Comparison of thrombin generation assay with conventional coagulation tests in evaluation of bleeding risk in patients with rare bleeding disorders.

Based on the premise that the capacity of plasma to generate thrombin in vitro is a comprehensive and precise functional test of the clotting system, we designed a cross-sectional, single-center study involving 83 patients with rare bleeding disorders (RBDs) to compare the usefulness of the thrombin generation (TG) assay versus conventional tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT) in predicting bleeding risk in patients with RBD in southern Iran. The TG parameters consisted of endogenous thrombin potential, lag time, peak, time to peak (ttPeak), and start tail. The area under the receiver-operating characteristic (ROC) curve showed statistically significant associations between bleeding risk and lag time, ttPeak, and start tail.

Management of von Willebrand disease in developing countries.

A variety of treatment options are available at present for patients with von Willebrand disease (vWD), some of which are affordable for patients in developing countries. For most patients who have type 1 vWD, desmopressin acetate (DDAVP) is the treatment of first choice, at least for minor bleedings and for prophylaxis. It is advisable, however, to use a test dose first to note the patient's response.

Carrier detection and prenatal diagnosis of hemophilia in developing countries.

Hemophilia A and B, inherited as X-linked recessive traits, are the most common hereditary hemorrhagic disorders caused by a deficiency or dysfunction of coagulation factor VIII (FVIII) or FIX, respectively. Hemophilia is prevalent worldwide, without ethnic or geographic limitations, and remains a life-threatening and often disabling condition. Advances in molecular medicine in this century have markedly improved hemophilia treatment.

Long-term lamivudine monotherapy in renal-transplant recipients with hepatitis-B-related cirrhosis.

Background: Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in renal-transplant recipients. The aim of the study was to assess the efficacy and safety of long-term lamivudine monotherapy in renal-transplant recipients with HBV-related cirrhosis.

Methods: Seventeen such patients [median age: 45 years; 7 with hepatitis B e antigen (HBeAg)] received daily oral doses of 75-150 mg lamivudine for a median of 48 (range 11-81) months.

Catheter-related thrombosis in hematologic patients.

For many years central venous catheters (CVC) have been utilized to monitor hemodynamics and to deliver parenteral nutrition, blood products, pharmacological therapies or infusion fluids. Recently, CVC use has greatly increased with significant impact on the administration of chemotherapy, stem cell transplantation and other treatments to cancer patients. However, CVC use may be accompanied by a variety of side-effects, which increase with the duration of implantation.

Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics.

Background & Aims: Hyperhomocysteinemia, a risk factor for thrombosis, recurrent miscarriages, and osteoporosis, might derive from acquired folate and vitamin B 12 deficiencies and from a C677T mutation in methylene-tetrahydrofolate reductase (MTHFR) gene. Undiagnosed gluten-sensitive enteropathy (GSE) is associated with vitamin deficiencies, osteoporosis, and recurrent miscarriages. We evaluated the prevalence and the risk factors for hyperhomocysteinemia in patients with newly diagnosed GSE.

Use of intravenous immunoglobulin in patients with acquired von Willebrand syndrome.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease. Unlike the congenital form, AVWS usually occurs in individuals with no personal or family history of bleeding disorders. According to an international registry, AVWS is mainly associated with lymphomyeloproliferative, immunologic, and cardiovascular disorders, as well as with solid tumors and other miscellaneous conditions; however, the prevalence of AVWS in these underlying disorders is still unknown.

Risk factors for thrombophilia in extrahepatic portal vein obstruction.

Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for thrombophilia screening, including the search for gain-of-function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, for odds ratios of 4.

Molecular diversity and thrombotic risk in protein S deficiency: the PROSIT study.

The Protein S Italian Team (PROSIT) enrolled 79 protein S (PS) deficient families and found 38 PROS1 variations (19 novel) in 53 probands. Of these, 23 variants were selected for expression in'vitro, to evaluate their role as possible causative variants. Transient expression showed high secretion levels (>75%) for three variants, which were considered neutral.

Hepatitis C reactivation in patients with chronic infection with genotypes 1b and 2c: a retrospective cohort study of 206 untreated patients.

Background: We previously described hepatitis reactivation in two carriers of the hepatitis C virus (HCV) genotype 2c.

Aim: To assess the relationship between HCV genotypes and risk of hepatitis reactivation, we studied the course of aminotransferases in patients infected with the two relevant genotypes in Italy.

Patients: A cohort of 100 patients with genotype 2c chronic hepatitis and 106 with genotype 1b were subjected to surveillance.

Laboratory detection of inherited thrombophilia: a historical perspective.

Considerable progress has been made in determining the molecular bases of inherited thrombophilia in the last 25 years. There are several genetic abnormalities that can be detected in the laboratory and are currently recognized to be unequivocally associated with an increased tendency to develop venous thrombosis. Testing for inherited and acquired causes of thrombophilia may make counseling more focused in ostensibly healthy members of thrombophilic families (i.

Tissue plasminogen activator antigen is strongly associated with myocardial infarction in young women.

Women who develop acute myocardial infarction (AMI) at a young age have fewer classical risk factors and less coronary stenosis than older women. In this rare population, it is plausible that a heightened hemostatic system may play an important mechanistic role in thrombus formation and in the development of AMI. We chose to investigate whether or not there is an association between premature AMI and the plasma concentrations of five hemostatic measurements that had been previously established as risk factors for AMI, and of the inflammation marker C-reactive protein (CRP).

Exploring the relationships between inflammatory response and coagulation cascade in inflammatory bowel disease.

Background: The inflammatory network and the coagulation cascade are strictly correlated biological systems. Inflammatory Bowel Diseases (IBD) are characterised by a prothrombotic state, a hypercoagulability state and an increased prevalence of thromboembolic events.

Methods: We reviewed the IBD literature in which the relationships between inflammation and coagulation were evaluated.

The P303T mutation in the human factor VII (FVII) gene alters the conformational state of the enzyme and causes a severe functional deficiency.

We report the results of in vitro expression and biochemical characterization of the naturally occurring type II mutation Pro303Thr (P303T) in the factor VII (FVII) gene. Recombinant activated mutated FVII (FVIIa303T), compared with the activated wild-type FVII (FVIIaWT), showed reduced amidase activity toward synthetic substrates, especially when the observed reduced binding affinity for human soluble tissue factor (TF) (K(d) from 4.4 nmol/l for FVIIaWT to 17.

von Willebrand factor cleaving protease (ADAMTS-13) and ADAMTS-13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura.

The congenital or acquired deficiency of the von Willebrand factor (VWF) cleaving protease, ADAMTS-13 has been specifically associated with a diagnosis of thrombotic thrombocytopenic purpura (TTP), a microangiopathy characterized by the formation of occlusive platelet thrombi. The mechanisms of TTP were investigated in 100 patients diagnosed on the basis of the presence of at least three of the following: thrombocytopenia, haemolytic anaemia, elevated serum levels of lactate dehydrogenase and neurological symptoms. Plasma levels of ADAMTS-13 were severely reduced (<10% of normal) in 48%, moderately reduced (between 10% and 46%) in 24% and normal (>46%) in 28%.

Clinical diagnosis of von Willebrand disease.

von Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is caused by quantitative (Types 1 and 3) or qualitative (Type 2) defects of von Willebrand factor (VWF). VWD is inherited by autosomal dominant or recessive pattern, but women with milder VWD forms seem to be more symptomatic than men. Mild VWD forms are both under- and misdiagnosed.

Serum levels of hepatitis C virus core antigen as a marker of infection and response to therapy.

Objectives: Hepatitis C virus (HCV) core antigen is a recently developed marker of hepatitis C infection. We compared the predictive power of HCV core antigen with reverse transcription polymerase chain reaction (RT-PCR) and branched DNA assay for HCV-RNA as markers of infection and response to interferon therapy.

Methods: Four hundred and forty-four sera from 111 patients (65 men, 52 yr) with chronic hepatitis C, receiving ribavirin together with standard interferon (n = 61) or pegylated interferon (n = 50) were retrospectively investigated.

Long-term aspects of hemophilia B treatment: part II.

This paper focuses on the benefits of prophylaxis, compared with on-demand therapy, in achieving long-term treatment goals in hemophilia patients. While primary treatment goals are to prevent joint damage and improve quality of life, other issues such as treatment costs-balanced against improvements in health status and direct and indirect costs of hemophilic arthropathy-need to be considered. The ESPRIT study (Evaluation Study on Prophylaxis: a Randomized Italian Trial), a 10-year trial comparing on-demand and prophylactic treatment in terms of efficacy, safety, and cost, is discussed.

A rare inherited coagulation disorder: combined homozygous factor VII and factor X deficiency.

The combined presence in the homozygous state of more than one recessively transmitted coagulation defect may rarely occur in countries with a high rate of consanguinity. In an Iranian family consisting of two parents (second cousins) and two affected siblings, initial phenotypic analysis led to a diagnosis of mild FX deficiency (10-19% FX activity, 42-54% FX:Ag), and genotyping revealed a new homozygous missense mutation in the corresponding gene (Ser3Cys). As both of the sibs had a severe bleeding history that was not compatible with mild deficiency of FX, further phenotypic analysis revealed the additional presence of severe FVII deficiency (<1% FVII activity; 63-111% FVII:Ag) associated with the homozygous missense gene mutation Cys310Phe.

Efficacy and inhibitor development in previously treated patients with haemophilia A switched to a B domain-deleted recombinant factor VIII.

There have been recent reports of unexpected poor efficacy of a B-domain-deleted recombinant factor VIII (BDD-rFVIII) in haemophiliacs, and inhibitor development in previously treated patients (PTPs) switched to BDD-rFVIII. The results of a 6-month prospective study of 25 PTPs and of a retrospective survey of 94 PTPs, all switched to BDD-rFVIII, were used to evaluate efficacy and inhibitor development. The prospective study showed that 89% of 362 bleeds were controlled by one to two infusions, reproducing the efficacy profiles of other recombinant products (rFVIIIs).

Acquired von Willebrand syndrome 2004: International Registry--diagnosis and management from online to bedside.

The acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease. Unlike the congenital form, AVWS usually occurs in individuals with no personal or family history of bleeding. Large studies on AVWS are not available, diagnosis remains difficult and treatment empirical.

Health status and health-related quality of life of children with haemophilia from six West European countries.

A multicentre, international, cross-sectional study was carried out in the frame of field testing of the first haemophilia-specific quality-of-life (QoL) questionnaire (Haemo-QoL). The aim of this paper is to describe health status and health care and their impact on QoL in haemophilic children in Western Europe. Children aged 4-16 years with severe haemophilia without inhibitors were enrolled by 20 centres in France, Germany, Italy, the Netherlands, Spain and the United Kingdom.

A sensitive ristocetin co-factor activity assay with recombinant glycoprotein Ibalpha for the diagnosis of patients with low von Willebrand factor levels.

Background And Objectives: The assay of ristocetin co-factor activity of von Willebrand factor (VWF:RCo) is used in the screening of patients with suspected von Willebrand's disease (VWD), the most frequent inherited bleeding disorder. A correct diagnosis of VWD relies on platelet agglutination tests that have a low accuracy within and between assays. A more accurate VWF:RCo assay would improve VWD diagnosis and classification.

Phenotype-genotype characterization of 10 families with severe a subunit factor XIII deficiency.

Factor XIII (FXIII) deficiency is a very rare severe autosomal bleeding disorder with a frequency of 1:2,000,000 in the general population and only a few patients have been genetically characterized so far. We report a phenotype-genotype characterization of 10 unrelated Iranian patients. Two FXIII (transglutaminase) activity assays showed no FXIII activity, except a conserved residual activity in patients receiving prophylactic substitution treatment.

Antibodies to tissue-type plasminogen activator (tPA) in patients with antiphospholipid syndrome: evidence of interaction between the antibodies and the catalytic domain of tPA in 2 patients.

The causes of thrombosis and pregnancy loss in antiphospholipid syndrome (APS) are still unknown, although several hypotheses have been proposed and hypofibrinolysis has been implicated. Anti-tissue-type plasminogen activator (tPA) antibodies may induce fibrinolytic defects and preliminary data indicate an association with thrombosis in APS. We measured plasma anti-tPA antibody levels in 91 consecutive patients with APS, 91 healthy controls, 40 patients with antiphospholipid antibodies without APS symptoms, and 23 patients with systemic lupus erythematosus (SLE) without antiphospholipid antibodies and APS symptoms.