Inhibition of Thrombotic Side Effects of II, VII, IX and X Concentrates

1975 ◽  
Author(s):  
A. J. Johnson ◽  
V. E. Macdonald ◽  
D. Brandt ◽  
S. Middleton ◽  
J. K. Smith
Keyword(s):  
Side Effects ◽  
Antithrombin Iii ◽  
Coagulation Factors ◽  
Thrombin Time ◽  
Average Yield ◽  
Clotting Time ◽  
Clotting Factors ◽  
Partial Activation ◽  
Peg Treatment ◽  
Fractionation Method

Well documented thrombotic side effects of II, VII, IX and X concentrates are thought to be due to spontaneous partial activation of one or more coagulation factors. Using the unactivated PTT method of Kingdon and the thrombin time as global assays of activation, we have confirmed this concept. It has been suggested that heparin should be added to the concentrate, but preparations vary in antithrombin content and activated factor. The amount of heparin for each preparation would have to be titrated in order to neutralize the activated factors without anticoagulating the patient. We sought to extend the range of added heparin without producing an anticoagulant effect, by adding heparin to the concentrates prior to use of the PEG fractionation method to remove the hepatitis antigen. Thus, heparin-activated antithrombin III can inhibit activated clotting factors while residual free heparin is removed by PEG fractionation. When 1 unit of heparin per mg of protein in the concentrate was added prior to PEG treatment, the final products from more than 80 runs on 15 batches (3 major manufacturers) were almost invariably neutral; neither anticoagulated nor activated. The thrombin clotting time, when measured, was 6-24 hours. The average yield with use of the PEG fractionation method was 85%; depending on the initial purity of the concentrate, the final product had an additional purification of 1.0-2.5 X that of the starting material.(Supported in part by USPHS Grant HL 15596 and HRC (N.Y.) 1-681.)

scholarly journals The anticoagulant mechanism of action of heparin in contact-activated plasma: inhibition of factor X activation

Blood ◽  
1985 ◽  
Vol 65 (5) ◽  
pp. 1226-1231 ◽  
Author(s):  
TB McNeely ◽  
MJ Griffith
Keyword(s):  
Antithrombin Iii ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Factor X ◽  
Clotting Time ◽  
Intrinsic Pathway ◽  
Blood Coagulation Factors ◽  
Factor Ixa ◽  
Factor X Activation

Abstract The effects of heparin on the activation of blood coagulation factors IX and X in contact-activated plasma were determined in the present study. In the presence and absence of 0.5 U/mL heparin, the amounts of factor IX that were cleaved 30 minutes after the addition of calcium and phospholipid to plasma exposed to glass (ie, contact activated) were essentially identical. In the absence of heparin, however, the plasma clotting time was between three and four minutes, while in the presence of heparin, the clotting time was approximately 40 minutes. More factor IXa was inhibited by antithrombin III in the presence of heparin than in its absence, but factor IXa levels sufficient for factor X activation appeared to be present in the heparinized plasma. Neither an increase in factor Xa nor a decrease in factor X was detected, however, in heparinized plasma. We conclude that the step in the intrinsic pathway of coagulation that is inhibited in the presence of heparin is at the level of factor X activation.

Bleeding in Uremic Patients after Carbenicillin

1976 ◽  
Vol 36 (01) ◽  
pp. 115-126 ◽  
Author(s):  
K Andrassy ◽  
E Weischedel ◽  
E Ritz ◽  
T Andrassy
Keyword(s):  
Platelet Function ◽  
Antithrombin Iii ◽  
Serum Levels ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Hemorrhagic Diathesis ◽  
Thrombin Time ◽  
Antithrombin Iii Activity

SummaryHemorrhagic diathesis was observed in patients with renal insufficiency after carbenicillin at serum levels > 300 μg/ml. Normal coagulation factors (F. I, II, V, VII, VIII, X), normal PTT, normal platelet counts, negative ethanol gelation test (fibrin monomers) were found as well as a prolongation of thromboplastin time (Quick), thrombin time, reptilase time and thrombin coagulase time. Platelet function was disturbed. In addition, the plasmatic system was involved: inhibition of fibrinogen-fibrin conversion (Belitser assay) and enhanced antithrombin III activity; in vivo the latter was ascribed to a heparin-like activity. In vitro, abnormal fibrinogen-fibrin conversion and a modified electrophoretic mobility of antithrombin III was seen: however an enhanced antithrombin III activity in vitro was not found with carbenicillin and various penicillin derivatives.This study demonstrates that carbenicillin, in addition to its known effect on platelet function, also disturbs the plasmatic coagulation system. This additional effect of carbenicillin is clinically important since protamin chloride effectively blocks bleeding without interfering with antibacterial activity.Both penicillin and penicillin derivatives have been shown to interfere with hemostasis and to cause clinically manifest hemorrhagic diathesis (Fleming and Fish 1947, Lurie et al. 1970a, b, McClure et al. 1970, Yudis et al. 1972, Demos 1971, Waisbren et al. 1971). Carbenicillin interferes with ADP-, collagen- or thrombin-induced platelet aggregation and with the release reaction both in vivo (McClure et al. 1970, Cazenave et al. 1973) and in vitro (McClure et al. 1970, Cazenave et al. 1973). In addition Lurie and colleagues (1970b) concluded that an inhibition of the conversion of fibrinogen to fibrin is involved although no experimental details were given. Later Brown and colleagues (1974) concluded that carbenicillin at usual dose levels “only affects the platelet component of hemostasis and has little effect on fibrin formation or other phases of coagulation in patients with normal renal function”.

Haemostatic Studies in Carbohydrate-deficient Glycoprotein Syndrome Type I

1996 ◽  
Vol 76 (04) ◽  
pp. 502-504 ◽  
Author(s):  
A Fiumara ◽  
R Barone ◽  
P Buttitta ◽  
R Musso ◽  
L Pavone ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Protein C ◽  
Antithrombin Iii ◽  
Plasma Concentrations ◽  
Protein S ◽  
Coagulation Factors ◽  
Type I ◽  
Clotting Factors ◽  
Blood Coagulation Factors ◽  
D Dimer

SummaryCDG syndrome (CDGS) type I is the most frequent form of a group of metabolic disorders characterised by a defect of the carbohydrate moiety of glycoproteins. A large number of plasma glycoproteins, including clotting factors and inhibitors, are decreased and stroke-like episodes have been described in about half of the reported patients. We studied blood coagulation factors, inhibitors and D-dimer plasma levels in four subjects, aged 12-23 years, with CDGS type I. Factors VIII, XI, antithrombin III activity, antigen plasma levels of antithrombin III, free protein S and protein C were decreased whereas protein C as activity was normal. In addition two patients had reduction of factors II, V, VII, IX, X reflecting the phenotypic heterogeneity associated with CDGS type I. D-dimer plasma concentrations were elevated in all subjects. The hypercoagulable state as consequence of the combined deficiencies of coagulation inhibitors could contribute to the stroke-like phenomena in CDGS type I.

THE EFFECT OF THE VENOM OF THE ORIENTAL HORNET ON COAGULATION FACTORS

1987 ◽  
Author(s):  
A Kornberg ◽  
S Kaufman ◽  
L Silber ◽  
J Ishay
Keyword(s):  
Human Plasma ◽  
Degradation Products ◽  
Anticoagulant Activity ◽  
Coagulation Factors ◽  
Plasma Fibrinogen ◽  
Thrombin Time ◽  
Clotting Factors ◽  
Viii And Ix

The extract from the venom sac of Vespa orientalis (VSE) inactivates exogenous and endogenous thromboplastin (Joshua and Ishay, Toxicon, 13:11-20,1975). The prolongation of both prothrombin time (PT) and recalcification time suggests inactivation of other factors. The aim of the present study is to investigate the effect of VSE on clotting factors. A lyophilized VSE with protein concentration of 5 mg/ml was used. Studies were performed in vitro with human plasma and in vivo in cats. Routine methods were employed for the assay of PT, activated tissue thromboplastin (APTT), thrombin time (TT), fibrinogen degradation products (FDP), fibrinogen and factors V,VII,VIII,IX,X. Human plasma was incubated with various concentrations of VSE (0,1,5,10,50,100 μg/ml) for 60 min and for various incubation times (0,5,15,30,+ 60,90,120 min) with 50 μg/ml VSE (n=8). 1 μg/ml VSE prolonged PT from 13.5 to 16 sec (p<0.05) and APTT from 62 to 180 sec. PT was maximal (17.7 sec) with 10 μg/ml and APTT (442 sec) with 50 μg/ml VSE. Factors V,VII,X decreased gradually from 94-105% to 11%,11% and 29% with 100 μg/ml VSE and VIII and IX to 1% even with 1 μg/ml VSE. After 5 min with constant concentration of VSE (50 μg/ml) PT was 14.9 sec (normal 13 sec) and APTT 165 sec (normal 54 sec). Both were maximal (17.5 and 298 sec) after 60 min. Factors VII and X decreased to 13% and 32% and VIII and IX to >1% after 60 min of incubation. Injection of 5 mg/kg VSE to cats (n=6-8) resulted in prolongation of PT from 9.4 to 11.2 sec and of APTT from 19.5 to 63 sec after 5 min. Both were maximal after 90 min (12.3 and 127 sec). Factors V,VII and X decreased from 100% to 7.6%, 13% and 37% and VIII and IX to 1% after 10 min. In all experiments TT and plasma fibrinogen were not affected and FDP were normal. Heating of VSE for 5 min at 80°C abolished completely the anticoagulant activity but dialysis for 24 hr at 4°C had no effect on it. The activity was eluted on Sephadex-25 both in void and post void volumes. The results show that VSE has a potent anticoagulant activity against various factors. Factors VIII and IX are markedly decreased. The effect on V, VII and X is moderate. Plasma fibrinogen is not affected. The nature and clinical significance of the anticoagulant activity merit further investigation.

Effect of heparin on chronically induced intravascular coagulation in dogs

1975 ◽  
Vol 229 (2) ◽  
pp. 449-454 ◽  
Author(s):  
Owen CA ◽  
EJ Bowie
Keyword(s):  
Factor Viii ◽  
Prothrombin Time ◽  
Antithrombin Iii ◽  
Plasma Fibrinogen ◽  
Factor V ◽  
Thrombin Time ◽  
Turnover Rates ◽  
Clotting Factors ◽  
Intravascular Coagulation ◽  
Absolute Concentrations

When intermediate-strength thromboplastin was continuously infused into dogs for 10 days or more, platelet counts decreased sharply and factor VIII concentrations decreased by more than 50%. There was little change in plasma fibrinogen, prothrombin, factor V, antithrombin III, plasminogen, prothrombin time, and thrombin time values. When heparin was infused (25-50 U/kg per h) along with the same thromboplastin, there was no change in onset or degree of thrombocytopenia. However, the decrease in factor VIII was abolished and there were significant increases in fibrinogen, prothrombin, and factor V. The absolute concentrations of the various clotting factors seemed to give no indication of their turnover rates. Unexplained is the remarkable heparin tolerance that developed in these dogs.

Results in Preventing Thrombosis By Low-Dose Heparin in Consideration of Heparin Concentration and Antithrombin III in

1979 ◽  
Author(s):  
V. Tilsner ◽  
U. Müller
Keyword(s):  
Low Dose ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Optimal Dosage ◽  
Thrombin Time ◽  
Normal Limits ◽  
Dose Heparin ◽  
Treatment Plans ◽  
Low Dose Heparin

The antithrombotic effect of low-dose heparin has been ascertained clinically. The postoperative activation of the coagulation factors must be decreased, without increasing any bleeding tendencies. In order to determine the optimal dosage in low-dose heparin prophylaxis we examined the RCT, PTT, TT, Factor Xa, AT III and heparin concentrations in 400 patients prior to and following emergency surgery. Any thrombotic or haemorrhagic complication was registered. All 100 cases received one of the following treatment plans: 1) 5000 U heparin s.c. TID, 2) 7500 U heparin s.c. TID, 3) 100 U heparin/kg s.c. BID, 4) 150 U heparin/kg s.c. BID. Only plans 2 and 4 achieved a measureable heparin effect without increasing the risk of bleeding. The PTT did not shorten in either of these 2 groups and the thrombin time rose only occasionally to the upper normal limits. All other values remained within normal limits. The thrombo-embolic incidence amounted to 1% in groups 2 and 4, 2% in groups 3 and 5% in the first group.

Changes in the Plasma Level of Heparin and Coagulation Factors During the Postoperative Prophylaxis with Heparin and Heparin-Dihydroergotamin.

1979 ◽  
Author(s):  
S. Popov-Cenic ◽  
K. Schander ◽  
F. Etzel
Keyword(s):  
Plasma Level ◽  
Prospective Study ◽  
Preliminary Data ◽  
Antithrombin Iii ◽  
Coagulation Factors ◽  
Abdominal Hysterectomy ◽  
Thrombin Time ◽  
Combined Administration ◽  
Postoperative Prophylaxis ◽  
Heparin Prophylaxis

In a randomised prospective study a homogenous total of 70 women undergoing abdominal hysterectomy and bilateral adnexectomy is subdivided in 7 different groups with the following treatment schadules: A. no postoperative prophylaxis of thromboembolism, B. every 12 hrs 0.5 mg dihydroergotamin (DHE), C. every 12 hrs 2500 I.U . Na-heparin +DHE, D. every 12 hrs 5000 I.U. heparin, E. every 12 hrs 5000 I.U. heparin + DHE, F. every 8 hrs 5000 I.U: heparin, G. every 8 hours 5000 I.U. heparin + DHE.The following parameters are examined pre- and postoperatively as well as on the first, second and seventh postoperative day prior to and 3 hrs after the respective treatments: plasma-levels of heparin, anti Xa and antithrombin III with chromogenous substrate 2160 and 2222, PTT and plasma thrombin time as well as the factors of the coagulation and fibrinolytic system.The preliminary data indicate that under the combined administration of heparin plus dihydroergotamin heparin levels rise further and PTT is more prolonged as compared to heparin prophylaxis alone.

scholarly journals A Comparison of the Anticoagulant Actions of Commercially Available Contrast Media (CM)

1977 ◽  
Author(s):  
Rogelio Moneada ◽  
Jawed Fareed ◽  
Harry Messmore ◽  
Terrence Demos
Keyword(s):  
Sodium Chloride ◽  
Contrast Media ◽  
Toluidine Blue ◽  
Partial Thromboplastin Time ◽  
Antithrombin Iii ◽  
Thrombin Time ◽  
Clotting Factors ◽  
Antithrombin Activity ◽  
Viii And Ix

Previous studies have reported on the anticoagulant effect of commercially available contrast media used in diagnostic radiology. The purpose of this study is to compare the anticoagulant actions of these agents in vitro. Eight commercially available contrast medias were supplemented to citrated human plasma (CNP) in 1:10, 1:20 and 1:50 proportions; isomolar sucrose, glucose, sodium chloride, and saline supplemented CNP were used as controls. Prothrombin time (FT) , partial thromboplastin time (PTT), thrombin time (TT), antithrombin-III, plasminogenplasnun and factor assays were performed at 0 time, 30 minutes and 2 hours after incubation at 37°C. No significant alteration of the coagulation parameters were observed at 1:50 dilution, however at 1:10 and 1:20 dilution, most contrast media produced aberration of clotting parameters. The antithrombin potency of these contrast media at a 1:10 dilution ranged from 0.3-1.3 u/ml heparin. In addition, this antithrombin activity was synergistic with heparin. The antithrombin activity of these agents was not neutralized by protamine sulfate, polybrene or toluidine blue in the amounts which neutralized 1 u/ml heparin. Analysis of various clotting factors revealed that factors II, V, VII and XII were not affected by contrast media. Factors VIII and IX were depressed significantly. These changes were mainly dependent on the concentration of meglumine in the contrast media. Similar studies on the blood obtained from patients infused with contrast media for diagnostic purposes are in progress in our laboratory.

scholarly journals Familial Primary Fibrinolysis

1977 ◽  
Author(s):  
Z. Currimbhoy
Keyword(s):  
Birth Control ◽  
Antithrombin Iii ◽  
Clot Lysis ◽  
Thrombin Time ◽  
Maternal Grandmother ◽  
Clotting Factors ◽  
Fibrin Plate ◽  
Α2 Macroglobulin ◽  
Birth Control Pills ◽  
Work Up

This study reports on a unique family with primary fibrinolysis. A 31-year-old female had hematuria of one month’s duration. She had a previous episode of hematuria lasting 3 weeks and a hysterectomy for menorrhagia. Her 10-year-old daughter bled from the gums at the age of 9 months for one week. All clotting factors (including Factors VIII, V and XIII) were normal, except Fibrinogen. The mother’s Fibrinogen varied from 110 to 165 mg%, and the daughter’s from 90 to 146 mg%. The diluted Thrombin Time and Reptilase times were normal. The most striking and constant defect was in the fibrinolytic system. These studies were performed over a 4 month period. Euglobulin clot lysis, done on the mother repeatedly and on the daughter twice, were abnormally short, varying from 60 to 100 minutes, with FSP>10 and <40 ug/ml or <10 ug/ml. Active lysis was present on fibrin plates. α2 macroglobulin, α1 antitrypsin and Antithrombin III were normal, as was plasminogen immunologically. Platelet count and functions were normal. The maternal grandmother bled profusely twice after two gynecological procedures and once needed a blood transfusion. She was then put on birth control pills. Work-up on the pill revealed a Fibrinogen of 217 mg%, but no clot formed when attempting to evaluate euglobulin lysis. Off the pill, Fibrinogen was 167 mg%, euglobulin clot lysis 30 mins,, and there was a zone of lysis on the fibrin plate.The congenital loss of an inhibitor to plasminogen activator could explain these results.

An Abnormal Fibrinogen in a Venezuelan Family

1975 ◽  
Author(s):  
N. B. Bosch ◽  
G. Arocha-Piñango
Keyword(s):  
Autosomal Dominant ◽  
Antithrombin Iii ◽  
Normal Values ◽  
Frozen Storage ◽  
Thrombin Time ◽  
Clotting Time ◽  
Autosomal Dominant Trait ◽  
K Value ◽  
Ca Ions ◽  
Fibrin Monomers

An apparently new fibrinogen abnormality, inherited as an autosomal dominant trait, was found in 4 members of a family affected with moderate bleeding. Prolongation of plasma prothrombin, thrombin and Reptilase times and normal concentration of fibrinogen were observed. Normal values of platelet aggregation, FDP and antithrombin III levels were obtained. The k value of the thromboelastogram was slightly increased. Factor XIII was 50 to 60% (Beringwerke F XIII kit) and 100% by radial inmuno diffusion. Photometric study of thrombin induced polymerization of fibrin in plasma or purified fibrinogen and the aggregation of monomers in plasma measured by a two stage method, were abnormal. Marked prolongation of the clotting time of fibrin monomers were observed at pH over 7.4. Alterations of polymerization curves and plasma thrombin time were accentuated by raising molarity and ameliorated by Ca ions, increasing thrombin concentration and frozen storage. Normal plasma was slightly inhibited by patient’s plasma in these tests.Normal electrophoretic mobility of the abnormal fibrinogen was shown on cellulose acetate, Polyacrylamide and inmunoelectrophoresis. Ouchterlony inmunodiffusion revealed non-identity pattern with normal fibrinogen.

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