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PubMedDate not supplied

Antithrombin III, plasminogen, plasmin, and alpha-2-antiplasmin in donor blood and plasma components.

The functional levels of antithrombin III, plasminogen, plasmin, and alpha-2-antiplasmin were evaluated in sequentially derived fresh frozen plasma, cryoprecipitate, and cryo-poor plasma aliquots from 20 registered blood donors. Antithrombin III is the major plasma inhibitor of the serine proteases of the procoagulant system. Plasminogen, the proenzymatic form of plasmin, is the primary endogenous profibrinolytic moiety; alpha-2-antiplasmin is the principal intermediate acting inhibitor of plasmin. As congenital or acquired deficiencies of antithrombin III and/or plasminogen predispose to thrombosis, and as these agents may be consumed in acute thrombosis, the goal of this investigation was to discern those plasma components which potentially might maximize both antithrombotic and fibrinolytic activities if used therapeutically. Using enzyme specific synthetic substrate methods, it was determined that no spontaneous plasmin activity was evident through phlebotomy or component processing and storage. Analysis of variance showed antithrombin III to be significantly decreased in cryoprecipitate as compared to the other components (p less than 0.0001). Furthermore, the level of antithrombin III or plasminogen in cryo-poor plasma and fresh frozen plasma was not statistically different. Also, the alpha-2-antiplasmin level was not statistically different among the specimen groups. Since fresh frozen plasma and cryo-poor plasma contain comparable total quantities of antithrombin III and plasminogen and as most of the activity of factors I, V, VIII, and XIII is diverted into cryoprecipitate, it is suggested that cryo-poor plasma may be preferable to fresh frozen plasma for the treatment of thrombosis associated with or complicated by antithrombin III and/or plasminogen deficiency.

Antithrombin III↗
PubMedDate not supplied

Allelic affinities between the F13A common gene products inferred by the analysis of an (AAAG)n STR polymorphism within the 5' untranslated region.

Factor XIII a subunit (F13A) is the last enzyme in the blood coagulation cascade. It is characterized by extensive genetic polymorphism defined by 4 common alleles, F13A*1A, 1B, 2A and 2B and a few rare variants, some responsible for severe coagulation deficiencies. In order to infer the evolutionary affinities between the common F13A alleles we have applied PCR techniques to study, in a Northern Portuguese sample, a short tandem repeat polymorphism located within the 5' untranslated region of the F13A gene. The analysis of the molecular heterogeneity within the F13A gene products revealed that the four biochemical variants shared very similar, truncated, distributions of STR alleles and showed no signs of predominant haplotypic associations. These findings seem to support both the inferences that intragenic recombination played an important role in the generation of molecular diversity within each of the four main F13A alleles and that all the four F13A alleles must be rather old. Molecular heterogeneity levels allowed the identification of 1B as the oldest F13A allelic state, and 2A as the most recently generated allele, but were not different enough to accurately track the divergence of alleles 1A and 2B. However, additional analysis of linkage disequilibrium patterns indicates that 1B-->2B-->1A-->2A is the most likely evolutionary order of appearance of F13A main protein alleles, confirming and extending a previous hypothetical model inferred from their molecular features.

5' Untranslated Regions↗
PubMedDate not supplied

[Besides fibrinogen, are haemostatic, coagulation and/or fibrinolytic parameters predictors or markers of the risk of cardiovascular events?].

Most cardiovascular events result from a thrombotic complication of atherosclerotic lesions. In arterial vessels such as the coronary bed, an interrelationship of haemostatic, coagulation and fibrinolytic factors is implicated. While it can be demonstrated that fibrinogen is a risk factor/marker, the role of other factors is not well established. Under arterial flow conditions, platelets are predominantly involved in the thrombotic reaction. Yet, apart from a large increase in the platelet count, the involvement of platelet parameters in cardiovascular risk is not clearly evident. The lack of definitive platelet markers is at least partly due to the difficulty of studying platelet function ex vivo. Several polymorphisms of platelet glycoproteins carrying a moderate increase in risk have been reported, but only in younger patients. One potentially important factor for coagulation is the fibrin structure, which is dependent on fibrinogen, the rate of thrombin generation, the activity of factor XIII and the interrelationship of the cells concerned, all of which act on its sensitivity to thrombosis. Coagulation factors largely affect the rate of thrombin generation. The activity of the fibrinolytic system (and principally any deficiency) has a role in the cardiovascular risk. General markers of cardiovascular risk such as D-dimers are potentially useful, but they increase with thrombin generation and are decreased by a deficiency in fibrinolysis. Furthermore, possibly because they are not indicative of the fibrin structure, they are poorly correlated with clinical events. The poor significance of the available haemostatic, coagulation and/or fibrinolytic parameters is probably due to their lack of representativeness, since haemostatic, coagulation and fibrinolytic systems are all involved in the thrombotic response (and some in atherogenesis itself). Atherogenesis is a multifactorial process and numerous moderate risk factors act in association. Better predictability of the haemostatic tests would probably result from both the design of more representative tests and the evaluation of multiple parameters, and would lead to the definition of a risk score. Technological advances will make this possible.

Biomarkers↗
PubMed1996

Molecular basis for protein S hereditary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. The French Network on Molecular Abnormalities Responsible for Protein C and Protein S Deficiencies.

Circulating protein S (PS) is partly bound to C4b-binding protein, and only free PS can act as a cofactor for protein C (PC), a natural anticoagulant. Two types of PS deficiencies are commonly observed in patients with unexplained thrombosis, and they are characterized by having both a low total PS level and a low free PS level (type I) or by having only a low free PS level (type IIa). To elucidate the genetic mechanisms responsible for these two plasma phenotypes, we screened 118 symptomatic patients with type I or type IIa PS deficiency for a PS gene coding sequence variation. A total of 34 mutations, 17 of which were novel, were identified in 65 propositi (70% in type I and 44% in type IIa). In type I deficiency, 29 different mutations were distributed throughout the coding sequence. In type IIa deficiency, five different missense mutations were clustered in exons XII and XIII, with a Ser 460 to Pro mutation accounting for most cases (82%). This points to a role of the domain encoded by exons XII and XIII in the distribution between bound and free PS. The Ser 460 to Pro mutation was associated with the factor V Arg 506 to Gin mutation or a PC gene mutation in about half the patients, suggesting a cooperative effect on clinical expression.

DNA Mutational Analysis↗
PubMed1982

Ultrastructure of clots during isometric contraction.

We explored the retraction or contraction of platelet-fibrin clots under isometric conditions. In the presence of micromolar calcium clots of normal platelet-rich plasma developed tension at an initial rate of 0.1 to 0.2 g/min per cm2 (initial cross-sectional area). Electron microscopy of clots fixed after attaining a force of 1.6 g/cm2 revealed platelets with elongated bodies and pseudopods in close apposition to fibrin strands which were oriented in cablelike fashion in the direction of tension. The development of tension could not be explained simply on the basis of platelet-platelet association and interaction alone. First, factor XIII-dependent cross-linking of fibrin fibers was critical to normal isometric contraction. Second, tension decreased linearly, rather than exponentially, when the platelet count in the platelet-fibrin clot was decreased, suggesting that platelets must be interacting with another component (i.e. fibrin). Thrombasthenic platelets, deficient in fibrinogen receptors, failed to develop tension or to align fibrin strands or pseudopods in the clot. Platelet-fibrin clots treated with vincristine to disassemble microtubules or cytochalasin B to disrupt microfilaments failed to develop tension and relaxed if these agents were added after tension had developed. Relaxation under these conditions, however, was not associated with loss of orientation of fibrin strands. Our findings suggest that platelet-fibrin interaction in clots under isometric conditions leads to orientation of fibrin strands and platelets in the direction of force generation. Tension develops as platelets simultaneously attach to and spread along fibrin strands, and contract. The contraction draws some fibrin into platelet-fibrin clumps and aligns other strands in the long axis of tension. The achievement and maintenance of maximum tension appears to depend on the development of platelet-fibrin attachments and extension of platelet bodies and long pseudopods containing bundles of microfilaments and microtubules along the oriented fibrin fibers.

Blood Platelets↗
PubMed2006

Contact activation prolongs clot lysis time in human plasma: role of thrombin-activatable fibrinolysis inhibitor and Factor XIII.

BACKGROUND: Contact activation system proteins (e.g., Factor XII, kallikrein) have been implicated as direct or indirect activators of plasminogen. However, contact activation and Factor XI have enhanced thrombin-activatable fibrinolysis inhibitor (TAFI) activation and decreased fibrinolysis, and Factor XIII (FXIII) also delays fibrinolysis via alpha(2)-anti-plasmin deposition on fibrin polymers. Thus, the goals of this study were to define how fibrinolysis is modulated in human plasma by contact or tissue factor (TF) activation, and what role TAFI and FXIII plays in this system. METHODS: Normal, TAFI-deficient and TAFI-deficient/FXIII-supplemented plasma was exposed to tissue-type plasminogen activator and activated with either celite or TF. Clot growth/disintegration kinetics were documented with thrombelastography. RESULTS: Normal plasma activated with celite had significantly prolonged onset and duration of clot lysis compared with samples activated with TF. TAFI-deficient plasma activated with celite was noted to have a duration of clot lysis not different from samples activated with TF, but a significant difference in time to onset of lysis persisted. Celite activation of TAFI-deficient/FXIII-supplemented plasma showed significantly prolonged onset and duration of clot lysis compared with samples activated with TF. CONCLUSIONS: Primarily TAFI, and to a lesser extent FXIII, contributed to contact system protein-mediated attenuation of fibrinolysis. Clinical investigation of these phenomena is warranted in clinical settings involving contact activation (e.g., intra-aortic balloon pumps and ventricular assist devices) to determine whether these devices modulate fibrinolysis and perhaps contribute to thromboembolic morbidity.

Carboxypeptidase B2↗
PubMed2005

Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers: a randomized, placebo-controlled, double-blind, multi-dose study.

Factor XIII (FXIII) is a plasma transglutaminase that covalently cross-links fibrin proteins to one another and to other proteins, increasing the mechanical strength of blood clots. Endogenous FXIII is the final enzyme in the clotting cascade and circulates as a heterotetramer comprising 2 FXIII-A subunits and 2 FXIII-B subunits. Recombinant human FXIII A2 (rFXIII) homodimer is produced in Saccharomyces cerevisiae. Upon injection, rFXIII combines with the free FXIIIB subunit that circulates in excess to form the rA2B2 tetramer. In this placebo-controlled, double-blind, multi-dose study, the safety, pharmacokinetics, and pharmacodynamics of rFXIII were studied in 24 healthy volunteers, who were randomized in 2 cohorts of 12 subjects each. In each cohort, 8 subjects received 5 daily intravenous doses of rFXIII (10 or 25 U/kg), and 4 subjects received placebo. Recombinant FXIII was well tolerated. No deaths or serious adverse events occurred. The type and frequency of adverse events showed no pattern or dose response. No clinically significant changes in haematology, serum chemistry, or urinalysis laboratory values were observed. No clinical coagulopathy or thrombosis was observed. Recombinant FXIII did not produce any anti-yeast or anti-FXIII antibodies. After 5 daily doses of rFXIII, accumulation indices indicated a 3 to 4fold accumulation of rFXIII in plasma. The elimination half-life, estimated for rFXIII as the heterotetramer, ranged from 228-346 hours for the 10U/kg dose group and 167-197 hours for the 25U/kg dose group. The safety, pharmacokinetic, and immunogenic profile of rFXIII suggests it may have potential use in patients with congenital or acquired FXIII deficiency.

Adolescent↗
PubMed1999

Four cases of bleeding diathesis in children due to congenital plasminogen activator inhibitor-1 deficiency.

Congenital plasminogen activator inhibitor-1 (PAI-1) deficiency is an extremely rare disorder characterized by a bleeding diathesis that begins in childhood due to hyperfibrinolysis as a result of decreased PAI-1 activity. We now present 4 unrelated pediatric cases of congenital PAI-1 deficiency. All 4 patients had a history of recurrent episodes of subcutaneous bleeding beginning in early childhood. These episodes were characterized by abnormal prolonged bleeding after trauma, tooth extraction, and surgical procedures, as well as by rebleeding following initial hemostasis. The 2 female patients both had symptoms compatible with hypermenorrhea. The family history was positive in 2 of the 4 patients. Hemostatic screening studies in all 4 patients revealed no abnormalities. Testing for factor XIII antigen, von Willebrand factor antigen, ristocetin cofactor activity, alpha(2)-plasmin inhibitor (alpha2PI) activity, and plasminogen activity was normal. The euglobulin lysis times were shortened in all cases as compared with those in normal control subjects. None of the patients had elevated tissue plasminogen activator (tPA) antigen levels, but PAI activity was markedly decreased in all cases. Three of the patients also had reduced levels of PAI-1 antigen. There tended to be a reduction in tPA-PAI-1 complex in all cases. In addition, 2 patients had elevated PIC (plasmin-alpha2PI complex). Tourniquet tests were performed in 2 patients, with no appreciable rise in PAI-1 activity or PAI-1 antigen levels. The administration of tranexamic acid clearly improved hemorrhagic symptoms in these patients. We considered PAI-1 deficiency to be the likely etiology of the congenital bleeding diatheses in these 4 cases.

Adolescent↗
PubMed2006

[Fibrin monomer and factor XIII: a new concept for unexplained intraoperative coagulopathy].

Unexplained intraoperative coagulopathies continue to be a diagnostic and therapeutic dilemma. The pathophysiology behind unexplained intraoperative coagulopathies is of great variety and complexity (preexisting coagulopathies, dilutional coagulopathy, interactions of medications etc.). We have shown in prospective studies that patients undergoing elective surgery who develop "unexplained" intraoperative coagulopathies have significantly less FXIII per unit thrombin available at any point in time (i.e. already preoperatively) than patients without such coagulopathies. The consequence is a significant loss of clot firmness associated with an increase in intraoperative blood loss. Thus, these patients have less cross-linking capacity to begin with, which explains their preoperatively increased fibrin monomer concentration. The association of increased preoperative fibrin monomer and increased intraoperative blood loss was prospectively evaluated and confirmed in a separate clinical study. It is important to note that the acquired or (compared to the amount of thrombin generated) relative F. XIII deficiency in situations with surgical stress shows early clinical relevance (even if only mild to moderate changes are present); this differs from the experiences with patients with inborn FXIII deficiency, where a pronounced deficiency must be present to have clinically significant spontaneous bleeding. Patients undergoing elective surgery, without clinically obvious coagulopathy but increased preoperative fibrin monomer concentration (as a marker of decreased crosslinking capacity) are at risk for increased intraoperative blood loss. This new concept helps to explain the pathophysiology behind unexplained intraoperative coagulopathies and thus allows for corresponding treatment strategies. Further clinical studies for early detection and interventions in patients with such coagulopathies are necessary.

Blood Coagulation↗
PubMed2004

Possible role of factor XIII subunit A in Fcgamma and complement receptor-mediated phagocytosis.

Besides its traditional role in hemostasis, factor XIII subunit A (FXIII-A) is supposed to function as a cellular transglutaminase and to be involved in certain intracellular processes, including cytoskeletal remodeling. To investigate its intracellular role, the aim of the present study was to follow changes in FXIII-A production in combination with the receptor-mediated phagocytic activities of monocytes/macrophages and to examine the phagocytic functions of monocytes in patients with FXIII-A deficiency. Human blood monocytes were isolated from the buffy coats of healthy volunteers and cultured for 4 days. The FcgammaR-mediated phagocytosis of sensitized erythrocytes (EA) and the complement receptor (CR)-mediated phagocytosis of complement-coated yeast particles were studied during monocyte/macrophage differentiation. Changes in the gene expression of FXIII-A were detected by real-time quantitative RT-PCR. FXIII-A protein production was investigated with fluorescent image analysis at single cell level and Western immunoblot analysis. Both the FcgammaR and CR-mediated phagocytosis increased during culturing, which peaked on day 3. The phagocytic activity of the cells could be markedly inhibited with monodansylcadaverine, an inhibitor of the transglutaminase-induced crosslinking of proteins. The phagocytosis of EA, complement-coated and uncoated yeast particles was found to be strongly diminished in monocytes of FXIII-A deficient patients. The phagocytic functions of cultured cells showed a change in parallel with the alterations in FXIII-A mRNA expression, as well as with that in FXIII-A in protein synthesis detected by image and Western immunoblot analyses in concert. Our results suggest that FXIII-A plays a role in the Fcgamma and complement receptor-mediated phagocytic activities of monocytes/macrophages.

Blotting, Western↗