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PubMed1993

A unique pattern of coagulation abnormalities in carbohydrate-deficient glycoprotein syndrome.

The carbohydrate-deficient glycoprotein syndromes are a recently individualized group of genetic multisystemic disorders. A predominant feature is a severe involvement of the central and peripheral nervous system resulting in psychomotor retardation, seizures, ataxia, and, mostly after infancy, stroke-like episodes. The hallmark biochemical feature is a carbohydrate deficiency in a large number of serum glycoproteins. Because coagulation factors and inhibitors are also glycoproteins, we performed a systematic study of these factors and inhibitors in nine patients with carbohydrate-deficient glycoprotein syndrome. All showed a decreased activity of factor XI and of the coagulation inhibitors antithrombin III and protein C. In five of seven patients more than 1 y old, there was also a (less pronounced) decrease of protein S and of heparin cofactor II. This combined coagulation inhibitor deficiency could explain the stroke-like episodes occurring in these children.

Adolescent↗
PubMed1984

Prolonged activated partial thromboplastin time and deficiency of high molecular weight kininogen in brown Norway rat mutant (Katholiek strain).

Activated partial thromboplastin time (APTT) was examined in Brown Norway (B/N) Katholiek rat, which was previously reported as high molecular weight kininogen deficient. APTT of B/N Katholiek was prolonged to 35 sec in comparison with B/N Kitasato and SD rat, showing APTT of 22-24 sec. The mixture of B/N Katholiek plasma and B/N Kitasato plasma (1:1) showed normal APTT value. B/N Katholiek plasma corrected the abnormally prolonged human coagulation factor deficient plasmas, such as XI, XII and prekallikrein deficient plasmas, while it did not correct the APTT of HMW kininogen deficient, Fitzgerald plasma. Intravenous injection of bromelain, which was previously reported to produce prolonged hypotension through the activation of factor XII to release bradykinin, induced slight effect in Katholiek rat, while in Kitasato rat it showed prolonged hypotension in similar degree as SD rat. Contents of coagulation factors in B/N Katholiek thus measured as well as the values of prekallikrein and HMW kininogen previously reported were summarized and suggested that B/N Katholiek rat could be similar deficiency as Fitzgerald trait.

Animals↗
PubMed1993

Evaluation of solvent/detergent treated plasma in the management of patients with hereditary and acquired coagulation disorders.

Haemostatic efficacy and pharmacokinetic analysis of solvent/detergent (S/D) treated, virus inactivated plasma (Octaplas, Germany) was evaluated in eight patients with hereditary factor VII, X and XI deficiency and in three patients with acquired coagulation disorders due to liver disease. The patients received the S/D plasma for treatment of haemarthrosis, menorrhagia or before surgical procedures. In all the patients the S/D plasma was sufficient to prevent or stop bleeding. Side effects included urticaria (one patient) and moderate anaphylactoid reaction (one patient). No evidence of plasma-born viral infections was observed up to 12 months after the treatment (95% confidence limits 0-22%). Calculated mean half-life of coagulation factors VII, X and XI was 4.36 h, 49.21 h and 44.5 h, respectively, similar to that observed with fresh-frozen plasma. Because of retained coagulation factor integrity and improved viral safety, S/D plasma could be considered a superior alternative to standard fresh-frozen plasma.

Adult↗
PubMed1997

Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy.

In type 1 Gaucher disease a bleeding tendency occurs which is partly caused by thrombocytopenia due to massive splenomegaly. In addition, low levels of factors IX and XI have been described. The mechanism responsible for these clotting factor abnormalities is unknown. We performed a detailed study of parameters of coagulation and fibrinolysis in 30 type 1 Gaucher disease patients (14 splenectomized) before and after treatment with enzyme supplementation therapy. Pre-treatment aPTT and PT were prolonged in 42% and 38% of patients, respectively. In 30-60% serious deficiencies (< 50%) of coagulation factors XI, XII, VII, X, V and II were observed. The low levels of factor V correlated with platelet count and were inversely associated with splenic volume. Levels of inhibitors were mildly decreased. Markers for activation of coagulation (thrombin-antithrombin (TAT) complex) and fibrinolysis (PAP complex, fibrin cleavage product D-dimer) were significantly elevated, especially in the splenectomized patients, indicating ongoing activation of these processes. After 12 months of enzyme supplementation therapy partial correction occurred. Thus, severe disorders of the coagulation system occur in Gaucher disease, contributing to the bleeding tendency. The deficiencies may be the result of consumption of coagulation factors caused by ongoing low-level coagulation activation. possibly due to mononuclear cell activation.

Adult↗
PubMed1965

A study of antihaemophilic globulin (factor VIII) consumption.

A study has been made of the rate of disappearance of factor VIII during the clotting of normal plasma samples and of samples deficient in factors V, VII, IX, X, XI and XII. The rate of disappearance (or consumption) of factor VIII was the same in the normal and factor VII deficient samples. Delayed disappearance of factor VIII was observed in samples deficient in factors V, IX, X, XI and XII. The significance of the findings to the theory of blood coagulation is discussed.

Blood Coagulation↗
PubMedDate not supplied

Fletcher factor deficiency (Report of a new case).

A new case of Fletcher factor (prekallikrein) deficiency is described. The patient did not have any abnormal bleeding tendency, but showed defective intrinsic thromboplastin production and reduced fibrinolytic system activity; he had no factor VIII, IX, XI and XII deficiencies. His plasma did not contain any detectable prekallikrein levels.

Adult↗
PubMed2001

In vitro factor XI activation mechanism according to an optimized model of activated partial thromboplastin time test.

Whether the in vitro activation of factor XI in plasma is mediated by thrombin or by auto-activation remains a controversial question. In this context, we have simulated theoretical activated partial thromboplastin time (aPTT) by means of a program based on a body of 22 essential elementary reactions implemented with rate constants quoted in current literature. To meet self-consistency in input data issued from varying sources, the results were optimized using the simplex treatment. The performance of the model was systematically evaluated considering the extent of the deviations observed between predicted aPTT and laboratory measurements conducted on normal and factor VIII, IX, XI and XII single-factor deficient plasma. The influence of the auto-activation or thrombin-mediated activation of factor XI on these aPTTs was tested separately after insertion of these reactions in the model. According to the best fits, a mechanism accounting for an auto-activation reaction of activated factor XI rather than a positive feedback reaction mediated by thrombin seemed more likely. Based on this conclusion, a chart of self-consistent rate constant values accounting for the intrinsic pathway of coagulation under static conditions is proposed.

Blood Coagulation↗
PubMed1990

The RIIIS/J inbred mouse strain as a model for von Willebrand disease.

Mice of the RIIIS/J inbred strain have prolonged bleeding times (greater than 15 minutes) after experimental injury when compared with normal C57BL/6J mice (1.8 minutes) and other strains of mice. The prolonged bleeding time was accompanied by normal platelet counts. Platelet aggregation with collagen and agglutination with ristocetin were not significantly altered in RIIIS/J mice. Also, platelets from RIIIS/J mice had normal serotonin content and normal numbers of dense granules by electron microscopy. Thus, the bleeding abnormality is not due to platelet storage pool deficiency as has been found in several other mouse mutants. The activated partial thromboplastin time (APTT) which plasma from RIIIS/J mice was prolonged compared with normal mice, and factor VIII:C activity and von Willebrand antigen levels were one half to one third that of normal mouse plasma. Factor XI activity was also significantly deficient (levels at 42% to 64% of normal). Plasma of RIIIS/J mice contained the full complement of multimers of von Willebrand factor, although each multimer was lower in concentration compared with that in normal mice. Platelet alpha-granule von Willebrand antigen levels were similar to those of normal mice. The prolonged bleeding time of RIIIS/J mice was corrected by treatment with desmopressin. Heterozygous C57BL/6J x RIIIS/J F1 animals had low plasma von Willebrand antigen levels like the RIIIS/J parent and had variable bleeding times. Inheritance of the bleeding tendency was as an incomplete dominant, autosomal trait. These data indicate the RIIIS/J strain is a suitable animal model for type IA von Willebrand disease.

Animals↗
PubMed2004

[Congenital deficiencies of coagulation factors and acquired inhibitors leading to bleeding disorders].

This review focuses on symptoms, course and treatment of bleeding disorders due to hereditary coagulation factor deficiencies and acquired inhibitors, mentioning as well the pathophysiologic and molecular genetic aspects and diagnostic particularities. The review of haemophilia A and B deals with carrier problems, replacement therapy, additional haemostatic agents such as antifibrinolytics and desmopressin, the treatment of typical haemorrhages, haemophilia with inhibitors and future therapeutic options. Of the autosomal homozygous bleeding disorders such as von Willebrand disease type 3, afibrinogenaemia, factor XIII-, VII- and XI-deficiency each has its particularities influencing treatment strategies. The last chapter discusses acquired bleeding disorders such as acquired haemophilia A, von Willebrand disease, factor V deficiency and the hypoprothrombinaemia lupus anticoagulant syndrome, the different modes of inhibition, diagnostics and principles of treatment.

Blood Coagulation Disorders↗
PubMed1989

[Physiopathology of kinin forming system in reproduction].

We studied contact factors and kinin-kallikrein in normal non-pregnant and pregnant women, FXII deficient toxemia and DIC. The results obtained are as follows: 1. The levels of plasma prekallikrein, high molecular weight kininogen, kallikrein inhibitor, and C-1 INA were gradually decreased at delivery, and the levels of kallikrein like activity and bradykinin were increased during pregnancy and at the time of parturition. These facts indicate that kinin kallikrein systems played important role in uterine contraction. 2. The levels of contact factors (FXII and FXI) were lower at delivery than those of term. 3. In rat uterus, specific binding of bradykinin was observed by the method of radio receptor assay in the pelet of 10,000 X g fetal membranes, and its activity was 38%. 4. A synthetic kallikrein inhibitor (OS-291, MS) and bradykinin antagonist inhibited completely spontaneous uterine contraction of Wistar rats during delivery. 5. In the case of FXII deficiency, the levels of plasma prekallikrein, high molecular weight kininogen were normal, but at delivery, these levels were lower than those of term. The levels of kallikrein like activity which was half of normal parturition level was increased at parturition. 6. In cases of DIC (17) and severe toxemia (22), plasma prekallikrein levels were lower than the normal controls. The decrease was due to consumption of plasma prekallikrein to kallikrein activation.

Animals↗
PubMed2004

Real-time quantitative PCR analysis of factor XI mRNA variants in human platelets.

Coagulation factor XI (FXI) plays an essential role in blood coagulation. A deficiency of FXI is an unusual hemorrhagic diathesis in that the bleeding tendency can be highly variable, ranging from severe deficiencies with no symptoms to mild and moderate deficiencies requiring multiple blood transfusions for hemorrhages. This variability in bleeding has been attributed to a number of factors including the presence of a novel form of FXI associated with platelets, which ameliorates the bleeding in some cases of FXI deficiency. However, the nature of this platelet FXI molecule is controversial. Hsu et al. (J Biol Chem 1998; 273: 13787-93) suggest that it is a product of normal FXI - but lacking exon V whilst Martincic et al. (Blood 1999; 94: 3397-404) were unable to detect this alternatively spliced variant using RT-PCR. In order to resolve this controversy, we have employed the highly sensitive technique of real-time quantitative RT-PCR using RNA isolated from FXI-deficient patients. Our results indicate that the platelets of both normal and FXI deficient individuals contain FXI mRNA that is identical to the mRNA found in liver. An exon V deleted splice variant was not detected. Thus the FXI message is not alternatively spliced in platelets and therefore would not be able to produce an unusual FXI protein.

Alternative Splicing↗
PubMed2002

Changes in high molecular weight kininogen levels during and after cardiopulmonary bypass surgery measured using a chromogenic peptide substrate assay.

High molecular weight kininogen (HK) is a co-factor in the blood-contact activation system. A chromogenic peptide substrate assay for HK (HKcs) has been developed in which test plasmas are mixed with diluted HK-deficient plasma and incubated with a soluble contact system activator that activates prekallikrein and factor XII. Calcium chloride, a synthetic thrombin inhibitor and a chromogenic peptide substrate for activated factor X (FXa) are then added. The FXa generated cleaves the FXa substrate releasing p-nitroanaline, which is measured photometrically. Test plasma HK values were calculated from a standard curve generated using a pooled normal plasma. Acceptable intra-assay and inter-assay precision values were obtained and levels of HK up to 200% were measurable. The assay measured HK in plasmas deficient in factor XII, prekallikrein and factor XI, was not affected by antiphospholipid antibodies and gave an acceptable correlation (r = 0.95) when normal plasmas and mixtures of HK-deficient and normal pooled plasma, calculated to give HK levels of 25 and 50%, were compared using HKcs and a HK one-stage clotting assay. The HKcs was used to measure HK levels in seven patients undergoing cardiopulmonary bypass (CPB). HK levels fell significantly during CPB (P = 0.0014) and were significantly higher (P = 0.016) 6 days after CPB, suggesting that HK may be a positive acute-phase reacting protein.

Acute-Phase Proteins↗
PubMed1995

The rarer inherited coagulation disorders: a review.

Of the inherited bleeding disorders, haemophilia A, haemophilia B and von Willebrand's disease make up together well over 80% of those registered with the UK Haemophilia Centre Directors. The common simple screening tests of coagulation may overlook some of the more rare disorders and it is clearly important that such uncommon bleeding disorders are excluded during the course of the investigation of children considered to be suffering from non-accidental injury. In this article, some of the rare inherited bleeding disorders are considered, including haemophilia B Leyden, deficiencies of factors VII, X, XI, and XII, as well as inherited defects of platelet number and function. Presenting features are described and recommendations regarding appropriate therapy given. In order to assist in advancing understanding of the biochemistry and molecular genetics of these disorders, clinicians are encouraged to share clinical information and, where appropriate, blood samples with interested research workers.

Blood Coagulation Disorders↗
PubMed1994

Coagulation factors and markers of activation of coagulation in homocystinuria (HOCY): a study in two siblings.

Homocystinuria due to cystathionine-beta-synthase deficiency (CBS-def-HOCY) initially often present with thromboembolic events. In most cases in which coagulation factors have been analysed, a deficiency of AT-IIIc and factor VIIc has been reported, the cause of which has not been elucidated. Activation of coagulation with consumption of coagulation factors has been postulated as the mechanism. This paper reports a longitudinal study of two patients: patient 1 with thromboembolic disease and his asymptomatic sister, patient 2. Before start of therapy in patient 1, a reduction of FVIIc, other coagulation factors, and AT-IIIc was found. Markers of activation of coagulation (F1 + 2, TAT, FM, D-dimers) were elevated only in patient 1, and only at the time of thrombotic complications. In patient 2 reduced levels of FVIIc and other coagulation proteins, and a low borderline AT-IIIc level was found. Thus, in the two patients, sustained activation of coagulation can be reasonably excluded to be the cause of low levels of coagulation proteins. Vitamin therapy with 15 mg folate and 600 mg pyridoxine per day led to almost complete normalization of amino acids in urine and plasma. Thrombosis has not recurred to date. FVIIc and the other coagulation proteins and AT-IIIc increased in parallel with the biochemical remission. Direct inhibition of the activity of AT-III and coagulation factor VIII and other factors by homocysteine was attempted in vitro but could not be shown at HC concentrations known to occur in the plasma of HOCY patients. Therefore, in these patients, deficient synthesis of coagulation factors and AT-III due to a disturbance of amino acid metabolism is still the most probable explanation for the observed low levels.

Adult↗
PubMed1976

Procoagulant and platelet aggregating properties of antilymphocyte sera.

Ten anti-human lymphocyte sera in clinical use at six transplant centers and five anti-nonhuman lymphocyte sera were studied for their procoagulant and platelet-aggregating properties. This investigation was initiated following the observation of a clinical episode of renal artery thrombosis, associated with the use of one of the sera in a patient who had received a cadaveric renal transplant. The procoagulant from this serum shortened the clotting times of individual samples deficient, respectively, in factors XII, XI IX, X VIII, and VII. Esterolytic activity, demonstrated on the substrate benzoylarginine ethyl ester, was completely inhibited by phenylmethylsulfonyl fluoride, but coagulant activity was variably affected. The platelet-aggregating activity (PAA) has been identified as a complement-fixing gamma G antibody that was absorbed from the antilymphocyte serum (ALS) with human spleen lymphocytes. Five of the ten anti-human lymphocyte sera showed varying procoagulant activity (PCA), and six sera demonstrated PAA. Three sera contained both activities. The presence of both PCA and PAA in the same preparation may predispose patients to thrombotic events, particularly if administered intravenously. Sera should be screened for PCA and PAA prior to clinical use, and sera with these properties should be used with caution.

Animals↗
PubMedDate not supplied

Rheological approach to the analysis of blood coagulation in endothelial cell-coated tubes: activation of the intrinsic reaction on the erythrocyte surface.

Coagulation of blood in cultured endothelial cell-coated tubes was examined using a rheological technique. Coagulation of recalcified, platelet-free plasma in contact with an endothelial cell monolayer did not occur within the experimental time period (more than 150 min). The endothelial cell surface did not activate the intrinsic coagulation reaction or the extrinsic coagulation reaction initiated by tissue factor. The time of onset of coagulation in platelet-free plasma supplemented with erythrocytes was nearly the same as that of whole blood (31.2 +/- 5.5 min), which was shorter than that for platelet-rich plasma (54.3 +/- 14.3 min) and platelet-free plasma supplemented with granulocytes (58.3 +/- 6.3 min). In factor VII-, XI- or XII-deficient, platelet-free plasma supplemented with erythrocytes, the time of onset of coagulation was about 30 min. The coagulation of factor IX-deficient, platelet-free plasma supplemented with erythrocytes, however, did not occur within the experimental time period. These data suggest that activation of factor IX on the erythrocyte surface is capable of activating the intrinsic coagulation system.

Adult↗
PubMed2000

Nonsense mutation in exon V of the factor XI gene does not abolish platelet factor XI expression.

Factor XI (FXI) is a plasma glycoprotein produced by the liver that plays an essential role in blood coagulation. Individuals deficient in this protein are prone to bleeding following trauma or surgery. Well-washed platelets possess FXI-like activity and FXI antigen that differs in molecular weight from plasma FXI and is associated with FXI mRNA from platelets in which exon V is absent. Some individuals deficient in plasma FXI produce the platelet form of the protein. The molecular basis for the presence of platelet FXI in plasma FXI-deficient patients is unknown. In the current study, to help determine the mechanism for this differential expression, the FXI genotype was determined for three plasma FXI-deficient individuals who express platelet FXI. All three individuals had a nonsense mutation encoding a stop codon in exon V of the FXI gene that would result in a severely truncated polypeptide. An exon V nonsense mutation in the FXI gene combined with the absence of exon V in platelet FXI mRNA provides a plausible mechanism for the differential expression of platelet FXI in plasma FXI-deficient patients.

Blood Platelets↗