Autoprothrombin C in Irregular Blood Clotting

1962 ◽  
Vol 08 (01) ◽  
pp. 001-020
Author(s):  
Walter H. Seegers ◽  
Eva Marciniak
Keyword(s):  
Blood Clotting ◽  
Hemophilia A ◽  
Deae Cellulose ◽  
Hemophilia B ◽  
Factor Vii ◽  
Factor X ◽  
The Common ◽  
Autoprothrombin C ◽  
Derivatives Of ◽  
Autocatalytic Activation

SummaryIn this study autoprothrombin C was considered in relationship to the hemorrhagic diseases. Concentrates of autoprothrombin C were made from purified prothrombin known to be homogeneous by several criteria. These autoprothrombin C preparations were free of thrombin, and were almost a single component when analyzed by centrifugation. Autoprothrombin C corrected the partial thromboplastin time and produced prothrombin consumption in all the plasmas obtained from patients with hemorrhagic diseases except parahemophilia. In the case of hemophilia B prothrombin consumption was obtained with the addition of purified prothrombin or purified autoprothrombin II. In the case of Stuart plasma prothrombin consumption was rapid after the addition of purified prothrombin or purified prothrombin chromatographed on Amberlite ICR-50, but not after the addition of purified prothrombin that was chromatographed on DEAE cellulose. The latter prothrombin is an abnormal prothrombin molecule and does not readily yield autoprothrombin C. It is concluded that Stuart prothrombin is abnormal and that this is a molecular disease. There is no need to postulate the existence of factor X to account for the irregular prothrombin activation in Stuart plasma. The most important question considered was how can autoprothrombin C be generated from prothrombin to promote the autocatalytic activation of prothrombin. Certain prothrombin molecules do not yield this enzyme, but normal prothrombin does. However, it does so only under certain conditions of activation. By applying the new knowledge of prothrombin chemistry to blood clotting irregularities in hemorrhagic diseases the following main considerations highlight the common deviations: 1. Abnormal prothrombin molecule, 2. Changes related to the derivatives of prothrombin, 3. Accessories needed for the generation of autoprothrombin C so it can function in auto-catalysis are irregular, and 4. Accessories needed for the function of autoprothrombin C after it is out of the prothrombin molecule are irregular. In the first group is Stuart Plasma. In the second group falls hemophilia B (autoprothrombin II) and the so-called factor VII deficiency (autoprothrombin I). In the third group is hemophilia A. In the fourth group is parahemophilia, and the platelet abnormalities.

The Activation of Human Factor X in Sodium Citrate: the Role of Factor VII

1976 ◽  
Vol 36 (01) ◽  
pp. 104-114 ◽  
Author(s):  
D. L Aronson ◽  
A. J Mustafa
Keyword(s):  
Sodium Citrate ◽  
Human Factor ◽  
Deae Cellulose ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X

SummaryHuman factor X was purified by several different procedures yielding products which had varying amounts of factor VII and factor IX. Treatment with CHC13 during the fractionation of the factor X removed 95% of the factor VII and factor IX activity and the resulting factor X activated more slowly when incubated in 25% sodium citrate. Removal of residual factor VII by DEAE cellulose chromatography yielded a factor X which activated still more slowly and less completely. When the factor VII, removed by chromatography, was added to the chromatographed factor X, the ability to be activated in 25% sodium citrate was restored. Confirmatory evidence for the role of factor VII in this reaction was the inhibition of the conversion of the factor X by both DFP and SBTI.

DICOUMAROL STUDIES: I. ORAL ADMINISTRATION OF SYNTHETIC DICOUMAROL TO VARIOUS CLASSES OF SHEEP AND CATTLE

1963 ◽  
Vol 43 (2) ◽  
pp. 344-352 ◽  
Author(s):  
J. H. Linton ◽  
B. P. Goplen ◽  
J. M. Bell ◽  
L. B. Jaques
Keyword(s):  
Vitamin K ◽  
Blood Clotting ◽  
Post Partum ◽  
Late Pregnancy ◽  
Cumulative Effects ◽  
Factor Vii ◽  
Factor X ◽  
Clotting Time ◽  
Sodium Bisulphite ◽  
Bull Calves

In one experiment 3 steers, 4 bull calves and 4 wether lambs were orally administered 2 milligrams dicoumarol per kilogram body weight and blood-clotting time measurements were made over a 4-day period. All animals responded to the dicoumarol but differences were evident between sheep and cattle; sheep were apparently more tolerant of the drug.The ’one-stage prothrombin’ test was more reliable and sensitive than the clotting tests employed for factor VII, factor X and prothrombin concentration.In a second experiment, 16 ewes in late pregnancy were fed rations containing 0 to 30 p.p.m. of synthetic dicoumarol and vitamin K3 as a cross treatment. Evidence of abnormal clotting power of ewe blood was observed in ewes fed diets containing 10 p.p.m. of dicoumarol. There was some indication of cumulative effects at this level after 32 days on test. At intake levels of 20 and 30 p.p.m. clotting times were affected more markedly and some ewes exhibited extended bleeding times after 2 to 4 weeks on test. No unusual hemorrhaging occurred at parturition. In general, the lambs’ blood did not reflect the pre- or post-partum dicoumarol intake of their mothers but a few lambs, as in the case of the ewes, exhibited low tolerance for dicoumarol without showing much disturbance in terms of clotting time. A large single oral dose of menadione sodium bisulphite demonstrated the effectiveness of vitamin K3 as an antidote. However, vitamin K3 as a ration supplement at 12 milligrams per pound feed failed to protect ewes against the effects of dicoumarol.

scholarly journals Novel Insights and New Developments Regarding Coagulation Revealed by Studies of the Anti-Factor IXa (Activated Factor IX)/Factor X Bispecific Antibody, Emicizumab

2020 ◽  
Vol 40 (5) ◽  
pp. 1148-1154
Author(s):  
Koji Yada ◽  
Keiji Nogami
Keyword(s):  
Hemophilia A ◽  
Activated Protein C ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
New Developments ◽  
Activated Factor Vii ◽  
Factor Ixa ◽  
Thrombin Activation ◽  
No Activation

Emicizumab is a humanized anti-FIXa/FX (factor IXa/X) bispecific monoclonal antibody that mimics FVIIIa (activated factor VIII) cofactor function. The hemostatic efficacy of emicizumab has been confirmed in clinical studies of patients with hemophilia A, irrespective of the presence of FVIII inhibitors. Emicizumab differs in some properties from FVIIIa molecule. Emicizumab requires no activation by thrombin and is not inactivated by activated protein C, but emicizumab-mediated coagulation is regulatable and maintains hemostasis. A small amount of FIXa (activated factor IX) is required to initiate emicizumab-mediated hemostasis, whereas tissue factor/FVIIa (activated factor VII)-mediated FXa (activated factor X) and thrombin activation initiates FVIIIa-mediated hemostasis. Fibrin formation, followed by fibrinolysis, appears to be similar between emicizumab- and FVIIIa-mediated hemostasis. These results suggest possible future uses of emicizumab for treating hemorrhagic diseases other than hemophilia A and reveal previously unobservable behaviors of procoagulation and anticoagulation factors in conventional hemostasis. Here, we have reviewed novel insights and new developments regarding coagulation highlighted by emicizumab.

scholarly journals Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

2020 ◽  
Vol 120 (10) ◽  
pp. 1357-1370
Author(s):  
Georg Gelbenegger ◽  
Christian Schoergenhofer ◽  
Paul Knoebl ◽  
Bernd Jilma
Keyword(s):  
Clinical Trials ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor X ◽  
Current Standard ◽  
Bleeding Events ◽  
Recombinant Activated Factor Vii

AbstractHemophilia A, characterized by absent or ineffective coagulation factor VIII (FVIII), is a serious bleeding disorder that entails severe and potentially life-threatening bleeding events. Current standard therapy still involves replacement of FVIII, but is often complicated by the occurrence of neutralizing alloantibodies (inhibitors). Management of patients with inhibitors is challenging and necessitates immune tolerance induction for inhibitor eradication and the use of bypassing agents (activated prothrombin complex concentrates or recombinant activated factor VII), which are expensive and not always effective. Emicizumab is the first humanized bispecific monoclonal therapeutic antibody designed to replace the hemostatic function of activated FVIII by bridging activated factor IX and factor X (FX) to activate FX and allow the coagulation cascade to continue. In the majority of hemophilic patients with and without inhibitors, emicizumab reduced the annualized bleeding rate to almost zero in several clinical trials and demonstrated a good safety profile. However, the concurrent use of emicizumab and activated prothrombin complex concentrate imposes a high risk of thrombotic microangiopathy and thromboembolic events on patients and should be avoided. Yet, the management of breakthrough bleeds and surgery remains challenging with only limited evidence-based recommendations being available. This review summarizes published clinical trials and preliminary reports of emicizumab and discusses the clinical implications of emicizumab in treatment of hemophilia A.

A case of rare inhibitory coagulopathy - acquired hemophilia A

2010 ◽  
Vol 94 (10) ◽  
pp. 775-779
Author(s):  
V. I. Ershov ◽  
Dar’ya A. Budanova ◽  
I. Yu. Gadaev ◽  
O. V. Bochkarnikova ◽  
I. Ya. Sokolova ◽  
...  
Keyword(s):  
Rare Disease ◽  
Blood Clotting ◽  
Hemophilia A ◽  
Coagulation System ◽  
Clotting Factor ◽  
Factor X ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Hemostatic Therapy ◽  
Blood Clotting Factor

Inhibitory coagulopathy is a rare variant of hemorrhagic syndrome. Acquired hemophilia A is caused by the formation of inhibitors (antibodies) to Factor VIII of the blood coagulation system leading to impaired activation of the key stage of blood clotting (factor X) and development of hemorrhagic syndrome of different severity. Acquired hemophilia A is a rare disease with an incidence of 1.38-1.48 per 1 million population per year. We report a case off severe idiopathic acquired hemophilia A in a 53 year-old woman manifest as skin hemorrhages, subcutaneous and intramuscular hematomas. Hemostatic therapy described in the article resulted in the elimination of hemorrhagic syndrome and complete remission. This case represents a rare disease the knowledge of which can be useful for preventing the development of debilitating complications, and sometimes saving the patient’s life.

Effect of physical exercise on blood clotting and fibrinolysis

1963 ◽  
Vol 18 (2) ◽  
pp. 337-344 ◽  
Author(s):  
Sotirios G. Iatridis ◽  
John H. Ferguson
Keyword(s):  
Blood Clotting ◽  
Normal Subjects ◽  
Factor Vii ◽  
Strenuous Exercise ◽  
Factor Xii ◽  
Factor V ◽  
Factor X ◽  
Plasma Factor ◽  
Deficient Subject ◽  
Direct Activator

The effect of strenuous exercise on the clotting and fibrinolytic systems was studied on 1 Hageman-deficient and 59 normal subjects (males aged 18–37 years). In the normal subjects there was a significant shortening of the whole-blood clotting time and of the partial thromboplastin time both in glass and in siliconized tubes. Plasma factor VIII (AHF or AHG) assays rose to 188% (average), but the specificity of the test is questioned. Factor XII (HF) increased to 318% (average) unequivocally. A postexercise increased heparin tolerance was also noted. There was no significant increase in the levels of fibrinogen, prothrombin, factor V (AcG), or factor VII (proconvertin) and factor X (Stuart). Fibrinolytic activity as measured by the euglobulin lysis and plasma plate methods increased significantly in most of the normal subjects. The data suggest that the fibrinolytic factor which increases after exercise is not active plasmin, but is related to the “activator” mechanisms. A plasma lysokinase (indirect activator) seems to preponderate in over half the cases. In 20% of cases a plasminoplastin (direct activator) may be involved. In the Hageman-deficient subject there was no improvement in clotting, and the slight changes in some of the fibrinolysis tests were nonsignificant. Submitted on October 16, 1962 Submitted on October 16, 1962

Studies on the Fate of Coagulation Factors during the Clotting of Normal and Pathological Blood

1959 ◽  
Vol 03 (04) ◽  
pp. 578-587
Author(s):  
Cecil Hougie
Keyword(s):  
Blood Coagulation ◽  
Hemophilia A ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor Vii ◽  
Normal Blood ◽  
Modern Concept ◽  
Factor V ◽  
Mild Case

SummaryIn a mild case of Stuart factor (SF) deficiency and in a patient with hemophilia B (factor IX deficiency) consumption of AHF (factor VIII) was normal but was abnormal in more severe examples of these diseases. This finding reconciles previously conflicting reports. Factor V utilisation was abnormal in moderately severe cases of SF deficiency, hemophilia A and hemophilia B but normal in mild cases of SF deficiency and hemophilia B. A mild case of hemophilia A was not studied. These findings would be expected from the modern concept of blood coagulation. However, the findings with respect to AHF are equally well explained if AHF is destroyed by some intermediate product of blood coagulation, such as thrombin, appearing at the time of the appearance of fibrin.The concentration of SF was found to remain constant during the clotting of both normal blood and blood deficient in factor VILThe concentration of factor VII during the coagulation of normal blood remained constant until the appearance of fibrin. The concentration then increased, but this finding was not consistently obtained. No abnormality in the fate of factor VII during the clotting of blood deficient in SF was found.

scholarly journals A novel type of putrescine (diamine)-acetylating enzyme from the nematode Ascaris suum

1989 ◽  
Vol 260 (1) ◽  
pp. 265-269 ◽  
Author(s):  
R M Wittich ◽  
R D Walter
Keyword(s):  
Parasitic Nematode ◽  
Ascaris Suum ◽  
Deae Cellulose ◽  
Reproductive Tissue ◽  
Freezing And Thawing ◽  
Acetyl Coa ◽  
Michaelis Constants ◽  
The Common ◽  
Derivatives Of ◽  
Thawing Procedure

A cytosolic enzyme catalysing the acetylation of the diamines putrescine, cadaverine, 1,3-diaminopropane and 1,6-diaminohexane has been partially purified from reproductive tissue of the intestinal parasitic nematode Ascaris suum. The enzyme formed N-acetylated derivatives of the above diamines when incubated in the presence of acetyl-CoA. The Michaelis constants (Km) for the above diamines were 0.25 nM, 0.1 mM, 1.25 mM and 0.4 mM respectively, and the apparent Km for acetyl-CoA was 7.7 microM. sym-Norspermidine was also acetylated by this enzyme preparation, and, at a much lower rate, the enzyme acted on sym-norspermine. The common polyamines, spermidine and spermine, and histones were not substrates. Purification steps involved a freezing-and-thawing procedure to release enzyme activity from unknown inhibitors, DEAE-cellulose chromatography and affinity chromatography on cadaverine-Sepharose, from which the enzyme was eluted by increasing ionic strength. The enzyme exhibited an apparent Mr of about 38,000-40,000, and it consisted of at least two subunits, of which the catalytic one had an Mr of about 13,000. The partially purified enzyme showed no deacetylase activity, and its activity was competitively inhibited by the product N-acetylputrescine, but not by CoA. The name putrescine N-acetyltransferase is suggested for this enzyme, which may have an important function in the degradation of diamines of lower eukaryotes.

Pathways of Blood Clotting Initiation by Cancer Cells

1979 ◽  
Author(s):  
N. Semeraro
Keyword(s):  
Cancer Cells ◽  
Blood Clotting ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Ehrlich Carcinoma ◽  
Factor V ◽  
Factor X ◽  
Experimental Tumors ◽  
Activate Coagulation Factor ◽  
Available Information

Although available information indicates that cancer cells may activate blood coagulation, the precise mechanism remains still uncertain. A procoagulant with characteristics of tissue thromboplastin has been found in human benign and malignant tissues and in some experimental tumors. On the other hand it has been reported that extracts from malignant tissues directly activate coagulation factor X, due to the presence of a serine protease. We have investigated the procoagulscitic fluid. Cells from Lewis lung carcinoma (primary and metastasis), Ehrlich carcinoma ascites and JW sarcoma ascites were able to shorten markedly the recalcification time of normal, factor VIII and factor VII-deficient, not of factor X-deficient human plasma. The same cells did generate thrombin when mixed with a source of prothrombin and factor X, absorbed bovine serum (as a source of factor V), phospholipid and CaCl2.Cells from Sarcoma ISO ascites were completely inactive in both test systems. It was a included that cells from some experimental tumors, similarly to normal platelets, possess the capacity to directly activate coagulation factor X. This suggests the existence of an alternative “cellular” pathway in blood clotting initiation distinct from both the intrin sic and extrinsic mechanisms.(Supported by Italian CNR and NIH, NCI, USA).

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