Inherited thrombophilia: Part 1.
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Animals↗
Biomedical subjects
K A Bauer
Publications and source records attributed to K A Bauer.
Inherited thrombophilia: Part 2.
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Humans↗
Activation of the hemostatic mechanism during thrombolysis in patients with unstable angina pectoris.
In patients with myocardial infarction, thrombolytic therapy induces a paradoxical activation of the hemostatic mechanism. In patients with unstable angina, the effect of thrombolysis on the coagulation cascade is unknown. We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A in consecutive patients with unstable angina randomized to receive placebo alone (n = 23), streptokinase 1,500,000 IU over 1 hour followed by a 48-hour placebo infusion (n = 21), or streptokinase 250,000 over 1 hour followed by a continuous infusion of 100,000 IU per hour over 48 hours (n = 20). All the patients received intravenous heparin for 72 hours. The plasma levels of the different markers were measured at baseline, 90 minutes, 24 hours, and 48 hours after the start of therapy. The median baseline plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A were similar in the three treatment groups. In comparison with placebo, an increase in plasma prothrombin fragment 1 + 2 and fibrinopeptide A, was observed after 90 minutes in the two groups receiving thrombolysis. After 24 and 48 hours, the prothrombin fragment 1 + 2 levels remained significantly higher only in the patients receiving the 48-hour streptokinase infusion. In patients with unstable angina, thrombolytic therapy induces an activation of the hemostatic mechanism, despite concomitant heparin administration; in those receiving a prolonged streptokinase infusion, the activation of coagulation persists for as long as the drug is administered.
Aged↗
Determinants of plasma factor VIIa levels in humans.
Several enzymes can activate factor VII in vitro, but the protease responsible for generating factor VIIa in vivo has not been determined. Using recombinant tissue factor that has undergone a COOH-terminal truncation, a sensitive functional assay has been established for measuring plasma factor VIIa levels. To evaluate the mechanism responsible for the generation of factor VIIa in vivo, we measured the levels of this enzyme after administering purified concentrates of factor IX and factor VIII to patients with severe deficiencies of these clotting factors. In patients with hemophilia B, factor VIIa levels were initially reduced to 0.5 +/- 0.1 ng/mL and gradually increased to normal after infusing 100 U/kg of body weight (BW) of factor IX. Despite these increases, there were no significant changes in the generation of factor Xa or thrombin. In patients with hemophilia A, only a slight reduction in factor VIIa levels (2.5 +/- 1.3 ng/mL) was observed as compared with controls (3.3 +/- 1.1 ng/mL) and no significant changes were observed after factor VIII levels were normalized. The administration of recombinant factor VIIa (10 micrograms/kg BW) to patients with factor VII deficiency increased the mean circulating level of the enzyme to 118 ng/mL, but this only resulted in normalization of the levels of the activation peptides of factor IX and factor X. The above data indicate that factor IXa is primarily responsible for the basal levels of free factor VIIa generated in vivo (ie, in the absence of thrombosis or provocative stimuli) and that changes in the plasma concentrations of free factor VIIa in the blood do not necessarily lead to alterations in the extent of factor X activation.
Adolescent↗
Hypercoagulability in centenarians: the paradox of successful aging.
With advancing age, an increasing number of healthy individuals have laboratory signs of heightened coagulation enzyme activity. Such biochemical hypercoagulability might be the basis of either the increased thrombotic tendency occurring with age or a harmless manifestation of this process. To see whether these alterations are also present in the very elderly who had aged successfully, 25 healthy centenarians were studied and results of coagulation and fibrinolysis measurements were compared with those obtained in two control groups of healthy adults, 25 ranging in age from 18 to 50 years and 25 from 51 to 69 years. Older controls had, in general, slightly higher values of several coagulation and fibrinolysis measurements than younger controls. Centenarians had striking signs of heightened coagulation enzyme activity, as assessed directly by measuring activated factor VII in plasma (P < .01, compared with either control group) or indirectly by measuring the plasma levels of the activation peptides of prothrombin, factor IX, factor X, and thrombin-antithrombin complexes (all P < .001). Heightened coagulation enzyme activity was accompanied by signs of enhanced formation of fibrin (high fibrinopeptide A, P < .001) and secondary hyperfibrinolysis (high D-dimer and plasmin-antiplasmin complex, P < .001). Plasma concentrations of fibrinogen and factor VIII were higher than in controls, whereas other coagulation factors were not elevated. In conclusion, this study shows the very elderly do not escape the state of hypercoagulability associated with aging, but that this phenomenon is compatible with health and longevity. Hence, high plasma levels of the coagulation activation markers in older populations do not necessarily mirror a high risk of arterial or venous thrombosis.
Adolescent↗
Factor IXa inhibition by protease nexin-2/amyloid beta-protein precursor on phospholipid vesicles and cell membranes.
Protease nexin-2/amyloid beta-protein precursor (PN-2/A beta PP) is a Kunitz-type protease inhibitor which has been shown to be a tight-binding inhibitor of enzymes, factors XIa and IXa (FIXa), suggesting a role for this protein in hemostasis. Since coagulant reactions are modulated on biologic surfaces, we investigated how 25:75 (mol/mol) phosphatidylserine/phosphatidylcholine vesicles (PSPC), thrombin-activated platelets, or umbilical vein endothelial cells influence inactivation of FIXa by PN-2/A beta PP. The Km of human or porcine FIXa activation of human factor X in the presence of PSPC, activated platelets, or endothelial cells in the absence or presence of thrombin-activated factor VIII (FVIIIa) was similar, (0.05-0.39 microM). The presence of FVIIIa increased the catalytic efficiency (kcat/Km ratio) of human and porcine factor IXa's activation of factor X 4952-406-fold, respectively. In the presence of PSPC, the Ki of human and porcine FIXa inhibition by PN-2/A beta PP was Ki = 1.9 x 10(-9) M and 5.8 x 10(-9) M, respectively. After the addition of FVIIIa to the reaction, the Ki for both human and porcine FIXa inhibition by PN-2/A beta PP on PSPC increased 13- and 4-fold to Ki = 2.5 x 10(-8) M and 2.4 x 10(-8) M, respectively. These Ki for inhibition of human FIXa on phospholipid vesicles by PN-2/A beta PP were similar when factor X activation was measured by chromogenic or activation peptide release assays. FVIIIa reduced the inhibition of FIXa by PN-2/A beta PP only in the presence of PSPC.(ABSTRACT TRUNCATED AT 250 WORDS)
Amyloid beta-Protein Precursor↗
Thrombin generation and activity during thrombolysis and concomitant heparin therapy in patients with acute myocardial infarction.
OBJECTIVES: This prospective study investigated the behavior of thrombin generation and activity during thrombolysis and concomitant heparin administration. BACKGROUND: It has been shown that during thrombolytic therapy there is an increase in thrombin generation and activity. Increased thrombin activity is suppressed by concomitant intravenous heparin, but it is unknown whether thrombin generation is also affected. METHODS: Thrombin generation was assessed by measuring prothrombin fragment 1 + 2 and thrombin-antithrombin complex plasma levels and thrombin activity by measuring fibrinopeptide A plasma levels. Serial blood samples were obtained before and at 90 min and 24 and 48 h after the administration of streptokinase (15 patients), recombinant tissue-type plasminogen activator (15 patients) or anistreplase (13 patients). An intravenous bolus of heparin (5,000 IU) was administered before the start of thrombolytic therapy, followed by an infusion of 1,000 U/h to maintain an activated partial thromboplastin time > 1.5 times baseline. RESULTS: During thrombolytic and concomitant heparin therapy, there was an increase in the plasma levels of prothrombin fragment 1 + 2 (baseline 1.08 vs. 2.73 nmol/liter, p < 0.001) and thrombin-antithrombin complex (baseline 6.5 vs. 17.1 micrograms/ml, p < 0.01) at 90 min, whereas no change was observed in fibrinopeptide A at 90 min (baseline 2.8 vs. 3.0 nmol/liter, p = NS). CONCLUSIONS: During thrombolytic therapy with both fibrin-specific and non-fibrin-specific drugs, there is an increase in thrombin generation despite concomitant administration of intravenous heparin.
Aged↗
The effects of quality and timing of venepuncture on markers of blood coagulation in healthy middle-aged men.
Effects of the quality and the time of venepuncture on factor VII coagulant activity (VIIc) and the concentrations of fibrinogen, prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) were sought in 2665 men, of whom 2334 were re-examined after about one year. Venepunctures were categorised as satisfactory, not fully satisfactory or unsatisfactory according to pre-defined criteria. Neither the quality nor timing of the venepuncture influenced VIIc or fibrinogen concentration. However, at baseline and re-examination F1 + 2 and FPA were increased on average by about 9% and 45% respectively when venepunctures were not fully satisfactory, and by about 11% and 100% when unsatisfactory. Plasma collected after 1500 h had slightly but significantly lower levels of F1 + 2 and FPA than samples taken earlier, possibly due to circadian rhythm. The results emphasise the need for careful surveillance of the venepuncture procedure and the value of FPA when using F1 + 2 as a marker of risk of thrombosis.
Antigens↗
Management of patients with hereditary defects predisposing to thrombosis including pregnant women.
In general, the current recommendations for treating and prophylaxing thrombotic patients with hereditary defects are similar to those for thrombotic individuals without a defect. Determinations as to the need for long-term anticoagulation require that a clinical assessment be made regarding the relative benefit in preventing thrombotic episodes versus the risk of increased bleeding. With our newly found ability to identify genetic risk factors in a substantial fraction of patients with venous thrombosis and pulmonary embolism, it will be possible to perform rigorously designed studies to determine whether they should be managed with more prolonged or intense anticoagulation after a thrombotic event or more aggressive prophylactic regimens in high risk situations such as a total hip replacement.
Abnormalities, Drug-Induced↗
Low prevalence of the factor V Leiden mutation among "severe" hemophiliacs with a "milder" bleeding diathesis.
Patients with hemophilia A and B and factor levels than 1 percent of normal bleed frequently with an average number of spontaneous bleeding episodes of 20-30 or more. However there are patients with equally low levels of factor VIII or factor IX who bleed once or twice per year or not at all. To examine whether the presence of a hereditary defect predisposing to hypercoagulability might play a role in ameliorating the hemorrhagic tendency in these so-called "mild severe" hemophiliacs, we determined the prevalence of prothrombotic defects in 17 patients with hemophilia A and four patients with hemophilia B selected from 295 and 76 individuals with these disorders, respectively, followed at a large Italian hemophilia center. We tested for the presence of the Factor V Leiden mutation by PCR-amplifying a fragment of the factor V gene which contains the mutation site and then digesting the product with the restriction enzyme MnlI. None of the patients with hemophilia A and only one patient with hemophilia B was heterozygous for Factor V Leiden. None of the 21 patients had hereditary deficiencies of antithrombin III, protein C, or protein S. Our results indicate that the milder bleeding diathesis that is occasionally seen among Italian hemophiliacs with factor levels that are less than 1 percent cannot be explained by the concomitant expression of a known prothrombotic defect.
Factor V↗
Brief report: variability of thrombosis among homozygous siblings with resistance to activated protein C due to an Arg-->Gln mutation in the gene for factor V.
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Arginine↗
Molecular analysis of Polish patients with factor VII deficiency.
We analyzed the mutations in patients from 10 Polish kindreds with a bleeding diathesis due to factor VII deficiency. Patients from eight families had plasma levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) that were less than 4% of normal. The coding sequence of the factor VII gene was amplified from genomic DNA by polymerase chain reaction (PCR). Sequencing demonstrated a C to T transition at position 10798 resulting in Ala294Val, a G to A transition at 10976 resulting in Arg353Gln, and a single bp deletion at 11125 to 11128 causing a frameshift mutation in the triplet encoding amino acid 404. Homozygosity for the three sequence alterations was confirmed with the restriction enzymes AvaII and MspI and allele specific PCR, respectively. A homozygous patient from a ninth family with levels of VII:C and VII:Ag of 4% and 17%, respectively, had Ala294Val and the frameshift mutation, but not Arg353Gln. Investigation of a homozygous patient from a tenth kindred with VII:C and VII:Ag of 11% and 47%, respectively, demonstrated Ala294Val and Arg353Gln, but not the frameshift mutation. Based on the above data, we conclude that the frameshift mutation in the codon for amino acid 404 is associated with marked reductions in VII:C, Arg353Gln can decrease plasma levels of factor VII in the presence of other mutations in the factor VII gene, and Ala294Val results in a dysfunctional factor VII molecule.
Alleles↗
Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients.
Virally inactivated, high-purity factor XI concentrates are available for treatment of patients with factor XI deficiency. However, preliminary experience indicates that some preparations may be thrombogenic. We evaluated whether a highly purified concentrate produced signs of activation of the coagulation cascade in two patients with severe factor XI deficiency infused before and after surgery. Signs of heightened enzymatic activity of the common pathway of coagulation (elevated plasma levels of prothrombin fragment 1 + 2 and fibrinopeptide A) developed in the early post-infusion period, accompanied by more delayed signs of fibrin formation with secondary hyperfibrinolysis (elevated D-dimer and plasmin-antiplasmin complex). These changes occurred in both patients, but were more severe in the older patient with breast cancer when she underwent surgery, being accompanied by fibrinogen and platelet consumption. There were no concomitant signs of heightened activity of the factor VII-tissue factor mechanism on the factor Xase complex (plasma levels of activated factor VII and of factor IX and X activation peptides did not increase). The observed changes in biochemical markers of coagulation activation indicate that concentrate infusions increased thrombin generation and activity and that such changes were magnified by malignancy and surgery. Because some factor XI concentrates may be thrombogenic, they should be used with caution, especially in patients with other risk factors for thrombosis.
Adult↗
Hypercoagulability--a new cofactor in the protein C anticoagulant pathway.
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Blood Coagulation↗
Activation markers of coagulation.
Advances in our understanding of the biochemistry of the haemostatic mechanism have led to the development of sensitive methods for measuring peptides, enzyme-inhibitor complexes or enzymes that are liberated with the activation of the coagulation system in vivo. Studies employing these markers indicate that a biochemical imbalance between procoagulant and anticoagulant mechanisms can be detected in the blood of humans prior to the appearance of thrombotic phenomena. Properly designed prospective studies will be required to determine whether these assay techniques will enable us to identify individuals who are entering a clinically relevant hypercoagulable state, and intervene with appropriate therapy prior to the onset of overt thrombotic disease.
Animals↗
Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.
BACKGROUND: The blood coagulation system is activated in the acute phase of unstable angina and acute myocardial infarction. However, it remains unclear whether augmented function of the hemostatic mechanism serves only as a marker of the acute thrombotic episode or whether a hypercoagulable state persists for a prolonged period after clinical stabilization. METHODS AND RESULTS: We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) in consecutive patients presenting with unstable angina (n = 81) or acute myocardial infarction (n = 32), respectively. At 6 months, plasma determinations were repeated in patients experiencing an uneventful clinical course (unstable angina, n = 57; myocardial infarction, n = 23). We quantitated the plasma levels of F1 + 2 and FPA in control patients with stable angina (n = 37) or healthy individuals (n = 32) who were matched for age and sex. The median plasma concentrations of F1 + 2 and FPA are significantly higher in patients presenting with unstable angina (F1 + 2, 1.08 nmol/L; FPA, 2.4 nmol/L) or acute myocardial infarction (F1 + 2, 1.27 nmol/L; FPA, 3.55 nmol/L) compared with patients with stable angina (F1 + 2, 0.74 nmol/L; FPA, 1.3 nmol/L; P < .0001) or healthy individuals (F1 + 2, 0.71 nmol/L; FPA, 0.80 nmol/L; P < .0001). At 6 months, the median plasma levels of F1 + 2 in patients exhibiting an uneventful clinical course did not differ from values obtained at admission (unstable angina, 1.26 versus 1.07 nmol/L, P = NS; myocardial infarction, 1.22 versus 1.29 nmol/L, P = NS), whereas the median plasma levels of FPA in the same two subpopulations were significantly reduced (unstable angina, 1.1 versus 2.9 nmol/L, P = .0003; myocardial infarction, 1.1 versus 3.0 nmol/L; P = .0028). CONCLUSIONS: During the acute phase of unstable angina and myocardial infarction, patients exhibit increased coagulation system activity. Over the next 6 months, patients with unstable angina or myocardial infarction experiencing an uneventful clinical course manifest a persistent hypercoagulable state with minimal generation of fibrin.
Adult↗
Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees.
Knowledge of the pathogenetic mechanisms responsible for the activation of the coagulation system associated with endotoxemia is important for the development of improved modalities for prevention and treatment. We analyzed the appearance in plasma of TNF, IL-6, and indices of coagulation and fibrinolytic system activation in normal chimpanzees after intravenous infusion of endotoxin. Endotoxin infusion elicited reproducible and dose-dependent elevations in serum TNF and IL-6, as well as marked increases in thrombin generation in vivo as measured by immunoassays for prothrombin activation fragment F1 + 2, thrombin-antithrombin III complexes, and fibrinopeptide A. Activation of the fibrinolytic mechanism was monitored with assays for plasminogen activator activity and plasmin-alpha 2-antiplasmin complexes. To potentially intervene in the molecular pathways elicited by endotoxin, pentoxifylline, an agent that interrupts "immediate early" gene activation by monocytes, or a potent monoclonal antibody that neutralizes tissue factor-mediated initiation of coagulation, were infused shortly before endotoxin. Pentoxifylline markedly inhibited increases in the levels of TNF and IL-6, as well as the effects on coagulation and fibrinolysis. In contrast, the monoclonal antibody to tissue factor completely abrogated the augmentation in thrombin generation, but had no effect on cytokine levels or fibrinolysis. We conclude that the endotoxin-induced activation of coagulation appears to be mediated by the tissue factor-dependent pathway, the fibrinolytic response triggered by endotoxin is not dependent on the generation of thrombin, and that the release of cytokines may be important in mediating the activation of both the coagulation and the fibrinolytic mechanisms in vivo.
Animals↗
Markers of hypercoagulability in patients with hemophilia B given repeated, large doses of factor IX concentrates during and after surgery.
Purer factor IX (FIX) concentrates have been produced for the treatment of hemophilia B in the attempt to reduce the risk of thrombotic complications associated with the use of prothrombin complex concentrates. To evaluate ex vivo whether or not FIX concentrates activate the coagulation system in conditions associated with a high risk for thrombosis, we measured markers of hypercoagulability in 10 patients with hemophilia B who underwent surgery, mainly orthopedic procedures, covered by multiple concentrate infusions (40-80 U/kg/day). Postinfusion plasma levels of prothrombin fragment 1 + 2 and factor X activation peptide did not differ significantly from the presurgical levels, neither before nor after each concentrate dose. Therefore, it appears that prolonged treatment of patients with hemophilia B undergoing high risk surgical procedures with high doses of FIX concentrate does not cause systemic activation of coagulation. This suggests that purified FIX concentrates are preferable to prothrombin complex concentrates for conditions associated with an increased risk of thrombosis.
Adolescent↗