scholarly journals The Thrombogram in Rare Inherited Coagulation Disorders: Its Relation to Clinical Bleeding

2002 ◽  
Vol 88 (10) ◽  
pp. 576-582 ◽  
Author(s):  
Raed Al Dieri ◽  
Flora Peyvandi ◽  
Elena Santagostino ◽  
Muriel Giansily ◽  
Pier Mannuccio Mannucci ◽  
...  
Keyword(s):  
Lag Time ◽  
Peak Height ◽  
Factor Vii ◽  
Clotting Factor ◽  
Severe Bleeding ◽  
Factor V ◽  
Bleeding Tendency ◽  
Factor X ◽  
Factor Xi ◽  
Factor Concentration

SummaryWe investigated the relation between clotting factor concentration, the parameters of the thrombin generation curve (the thrombogram) and the severity of clinically observed bleeding in patients with congenital deficiency of prothrombin (n = 21), factor V (n = 22), factor VII (n = 22), factor X (n = 10), factor XI (n = 7) and factor XII (n = 6). The parameters used were: area under the curve (endogenous thrombin potential, ETP), peak concentration of thrombin attained and lag time before manifest formation.Peak height and ETP varied linearly with the concentration of prothrombin. For the other factors these parameters hyperbolically approached to the 100% limit with increasing clotting factor concentration. Half normal ETP was seen at about the following concentrations: prothrombin (50%), factor V (1%), factor VII (2%), factor X (5%) and factor XI (1%). As a rule, the peak height was somewhat more sensitive to clotting factor decrease than the ETP was.In all the patients with severe bleeding symptoms the ETP was less than 20% of normal. Bleeding tendency was absent or mild in patients with an ETP of 30% or higher. This value (except for prothrombin) is already obtained at concentrations of clotting factor of 1%-2%, which corroborates the clinical observation that a severe bleeding tendency is only seen in severe clotting factor deficiencies (less than 1%). The one exception was a patient with factor VII deficiency and severe bleeding, who showed a normal ETP value, albeit with a decreased peak height and a prolonged lag-time.

Generation Of Coagulation Factors By The Isolated Rat Liver Perfused With A Synthetic Blood Substitute

1981 ◽  
Author(s):  
C A Owen ◽  
E J W Bowie
Keyword(s):  
Factor Viii ◽  
Rat Liver ◽  
Blood Substitute ◽  
Factor Ix ◽  
Factor Vii ◽  
Clotting Factor ◽  
Isolated Perfused Rat Liver ◽  
Factor Xii ◽  
Factor V ◽  
Factor X

Measuring the release of small amounts of a clotting factor from an isolated perfused rat liver is difficult if the perfusate already contains some of the factor. Further, platelet-containing perfusates generate a coagulant activity that may invalidate clotting assays.We have successfully employed a completely synthetic blood substitute for rat liver perfusions. The perfusate is “Fluosol-43” generously furnished by Alpha Therapeutic Corporation. The oxygen-carrying perfluorochemical is FC-43 (perfluorotributylamine) and the substitute for albumin is hydroxyethyl starch. Using the Brauer perfusion technique, we found that rat livers in 5 hours released an average of 2.3% of the normal plasma concentration of prothrombin, 8.4% factor V, 16.2% factor VII, 7.0% factor IX, 3.7% factor X, 28.3% factor XI and 12.3% factor XII. Antithrombin III and plasminogen were also generated.Only minute amounts of factor VIII were released unless serum, cryoprecipitate or cryoprecipitate-free plasma was added; then the yield was 8.8% on average. The more “venom factor” (platelet aggregability with Bothrops alternata venom) added to the synthetic perfusate, the more factor VIII was released.

scholarly journals RASopathies and hemostatic abnormalities: key role of platelet dysfunction

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Francesca Di Candia ◽  
Valeria Marchetti ◽  
Ferdinando Cirillo ◽  
Alessandro Di Minno ◽  
Carmen Rosano ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Screening Tests ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Factor V ◽  
Bleeding Tendency ◽  
Factor X ◽  
Platelet Response ◽  
Platelet Dysfunction ◽  
Clotting Factors

Abstract Background Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. Patients and methods Forty-nine individuals (PTPN11, n = 27; SOS1, n = 7; RIT1, n = 3; SPRED1, n = 1; LZTR1, N = 3; RAF1, n = 2; BRAF, n = 4; MEK1, n = 1; MEK2, n = 1), and 49 age- and sex-matched controls were enrolled. The “Paediatric Bleeding Questionnaire Scoring Key” was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. Results Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11, 3 in SOS1, 2 in RIT1, 1 in BRAF, and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p = 0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV, p = 0.001), FVII (p = 0.003), FX (p = 0.0008) and FXIII (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with factor V (p = 0.002), factor VII (p = 0.003), factor X (p = 0.002) and factor XIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma (p = 0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with factor V levels (p = 0.03). Conclusions Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

Very Low Activated Factor VII and Reduced Factor VII Antigen in Familial Abetalipoproteinaemia

1998 ◽  
Vol 80 (08) ◽  
pp. 233-238 ◽  
Author(s):  
K. A. Mitropoulos ◽  
M. N. Nanjee ◽  
D. J. Howarth ◽  
J. C. Martin ◽  
M. P. Esnouf ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Positive Association ◽  
Factor Ix ◽  
Factor Vii ◽  
Unesterified Fatty Acid ◽  
Factor Xii ◽  
Factor X ◽  
Factor Xi ◽  
Activated Factor Vii ◽  
Normal Mean

SummaryAbetalipoproteinaemia is a rare disorder of apolipoprotein B metabolism associated with extremely low plasma concentrations of triglyce-ride. To discover whether the general positive association between factor VII and triglyceride levels extends to this condition, 5 patients were compared with 18 controls. All patients had a triglyceride below 100 μmol/l. Plasma unesterified fatty acid concentration was normal. Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B. The patients’ mean factor VII activity and factor VII antigen were also significantly reduced to 54% and 63% of those in controls, respectively. Mean factor XI activity and tissue factor pathway inhibitor activity were reduced in patients to 70% and 75% of control values respectively, while factor XII, factor XI antigen, factor X, prothrombin and protein C were normal.

Inhibitor treatment by rituximabin congenital haemophilia A

2009 ◽  
Vol 29 (02) ◽  
pp. 151-154 ◽  
Author(s):  
Escuriola Ettingshausen ◽  
R. Linde ◽  
G. Kropshofer ◽  
L.-B. Zimmerhackl ◽  
W. Kreuz ◽  
...  
Keyword(s):  
B Cell ◽  
Immune Tolerance ◽  
High Titre ◽  
Clotting Factor ◽  
Severe Bleeding ◽  
High Morbidity ◽  
Haemophilia A ◽  
Concomitant Treatment ◽  
Bleeding Tendency ◽  
Severe Haemophilia

SummaryThe development of neutralizing alloanti-bodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection. Conclusion: Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.

Self-Damping Mechanism in Blood Coagulation

1974 ◽  
Vol 32 (01) ◽  
pp. 057-064 ◽  
Author(s):  
Y Nemerson ◽  
S.A Silverberg ◽  
J Jesty
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Calcium Ions ◽  
Control Mechanism ◽  
Factor Vii ◽  
Damping Factor ◽  
Factor V ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Two Systems

SummaryTwo reactions of the extrinsic pathway of coagulation, the activations of Factor X and prothrombin, have been studied in purified systems and shown to be self-damping. Factor X was activated by the tissue factor - Factor VII complex, and prothrombin by two systems: the coagulant protein of Taipan venom, and the physiological complex of activated Factor X, Factor V, lipid, and calcium ions. In each case the yield of enzyme, activated Factor X or thrombin, is a function of the concentration of activator. These and other observations are considered as a basis for a control mechanism in coagulation.

The Lupus Inhibitor: A Study of Its Heterogeneity

1981 ◽  
Vol 46 (04) ◽  
pp. 734-739 ◽  
Author(s):  
M C Coots ◽  
M A Miller ◽  
H I Glueck
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Inhibitory Activity ◽  
Inhibition Test ◽  
Clotting Factor ◽  
Factor Xii ◽  
Factor V ◽  
Systemic Lupus ◽  
Factor Xi ◽  
Factor Specificity

SummaryThe plasmas of six patients with prolonged activated partial thromboplastin times were studied in detail. In five of the six, the Russell’s viper venom and prothrombin times were likewise prolonged. Five of the patients had documented systemic lupus erythematosus; one lacked the necessary criteria for this diagnosis. On quantitation, factor XI was decreased in all six; factors X and XII were diminished in five of the six. When tested for inhibitory activity, plasma from each of the patients prolonged the celite eluate inhibition test for factor XII and/or XI inhibition. In the formation of the Xa-V-phospholipid-Ca2+ complex (prothrombinase), factors X and Xa were inhibited to a greater degree than factor V or the phospholipid. Finally, each plasma was isofocused, the inhibitory fractions were identified and the clotting factor specificity of each inhibitory peak was determined.Fractions inhibitory against factors XI and XII isofocused with the IgG in each patient’s plasma. Based on the data presented from these six patients, the “lupus inhibitor” is in fact a heterogeneous collection of inhibitors directed against factors XII, XI and X rather than a homogeneous entity.

scholarly journals The Influence of Fibrinogen and Fibrin on Thrombin Generation - Evidence for Feedback Activation of the Clotting System by Clot Bound Thrombin

1994 ◽  
Vol 72 (05) ◽  
pp. 713-721 ◽  
Author(s):  
Rachana Kumar ◽  
Suzette Béguin ◽  
H Coenraad Hemker
Keyword(s):  
Snake Venom ◽  
Thrombin Generation ◽  
Platelet Rich Plasma ◽  
Lag Time ◽  
Factor Vii ◽  
Factor V ◽  
Clotting System ◽  
Platelet Poor Plasma ◽  
Normal Plasma ◽  
System Factor

SummaryIn plasma the bulk of thrombin generation takes place after a clot has formed. We therefore investigated in what way the clot influences thrombin generation in plasma. The forming clot withdraws thrombin from free solution. Consequently less thrombin activity is found and less thrombin-inhibitor complexes are formed. The thrombin that is adsorbed to the clot reduces the lag time before thrombin generation in intrinsically or extrinsically triggered platelet poor plasma as well as in platelet rich plasma. We investigated the mechanism of this activation.Clots were obtained by recalcification of plasma or by the addition of thrombin-like enzymes (Reptilase, Agihal) from snake venoms. They were thoroughly washed until the washing fluid was devoid of any detectable clotting enzyme activity. In platelet poor plasma (PPP), thrombin-induced clots shorten the factor Va-dependent lag-time of thrombin generation in the extrinsic system as well as the factor VUIa-dependent thrombin generation in the intrinsic system. Factor V or factor VII preparations that in itself hardly influence thrombin generation patterns aquire the capacity to shorten these lag-times when incubated with clot. The last washing fluid of the clot is inactive. Snake venom induced clots are not active either. Clots that are incubated in heparinised plasma for 1 h or more are as active as clots from normal plasma are. A role of factor Xa can not be excluded but must be minor because a clot made by addition of thrombin to plasma from which the factors II, VII, IX and X have been removed is as active as a clot from normal plasma is.When added to recalcified platelet rich plasma (PRP), in which the lag-time of thrombin formation is dependent upon activation of platelet procoagulant phospholipid activity, any type of clot shortens the lagtime before the burst of thrombin generation. Clots that are obtained by snake venom enzymes are also active in this system. This indicates that fibrin alone is capable to induce the procoagulant phospholipid activity in platelets.We conclude that three known thrombin-dependent feedback activations in the clotting system (factor V, factor VIII and platelets) are efficiently supported by thrombin bound to the fibrin clot and that there is an additional activating effect of fibrin on the procoagulant action of platelets.

scholarly journals Activation of human factor VII during clotting in vitro

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 218-226 ◽  
Author(s):  
LV Rao ◽  
SP Bajaj ◽  
SI Rapaport
Keyword(s):  
Tissue Factor ◽  
Glass Tube ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Factor Xii ◽  
Factor X ◽  
Normal Plasma

Abstract We have studied factor VII activation by measuring the ratio of factor VII clotting to coupled amidolytic activity (VIIc/VIIam) and cleavage of 125I-factor VII. In purified systems, a low concentration of Xa or a higher concentration of IXa rapidly activated 125I-factor VII, yielding a VIIc/VIIam ratio of 25 and similar gel profiles of heavy and light chain peaks of VIIa. On further incubation, VIIa activity diminished and a third 125I-peak appeared. When normal blood containing added 125I- factor VII was clotted in a glass tube, the VIIc/VIIam ratio rose fivefold, and 20% of the 125I-factor VII was cleaved. Clotting normal plasma in an activated partial thromboplastin time (APTT) system yielded a VIIc/VIIam ratio of 25 and over 90% cleavage of 125I-factor VII. Clotting factor XII-deficient plasma preincubated with antibodies to factor X in an APTT system with added XIa yielded a VIIc/VIIam ratio of 19 and about 60% cleavage, which indicates that IXa, at a concentration achievable in plasma, can effectively activate factor VII. Clotting normal plasma with undiluted tissue factor yielded a VIIc/VIIam ratio of 15 to 20 and 60% cleavage of 125I-factor VII, whereas clotting plasma with diluted tissue factor activated factor VII only minimally. We conclude that both Xa and IXa can function as significant activators of factor VII in in vitro clotting mixtures but believe that only small amounts of factor VII may be activated in vivo during hemostasis.

scholarly journals Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽  
1979 ◽  
Vol 53 (3) ◽  
pp. 366-374 ◽  
Author(s):  
LR Zacharski ◽  
R Rosenstein
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Coagulation Factors ◽  
Human Saliva ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Total Protein Content ◽  
Factor X ◽  
Clotting Factors

Abstract The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

Prothrombin Activation Is Increased among Asymptomatic Carriers of the Prothrombin G20210A and Factor V Arg506Gln Mutations

2000 ◽  
Vol 84 (09) ◽  
pp. 396-400 ◽  
Author(s):  
Steve Humphries ◽  
Belinda Smillie ◽  
Lily Li ◽  
Jacqueline Cooper ◽  
Samad Barzegar ◽  
...  
Keyword(s):  
Factor Viia ◽  
Conclusive Evidence ◽  
Factor Ix ◽  
Factor Vii ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Factor X ◽  
Coagulation Proteins ◽  
Prothrombin Activation

SummaryThe risk of venous thrombosis is increased in individuals who carry specific genetic abnormalities in blood coagulation proteins. Among Caucasians, the prothrombin G20210A and factor V Arg506Gln (FV R506Q) mutations are the most prevalent defects identified to date. We evaluated their influence on markers of coagulation activation among participants in the Second Northwick Park Heart Study, which recruited healthy men (aged 50–61 years) from nine general medical practices in England and Wales. They were free of clinical vascular disease and malignancy at the time of recruitment. Genotypes for the two mutations were analyzed using microplate array diagonal gel electrophoresis, and coagulation markers (factor XIIa; activation peptides of factor IX, factor X, and prothrombin; fibrinopeptide A) were measured by immunoassay. Factor VII coagulant activity and factor VIIa levels were determined by a functional clotting assay. Among 1548 men genotyped for both mutations, 28 (1.8%) and 52 (3.4%) were heterozygous for prothrombin G20210A and FV R506Q, respectively. The only coagulation marker that was significantly associated with the two mutations was prothrombin activation fragment F1+2 [mean ± SD, 0.88 ± 0.32 nmol/L in men with prothrombin G20210A (p = 0.002) and 0.89 ± 0.30 in men with FV R506Q (p = 0.0001) versus 0.72 ± 0.24 among non-carriers for either mutation]. This data provides conclusive evidence that heterozygosity for the prothrombin G20210A as well as the FV R506Q mutations in the general population leads to an increased rate of prothrombin activation in vivo.

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