Pharmacokinetics of Optivate(®), a high-purity concentrate of factor VIII with von Willebrand factor, in patients with severe haemophilia A.

Optivate(®) is a high purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate, which is manufactured using two antiviral processes: solvent/detergent and terminal dry heating (80 °C for 72 h). A multicentre, non-randomized open-label study in 15 patients was conducted to test the pharmacokinetics (PK) of Optivate(®). PK variables were analysed for the patients' prior FVIII product (PK1), their first dose of Optivate(®) (PK2) and at 3 months therapy (PK3). Mean non-compartmental half-lives (h) were 14.1, 12.4 and 12.1, respectively (P = 0.45), mean clearances (mL h(-1) kg(-1)) were 3.6, 3.2 and 3.1, respectively (P = 0.051), MRTs (h) were 19.0, 17.3 and 17.4, respectively (P = 0.39) and mean AUC(0-48h) (h IU mL(-1)) were 14.3, 15.4 and 16.6, respectively (P = 0.051) and mean AUC(0-∞) (h IU mL(-1)) were 15.9, 16.4 and 17.9, respectively (P = 0.18). The recovery data from this PK study was aggregated with recovery data collected from another study, with similar design but devoid of the other PK measurements. A total of 309 recoveries were conducted in 70 patients. The overall mean recovery per subject across 27 Optivate(®) batches was 2.7 IU dL(-1) per IU kg(-1). There were no clinical differences between Optivate(®) and other FVIII products, and except for volume of distribution (Vd), no statistically significant differences were seen with respect to any of the other PK variables, or in recovery between weeks 0 and 12. Therefore, the PK of FVIII is not affected by the processes used to manufacture Optivate(®), which can be expected to be effective in the management of patients with haemophilia A.

Registry of inherited bleeding disorders in Poland--current status and potential role of the HemoRec database.

We present data collected in HemoRec, an Internet-based platform implemented in 2006 in 15 haemophilia treatment centres in Poland and compare them with the national registry of inherited bleeding disorders established since 1991 at the Institute of Haematology and Blood Transfusion in Warsaw. We also analyse the current status of haemophilia treatment in Poland as well as future perspectives. Data on 1102 patients registered in HemoRec were analysed and compared with 4294 patients in the national registry (status as at 17.08.2009). The number of patients with severe haemophilia, mild/moderate haemophilia and von Willebrand in HemoRec is 530, 328 and 54 (respectively), compared with 1199, 1167 and 1128 in the national registry. The mean age of all haemophilic patients registered in HemoRec is 26.2 years, compared with 37.3 years in the general Polish male population in 2008. The number of haemophilic patients with inhibitor registered in HemoRec is 102 compared with 155 in the national registry (resulting in a prevalence of 14.9% of all severe haemophilia A and 1.6% of all severe haemophilia B patients). HemoRec includes data on a representative group of Polish haemophilic patients, mostly with haemophilia and haemophilia with inhibitor. von Willebrand's disease is largely under-registered in Poland. The survival of Polish haemophilic patients is shorter than that in the general population. The number of inhibitor patients in Poland is relatively large and should be decreased by wider availability of immunotolerance induction in 2010.

Clinical assessment of Optivate®, a high-purity concentrate of factor VIII with von Willebrand factor, in the management of patients with haemophilia A.

Factor VIII (FVIII) concentrates have revolutionized the treatment of patients with haemophilia A. Concerns over the transmission of viral infections through these products have been addressed through stringent, donor-screening procedures and robust antiviral manufacturing steps. Bio Products Laboratory has developed a high-purity FVIII product with von Willebrand factor, Optivate(®). Its safety, tolerability and efficacy as prophylaxis and treatment of bleeds have been established in long-term studies. Seventy previously treated patients with severe haemophilia A, with ≥ 20 exposure days, were recruited into two long-term, multicentre, open-label studies. The protocols were virtually identical. Patients received Optivate(®) either prophylactically or on-demand. A mean of 159.0 EDs were experienced over 11,320 infusions. Under both conditions, Optivate(®) was well tolerated. Only 10% of patients experienced a treatment-related adverse event; the most commonly reported were headache (4% of patients) and dizziness (3% of patients). The mean number of bleeds/patient over the 2 year treatment period was 23.5 during prophylactic use and 70.4 during on-demand use. In patients treated prophylactically, clinical responses to breakthrough bleeds were rated by physicians as excellent or good and as very helpful or helpful by patients in 95% of bleeds. Clinical responses for on-demand patients were rated as excellent or good by physicians and helpful or very helpful by the patients for 91% of bleeds. There were no viral transmissions or inhibitors. The studies confirm the clinical efficacy and safety of Optivate(®) in both prophylactic and on-demand management of patients with haemophilia A.

An open clinical study assessing the efficacy and safety of Factor IX Grifols, a high-purity Factor IX concentrate, in patients with severe haemophilia B.

SUMMARY: Factor IX Grifols is a new high-purity plasma-derived FIX concentrate with two specific pathogen elimination steps. Until this study was performed, there were no detailed reports with an adequate number of patients on the clinical evaluation of this product. To determine the efficacy and safety of Factor IX Grifols for replacement therapy in previously treated patients with severe haemophilia B, this open, multicentre and non-randomized study included 25 male subjects over the age of 12 with severe haemophilia B. Patients underwent prophylaxis and treatment of bleeding episodes with Factor IX Grifols for 1 year. The clinical efficacy and safety of this product were assessed. Forty percent of the patients were children and adolescents (12-17 years old). During the 12 months follow-up, 1 446 000 IU of Factor IX Grifols were administered in 961 infusions (range 12-83 infusions per patient): 31% for prophylaxis and 69% for bleeding episodes. Only five major bleeding events were reported in two patients. These haemorrhages were successfully treated with a mean of 2900 IU per bleed (range 1500-4000 IU), and 1-3 infusions per bleed. The average time elapsed from the first infusion to resolution of bleeding was 43 h (median). Overall, haemostasis was rated as excellent or good by the investigator in 96% of the infusions. No product-related adverse events were reported. Factor IX Grifols is an effective and safe Factor IX concentrate and can be considered as a first line option for replacement therapy in haemophilia B patients.

Pharmacokinetic study of a high-purity factor IX concentrate (Factor IX Grifols) with a 6-month follow up in previously treated patients with severe haemophilia B.

Optimal replacement treatment in haemophilia B patients requires a good understanding of the pharmacokinetics of factor IX (FIX). The aim of this study was to compare the pharmacokinetic profile of Factor IX Grífols, a highly purified human FIX concentrate with two specific pathogen inactivation/removal steps, to that of available FIX preparations. The study was an open, non-randomized trial including 25 male subjects older than 12 years of age with severe haemophilia B. Pharmacokinetic profile of the FIX preparation regularly used by the subjects was determined as control. Pharmacokinetic profile of Factor IX Grifols was determined twice, one 7-15 days after control assessment and second after a 6 months period had elapsed. Results showed that all products had peak plasma levels of FIX:C within 30 min. Mean recovery was 1.3 +/- 0.3 IU dL(-1) per IU kg(-1) for Factor IX Grifols and 1.0 +/- 0.3 IU dL(-1) per IU kg(-1) for control products (P < 0.001). The mean terminal half-life (t(1/2)) for Factor IX Grifols was 26.7 h and 26.8 h for control product. Pharmacokinetic parameters after 6 months of treatment with Factor IX Grifols did not statistically differ from the parameters obtained with the first infusion. There were no adverse events related to Factor IX Grifols for the duration of the study. In conclusion, Factor IX Grifols has adequated pharmacokinetic properties comparable to the control plasma-derived FIX and these parameters remain stable after 6 months of treatment. Factor IX Grifols can be an effective and safe plasma-derived FIX concentrate for replacement therapy in haemophilia B patients.

Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study.

To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1-3; cytarabine (AraC) 200 mg/m2/day, days 1-7; cladribine (2-CdA) 5 mg/m2/day, days 1-5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16-60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.

Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis.

The aim of this study was to determine the efficacy and safety of subcutaneous weight-adjusted dose low molecular weight heparin (LMWH) compared with oral anticoagulant (OA) in the prevention of recurrent venous thromboembolism. In a prospective multicenter trial, 202 patients with symptomatic proximal deep vein thrombosis (DVT) were included. As soon as the diagnosis of DVT was confirmed by phlebography, 101 were randomly assigned to receive LMWH (nadroparin) for secondary prophylaxis and 101 to receive OA (acenocoumarol). Patients in both groups were initially treated with nadroparin in a dose of 85 anti-Xa IU/kg s.c. every 12 h. Secondary prophylaxis with either nadroparin, 85 anti-Xa IU/kg s. c. once daily, or acenocoumarol was continued for at least 3 months. Three patients in the LMWH group and 6 in the OA group were excluded from analysis for various reasons. During the one-year combined secondary prophylaxis and surveillance period, 7 of of the 98 evaluable patients (7.1%) in the LMWH group and 9 of the 95 evaluable patients (9.5%) in the OA group had a documented recurrence of venous thromboembolism (Fisher's exact test, p = 0.61). Of these, 2 patients who received LMWH and 7 patients on acenocoumarol had recurrences in the 3-month period of secondary prophylaxis. Four patients (4.1%) in the LMWH group developed bleeding complications during this study period, as compared with 7 (7.4%) in the OA group (Fisher's exact test, p = 0.37). There were two major bleedings, one in the LMWH group and one in the OA group. Eleven patients died, 5 (5.1%) in the LMWH group and 6 (6.3%) in the OA group. It is concluded that nadroparin in a dose of 85 anti-Xa IU/kg s.c. once daily provides an effective and safe alternative to oral anticoagulants in the secondary prophylaxis of DVT.

Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial.

In a prospective multicenter trial, 149 consecutive patients with phlebographically proven proximal and/or distal deep vein thrombosis of the leg were randomly allocated to receive subcutaneously for 10 days either low molecular weight heparin CY 216 (Fraxiparine) in a fixed dose or unfractionated heparin (UFH) in doses adjusted according to the activated partial thromboplastin time. Pre- and post-treatment phlebograms were assessed blindly using the Arnesen's score system in 134 patients available for analysis of the treatment efficacy. The mean phlebographic score after 10 days of treatment was significantly decreased in both groups (p less than 0.001) in comparison with the baseline score but the difference in score changes between the two groups was not statistically significant. There was an improvement in 45/68 patients (66%) in the Fraxiparine group and in 32/66 patients (48%) in the UFH group, and an increase in the thrombus size in 10/68 (15%) and 12/66 (18%), respectively. One symptomatic non-fatal pulmonary embolism and one major bleeding episode were observed in the UFH group. During a follow-up period of 3 months, two rethromboses had occurred in the UFH group and none in the Fraxiparine group. It is concluded that subcutaneous fixed dose Fraxiparine is safe and at least as effective as subcutaneous adjusted UFH in the treatment of deep vein thrombosis.

Binding of heparin to human endothelial cell monolayer and extracellular matrix in culture.

Endothelial binding of heparin contributes to its local antithrombotic action and catabolism. However, it is uncertain whether heparin may be bound to a damaged or even de-endothelialized vessel surface. Therefore, the binding of 3H-heparin to cultured endothelial cell monolayer and extracellular matrix was studied. The binding reached equilibrium after 4 h. 3H-heparin bound to endothelium could be displaced by unlabelled heparin which competed for about 80% of binding. The binding became saturable when the concentration of heparin exceeded 30-times the therapeutical value. Approximately 6 X 10(11) binding sites for heparin per cm2 of endothelium were calculated. Heparin was bound not only to endothelial cells but also to extracellular matrix, even when it was exposed in the absence of cells. About 40% of binding sites were localized in the extracellular matrix fraction. A similar affinity of binding of 3H-heparin to complete endothelium, endothelial cells and extracellular matrix was estimated /Kd of almost 1 microM/. The binding of heparin to extracellular matrix should be considered in the interpretation of heparin interaction with endothelium.

An alternative method for identifying the factor V gene Leiden mutation.

The recently described point mutation of nucleotide 1691 of the factor V gene is responsible for the factor V resistance to a cleavage with an activated protein C (APC-resistance). Despite the high sensitivity and specificity of the APC-resistance test as a screening method for the detection of the factor V APC-resistance, there is still a necessity to develop a simple, cheap and accurate DNA-based assay. Herein, two different ASO-PCR methods were used for the detection of the Leiden mutation. The first involved a direct ASO-PCR with a consensus FV N1 primer and a sequence specific primer for the 1691 bp "G" normal allele (FV G1) or a specific primer for the 1691 bp "A" mutant allele (FV A1). The second method consisted of direct ASO-PCR by using the consensus FV N1 primer and one of two primers with an additional T-->G mismatch at the penultimate position from the 3'-end. One primer was specific for the 1691 bp "G" normal allele (FV G2) and the other was specific for the 1691 bp "A" mutant allele (FV A2). These permit clear and easy distinctions between homozygous normal and heterozygous and homozygous mutant probands. We also tested a T-->A mismatched primer to compare our method with that recently reported by Bellisimo et al. We found that within a large range of PCR conditions, T-->G mismatched oligonucleotides discriminated better than T-->A mismatched between three factor V 1691 position genotypes. We therefore recommend our method for the screening of a single 1691G-->A nucleotide mutation in the factor V gene.

On the action of a heparan-like glycosaminoglycan (Hemovasal) on the mechanism of haemostasis and fibrinolysis.

Hemovasal produced by Manetti-Roberts, Florence, Italy, is a glycosaminoglycan obtained from porcine intestinal mucosa which belongs to the family of heparan sulfates. The substance was examined On 36 male survivors of myocardial infarction with an interval of at least 6 months after the acute event. No anticoagulants were given and ASA was withdrawn at least 2 weeks before the trial. Hemovasal was administered in 3 different i.m. doses as single injections. A further group received a daily oral dose of 300 mg for one week. A comparable placebo group of patients as well as a group of healthy volunteers was run in parallel. The coagulation profile showed only a slight prolongation of the aPTT, a trace of diminution of Antithrombin III and no activation of Heparin cofactor II. The fibrinolytic system showed an enhancement of the diurnal increase of t-PA without an alteration of the total increase of this activity. There was a considerable and highly significant diminution of the PAI-1 activity. This was dose dependent and could be found after i.m. as well as after oral administration. It was assumed that the thrombolytic effect which was repeatedly described was a consequence of the diminution of PAI-1.

The effect of a long-acting recombinant hirudin (PEG-hirudin) on experimental disseminated intravascular coagulation (DIC) in rabbits.

Reproducible disseminated intravascular coagulation in rabbits was provoked by two intravenous injections 24 hours apart of endotoxin from Salmonella enteritidis. There were mild symptoms of DIC before the second injection which considerably increased thereafter. In detail there was a sharp drop of the platelet count and a considerable diminution of Antithrombin III, of Protein C, Plasminogen and Antiplasmin as well as an appearance of fibrin monomer complexes and an increase of the aPTT. When PEG-hirudin in a single dose of 1 mg/kg BW was given simultaneously with the second injection of endotoxin the following alterations were observed: The drop of the platelet count and of the activities of Antithrombin III, Protein C, Plasminogen and Antiplasmin was significantly less pronounced. The fibrin monomer complexes were lower and the aPTT was less prolonged. The thrombin time, however, as a sign of a direct action of hirudin on thrombin was considerably more prolonged than in the controls. The combined effect of these alterations strongly points in the direction of a favourable influence of PEG-hirudin on the course of DIC. It is of special interest that 6 h after the intravenous injection of PEG-hirudin its full effect on the thrombin time was still detectable. This is apparently due to a longer half-life in circulation of PEG-hirudin than of natural hirudin.

Low molecular weight heparin and the heparin mobilisable pool of platelet factor 4 are reduced in young survivors of myocardial infarction.

The platelet factor 4 (PF4) mobilisation properties of low molecular weight heparin (Fraxiparine, Sanofi Winthrop, France) in young survivors of myocardial infarction (YSMI) and healthy volunteers have been investigated. The study group consisted of 42 YSMI less than 44 years old, all of them with angiographically proven occlusive coronary artery disease, studied 6 to 24 months after the acute event. The control group was composed of 30 healthy men of similar age. Subjects from the study and control groups were allocated to the following subgroups: those receiving 60 or 120 IU/kg b.w. of standard heparin (Polfa Kutno, Poland) and those receiving 60, 120 or 180 IC anti-Xa U/kg b.w. of low molecular weight heparin (Fraxiparine, Sanofi Winthrop, France) as a single intravenous injection. Additionally, in five YSMI patients the influence of prolonged aspirin administration (0.3g daily for more than 30 days) on the Fraxiparine mobilsable pool of PF4 and beta-thromboglobulin (beta-TG) concentration in the plasma was determined after injection of 180 IC anti-Xa U/kg b.w. of the drug. The PF 4 and beta-TG concentration in the plasma was evaluated using enzyme immunoassay methods before heparin or Fraxiparine intravenous injection and 2, 5, 10, 20, 30 and 60 min after. In both, the control and YSMI groups baseline PF4 levels were found to be normal. Moreover, similar marked dose-dependent increases of PF4 concentration in the plasma measured after 60 and 120 IU/kg b.w. of heparin as well as after 60 and 120 IC anti-Xa U/kg b.w. of Fraxiparine was found. The administration of 120 IU/kg b.w. of heparin resulted in a reduced rise in plasma PF 4 in YSMI as compared to healthy controls. The same phenomenon was observed when 180 IC anti-Xa U/kg b. w. of Fraxiparine was injected intravenously. In YSMI treatment with aspirin had no influence on the Fraxiparine mobilisable pool of PF 4 or the beta-TG concentration in the plasma. These results suggest that mobilisable pool of platelet factor 4 in young survivors of myocardial infarction derives from the "nonplatelet pool" and that reduction of heparin- or Fraxiparine-releasable pool of PF4 may reflect an impaired endothelium function, probably due to atherosclerosis.

Elevation of plasma fibrinogen in silent myocardial ischaemia.

High plasma levels of fibrinogen and plasminogen activator inhibitor (PAI-1) are reported to be correlated with coronary heart disease. Therefore the level of fibrinogen concentration in plasma was examined and verified for the possible correlation with the previously explored PAI-1 antigen and PAI-1 activity in the pathogenesis of premature atherosclerosis (Grzywacz et al., 1998, Blood Coagul Fibrinol. 9, 245-249). Examination included only men, aged 33-46 years, who were in a stable condition for at least six months after the acute event. They were divided into two subgroups: group A (n = 14) with and group B (n = 15) without ischaemic changes in 24 h Holter electrocardiogram. The number of involved vessels visible on the coronarography picture was similar in both groups. In the patients of group A the mean level of fibrinogen (3.92 vs 3.23 g/l, P < 0.05) was higher than in the controls (n = 15). No statistically differences were found between group B and control healthy subjects in any of the parameters measured. There were no correlation between fibrinogen concentration and PAI-1 antigen and activity levels, which were elevated in both groups of patients according to our previous study. Our results indicate that elevated levels of plasma fibrinogen and PAI-1 appeared in the group of patients with more severe disease, as revealed by silent myocardial ischaemia.

Impairment of plasma fibrinolysis in young survivors of myocardial infarction with silent ischaemia.

The aim of this study was to compare fibrinolytic parameters in two subgroups of young survivors of myocardial infarction: group A (n = 14) with silent myocardial ischaemia and group B (n = 15) without silent myocardial ischaemia, as assessed by 24 h Holter electrocardiogram monitoring. Only men aged 33-46 years who were in a stable condition at least 6 months after the acute event were included in the survey. All patients were normolipaemic or had only mild hyperlipidaemia, non-diabetic, normotensive, non-current smokers and with a normal body mass index. The control group consisted of 15 age-matched healthy men. Blood samples were taken at 7.30 a.m. In the group A patients, we found higher mean levels of tissue plasminogen activator (t-PA) total antigen (11.1 versus 6.9 ng/ml, P < 0.01), its inhibitor plasminogen activator inhibitor-1 (PAI-1) antigen (58.1 versus 34.8 ng/ml, P < 0.01), PAI-1 activity (4.9 versus 3.4 U/ml, P < 0.05) and tPA-PAI-1 complexes (5.1 versus 3.5 ng/ml, P < 0.05) as well as a lower level of t-PA activity (0.5 versus 0.8 IU/ml, P < 0.01) and free t-PA antigen (0.8 versus 1.3 ng/ml, P < 0.01) compared with the controls. However, group A patients exhibited higher PAI-1 antigen levels (58.1 versus 41.6 ng/ml, P < 0.05) than those without silent ischaemia. There were no differences between group B and controls in any of the parameters measured. Our results indicate that patients with more severe disease, as revealed by silent myocardial ischaemia, had lower levels of free t-PA as a result of the excess of PAI-1.

The treatment of acute myeloid leukemia with mitoxantrone, etoposide and low-dose cytarabine in elderly patients - a report of Polish Acute Leukemia Group (PALG) phase II study.

The common dilemma in the treatment of elderly patients with acute myeloid leukemia (AML) is whether to use intensive myelosuppresive therapy with higher risk of treatment related mortality (TRM), but a chance for complete remission (CR), or to treat less intensively in order to prolong survival time with a better quality of life. The aim of this prospective, phase II study was to assess the efficacy and toxicity of low dose combination induction treatment consisted of cytarabine at a dose of 10 mg/m2 every 12 h s.c. for 7 days, VP-16 at a dose of 100 mg/day p.o. for 7 days and mitoxantrone at a dose of 6 mg/m2 i.v daily on days 1-3. Two induction courses were planned. In the group of 44 patients 12 (27%) achieved CR, 4 (9%) patients were in PR and there were 9 (20%) early deaths (ED). Age, performance status, preceding myelodysplastic syndrome, karyotype, WBC and % of blasts in bone marrow were not significant prognostic factors for CR probability. The following initial factors appeared to be related to a shorter duration of survival time from the start of treatment: age >70 (p<0.03), poor performance status (p<0.03), and % of BM blasts 50 (p<0.05). We conclude that, despite promising results in the pilot study the efficacy of this induction treatment is not better than the efficacy of other regimens. The hematological toxicity of this treatment seems to be comparable with "3+7" regimen.

[Platelet activation in young men after myocardial infarction: its relation to metabolic coronary risk factors]. / Aktywacja plytek krwi u mlodych mezczyzn po przebytym zawale serca. Zaleznosc od metabolicznych czynników zagrozenia wiencowego.

Selected parameters of platelet function as well as their relationship with metabolic coronary risk factors are studied in a group of 40 young survivors (aged 30-40 years) of myocardial infarction, now presenting stable coronary disease. Nineteen healthy men, of approximately similar age-span, constituted the control group. The following parameters were determined: platelet survival half-time (via non-isotope method), intraplatelet activity of cyclooxygenase and lipoxygenase pathway of arachidonic acid (by measurements of malondialdehyde concentration before and after incubation with acetylsalicylic acid acid) and 125-I-fibrinogen binding to platelets. Moreover, the plasmatic concentration of total cholesterol, HDL-cholesterol, triglycerides, phospholipids, Apo A and B, total beta lipoproteins, glucose, uric acid as well as percentages of beta, prebeta, alpha lipoproteins and glycosylated hemoglobin were also studied. Platelet survival half-time in patients was significantly shortened (3.64 +/- 1.37 days) when compared with the control group (4.97 +/- 1.7 days). A higher intraplatelet activity of lipoxygenase pathway (2.02 +/- 0.62 and 1.49 +/- 0.54 nmol MDA/10(9) platelets, respectively) was also found. However, activity of cyclooxygenase pathway of arachidonic acid and 125-I-fibrinogen binding to platelets remained unchanged. Shortened platelet survival half-time and the hyperactivity of intraplatelet lipoxygenase pathway correlated with a reduced plasmatic concentration of HDL-cholesterol (r = 0.323, p less than 0.05 and r = -0.451, p less than 0.05, respectively). The remaining parameters of platelet function were not statistically related to metabolic risk factors. The values of platelet function indicators in subgroups of patients divided according to family history of coronary heart disease, oral glucose load test result, and submaximal exercise test result did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

[Laboratory diagnosis of congenital platelet function disorders]. / Laboratoryjna diagnostyka wrodzonych zaburzen czynnosci plytek krwi.

Up-dating of diagnostics of hereditary platelet disorders has been done. Due to the development of laboratory techniques some of the thrombopathies are now well characterized at the molecular level, and it can be seen that the classification of these defects has greatly progressed. However, the most frequent inherited disorders of platelet function encountered fall into the class "platelet secretion defect" and remain incompletely defined. Evidence of storage pool deficiency should be considered in all patients with an unexplained prolongation of the bleeding time, even in the absence of the classical aggregation abnormalities.

[Progress in the detection of intravascular activation of fibrinolysis]. / Postepy w diagnostyce wewnatrznaczyniowej aktywacji fibrynolizy.

Methods for measuring antigen and activity of plasminogen activators (t-PA, u-PA), plasminogen activator inhibitors (PAI-1, PAI-2) and their complex have been improved in the past few years, but few comparative data are available and they should be standardized. In particular the commercial kits for determination of PAI-1 activity seem to be not accurate for the measurement of PAI-1 in plasma. The amount of generated plasmin can be measured as plasmin-alpha-2-antiplasmin complex (PAP). There are also some new tests which could differentiate between fibrinogenolysis (FgDP) and fibrinolysis (FnDP, D-dimer) as between primary and secondary activation of fibrinolysis (B beta 15-42 peptide). Normal D-dimer plasma concentration allows for the ruling out of venous thromboembolism with high probability, but the specificity of this tests is poor.

[Markers of intravascular activation of coagulation]. / Markery wewnatrznaczyniowej aktywacji krzepniecia.

New markers of intravascular activation of coagulation have been developed, based on advance in our understanding of the biochemistry of the haemostatic mechanism. These are sensitive methods for measuring of peptides liberated with the generation of thrombin (factor IX activation peptide, factor X activation peptide, peptide F1 + 2), for measuring concentration of enzyme-inhibitor complexes (eg. thrombin-antithrombin III-TAT complexes), as well as for investigating the effect of thrombin on fibrinogen (fibrinopeptide A-FPA) or on protein C (protein C activation peptide). Studies employing these markers indicate that a state of hypercoagulability can be detected in the blood of humans prior to the appearance of thrombotic phenomena. However, further studies will be required to determine whether these methods can identify individuals who are entering a clinically relevant hypercoagulable state as well as to monitor an antithrombotic treatment.