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PubMed1992

Studies of surface activated coagulation: antisera binding onto methyl gradients on silicon incubated in human plasma in vitro.

Human plasma proteins factor XII, high molecular weight kininogen, prekallikrein, factor XI and fibrinogen, participate in surface-initiated coagulation. Antisera binding to methyl gradients made on hydrophilic silicon was studied after immersion in normal and deficient human blood plasma. Scanning ellipsometry was used to quantify the adsorbed organic material. The hydrophilic part of the gradient deposited anti-factor XII and anti-high molecular weight kininogen, but low amounts of anti-fibrinogen. Increased amounts of anti-fibrinogen bound onto the hydrophobic part, and the intermediate gradient region with mixed polar-nonpolar surface characteristics bound low amounts of anti-factor XII, anti-high molecular weight kininogen and anti-fibrinogen. Tentatively, in this gradient region, simultaneous polar and non-polar surface characteristics result in a low-level of surface-activated coagulation. Surfaces immersed in heparinized-and EDTA-plasma indicate different antisera depositions.

Adsorption↗
PubMed1992

Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase.

Severe bleeding resulting from excessive fibrinolysis has been observed in patients with primary amyloidosis. The authors studied a patient with this hemostatic disorder before and during therapy with epsilon-aminocaproic acid. Excessive fibrinolysis was associated with depressed plasma concentrations of coagulation Factors XII, XI, high-molecular-weight kininogen, and Factors VIII and V; and plasminogen and alpha-2-plasmin inhibitor. These deficiencies were corrected with treatment. The functional and antigenic concentrations of tissue plasminogen activator and plasminogen activator inhibitor in the patient's plasma were normal. Urokinase-type activator activity and antigen were three to five times elevated in the patient's plasma. Results of immunoprecipitation showed that single-chain urokinase-type activator was the primary urokinase-type activator species in the patient's plasma. Excessive fibrinolysis in patients with amyloidosis results from increased plasma single-chain urokinase-type activator activity.

Amyloidosis↗
PubMed2004

Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo.

To analyze the biological role of factor XII (FXII, Hageman Factor) in vivo, we generated mice deficient for FXII using a gene targeting approach on two distinct genetic backgrounds, i.e. mixed C57Bl/6J X 129X1/SvJ and inbred 129X1/SvJ. Homozygous FXII knockout (FXII(-)/(-)) mice showed no FXII plasma activity and had a markedly prolonged activated partial thromboplastin time (aPTT). In contrast, coagulation factors XI, VIII, IX, X,VII, V, II and fibrinogen did not differ between FXII(-/-) mice and their wild-type littermates. Heterozygous matings segregated according to the Mendelian inheritance indicating that FXII deficiency does not increase fetal loss. Furthermore, matings of FXII(-/-) males and FXII(-/-) females resulted in normal litter sizes demonstrating that total FXII deficiency in FXII(-/-) females does not affect pregnancy outcome. Also, gross and histological anatomy of FXII(-/-) mice was indistinguishable from that of their wild-type littermates on both genetic backgrounds. Thus it appears that deficiency of murine FXII does not cause thrombophilia or impaired fibrinolysis in vivo. These results indicate that FXII deficiency does not affect hemostasis in vivo and we anticipate that the FXII(-/-) mice will be helpful to elucidate the biological role(s) of FXII in health and disease.

Animals↗
PubMed2004

Beta 2 glycoprotein I--function in health and disease.

Beta-2 glycoprotein I (beta2GPI) is the principal target of autoantibodies in the antiphospholipid syndrome (APS). It is abundant in human plasma and shares high homology between different mammalian species. Although the exact physiological function of beta2GPI has not been fully elucidated, several interactions have been described with other proteins and with negatively charged surfaces, such as anionic phospholipids, dextran and heparin. beta2GPI is involved in the coagulation pathway, exerting both procoagulant and anticoagulant activities. Plasma from beta2GPI-deficient mice exhibits impaired thrombin generation in vitro. Recently, it has been demonstrated that beta2GPI binds factor (F) XI in vitro at concentrations lower than those of the protein in human plasma, and this binding inhibits FXI activation to FXIa by thrombin and FXIIa. Proteolytic cleavage of the fifth domain of beta2GPI abolishes its inhibition of FXI activation and results in reduced ability of the cleaved beta2GPI to bind phospholipids. It retains its ability to bind FXI. In vivo activation of FXI by thrombin is thought to be an important mechanism by which coagulation is accelerated via components of the contact activation pathway. Thus beta2GPI may attenuate the contact activation pathway by inhibiting activation of FXI by thrombin. Moreover, because beta2GPI is the dominant autoantigen in patients with APS, dysregulation of this pathway by autoantibodies may be an important mechanism for thrombosis in patients with APS.

Abortion, Habitual↗
PubMed1980

[Physiologic values of coagulation factors in newborn infants].

Hemorrhagic tendencies are frequently seen in the neonatal period. From the practical point of view, recognition of physiologic deficiencies of coagulation factors and hemostasis is essential, for the differential diagnosis of hemorrhagic syndromes and adequate treatment. Values of coagulation factors in the newborn and comparison of our results and the results of other authors are presented. It seems that there are no essential changes in hemostasis of term infant, but many coagulation factors exhibit deficient clotting activity as like vitamin K-dependent factors (II, VII, IX, X). Values of fibrinogen, F. XI, XII, XIII are decreased. Those factors which physiologically low in the term infant reach normal adult levels in a few weeks, with the exception of factors IX and XI which may require several months to reach normal levels. In the same time authors presented the results of coagulation factors in mothers during delivery and term infants, to explain the nature of the disorders. For the investigation of these physiological defects, screening tests can be used.

Blood Coagulation Factors↗
PubMed2001

High molecular weight kininogen deficiency: a patient who underwent cardiac surgery.

A 66 year old male, referred for cardiac surgery, was found to have high molecular weight kininogen deficiency (activity <1%). Apart from activated partial thromboplastin time (APTT) >300 s, tests of haemostasis were otherwise normal (factors VIII, IX, XI, XII and prekallikrein). No inhibitor of coagulation was found. The activated coagulation time (ACT) was 800 s pre-operatively and >1000 s after heparin. Heparin levels were measured directly by an anti-Xa chromogenic assay, with values of between 2.9 and 3.2 u/ml during cardiopulmonary bypass. Thrombin-antithrombin levels rose from 2.3*g/l before surgery to a peak of 83.5*g/l at the end of cardiopulmonary bypass. Cross linked fibrin d-dimers (XDP) levels rose from 100 ng/ml before operation to 600 ng/ml after protamine administration. The patient had no excess bleeding and no thrombotic complications from surgery. This patient shows that high molecular weight kininogen is not required for thrombin formation or fibrinolysis during cardiac surgery and illustrates the need to measure heparin directly in patients with such contact factor deficiencies.

Aged↗
PubMed2001

Update on selected inherited venous thrombotic disorders.

The inherited thrombophilias are a group of inherited conditions that predispose to thrombotic events. Most of the inherited thrombotic disorders are associated with venous thromboembolism rather than arterial thrombosis. Frequently, one or more predisposing genetic factors and/or environmental risk factor are identified in thrombosis patients. Significant advances in the identification of etiologies of inherited thrombosis have recently been reported. The most common inherited thrombotic disorders include activated protein C (APC) resistance (factor V Leiden), hyperhomocysteinemia, the prothrombin gene variant G20210A, elevated factor VIII levels, and deficiencies of thrombomodulin, protein C, protein S, and antithrombin. Less well characterized disorders include elevated factor IX, X, and XI levels. Recognition of these disorders now permits a laboratory diagnosis in approximately 70% of patients being evaluated for inherited thrombosis. This review focuses on the clinical and laboratory aspects of some of the most common inherited venous thrombotic disorders, including APC resistance, hyperhomocysteinemia, the prothrombin G20210A mutation, and elevated coagulation factor levels.

Blood Coagulation Factors↗
PubMed1985

Danazol-induced factor VIII and IX bypassing activity in hemophiliacs.

Danazol, a synthetic androgen reported to increase factor VIII and IX activity levels, was given to 6 hemophiliacs. With danazol therapy (600 mg/da) the APTTs shortened by 30-45% of pre-treatment times. However, the activity levels of the deficient factors did not increase significantly nor consistently with the APTT change. The prothrombin times and activity levels of factors XI and XII also did not change during the study period. Addition of plasma from danazol-treated patients to plasma with a known factor VIII inhibitor and to plasma from an untreated severe hemophilia A patient caused a similar shortening of the respective APTTs. Absorption of the danazol plasma with precipitating antibody against factor VIII and IX did not remove the APTT correcting principal. The data suggest that danazol may cause the de novo appearance of an intrinsic coagulation pathway activator having factor VIII and IX bypassing activity.

Calcium↗
PubMed1979

Activation of coagulation and disseminated intravascular coagulation in the newborn.

Human newborns have certain hemostatic "deficiencies" which seem to be peculiar to this period of life, such as reduced factors II, VII, IX, X, XI, and XII, reduced antithrombin III levels, and reduced plasminogen levels. However, they are capable of activating the coagulation mechanism to elicit either the entity of disseminated intravascular coagulation or the occurrence of localized and diffuse thrombotic events. The mechanisms involved have yet to be defined. Evidence has been presented to suggest that preterm infants may manifest a variant form of disseminated intravascular coagulation in which thrombocytopenia is not present.

Adult↗
PubMed2004

Mutations within the protein Z-dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia.

Protein Z-dependent protease inhibitor (ZPI) is a serpin that inhibits the activated coagulation factors X and XI. The precise physiological significance of ZPI in the control of haemostasis is unknown although a deficiency of ZPI may be predicted to alter this balance. The coding region of the ZPI gene was screened for mutations using denaturing high-performance liquid chromatography. 16 mutations/polymorphisms within the coding region of ZPI were identified including two mutations, which generated stop codons at residues R67 and W303. We observed nonsense mutations within the ZPI gene in 4.4% of thrombosis patients (n = 250) compared with 0.8% of controls (n = 250). The difference in distribution of stop codon mutations between thrombosis patients and controls was significant (P = 0.02) with an odds ratio of 5.7 (95% confidence interval, 1.25-26.0). Our results suggest an association between ZPI deficiency and venous thrombosis and we propose that ZPI deficiency is potentially a new form of thrombophilia.

Adult↗
PubMed1985

Intrinsic coagulation pathway in end-stage renal disease associated with spinal cord injury treated with hemodialysis.

Plasma procoagulant activities of factors XII, XI, IX, and VIII and plasma concentrations of factor XII antigen and high molecular weight kininogen (HMK) were determined in nine men with chronic renal failure (CRF) associated with long-standing spinal cord injury (SCI) treated with hemodialysis. The results were compared with those obtained in a group of 10 ambulatory CRF patients and 8 normal volunteers (control group). Congenitally deficient plasmas were used as the substrate for the measurement of procoagulant activities in a one-stage clotting assay. Monospecific antibodies were employed in the measurement of factor XII antigen and HMK using gradient plate immunodiffusion and rocket immunoelectrophoresis. Factor XII coagulant activity and antigen concentration were significantly increased in the SCI group. The mean values for plasma factor XI and IX activities in the SCI group were comparable with those observed in the ambulatory patients and normal control group. However, marked variations in factor XI and IX levels were noted among the SCI patients with a few instances of mild to moderate factor deficiencies and several cases of markedly elevated levels. Factor VIII activity was markedly increased, with only two of the nine patients exhibiting normal values. HMK concentration in the SCI group was comparable with values obtained for the other groups. Following dialysis, factor XII antigen concentration rose and factor XI activity fell slightly but significantly. The results indicate that the combination of CRF and long-standing SCI is associated with marked aberrations of intrinsic coagulation pathway. The underlying mechanisms and the clinical consequences of these abnormalities are not known and require further investigation.

Adult↗
PubMed1982

Adult nephrotic syndrome and acquired coagulopathies: Hageman factor deficiency.

Analysis of tests of coagulation and fibrinolysis from 20 adult nephrotics prior to the onset of therapy disclosed that 40 percent had low factor XII levels. The mean factor XI was normal. The platelet count and fibrinogen concentration were elevated. The findings of this study on adults are similar to those of Honig and Lindley(21) in the nephrotic syndrome of childhood. Subjects with minimal change disease constituted a small (15 percent) but readily segregated subpopulation without evidence of fibrinolysis in association with low factor XII activity. Prolongation of the activated partial thromboplastin time corresponded in every instance with factor XII activities of ≤30 percent. Lengthening of the one stage prothrombin time was not directly attributable to factor deficiencies.

Adult↗
PubMed1993

Paradoxic effect of multiple mild coagulation factor deficiencies on the prothrombin time and activated partial thromboplastin time.

Single coagulation factor deficiencies predictably prolong the prothrombin time (PT) and activated partial thromboplastin time (APTT) at levels below 35% of normal activity. Acquired coagulopathies generally are characterized by multiple coagulation factor deficiencies. The effect was studied of such combined deficiencies on the PT/APTT using plasma from patients congenitally deficient in specific factors and pooled normal plasma. The PT begins to lengthen when individual factor levels fall below 25%. The APTT becomes prolonged when the levels of Factor V fall below 45%; the levels of Factors II and XI fall below 40%; and the levels of Factors I, V, VII, VIII, IX, and XII fall below 25% of normal. When plasma samples containing 50% activity of a single factor and 100% of all other factors were prepared by mixing the congenitally deficient plasma samples with the normal pool, the resulting mixtures had normal PT and APTT values. However, when two of these 50% factor-deficient plasmas were combined so that the mixture contained 75% activity of two coagulation factors and 100% of all other factors, the resulting PT and APTT were prolonged over the clotting times of either 50% factor-deficient plasma. Similar findings were obtained in patients with mild factor reductions caused by warfarin treatment. These data indicate that prolongations of the PT and APTT in disorders of coagulation affecting multiple factors represent less of a reduction in factor levels than is generally appreciated. This may explain the poor clinical correlation between abnormalities in these test results and clinical bleeding in acquired disorders of hemostasis.

Blood Coagulation Factors↗
PubMed1998

Anticoagulant profile of iopamidol and meglumine amidotrizoate and their lack of thrombin generation: an in vitro study.

The aim of this in vitro study was to sketch the subtle anticoagulant profile of iopamidol 300 mg l/ml (low osmolality non ionic contrast medium) and meglumine amidotrizoate 370 mg l/ml (high osmolality ionic contrast medium) in situations where variable amounts of clotting factors are observed and to check whether thrombin-generation significantly occurred in non anticoagulated blood-contrast materials mixtures. In the first experiment, mixtures of deficient plasmas with a routine plasma pool provided different ranges with variable amounts of clotting factors II, V, VIII, X, XI and XII. For each clotting factor level studied within these ranges, an activated partial thromboplastin time was determined with either contrast material loaded thromboplastin (5% v/v) or glucose loaded thromboplastin (5% v/v) used as a control. In the second experiment fibrino-peptide A (FpA) or modified antithrombin III (ATM) assays were performed in either (9:1) non anti-coagulated blood contrast materials mixtures or blood-glucose mixtures (control). Differing aPTT prolongation profiles were observed when clotting factors V, VIII, XI and XII were lowered in the plasma. However, neither iopamidol nor amidotrizoate induced an aPTT prolongation with decreasing clotting factor II. In the second experiment no significant thrombin generation was observed as both blood-contrast materials mixtures showed significantly lower FpA and ATM levels (p < 0.001) than glucose control after 5 minutes and 10 minutes incubation at room temperature. These findings provide evidence that the use of iopamidol in angiographic procedures does not increase risk of clotting or hemorrhage.

Anticoagulants↗
PubMed2006

Effects of aprotinin on plasma coagulation kinetics determined by thrombelastography: role of Factor XI.

BACKGROUND: Aprotinin is commonly administered in settings involving cardiopulmonary bypass and liver transplantation to decrease peri-operative bleeding. Thrombelastography has been utilized to monitor coagulation in these settings, and aprotinin delays clot initiation, presumably by inhibiting kallikrein; however, aprotinin also inhibits Factor XI (FXI), a contact system protein. Thus, it was hypothesized that celite-activated thrombelastography coagulation kin-etics would be decreased via aprotinin-mediated FXI inhibition. METHODS: Citrated normal plasma and prekallikrein-deficient (<1% normal activity) plasma were exposed to 0, 200, 400 or 800 kallikrein inhibitory units (KIU)/ml (n = 6 per condition). Samples were recalcified and celite-activated in a thrombelastograph, with clot initiation (R, s) determined. To confirm contact system specificity, additional prekallikrein-deficient samples with 0 or 800 KIU/ml aprotinin were activated with tissue factor (n = 4 per condition). RESULTS: Exposure of celite-activated, normal plasma to aprotinin 0, 200, 400 or 800 KIU/ml resulted in R values of 167 +/- 14, 253 +/- 10, 293 +/- 22 and 349 +/- 21 s, respectively, which were significantly different from one another (P < 0.05). Exposure of celite-activated, prekallikrein-deficient plasma to aprotinin 0, 200, 400 or 800 KIU/ml resulted in R values of 366 +/- 15, 630 +/- 64, 698 +/- 46 and 850 +/- 47 s, respectively, which were significantly different from one another (P < 0.05). There were no significant differences in R values between tissue factor-activated, prekallikrein-deficient plasma samples with 0 or 800 KIU/ml aprotinin. CONCLUSIONS: These data support a role for the inhibition of FXI as the mechanism for aprotinin-mediated delayed contact system clot initiation determined by thrombelastography.

Aprotinin↗