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The present study aimed at investigating the 4G/5G and -844G/A polymorphisms and plasma concentration of PAI-1 in patients with acute myocardial infarction (AMI) and chronic stable angina (CSA) in Indian population. It included 100 patients with AMI and stable angina and 100 healthy controls. All study subjects were typed for two PAI polymorphisms (4G/5G and -844G/A) through PCR-RFLP and level of PAI through ELISA. The comparison of AMI and CSA independently with control in terms of PAI-1 level was statistically significant but not between AMI and CSA. The frequency of 4G/4G and 4G/5G genotype and 4G allele was significantly higher in AMI cases than in control and was found to increase the risk of AMI. There was a significant relationship between 4G/5G polymorphism and AMI risk under the dominant and codominant genotype. The frequency of 4G/4G genotype and 4G allele was significantly higher in CSA cases than in control group and increases the risk of CSA. There was no significant association between 4G/5G polymorphism and CSA risk under recessive, dominant, and codominant models. The genotype and allelic frequencies difference between the cases (AMI and CSA) and control with regard to -844G/A polymorphisms were statistically nonsignificant. Also, we did not detect any significant association of -844G/A polymorphism with AMI and CSA in recessive, dominant, and codominant models. Along with the traditional risk factors, the 4G/5G allele polymorphism is an independent risk factor for the development of AMI. The detection of 4G/5G allele may therefore be helpful in primary prevention. Patients who carry the 4G/5G allele polymorphism have high concentrations of PAI-1, which might be involved in incidents leading to AMI. The present study for the first time revealed significant association of 4G/5G allele polymorphism with high risk of AMI in Indian population and will be helpful in identifying the genetic risk factors associated with AMI and CSA and for better management of diagnostic measures. [ABSTRACT FROM AUTHOR]

Albumin, the most abundant and long-lived serum protein, exhibits novel features as a carrier that can greatly enhance the pharmacological action of therapeutic payloads. Besides passive trafficking by enhanced permeability and retention effect, albumin has been shown to accumulate within the tumor environment or inflamed tissues by receptor-mediated active transport, lending itself to being a promising scaffold for targeted drug delivery. Albumin has recently been found to be a scavenger for amyloid-β with the potential to treat neurodegenerative diseases. The hydrophobic binding pockets, conjugatable thiol residue, and surface-exposed N- and C-termini in albumin inherently serve as useful spots for carrying various kinds of peptidyl and non-peptidyl drugs. Beyond its long-standing role as a half-life extender, albumin is emerging as a versatile drug carrier to aid numerous therapeutic agents that have poor pharmacokinetics, targetability, solubility, and instability in vivo. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding an in vitro comparative study which revealed the lower capacity of inhibitors on factors (FVIII) for natural FVIII/von Willebrand factor (VWF) complex compared with isolated FVIII.

Sensitivity to FVIII inhibitors of the native plasma‐derived (pd) FVIII/VWF complex vs. the complexes formed after exogenous FVIII infusion in the haemophilic patient has not been thoroughly studied. The role of VWF in the interaction of FVIII with inhibitors was studied in vitro using different combinations of VWF and FVIII concentrates. Normal plasma, pdFVIII/VWF and isolated FVIII (recombinant FVIII, B‐domain deleted and pdFVIII) were used. Titre (BU) was kinetically determined (up to 2h) in serial dilutions of inhibitor IgG (purified from a pool of plasmas with inhibitors) mixed with VWF and then incubated with the different FVIII. Inhibitor was also added to previously mixed VWF+FVIII. Residual FVIII:C was determined. TGA assays were performed with FVIII‐deficient plasma spiked with the FVIII‐VWF mixtures with/without an ESH‐8 antibody. Inhibitor titres for plasma and pdFVIII/VWF were comparable at all time points. Titres for all concentrates of isolated FVIII were significantly higher than those for plasma or pdFVIII/VWF (1.4–1.9 fold) even after preincubation with VWF. At t=0h, titres for plasma or pdFVIII/VWF were unquantifiable, but were detectable for isolated FVIII (0.6–1.6 BU). In contrast to pdFVIII/VWF, the decrease in thrombin generation parameters by isolated FVIII in the presence of ESH‐8 was significant (P<0.01) even when previously combined with VWF. In conclusion, VWF protection against FVIII inhibitor activity might be higher with native pdFVIII/VWF complex than with the corresponding compound formed from the isolated proteins. Bethesda assay titration using different FVIII concentrates would be advisable to guide the treatment of inhibitor patients. [ABSTRACT FROM AUTHOR]

The presence of VWF in plasma-derived FVIII (pdFVIII/VWF) products has been pointed out as a key difference with recombinant FVIII ( rFVIII) products with regard to immunogenicity. A Surface Plasmon Resonance (SPR) study was designed to characterize in detail the interaction between anti-FVIII (IgGs) from a severe haemophilia A patient, and FVIII from concentrates of different sources. Full-length rFVIII (preincubated or not with purified VWF), B domain-deleted (BDD)- rFVIII and pdFVIII/VWF were analysed. To ensure reproducible conditions for accurate determination of kinetic constants, a capture-based assay format was developed using protein G surfaces for specific and reversible coupling of endogenous anti-FVIII antibodies. Concentration ranges (n m) of FVIII products tested were 9-0.03 ( rFVIII) and 6-0.024 (pdFVIII/VWF). The association with antibodies was monitored for 3-5 min, whereas dissociation of the complex was followed for 5-20-240 min. A strong interaction of rFVIII and BDD- rFVIII with patient's IgG was detected with the KD values in the low picomolar range (5.9 ± 3.0 and 12.7 ± 6.9 p m, respectively) and very slow dissociation rates, while pdFVIII/VWF showed only marginal binding signals. The VWF complexed rFVIII displayed reduced binding signals compared with uncomplexed rFVIII, but the KD was still in the picomolar range (4.1 ± 1.9 p m) indicating insufficient complex formation. rFVIII, alone or bound to exogenously added VWF, showed high affinity for anti-FVIII IgGs from a severe haemophilia A patient whereas pdFVIII/VWF did not. These results are in agreement with those studies that point towards rFVIII concentrates to be more immunogenic than pdFVIII concentrates. [ABSTRACT FROM AUTHOR]

. Development of factor VIII (FVIII) inhibitors is the most severe and challenging complication of haemophilia A treatment and represents the highest economic burden for a chronic disease. Therefore, major research efforts are ongoing to optimize the therapeutic approaches able to minimize this complication. FVIII inhibitors have variable immuno-reactivity against different FVIII concentrates and generally have a lower reactivity against von Willebrand factor (VWF)-containing FVIII concentrates than plasma-derived FVIII (pdFVIII) or recombinant FVIII (rFVIII) that are devoid of VWF, in particular when the inhibitors are directed against the light chain of FVIII. This paper provides an overview of several in vitro and in vivo studies that compared three clinically available clinical FVIII products (Kogenate®, Bayer AG, Leverkusen, Germany; Advate®, Baxter Healthcare, Zurich, Switzerland; and Fanhdi®, Grifols S.A., Barcelona, Spain) in order to evaluate the functional actvity of the FVIII fractions in rFVIII that cannot bind VWF; explore the use of the thrombin generation assay (TGA) as a potential tool for optimizing the choice of FVIII concentrate for use in haemophilia A patients with inhibitors; compare the kinetics of the interactions between anti-FVIII antibodies and FVIII both in the presence/absence of VWF, using surface plasmon resonance. [ABSTRACT FROM AUTHOR]

. von Willebrand factor (VWF) has the capacity to form a complex with factor VIII (FVIII) which may modulate the immunogenicity of FVIII. It has been proposed that a significant fraction of recombinant FVIII (rFVIII) is unable to bind VWF. In an experimental model studied at the McMaster University in Canada, this VWF-unbound rFVIII fraction showed no coagulant function. Sulphation of FVIII tyrosine (Tyr) 1680 has been reported as essential for the interaction with VWF. In a study performed at the Grifols and CNS-CSIC in Spain, Tyr1680 sulphation was observed to be incomplete in rFVIII and complete in plasma-derived FVIII (pdFVIII). This could explain the incapability of some rFVIII molecules to bind VWF. Experience with immune tolerance induction (ITI) at the Bonn Haemophilia Centre indicates that only eradication of FVIII inhibitors allows safe haemostasis control and the option of prophylactic treatment. Various clinical trials were planned to evaluate the clinical role VWF-containing FVIII concentrates (FVIII/VWF). RES.I.ST (an acronym for REScue Immunotolerance STudy) is an international, prospective study aimed at assessing whether FVIII/VWF can induce ITI in high-risk haemophilia patients (RES.I.ST naïve) and whether patients who previously failed ITI with FVIII alone can be rescued with FVIII/VWF (RES.I.ST experienced). Enrolment started in November 2009. In the FAIReSt.Will (Fanhdi and Alphanate Italian Retrospective Study in Willebrand disease) study, 120 von Willebrand disease (VWD) patients treated with Fanhdi® or Alphanate® were retrospectively analysed. Efficacy was excellent and no side effects were reported. The ongoing PRO.Will study is a prospective, multicenter trial aimed at assessing the efficacy, safety and pharmacoeconomics of secondary long-term prophylaxis in patients with severe inherited VWD. [ABSTRACT FROM AUTHOR]

Thrombosis is a well-known clinical entity in systemic lupus erythematosus (SLE), and it is multifactorial. The most important risk factor is the presence of antiphospholipid antibodies (APLAs). However, approximately 40% of adults with SLE who are negative for APL A are diagnosed with thrombosis, indicating the importance of other risk factors. Thus, the thrombosis risk factors should be evaluated extensively and regularly and treated aggressively in every patient with systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Thrombosis is a well-known clinical entity in systemic lupus erythematosus (SLE), and it is multifactorial. The most important risk factor is the presence of antiphospholipid antibodies (APLAs). However, approximately 40% of adults with SLE who are negative for APL A are diagnosed with thrombosis, indicating the importance of other risk factors. Thus, the thrombosis risk factors should be evaluated extensively and regularly and treated aggressively in every patient with systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Objectives: Endothelial disturbance and excess inflammatory response are pathogenic mechanisms in pre-eclampsia (PE). Authors determine the clinical diagnostic role for thrombomodulin (TM), plasminogen activator inhibitor-1 (PAI-1) as endothelial markers and C-reactive protein (CRP), and interlukin-6 (IL-6) as inflammatory markers when tested independently or in combinations. Materials and methods: We conducted a retrospective study in a cohort of 185 women grouped as 80 women with PE, 55 normotensive pregnant and 50 healthy non-pregnant. Plasma levels of TM, PAI-1, CRP and IL-6 were examined using enzyme linked immunosorbent assays. Results: Median levels and the positivity rates for the investigated markers were higher in PE as compared to the other groups (P < 0.0001). Using linear regression analysis, the investigated markers were significantly correlated regarding healthy non-pregnant vs PE or normotensive pregnant vs PE. The sensitivity of PAI-1 was the highest (98%) among the tested biomarkers. Combination between the investigated markers revealed absolute sensitivity (100%) and reliable specificity especially when PAI-1 was combined with CRP at 83% specificity. Conclusions: Investigated endothelial and inflammatory markers revealed sensitive diagnostic test for PE. However, coupled combination between PAI-1 with CRP showed superior both sensitivity and specificity which represent a promising new approach for detection of PE. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms in plasminogen activator inhibitor-1 gene-675 4G/5G (PAI-1 4G/5G) are claimed to contribute to an increased risk of venous thromboembolism. Inherited thrombophilia, on the other hand, is associated with the occurrence of spontaneous abortions. The objective of this study was, to explore the significance of genetic polymorphisms of PAI-1 4G/5G with particular emphasis on 4G alleles in pregnant women suffering from venous thromboembolism or early spontaneous abortion, respectively. Therefore genetic PAI-1 4G/5G polymorphisms were studied in 108 pregnant females suffering from venous thromboembolism (n=69) or from spontaneous abortion (<20 week, n=39), respectively. Healthy volunteers (n=238) were taken as controls. The frequencies of 4G alleles (4G/4G or 4G/5G genotypes) of PAI-1 were significantly higher in venous thromboembolism (OR: 3.40, p=0.0088) and slightly higher, but not significantly, in abortions (RR: 2.33; p=0.1162) compared to controls. The incidence of 4G-carriers in females with abortion was 0.68 (-32%) compared to women suffering from venous thromboembolism alone. We conclude from these data, that the occurrence of PAI-1 4G/4G or 4G/5G genotypes, respectively, is clinically significant for the pathogenesis of venous thromboembolism in pregnancy but not for early abortion. [ABSTRACT FROM AUTHOR]

Provides overview of articles on clotting factor concentrates, published in the October 2, 2004 issue of "Haemophilia." "The Factor VIII Protein: Its Life Cycle and Structure Function Relationship," by E. Saenko and N. Ananyeva; "Mode of Action of Recombinant Factor VIIIA: Current and Future By-Passing Agents and Their Use in Acquired Hemophilia," by H. R. Roberts, C. Kempton and D. Monroe; "Assessment of Evidence for Preventive Treatment in Hemophilia: The Practicalities of Doing a Systematic Review," by K. Stobart.

Presents abstracts related to the use of clotting factor concentrates in hemophilia patients. 'Continuous Infusion as Replacement Therapy,' by P. Mali, M. Dolniear; 'Continuous Intravascular Coagulation in Patients With Haemophilia,' by I. Bokarev, A. Safonov et al.

A letter to the editor is presented related to tyrosine 1680 sulphation in recombinant FVIII concentrates which is incomplete.