PubMed1984

Evidence for the occurrence of a fast-acting inhibitor for tissue-type plasminogen activator in human plasma.

Human plasma contains a fast-acting t-PA inhibitor, which is not identical with alpha 2-antiplasmin or alpha 2-macroglobulin. The concentration of this inhibitor in normal plasma is highly variable, much lower than that of known plasma protease inhibitors, and in the range of physiologically occurring plasma concentrations of t-PA (0-2 IU/ml). The inhibitor binds to concanavalin A-Sepharose, is rather stable when heated, is not precipitated in euglobulin fractions and probably does not originate from platelets. The inhibitor seems to form a 190 Kd complex with t-PA. The relation between this plasma inhibitor and the recently discovered endothelial cell inhibitor is not yet clear.

Chromatography, Affinity↗
PubMed1984

Modulation of rapid plasminogen activator inhibitor in plasma by stanozolol.

Fibrinolytic activity in plasma euglobulin fractions can be increased by oral administration of stanozolol. This increase is not caused by increased synthesis or release of tissue-type plasminogen activator. A decreased level of fast acting t-PA inhibition is very probably the cause of the higher activity. These results suggest that this inhibition has a regulatory role on fibrinolysis in vivo.

Adult↗
PubMed1984

Stanozolol-induced changes in fibrinolysis and coagulation in healthy adults.

The effect of orally-administered stanozolol, 5 mg b.d. on fibrinolysis, coagulation and on various haematological and biochemical parameters have been studied in 16 healthy adults, 8 males and 8 females. Statistically significant enhancement of extrinsic (tissue-type) plasminogen activator activity was detected in all subjects studied. This was associated with significant increases in plasma plasminogen and a concomitant reduction in histidine-rich glycoprotein. There were no changes in plasma urokinase activity. Changes in the coagulation system included significant reduction in plasma fibrinogen and elevation of protein C and antithrombin III. Changes in plasma lipids included significant reduction of HDL cholesterol associated with an increase in LDL triglycerides. No change occurred in total cholesterol. There were no major differences between the sexes, nor were there serious side effects. The effects of stanozolol on extrinsic (tissue-type) plasminogen activator activity, "free" plasminogen, protein C and antithrombin III, argue strongly in favour of its therapeutic potential.

Adult↗