Showing papers in "Haemostasis in 1986"
TL;DR: In conclusion, LMW heparin appears of value in preventing the occurrence of DVT in an unselected elderly in-patient population.
Abstract: Two hundred and seventy patients over 65 years were included in a placebo-controlled randomized double-blind trial to determine whether a small dose of a low molecular weight (LMW) heparin prevents the occurrence of deep vein leg thrombosis (DVT) diagnosed by 125I fibrinogen scanning. LMW heparin (60 mg daily) significantly reduced the frequency of DVT from 9 to 3 percent (p = 0.03). Adverse drug reactions did not differ significantly between the 2 groups, except for the injection site hematomas that were more frequent in the LMW heparin group. In conclusion, LMW heparin appears of value in preventing the occurrence of DVT in an unselected elderly in-patient population.
211 citations
TL;DR: In this article, the authors summarize the knowledge that has accumulated in the last years in controlled clinical trials concerning the state of the diabetic hemostatic system and conclude that no conclusive picture of the role of hemostasis in the development of vascular lesions has emerged yet, as contradictive results have been found by many investigators.
Abstract: Diabetes mellitus is associated with a variety of vascular complications like diabetic retinopathy, myocardial infarction, stroke and peripheral vessel disease. These complications are of utmost importance because they lead to disability and premature death of the patients. The pathogenesis of these lesions has been thought to depend at least partly on defects in the hemostatic system. Many alterations of the coagulation and the fibrinolytic system as well as of the reaction of platelets have been found in diabetics. In general these tend to suggest a state of slightly activated coagulation, of increased platelet reactivity and of decreased fibrinolysis. However, no conclusive picture of the role of hemostasis in the development of vascular lesions in diabetics has emerged yet, as contradictive results have been found by many investigators. The aim of this review article is to sum up the knowledge that has accumulated in the last years in controlled clinical trials concerning the state of the diabetic hemostatic system.
153 citations
TL;DR: While the biological function of osteocalcin is unknown, it appears to be a highly specific osteoblastic marker produced during bone formation, and is rapidly becoming a clinically important diagnostic parameter of bone pathology.
Abstract: Osteocalcin is an abundant Ca2+-binding protein indigenous to the organic matrix of bone, dentin, and possibly other mineralized tissues. This protein contains 47-50 amino acid residues (molecular weight 5,200-5,900) depending on the species. Osteocalcin is distinguished by its content of three gamma-carboxyglutamic (Gla) residues. The vitamin-K-dependent biosynthesis of osteocalcin occurs in bone, and the protein is not homologous to the Gla-containing regions of known vitamin-K-dependent blood coagulation proteins. The two major structural features of osteocalcin which appear to control its function include: the 'Gla helix', a compact Ca2+-dependent alpha-helical conformation, in which the three Gla residues are aligned to facilitate adsorption to hydroxyapatite, and the 'COOH-terminal beta-sheet' which exhibits chemoattractant activity toward mononuclear leukocytes, specifically monocytes, the putative precursors of osteoclasts. While the biological function of osteocalcin is unknown, it appears to be a highly specific osteoblastic marker produced during bone formation, and is rapidly becoming a clinically important diagnostic parameter of bone pathology. This article reviews recent advances in the understanding of osteocalcin.
127 citations
TL;DR: It is concluded that subcutaneous heparin treatment with UH or LH appears safe and convenient and mean activity did not indicate a cumulative effect in either group.
Abstract: In a double-blind study, patients with phlebographically proven deep venous thrombosis (DVT) were treated with subcutaneous injections twice a day of either unfractionated heparin (UH; n = 27) or low molecular weight heparin (LH; n = 29) for 7 days, and the dose was adjusted until therapeutic range was reached, according to a chromogenic substrate anti-Xa assay. Forty-eight percent of the LH group did not need dose adjustment as compared to 24% of the UH group. During the course of heparin administration, deviation from initial heparin activity was frequent in both groups, but mean activity did not indicate a cumulative effect in either group. There was 1 incidence of pulmonary embolism (LH) and only 1 minor bleeding episode (UH). Half of the patients in both groups were phlebographically improved. We conclude that subcutaneous heparin treatment with UH or LH appears safe and convenient.
127 citations
TL;DR: In 9 patients who did not receive intravenous protamine sulfate, a good correlation was found between doses of PK 10169 infused, anti-IIa plasma level and blood loss, and a correlation between bleeding and anti-Xa or anti- IIa activities was not clearly evident.
Abstract: Neutralization of a low molecular weight (LMW) heparin fraction by protamine sulfate was evaluated in vitro and in vivo. Anti-Xa and anti-IIa activities were measured by amidolytic and coagulation methods (activated partial thromboplastin time, APTT). Fifteen patients (4 males and 11 females) underwent surgery with extracorporeal circulation. In vitro, anti-Xa and anti-IIa activities and APTT of unfractionated heparin were neutralized with a protamine/heparin (P/H) gravimetric ratio of 1.6, 1.33 and about 2, respectively. Anti-IIa activity and APTT induced by PK 10169 were completely corrected at a P/H ratio of 1 and 2, respectively, while anti-Xa activity was incompletely neutralized at a ratio of 5. In vivo, in 9 patients who did not receive intravenous protamine sulfate, a good correlation was found between doses of PK 10169 infused, anti-IIa plasma level and blood loss. In 3 patients who were treated prophylactically with protamine, bleeding was normal or only slightly increased. In 3 patients who received protamine because of hemorrhage, mean anti-Xa and anti-IIa were 2.3 and 0.54 U before and 1.32-0.06 U after neutralization. Bleeding was stopped by a second dose of protamine in 1 patient, but blood loss was abnormal in the other patients. However, a correlation between bleeding and anti-Xa or anti-IIa activities was not clearly evident.
121 citations
TL;DR: Its frequency, the various techniques used to diagnose the condition, its pathophysiology and approaches that can be used to manage patients with heparin-induced thrombocytopenia are summarized.
Abstract: Heparin-induced thrombocytopenia is the most frequent and the most important idiosyncratic haematological drug reaction. It is important for several reasons: first, because heparin is used so often, and the frequency of heparin-induced thrombocytopenia is high, the risk of a hospitalized patient developing heparin-induced thrombocytopenia is high. Second, heparin-induced thrombocytopenia poses a major therapeutic dilemma for the clinician - continue the heparin and risk a worsening of the thrombocytopenia, or stop the heparin and risk extension or embolism of the thrombus. Finally, a small subset of patients with heparin-induced thrombocytopenia develop the disastrous complication of heparin-induced thrombocytopenia plus arterial thrombosis. Some of these patients die. In this review, we will summarize some of the issues concerning heparin-induced thrombocytopenia, including its frequency, the various techniques used to diagnose the condition, its pathophysiology and approaches that can be used to manage patients with heparin-induced thrombocytopenia.
92 citations
TL;DR: T-PA is a specific thrombolytic agent which induces throm bolysis without causing extensive systemic activation of the fibrinolytic system.
86 citations
TL;DR: The bioavailability of PK 10169 was 3-fold greater than that of unfractionated heparin, due to more effective absorption after subcutaneous administration, and its anti-IIa and anti-Xa activities had half-lives of 40 and 275 min, respectively.
Abstract: The pharmacokinetics of unfractionated heparin and the low-molecular-weight (LMW) heparin PK 10169 after intravenous and subcutaneous injection were compared by crossover study in 8 healthy volunteers. The heparin concentrations in plasma were measured by a competitive binding assay, and anti-IIa and anti-Xa activities were also assayed. Unfractionated heparin was cleared after intravenous administration with a half-life of 35 min irrespective of assay method. However, the concentration of PK 10169 declined with the longer half-life of 60 min, and its anti-IIa and anti-Xa activities had half-lives of 40 and 275 min, respectively. Some of this anti-Xa activity may be mediated by a compound released by PK 10169 rather than by the LMW heparin itself. The bioavailability of PK 10169 was 3-fold greater than that of unfractionated heparin, due to more effective absorption after subcutaneous administration.
72 citations
TL;DR: A semiautomated method to avoid the complexity of the classical evaluation of morphometrical measurements in the measure of platelets interacting with subendothelium and has been demonstrated to be as effective as the classical morphometric evaluation.
Abstract: The use of the Baumgartner perfusion system allows the morphometric quantification of platelets interacting with vessel wall, however it presents the basic difficulties of morphometrical measurements. In order to facilitate the procedure of evaluation we developed a semiautomated method to avoid the complexity of the classical evaluation. Our system consists on an optical picture analysis system connected with a specially developed computer program which allows fast quantification. Simultaneously to the outlining of interacting platelets the computer program recognizes, corrects, selects and stores the information, in order to perform the final calculations as previously established. This system has been demonstrated to be as effective as the classical morphometric evaluation in the measure of platelets interacting with subendothelium. Potential sources of error such as subjectivity of the observers in selecting the class of interacting platelets are avoided. The use of this combined method opens the possibility to adapt the Baumgartner perfusion system to clinical routine and to the screening of drugs that modify platelet adherence.
70 citations
TL;DR: Plasminogen activator was purified from the soluble fraction of bronchoalveolar lavage fluid, and biological and immunological characteristics of the activator were examined by electrophoretic enzymography and showed a single band with a molecular weight of 53,000.
Abstract: Plasminogen activator was purified from the soluble fraction of bronchoalveolar lavage fluid, and biological and immunological characteristics of the activator were examined by electrophoretic enzymography. The purified fraction showed a single band with a molecular weight of 53,000. The enzyme activity was eliminated in the presence of DFP and did not display fibrin affinity. Immunological tests revealed that the plasminogen activator reacted with IgG of antiurokinase but not with that of tissue-type plasminogen activator. However, the plasminogen activator cleaved S-2288 to a greater extent than S-2444 in contrast to urokinase.
54 citations
TL;DR: The model described is capable of generating curves which show strong resemblance to those predicted by light scattering theory as well as those observed experimentally, including biphasic structures, based upon a highly simplified view of the in vitro aggregation process for normal platelets.
Abstract: Aggregometer tracings of light transmission through platelet-rich-plasma are routinely used for the clinical evaluation of platelet function. The analytical relation between the changing aggregometer curve tracings of the light extinction and the aggregation process remains unknown. A first-approximation equation for this relation is proposed, based upon a highly simplified view of the in vitro aggregation process for normal platelets. The model described is capable of generating curves which show strong resemblance to those predicted by light scattering theory as well as those observed experimentally, including biphasic structures.
TL;DR: K 2165 may be considered as effective an anticoagulant as heparin, with less effects on ex vivo platelet functions, and effectiveness, i.e. prevention of fibrin formation in the extracorporeal circuit.
Abstract: Ten patients on chronic intermittent hemodialysis treatment received either unfractionated heparin or low molecular weight (LMW) heparin K 2165 in a single-blinded randomized cross-over study to assess: (1) effects on hemostasis and ex vivo platelet functions, and (2) effectiveness, i.e. prevention of fibrin formation in the extracorporeal circuit. The 20 dialysis treatments were without untoward side effects, for both drugs used. The variation in the plasma anti-Xa activities was significantly less during K 2165 treatment than during heparinization. No differences between the drugs were observed regarding the Ivy bleeding time, platelet count and platelet aggregation (spontaneous, and induced by ADP and collagen). Plasma platelet factor 4 levels did not increase under K 2165 to such an extent as under heparin. Both drugs did not influence the plasma levels of β-thromboglobulin, thromboxane B2 and platelet serotonin content. K 2165 did not affect platelet adhesion to collagen, in contrast to heparin which substantially inhibited platelet adhesion. Under both treatments, 4 minor clots were observed in 4 artificial kidneys, despite plasma anti-Xa levels in between 0.19 and 0.46 U/ml. K 2165 may therefore be considered as effective an anticoagulant as heparin, with less effects on ex vivo platelet functions.
TL;DR: In this paper, the authors studied the disappearance of anticoagulant activities of a standard commercial heparin and of a low molecular weight (LMW)-heparin (PK 10169), administered as single intravenous injections, in patients with chronic renal failure.
Abstract: The disappearance of the anticoagulant activities of a standard commercial heparin and of a low molecular weight (LMW) heparin (PK 10169), administered as single intravenous injections, was studied in patients with chronic renal failure. Heparin and LMW heparin anticoagulant activities were determined by activated partial thromboplastin time (APTT) and chromogenic assays of anti-Xa and anti-IIa activities. Following heparin injection, a fast initial decay of anticoagulant activities preceded a slow convex disappearance curve, in semilogarithmic plots. These experimental data are in agreement with a model based on a predominant saturable mechanism of elimination of heparin in patients with renal failure. The disappearance of LMW heparin anti-Xa activity was obviously different, with linear or concave elimination curves, and longer apparent half-life. Taken together, our kinetic data and those previously reported in normal subjects strongly suggest that the mechanism of elimination of the LMW heparin studied is not saturable (at least for the tested dosages), and that the kidneys play a minimal role in the elimination.
TL;DR: The dose or administration interval of LMW heparin in this study caused significantly more bleeding complications, while APTT and AT III were similar in both groups, but anti-Xa activity was significantly higher in the LMWheparin group.
Abstract: In a randomized, prospective, double-blind multicenter trial, the effect of low-dose conventional heparin (5,000 IU/12 h) was compared to a low molecular weight (LMW) heparin fragment (5,000 antifactor Xa U/24 h). 432 patients 40 years or older undergoing elective abdominal surgery were included, 382 correctly treated. 45% had malignant diseases. The groups did not differ in risk factors. Analysis was made both on the basis of intention to treat and correct prophylaxis. No difference in results between these 2 groups was seen. Deep vein thrombosis (125I-fibrinogen) occurred in 4.3% of the low-dose heparin group and in 6.4 of the LMW heparin group. There was a significant delay in the onset of deep vein thrombosis in the LMW heparin group. Mortality, peroperative blood loss, transfusions or infectious complications did not differ. Hemorrhagic complications occurred significantly more often in the LMW heparin group (11.6%) than in the low-dose heparin group (4.6%). Significantly fewer patients experienced local injection pain in the LMW heparin group. APTT and AT III were similar in both groups, but anti-Xa activity was significantly higher in the LMW heparin group. Single daily LMW heparin injection reduced the frequency of deep vein thrombosis to the same level as low-dose heparin twice daily. The dose or administration interval of LMW heparin in this study caused significantly more bleeding complications.
TL;DR: The primary vitamin K-dependent event has now been shown to be the abstraction of the gamma-hydrogen of the substrate Glu residue with the concurrent formation of vitamin K 2,3-epoxide.
Abstract: Vitamin K is required as a cofactor for a microsomal enzyme that converts glutamyl residues in precursor proteins to gamma-carboxyglutamyl residues in completed proteins. These residues are essential for the biological function of prothrombin, factors VII, IX, and X, protein C, and protein S. Current data suggest that recognition of protein substrates by the carboxylase requires an unidentified protein-protein interaction in addition to the Glu substrate binding site. The primary vitamin K-dependent event has now been shown to be the abstraction of the gamma-hydrogen of the substrate Glu residue with the concurrent formation of vitamin K 2,3-epoxide. Coumarin anticoagulants appear to inhibit the microsomal vitamin K epoxide reductase and one of a number of microsomal quinone reductases. They therefore block vitamin K action by preventing the recycling of vitamin K epoxide to the quinone and to the active cofactor form, the hydroquinone. Excess vitamin K can reverse a coumarin anticoagulant effect as the nonsensitive quinone reductase can continue to furnish the active coenzyme.
TL;DR: It is concluded that a reduction in PDS-stimulated PGI2 production by the vascular wall can play an important role in the pathogenesis of vascular lesions in diabetes mellitus.
Abstract: Reduced prostacyclin (PGI2) production by the vascular wall has been proposed as a possible cause of macro- or microangiopathy in diabetes mellitus. In the present study, we confirmed the stimulatory activity on PGI2 (PSA) production in plasma-derived serum (PDS) by cultured aortic endothelial cells. Furthermore, the abnormality of PSA was examined in diabetic PDS. PSA in PDS from non-insulin-dependent diabetics significantly decreased as compared with that in PDS from age-matched control subjects. There was no difference in PSA in PDS between diabetic patients with and without vascular complications such as retinopathy and nephropathy. In addition, after treatment with dialysis, PSA in diabetic PDS was still not restored to that in normal PDS. These findings suggest that relatively heat-stable (56 °C, 30 min) and nondialyzable PGI2 stimulatory substance(s) may decrease in diabetic PDS. It is concluded that a reduction in PDS-stimulated PGI2 production by the vascular wall can play an important role in the pathogenesis of vascular lesions in diabetes mellitus.
TL;DR: Tests of coagulation and platelet function performed while receiving high-dose sulphonylurea therapy and at 1 and 3 months following their conversion to insulin suggest the introduction of an insulin regimen that improves glycaemic control might lead to a reversal of the 'hypercoagulable state' found in type II diabetes.
Abstract: Twenty type II (non-insulin-dependent) poorly controlled diabetics had tests of coagulation and platelet function performed while receiving high-dose sulphonylurea therapy and at 1 and 3 months following their conversion to insulin. Although no overall change in glycaemic control (assessed by glycosylated haemoglobin) was noted, a reduction in thrombin generation was observed, as judged by a significant fall in fibrinopeptide A concentrations. No changes in factor VIII coagulant activity (VIII:C), factor VIII-related antigen or antithrombin III were found. Glycosylated haemoglobin concentrations showed significant correlations with antithrombin III and factor VIII:C, suggesting that improved glycaemic control might lead to an improvement of antithrombin III function and lower factor VIIl·C concentrations. No changes in platelet function were detected. The introduction of an insulin regimen that improves glycaemic control might lead to a reversal of the ‘hypercoagulable state’ found in type II diabetes.
TL;DR: Data suggest a role for glucose, probably through a labile nonenzymatic glycation process, in determining the alteration of ATIII biological activity, and stress the hypothesis that glucose and heparin compete in vivo, both against the same catalytic residue of AT III.
Abstract: Alteration in antithrombin III (ATIII) biological activity, despite its normal plasma concentration, in diabetic subjects is shown in this report. This alteration is glycemia level-dependent, there existing an inverse correlation between fluctuations of daily blood glucose level, labile glycosylated hemoglobin and ATIII activity. The subcutaneous and endovenous heparin administration restores ATIII activity, but does not modify its plasma concentration in diabetics. Moreover, heparin treatment preserves ATIII activity from glycemia-induced alterations. These data suggest a role for glucose, probably through a labile nonenzymatic glycation process, in determining the alteration of ATIII biological activity. Moreover, showing the possibility by heparin administration to restore ATIII activity and preserve its biological function from effects of glycemia variations, stress the hypothesis that glucose and heparin compete in vivo, both against the same catalytic residue of ATIII.
TL;DR: It is shown that a low molecular weight derivative of heparin (PK 10169) and its subfractions can cause in vitro activation of platelets from normal human donors and this activation process is molecular-weight-dependent and involves the generation of thromboxane.
Abstract: The interactions of heparin or its fractions with platelets that cause heparin-induced thrombocytopenia or in vitro platelet activation are poorly understood. We have shown that a low molecular weight derivative of heparin (PK 10169) and its subfractions can cause in vitro activation of platelets from normal human donors. This activation process is molecular-weight-dependent and involves the generation of thromboxane. We have also examined the effect of the serum from a patient with immune heparin-induced thrombocytopenia on normal donors’ platelets incubated with heparin, PK 10169 or subfractions of PK 10169. It was found that the patient’s serum induced aggregation of normal donor platelets in the presence of heparin, PK 10169 or certain subfractions of PK 10169. This process also appears to be mediated by thromboxane generation.
TL;DR: It is postulated that certain drugs in addition to warfarin might reasonably be studied in controlled clinical trials of small cell carcinoma of the lung and that drugs other than warFarin might be effective for tumor types that are not responsive to this agent.
Abstract: Evidence indicates that progression of the Lewis lung carcinoma in mice and small cell carcinoma of the lung in humans is retarded by warfarin administration. This suggests that vitamin K-dependent pathways are of importance in the pathogenesis of these tumors. Available data were reviewed for these tumor types in an attempt to explore mechanisms and to gain insights that might guide the selection of other coagulation-reactive drugs for testing in future controlled clinical trials in small cell carcinoma of the lung. While many differences exist between the Lewis lung tumor and small cell carcinoma of the lung, both are rapidly growing malignancies of pulmonary origin that metastasize early to kill the host after a short time. Both are favorably influenced by combination chemotherapy and radiation therapy as well as anticoagulant treatment. Peripheral blood changes indicative of disseminated intravascular coagulation occur in each of these tumor types, and tumor cells from both are capable of interacting with the coagulation mechanism. While many details concerning the host-tumor interaction remain to be elucidated, the considerable and diverse information available for these tumor types provides a secure base for future investigation. It is postulated that certain drugs in addition to warfarin might reasonably be studied in controlled clinical trials of small cell carcinoma of the lung and that drugs other than warfarin might be effective for tumor types that are not responsive to this agent.
TL;DR: Raised levels of circulating basement membrane proteins may indicate connective tissue activity and development of diabetic microangiopathy in patients suffering from diabetes mellitus type I and II.
Abstract: Serum concentrations of two basement membrane components (7S collagen and laminin P1) were detected by specific radioimmunoassays in 70 patients suffering from diabetes mellitus type I and II with and without clinical signs of microangiopathy Serum levels of both antigens were increased compared to controls 7S collagen concentrations were significantly different between the diabetics with signs of microvascular damage and those without small-vessel disease (p less than 005) Laminin P1 concentrations were also elevated, but the difference between the two groups of diabetics was not significant (p less than 02) Raised levels of circulating basement membrane proteins may indicate connective tissue activity and development of diabetic microangiopathy In vitro 7S collagen is a moderate platelet activator inducing platelet spreading, aggregation, and malondialdehyde production Laminin activates platelet spreading As a part of the altered hemostatic system the activation of basement membrane components may contribute to the development of microvascular damage
TL;DR: The results suggest that PGI2 has a thrombolytic effect independent of any contribution from the vessel wall and that it is a more potent stimulator of thROMbolysis than inhibitor of haemostasis.
Abstract: The effects of prostacyclin (PGI2) on haemostasis and thrombolysis in human blood were investigated in vitro using the ‘Haemostatometer’. In freshly drawn native blood samples, 5 ng/ml PGI2 greatly in
TL;DR: All patients treated with defibrotide had normally functioning grafts: among the 30 patients on dipyridamole, 22 (73%) had satisfactory graft function, and the role of prevention, very likely the best approach, is still sub judice.
Abstract: In transplanted patients graft rejection is the most frequent complication in the first year after surgery. Vascular lesions (necrosis, intimal proliferation, thrombosis) are signs of poor prognosis and lead to irreversible loss of renal function and graft removal in most cases. The problem of vascular rejection is still not solved and the results of therapy unsatisfactory, both because of inadequacy of diagnosis and/or inadequacy of available therapy. The role of prevention, very likely the best approach, is still sub judice. In an attempt to explore the validity of prevention, 22 transplanted patients (group A) were given a new antithrombotic agent (defibrotide) immediately after surgery, and the results were compared with those of a well-matched group of 30 patients on dipyridamole (group B). Follow-up lasted 6–19 months (mean 9.9) for group A; 5–21 months (mean 12) for group B. In group A, 8 patients (36%) had rejection episodes. Antirejection therapy was followed by recovery of renal function in all cases. In group B, 9 patients (29%) had rejection crises and graft removal was necessary in 7 instances due to severe vascular lesions. At the end of follow-up, all patients treated with defibrotide had normally functioning grafts: among the 30 patients on dipyridamole, 22 (73%) had satisfactory graft function.
TL;DR: Comparison of a low molecular weight heparin revealed that it can inhibit fibrin formation in the extracorporeal circulation, that this property is largely reflected in its anti-factor Xa activity in plasma, and that a useful and effective dose of Kabi 2165 for haemodialysis may be 4,000 anti- Factor Xa U intravenous bolus + 750 anti-FactorXa U/h intravenous maintenance infusion.
Abstract: Anticoagulation during haemodialysis for chronic renal failure can be assessed by measurement of plasma fibrinopeptide A (FPA) levels as an objective method of monitoring the initial step in fibrin formation, in conjunction with visual inspection of the dialyser circuit for fibrin clot deposition. Employing this approach, unfractionated commercial heparin administered as an intravenous bolus followed by an intravenous maintenance dose (5,000 IU + 1,500 IU/h) was found to suppress almost completely fibrin formation and deposition during prolonged dialysis. Comparison of a low molecular weight heparin, Kabi 2165, revealed that it can inhibit fibrin formation in the extracorporeal circulation, that this property is largely reflected in its anti-factor Xa activity in plasma, and that a useful and effective dose of Kabi 2165 for haemodialysis may be 4,000 anti-factor Xa U intravenous bolus + 750 anti-factor Xa U/h intravenous maintenance infusion. This dose only minimally alters the KCCT and corresponds to approximately 60% of that of unfractionated heparin, which may be important in the long-term use of heparin in these patients.
TL;DR: There was no significant change in any of the platelet function parameters after the drug treatment compared with placebo, providing evidence against a relationship between serum cholesterol levels and in vitro platelets function.
Abstract: Platelet function parameters were studied in type II hyperlipoproteinemics in relation to baseline and drug-induced changes in serum cholesterol levels There were no significant differences between 2
TL;DR: The trial shows that defibrotide is an effective and safe drug for the prevention of DVT in gynecological surgery.
Abstract: Defibrotide, a new antithrombotic compound without anticoagulant activity, has been tested for prevention of deep venous thrombosis (DVT) in patients undergoing gynecological surgery (mainly hysterectomy). Eighty-nine women (mean age 48.5) were randomly allocated to defibrotide (44 patients) or placebo (45 patients). 800 mg defibrotide was given daily (200 mg intravenously 4 times a day), starting on the day before operation and then for the next 7 days. DVT were detected by the conventional 125I-fibrinogen test. The two groups were homogeneous for known risk factors (age, varicosities, obesity, neoplasia and previous thromboembolic episodes). The results showed a statistically significant reduction of DVT incidence in patients on defibrotide, as compared with those on placebo: 4/44 = 9% vs. 13/45 = 28.8% (p
TL;DR: Studies performed to investigate a possible nonenzymatic glucosylation of plasminogen showed that purified control plAsminogen incorporates 14C-glucose in a dose- and time-dependent manner and that in vitro glucosyation of control plasmine results in functional abnormalities, which resemble those observed with pl asminogen from diabetic patients.
Abstract: Kinetics of activation of plasminogen purified from the plasma of 3 uncontrolled diabetic patients by tissue type plasminogen activator revealed substrate inhibition in the fibrin-stimulated system. After improvement of metabolic parameters activation of plasminogen was found to be normal in 1 of these patients and partially improved in another patient. Studies performed to investigate a possible nonenzymatic glucosylation of plasminogen showed that purified control plasminogen incorporates 14C-glucose in a dose- and time-dependent manner and that in vitro glucosylation of control plasminogen results in functional abnormalities of plasminogen, which resemble those observed with plasminogen from diabetic patients as far as substrate inhibition in the fibrin-stimulated system is concerned.
TL;DR: The dynamics of D's antithrombotic effects after oral administration and D's thrombolystic activity after intravemous infusion on venous collagen-induced thrombosis in the rabbit are reported.
Abstract: Defibrotide (D) is a polydeoxyribonucleotide of mammalian origin that has no anticoagulant activity or hemodynamic effects but has considerable profibrinolytic and antithrombotic activities under several experimental conditions. In this paper the dynamics of D's antithrombotic effects after oral administration and D's thrombolystic activity after intravemous infusion on venous collagen-induced thrombosis in the rabbit are reported. D administered orally (12.5, 25 or 50 mg kg-1), from 0 to 360 min before thrombus induction, was able to impede thrombus formation in the first 2 h of growth. There is a linear correlation between the dose of D and peak activity and a correlation, described by a power function, between the dose and the area under the experimental inhibition curve. D infused intravenously (20, 31.7 or 50 mg kg-1 h-1 X 6 h) into rabbits with 24-hour-old thrombi, had significant and impressive dose-related thrombolytic activity. There is a direct relationship between the thrombolytic effect and plasma levels. In this experimental model, urokinase infused intravenously (750, 1,500 or 3,000 IU kg-1 h-1) had the same thrombolytic activity as D; heparin (76 IU kg-1 h-1) was completely ineffective and PGI2 showed a modest activity at 60 nmol kg-1 h-1. The antithrombotic and thrombolytic activities of D may be partly due to its ability to promote release of plasminogen activator factor and of prostacyclin from vascular tissue.
TL;DR: The studies suggest that PK 10169 may exert its clinical effects by multiple mechanisms which are only partially assessable by routine laboratory methods.
Abstract: Intravenous and subcutaneous administration of PK 10169 in healthy human volunteers were studied utilizing numerous old and new laboratory methods for the monitoring of the effects of this agent. In the intravenous studies, individual groups of 10 healthy volunteers were administered with 2,500-12,500 anti-Xa units (25-125 mg) PK 10169 as a single bolus, and blood samples were drawn at 30 min, 1, 4 and 24 h after the administration of the drug. In the subcutaneous studies, 4,000 anti-Xa units (40 mg) b.i.d. of PK 10169 were administered to a group of 10 healthy individuals for 7 consecutive days, and blood samples were drawn 6 h after each dose. Citrated blood samples collected from both studies were centrifuged, plasma was frozen at -70 degrees C in aliquots, and various laboratory parameters were determined in batches. In the intravenous studies, the global clotting assays (activated partial thromboplastin time and thrombin time) were only prolonged at initial stages of treatment, whereas a marked increase in the antiprotease and antifibrinopeptide A generation activity titer was observed for periods of up to 24 h. In the subcutaneous studies, no significant prolongation of the global clotting assays was noted; however, the anti-Xa levels were significantly increased throughout the study period (7 days). Only a trace of anti-IIa activity was observed. In contrast, a strong antifibrinopeptide A generation activity was observed in all samples which persisted after the discontinuation of PK 10169. These studies suggest that PK 10169 may exert its clinical effects by multiple mechanisms which are only partially assessable by routine laboratory methods.