Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina

Plasma viscosity, molecular markers of activated coagulation and fibrinolysis (fibrinopeptides A and B beta 15-42), coagulation factors (fibrinogen and factor VII) and antiplasmins were measured in 529 men aged 35-54 years and related to new angina pectoris (n = 117) and to coronary risk factors in controls without angina (n = 412). Five major risk factors (cigarette-smoking, blood pressure, cholesterol, triglyceride and body mass index) were each associated with increases in plasma viscosity, coagulation factors, and imbalance of coagulation over fibrinolysis (increased ratio of fibrinopeptide A/fibrinopeptide B beta 15-42). Increased viscosity and fibrinogen in smokers were partly reversed in ex-smokers, but the imbalance of coagulation and fibrinolysis persisted. Cholesterol and triglyceride were also associated with increased antiplasmin activity. In men with angina, only fibrinogen was elevated compared to controls. We suggest that increased plasma viscosity and an imbalance of coagulation over fibrinolysis may be mechanisms by which known risk factors promote arterial thrombosis, but are not present in stable angina.     

Thromboelastography, whole-blood haemostasis and recurrent miscarriage

BACKGROUND: Some cases of recurrent miscarriage have a thrombotic basis. Thromboelastography is a rapid, reproducible test of whole-blood haemostasis. METHODS: Thromboelastography was performed in 494 consecutive, non-pregnant women (median age 35 years; range 21-48) with a history of miscarriages at <12 weeks gestation (median 4; range 3-12) and 55 parous women (median age 33 years; range 20-41) with no history of pregnancy loss. The prospective outcome of untreated pregnancies amongst 108 women with recurrent miscarriage was studied. RESULTS: The maximum clot amplitude (MA) (median 66.0 mm; range 48.0-76.0) was significantly higher and the rate of clot lysis (LY30) (median 2.5%; range 0.5-7.8) significantly lower amongst women with recurrent miscarriage compared with controls (MA 61.5 mm; range 50.0-67.0; P = 0.01; LY30 4.9%; range 2.9-9.7; P = 0.01). The pre-pregnancy MA was significantly higher amongst women who subsequently miscarried (median 66.0 mm; range 54.0-73.0) compared with those whose had a live birth (median 61.7 mm; 48.0-71.5; P < 0.01). A pre-pregnancy MA >or=64 mm has a sensitivity of 68% and specificity of 82% to predict miscarriage. CONCLUSIONS: Thromboelastography identifies a subgroup of women with recurrent miscarriage to be in a prothrombotic state outside of pregnancy. Women in such a state are at increased risk of miscarriage in future untreated pregnancies.     

Molecular defects in CRM+ factor VII deficiencies: modelling of missense mutations in the catalytic domain of FVII

Summary. The molecular defects causing CRM+ factor VII deficiency were investigated in seven unrelated subjects and several members of their families.
Four missense mutations located in the catalytic domain of factor VII were found. The previously reported ³⁰⁴ArgGln substitution was present in the homozygous and heterozygous forms, with different polymorphic haplotypes, thus demonstrating that it is recurrent and frequent in the Italian population. The ³¹⁰Cys Phe substitution was found in the homozygous form and in the compound heterozygous condition with the nonsense mutation ³⁵⁶Trpstop. Two missense mutations, ²⁹⁸MetIle and ³⁴²GlyArg, were found in the homozygous and in the heterozygous condition respectively.
Molecular heterogeneity was further increased by finding of the ³⁵³ArgGln polymorphism in the doubly heterozygous condition with the 304 and 342 mutations.
Plausible explanations for loss of FVII function were found by inspecting a model of the serine protease domain of factor VIIa. Inefficient activation of the catalytic site is predicted for ²⁹⁸MetIle. ³⁴²GlyArg would directly distort the geometry of the 'oxyanion hole'preventing formation of a substrate enzyme intermediate. ³¹⁰Cyshe is predicted to have an adverse effect on tissue factor interaction. These mutations point to important regions of the factor VII molecule.     

Changes in the levels of factor VIII and von Willebrand factor in the puerperium

To determine changes in Factor VIII (FVIII) and von Willebrand Factor (VWF) in the first 3 days of the puerperium. A prospective study assessing FVIII clotting activity, VWF activity and antigen levels in 95 women (with singleton uncomplicated pregnancies) during labour and on days 1, 2 and 3 of the puerperium. There were no significant differences in FVIII, VWF:Ag and VWF:CB on days 1 and 2 of the puerperium compared with levels during labour. There was a significant decrease in VWF:Ag (P = 0.009) and VWF:CB (P = 0.04) on day 3. Age, ethnicity, duration of labour and mode of delivery did not have any significant effect on the changes in FVIII and VWF levels. The pregnancy induced increase in FVIII and VWF is maintained in the first 48 h after delivery. VWF levels start to decline on day 3 postdelivery.     

450 million years of hemostasis

Summary.  In mammalian blood coagulation, five proteases (factor VII [FVII]; factor IX [FIX]; factor X [FX]; protein C [PC] and prothrombin [PT]) act with five cofactors (tissue factor [TF]; factor V [FV]; factor VIII [FVIII]; thrombomodulin and protein S) to control the generation of fibrin. Biochemical evidence, molecular cloning data and comparative sequence analysis support the existence of all components of this network in all jawed vertebrates, and strongly suggest that it evolved before the divergence of teleosts over 430 million years ago. Phylogenetic analysis of the amino acid sequences of the Gla–EGF1–EGF2–SP domain serine proteases (FVII, FIX, FX, PC) and the A domain-containing cofactors (FV and FVIII) strongly supports the evolution of the blood coagulation network through two rounds of gene duplication, and supports the hypothesis that vertebrate evolution benefited from two global genome duplications. The jawless vertebrates (hagfish and lamprey) that diverged over 450 million years ago have a blood coagulation network involving TF, PT and fibrinogen. Preliminary evidence indicates that they may have a smaller complement of Gla–EGF1–EGF2–SP domain proteins, suggesting the existence of a 'primitive' coagulation system in jawless vertebrates.     

Use of a non-depleting anti-CD4 antibody to modulate the immune response to coagulation factors VIII and IX

The generation of antibodies to therapeutic factors VIII or IX is a major problem in the management of haemophilia and places potential limitations on the application of gene therapy. We have investigated the administration of a non-depleting anti-CD4 antibody for modulation of the immune response to human recombinant coagulation factors VIII and IX. In mice given these clotting factors, co-administration of anti-CD4 antibody significantly reduced the appearance of factor-specific antibodies. These data provide evidence that the neutralizing antibody response to exogenous coagulation factors may be controllable if non-depleting anti-CD4 antibody is co-administered at the time of initial replacement therapy.