fibrinopeptide-a and Hemorrhage

In summary, the following points have been presented. PK 10169 produced somewhat weaker effects on the coagulant tests in comparison to heparin in various whole blood and citrated plasma assays. In the synthetic substrate assays, PK 10169 produced a pronounced inhibition of various serine proteases in the AT III supplemented system. No significant inhibition was noted in the non-AT III systems. Preliminary data show that PK 10169-AT III complex is capable of producing direct inhibition of the generation of factors Xa and XIIa. In all platelet function tests studied, this agent failed to produce any modulating effects. PK 10169 did not produce an effect on the fibrinolytic system in vitro. However, analysis of blood samples obtained from animals treated in vivo with this agent suggests activation of fibrinolysis. Thus, the mechanism of action must involve certain cellular components or endogenous modulation of the heparin fraction. The newly developed FPA generation test can be modified by various activators or blood systems to mimic closely in vivo physiology. PK 10169 produces a dose response that is more sensitive and more global by this method than the amidolytic anti-Xa or anti-IIa. In contrast to heparin, larger amounts of platelet factor 4 and protamine sulfate are needed to neutralize the anti-Xa and anti-IIa actions of this agent. Additionally, the anti-IIa component is more susceptible to neutralization than the anti-Xa component. Our studies also suggest that PK 10169 is resistant to the action of certain heparin digestive systems, such as heparinase.

Topics: Antithrombin III; Blood Coagulation Tests; Blood Platelets; Factor X; Factor Xa; Factor XII; Factor XIIa; Fibrinolysis; Fibrinopeptide A; Hemorrhage; Heparin; Heparin Antagonists; Heparin Lyase; Humans; Kallikreins; Partial Thromboplastin Time; Peptide Fragments; Platelet Aggregation; Polysaccharide-Lyases; Prothrombin; Prothrombin Time; Thrombin; Thrombin Time

Topics: Animals; Antithrombin III; Biological Availability; Biotransformation; Blood Coagulation Tests; Chemical Phenomena; Chemistry; Disease Models, Animal; Drug Evaluation; Drug Stability; Factor X; Factor Xa; Fibrinolysis; Fibrinopeptide A; Hemorrhage; Heparin; Humans; Kinetics; Prothrombin; Pulmonary Embolism; Structure-Activity Relationship; Thrombophlebitis

Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism. Limited data support the clinical benefit of antithrombotic prophylaxis.. In this double-blind, multicenter trial, we evaluated the efficacy and safety of the ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients receiving chemotherapy for cancer. Patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were randomly assigned to receive subcutaneous semuloparin, 20 mg once daily, or placebo until there was a change of chemotherapy regimen. The primary efficacy outcome was the composite of any symptomatic deep-vein thrombosis, any nonfatal pulmonary embolism, and death related to venous thromboembolism. Clinically relevant bleeding (major and nonmajor) was the main safety outcome.. The median treatment duration was 3.5 months. Venous thromboembolism occurred in 20 of 1608 patients (1.2%) receiving semuloparin, as compared with 55 of 1604 (3.4%) receiving placebo (hazard ratio, 0.36; 95% confidence interval [CI], 0.21 to 0.60; P<0.001), with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of venous thromboembolism. The incidence of clinically relevant bleeding was 2.8% and 2.0% in the semuloparin and placebo groups, respectively (hazard ratio, 1.40; 95% CI, 0.89 to 2.21). Major bleeding occurred in 19 of 1589 patients (1.2%) receiving semuloparin and 18 of 1583 (1.1%) receiving placebo (hazard ratio, 1.05; 95% CI, 0.55 to 1.99). Incidences of all other adverse events were similar in the two study groups.. Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding. (Funded by Sanofi; ClinicalTrials.gov number, NCT00694382.).

Topics: Adult; Antineoplastic Agents; Double-Blind Method; Fibrinolytic Agents; Fibrinopeptide A; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Kaplan-Meier Estimate; Neoplasms; Risk Factors; Venous Thromboembolism

Efficacy of CY 222 for providing anticoagulation during hemodialysis was evaluated in three successive trials by rating quality of blood restitution (degree of coagulum formation in extracorporeal circulation) and by assay of fibrinopeptide A. Its safety was assessed by measurement of manual compression time necessary to ensure hemostasis of puncture points at end of session. Details of the first preliminary study were: 60 sessions in 11 chronic uremia patients; CY 222: 75, 150 and 300 A-Xa IC U/kg + 1,000 A-Xa IC U/h, then 150 and 300 A-Xa IC U/kg without continuous injection, compared with standard heparin (SH) at the usual dosage for each patient (60 +/- 13 IU/kg). Results showed CY 222 at 150 U/kg + 1,000 U/h to possess the same efficacy as SH and to give a shorter compression test time: for 150 U/kg the efficacy was satisfactory, although less than with SH, and compression times were shorter (interest in patients at risk of hemorrhage). For 300 U/kg, efficacy was superior (improved restitution and lower FPA level at end of seance: 6 ng/ml instead of 15 ng/ml.p less than 0.002) and compression times were identical. The second study to evaluate optimal dosage of CY 222 in chronic hemodialysis (CHD) involved: 10 patients; CY 222: 200 A-Xa IC U/kg and 250 A-Xa IC U/kg by single-dose injection. Results failed to demonstrate any significant difference in evolution of FPA levels, but restitution was better at 250 U/kg. In addition, investigation of the effect of rinsing of ECC with standard heparin before the session showed that its suppression did not alter effectiveness but improved tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Coagulation; Dose-Response Relationship, Drug; Fibrinopeptide A; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Random Allocation; Renal Dialysis; Risk Factors

Topics: Adult; Afibrinogenemia; Female; Fibrinopeptide A; Hemorrhage; Humans; Mutation; Pregnancy; Pregnancy Complications, Hematologic

From the snake venom of Agkistrodon acutus, two proteases, acuthrombin-A and acuthrombin-C, were isolated and purified to homogeneity. They can cleave the human fibrinogen to release the fibrinopeptide A and fibrinopeptide B with specific activity of 120 and 370 NIH units/mg, respectively; the fibrinogen-clotting activity can be inhibited distinctly by PMSF or DFP or EDTA, but not by heparin. The two proteases show also arginine-esterase activity hydrolyzing some synthetic substrates such as TAME and BAEE. Additionally, they are glycoproteins with an average content of 2.4% (acuthrombin-A) and 2.1% (acuthrombin-C) neutral carbohydrates, respectively. Acuthrombin-A has a MW of 13,900 as estimated by SDS-PAGE under reduced or nonreduced conditions and 28,000 as determined by gel filtration. For acuthrombin-C, there were two protein bands corresponding to MW of 13,900 and 14,800 on SDS-PAGE with different darkness under reduced or nonreduced conditions, while its MW was estimated to be 69,000 by gel filtration. The isoelectric points were 7.5 for acuthrombin-A and 5.0 for acuthrombin-C by isoelectric focusing. Neither acuthrombin-A nor acuthrombin-C has haemorrhagic or lethal activity. Acuthrombin-A has also a small amount of activity to activate the Factor XIII.

Topics: Agkistrodon; Animals; Blood Coagulation; Chromatography, Gel; Endopeptidases; Esterases; Factor XIII; Fibrinogen; Fibrinopeptide A; Fibrinopeptide B; Hemorrhage; Humans; Hydrolysis; Mice; Oxidation-Reduction; Peptide Hydrolases; Rabbits; Snake Venoms; Thrombin

A preparation of low molecular weight heparin (Fragmin) was administered to patients with multiorgan failure receiving continuous venovenous hemodialysis. Three patients received a high-dose regimen (35 IU/kg bolus followed by 13 IU/kg infusion), and 7 received a low-dose regimen (8 and 5 IU/kg, respectively) for 36 h. High-dose Fragmin was associated with minimal clotting in the extracorporeal circuit. Plasma fibrinopeptide A levels declined, and mean anti-Xa activity was in the range 0.47-0.79 IU/ml. The urea equilibration coefficient (UEC) (100% at initiation) remained above 90% throughout. All 3 patients had mild bleeding episodes, which led to discontinuation of Fragmin in 1. During all low-dose treatments, marked thrombus formation occurred in the extracorporeal circuit, and in 2, the circuit clotted within the study period. Fibrinopeptide A levels further increased in 4 patients, and mean anti-Xa activity was in the range 0.27-0.53 IU/ml. UEC declined appreciably in 3 treatments (including the 2 in which early circuit clotting occurred). One patient experienced a mild bleeding episode. The low-dose Fragmin regimen produced safer anticoagulation in patients at risk from bleeding and is suitable for prolonged renal support although the tendency to thrombosis may necessitate more frequent circuit changes.

Topics: Acute Kidney Injury; Adult; Aged; Blood Coagulation; Critical Care; Dalteparin; Female; Fibrinopeptide A; Hemorrhage; Humans; Male; Middle Aged; Renal Dialysis; Thrombosis

We describe a 50-year-old man with a severe acquired haemorrhagic syndrome. He had slightly prolonged clotting times using bovine thrombin, human thrombin and reptilase. His plasma contained a polyclonal IgG which interfered with the generation of fibrin monomers without inhibiting the aggregation of preformed monomers. The inhibitor delayed thrombin-induced fibrinopeptide A release. The IgG bound to insolubilized synthetic fibrinopeptide A (one binding site per molecule) and, with higher affinity, to fibrinogen (two binding sites per molecule). It did not bind to insolubilized fibrin monomers. The IgG did not impair the catalytic activity of thrombin toward a small synthetic substrate but inhibited the binding of thrombin to fibrinogen without binding to thrombin. The binding of the anti-fibrinopeptide A autoantibody to fibrinogen might have impaired thrombin-induced fibrinogen to fibrin conversion in vivo. This may have favoured the reported haemorrhagic syndrome which was associated with severe chronic renal insufficiency.

Topics: Autoantibodies; Binding Sites; Blood Coagulation Disorders; Fibrin; Fibrinogen; Fibrinopeptide A; Hemorrhage; Humans; Immunoglobulin G; Kidney Failure, Chronic; Male; Middle Aged; Thrombin

Platelet function and the clinical course of the disease were prospectively investigated in 29 patients with myeloproliferative disorders. Serial determinations (median: 5 investigations per patient within 17 months) of platelet aggregation, plasma and intraplatelet concentrations of beta-thromboglobulin (beta TG) and platelet factor 4 (PF4), and of fibrinopeptide A (FPA) plasma levels were carried out. In the chronic phase of polycythaemia vera, patients with thrombohaemorrhagic complications during the study period had higher platelet count, more severe platelet aggregation defects, and increased plasma levels of beta TG and FPA compared to patients without complications. However, thrombohaemorrhagic complications were not predicted by changes in these parameters in the individual patient during the chronic disease phase. When patients with chronic myelogenous leukaemia entered blast crisis, bleeding complications were related to thrombocytopenia, impaired platelet function and low intraplatelet concentrations of beta TG and PF4. Cytoreduction by chemotherapy in the chronic phase of CML did not alter beta TG and PF4 plasma levels, whereas treatment of polycythaemia rubra vera by venesection favourably influenced platelet alpha-granule secretion and increased intraplatelet concentrations of beta TG and PF4.

Topics: Adult; Aged; beta-Thromboglobulin; Blood Platelets; Female; Fibrinopeptide A; Hemorrhage; Hemostasis; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Male; Middle Aged; Myeloproliferative Disorders; Platelet Aggregation; Platelet Count; Platelet Factor 4; Polycythemia Vera; Primary Myelofibrosis; Prospective Studies; Thrombocythemia, Essential; Thrombosis

Subclinical plasma coagulation during cardiopulmonary bypass has been associated with marked platelet and clotting factor consumption in monkeys. To better define subclinical coagulation in man, we measured plasma fibrinopeptide A concentrations before, during, and after cardiopulmonary bypass. Patients were assigned to one of three groups of heparin management: group 1 (n = 10)--initial heparin dose 300 IU/kg, with supplemental heparin if the activated coagulation time fell below 400 seconds; group 2 (n = 6)--initial heparin dose 250 IU/kg, with supplemental heparin if activated coagulation time was less than 400 seconds; and group 3 (n = 5)--initial heparin dose 350 to 400 IU/kg, with supplemental heparin if whole blood heparin concentration was less than or equal to 4.1 IU/ml. Activated coagulation time and heparin concentration were measured every 30 minutes during cardiopulmonary bypass, and fibrinopeptide A was measured at hypothermia, normothermia, and whenever activated coagulation time was less than 400 seconds. Quantitative and qualitative blood clotting competence was assessed after cardiopulmonary bypass, including mediastinal drainage for the first 24 hours. Fibrinopeptide A values were markedly elevated during cardiopulmonary bypass but were well below the levels present before and after cardiopulmonary bypass. Fibrinopeptide A correlated inversely with heparin concentration during cardiopulmonary bypass (r = -0.46, p = 0.03), but higher fibrinopeptide A levels during cardiopulmonary bypass did not correlate with post-cardiopulmonary bypass coagulopathy. Group 3 patients received the highest heparin doses (p less than 0.05) and had the greatest postoperative blood loss (p less than 0.05). Protamine dose and heparin concentration during cardiopulmonary bypass correlated best with postoperative mediastinal drainage. Our findings support the following conclusions: (1) compensated subclinical plasma coagulation activity occurs during cardiopulmonary bypass despite activated coagulation time greater than 400 seconds or heparin concentration greater than or equal to 4.1 IU/ml; (2) post-cardiopulmonary bypass mediastinal drainage correlates strongly with increased heparin concentration during cardiopulmonary bypass (p less than 0.05) and protamine dose (p less than 0.05); and (3) during cardiopulmonary bypass at both normothermia and hypothermia, activated coagulation times greater than 350 seconds result in acceptable fibrinopeptide A levels and p

Topics: Blood Coagulation; Blood Coagulation Tests; Cardiopulmonary Bypass; Drug Administration Schedule; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Hemodilution; Hemorrhage; Heparin; Humans; Hypothermia, Induced; Middle Aged; Partial Thromboplastin Time; Protamines; Prothrombin Time

Over a 2-month period, 40 patients with untreated malignancy were studied for protein-C (PRC), antithrombin-III (AT-III), fibrinopeptide A (FPA), routine hemostatic screens, and presence of liver metastases to determine pretreatment changes of hemostasis and relate them to subsequent development of thrombotic or hemorrhagic complications. These patients were observed for a mean period of 18 months. There were 23 males and 17 females with a median age of 64 years. Nine patients had lung carcinoma, 8 colon carcinoma, 7 lymphoma, 5 breast carcinoma, 5 head and neck carcinoma, 2 acute leukemia, 2 prostate carcinoma, 1 adenocarcinoma of unknown primary, and 1 sarcoma. Eight patients had liver metastases. PRC was measured by ELISA, AT-III by radial immunodiffusion, and FPA by RIA. Four patients had decreased AT-III, 28 had decreased levels of PRC, and 39 had elevated levels of FPA. All patients with liver metastases had low PRC. Albumin levels were lower in patients with low PRC (mean 3.3 g/dL v 4.0 g/dL for others). Eight patients, five with liver metastases, developed thrombotic (4), hemorrhagic (3), or both (1) complications. Statistically significant associations were found between (1) presence of liver metastases and development of thrombotic and hemorrhagic complications (P less than .001), (2) presence of liver metastases and decreased PRC (P = .001), and (3) lower albumin levels and decreased PRC (P = .0001). Our study documents early changes of hemostasis in untreated malignancy. We extend previous observations that decreased PRC levels in malignancy may be due to poor synthetic functions of liver. Presence of liver metastases was the only factor associated with subsequent development of thrombotic and hemorrhagic complications. Biochemical markers of hemostatic abnormalities, even though encountered frequently at the time of presentation, are of little predictive value for development of thrombotic and hemorrhagic complications.

Topics: Adult; Aged; Aged, 80 and over; Antithrombin III; Female; Fibrinopeptide A; Hemorrhage; Hemostasis; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasms; Protein C; Prothrombin Time; Thrombosis

Topics: Disseminated Intravascular Coagulation; Electrophoresis, Polyacrylamide Gel; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Fibrinopeptide B; Hemorrhage; Humans; Models, Chemical; Molecular Weight; Thrombosis

Topics: Adult; Aged; Antithrombin III; Brain Diseases; Cardiopulmonary Bypass; Coronary Artery Bypass; Epoprostenol; Female; Fibrinopeptide A; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Postoperative Complications; Prostaglandins

Prothrombin complex concentrates (PCC) are known to carry a risk of thromboembolism. We have chosen to reassess the problem of detecting in vivo signs of activation of the clotting mechanism by assaying fibrinopeptide A (FpA) after PCC administration in hemophilic patients during bleeding episodes. FpA was significantly increased above baseline levels 15 to 60 min after the infusion of 19 doses of 5 different types of commercial PCC in 14 hemophilia B patients treated for bleeding episodes or dental extractions. A more marked increase followed 16 infusions of the activated PCC FEIBA and Auto IX in 4 hemophilia A patients with F. VIII inhibitors. There was no significant FpA change after F. VIII concentrates administered to a control group of 7 patients with hemophilia A. These findings suggest that circulation of thrombin occurs frequently after PCC administration, even though clinical manifestations of thromboembolism appear to be relatively rare.

Topics: Blood Coagulation Factors; Factor VIII; Fibrinogen; Fibrinopeptide A; Hemophilia A; Hemorrhage; Humans; Prothrombin