Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry.

OBJECTIVE: The European Acquired Haemophilia registry (EACH2) collected data on the demographics, diagnosis, underlying disorders, bleeding characteristics, treatment, and outcome of women with acquired haemophilia A (AHA), a rare and often severe bleeding disorder caused by autoantibodies directed against coagulation factor VIII. DESIGN: Prospective, multi-centre, large-scale, pan-European registry. SETTING: A total of 117 haemophilia centres in 13 European countries. POPULATION: Pregnancy-associated AHA. METHODS: Data were reported using a web-based electronic case report form. Diagnosis was based on the presence of a prolonged activated partial thromboplastin time, reduced coagulation Factor VIII level and positive inhibitor assay. MAIN OUTCOME MEASURES: Presenting characteristics, time to diagnosis, haemostatic treatment and outcome, immunosuppressive treatment and outcome. RESULTS: The EACH2 registry (n = 501) documented 42 (8.4%) cases of AHA associated with the peripartum period, a median Factor VIII level at diagnosis of 2.5 (range 0-25) IU/dl and inhibitor titre of 7.8 (range 0.7-348) BU/ml. Antepartum inhibitors were evident in eight women. Time to diagnosis of AHA after delivery was 89 (range 21-120) days. First-line haemostatic treatment was successful in 20/23 (87%) women treated. Bleeding episodes resolved in 17/18 (94%) women treated with a bypassing agent and 29/39 (74%) women achieved complete remission with first-line immunosuppressive treatment. Two babies experienced postnatal bleeding, suggesting transplacental transfer of the antibody. All women were alive at last follow-up. CONCLUSIONS: Although rare, pregnancy-associated AHA may cause severe bleeding-related morbidity. Once diagnosed, women respond well to haemostatic treatment with bypassing agents and immunosuppression. Awareness of peripartum AHA requires improvement to facilitate rapid and appropriate management.

Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia.

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

Guar gum improves insulin sensitivity, blood lipids, blood pressure, and fibrinolysis in healthy men.

A double-blind, placebo-controlled, cross-over study was carried out in 25 healthy, nonobese middle-aged men to test the effect of guar gum on glucose and lipid metabolism, blood pressure, and fibrinolysis. Ten grams guar or placebo granulate was given three times a day for 6 wk with a 2-wk run-in before and a wash-out period after. Decreases in fasting blood glucose (P < 0.001), cholesterol (P < 0.001), triglycerides (P < 0.05), plasminogen activator inhibitor-1 activity (P < 0.01), systolic blood pressure (P < 0.01), and diastolic blood pressure (P < 0.001) were seen during guar treatment when compared with placebo. Insulin sensitivity, measured with the euglycemic-clamp technique, increased (P < 0.01), adipose tissue-glucose uptake measured in vitro increased (P < 0.001), and 24-h urinary excretion of sodium and potassium increased (P < 0.001) during guar treatment. Fasting plasma insulin, renin, aldosterone, and fibrinogen concentrations as well as skeletal-muscle electrolytes, urinary catecholamines, and body weight remained unaltered. These findings support a role for guar in the treatment of the metabolic syndrome in which insulin resistance seems to play a pivotal role.

Management of haemophilia A with antibodies--the effect of combined treatment with factor VIII, hydrocortisone and cyclophosphamide.

Immune tolerance has by several methods been induced in haemophiliacs with antibodies. A conversion of "high responders" into "low responders" was previously reported after repeated moderate factor IX doses over periods of 7-10 days in combination with cyclophosphamide and steroids in two patients with haemophilia B and inhibitors. This paper reports similar results in a haemophilia A patient by giving factor VIII, cyclophosphamide, and steroids during relatively short periods of time (7-8 days). The anamnestic response markedly decreased already following the first treatment and never exceeded a level of 1 u/ml (approximately 3 BU/ml) even when boosted with ordinary factor VIII doses for only 3 days. It is concluded that the markedly decreased secondary antibody response is most probably the result of factor VIII given at short intervals (twice a day) for periods of up to about one week when given in combination with cyclophosphamide and steroids. The same effect may be achieved by other methods. The treatment schedule suggested in the present paper is, however, simple and avoids long periods of high antibody levels. Furthermore, the total factor VIII dose used is lower than suggested in most other treatment schedules, which makes the treatment substantially less expensive.

Treatment of venous thromboembolism in patients with congenital deficiency of antithrombin III.

The treatment course of all thromboembolic events in the patients with congenital deficiency of antithrombin III (AT III) in the national Swedish register was reviewed in order to assess the appropriate medical therapy in this situation. The medical treatment of 70 events of venous thromboembolism was evaluated. There were eight cases with signs of clinical progression. The risk of therapeutic failure with heparin could be as low as 1.5% or as high as 9.2%. It would not be cost-effective to substitute with concentrates of AT III in every case with congenital deficiency thereof in connection with acute venous thromboembolism. "Heparin resistance" does not seem to be a problem in the vast majority of these patients.

The effect of various anticoagulant/antiplatelet mixtures on determination of plasminogen activator inhibitor, platelet proteins and hemostasis parameters.

Blood collected in different anticoagulant/antiplatelet agents (ETP, EDTA, citrate, citrate/citric acid pH 4.5 and CTAD) was compared with respect to determination of PAI-1 activity and PAI-1 antigen. beta TG and PF4 were analysed as markers of platelet release. Both the middle layer and the remaining layer of the plasma were studied. Moreover vWF:Ag, FVII:Ag, ECLT, t-PA:Ag, t-PA activity, APTT, VIII:C and VII:C were assayed in blood collected in citrate and CTAD. PAI-1 activity showed the same level in all citrate based anticoagulants and ETP and no increase was found in blood standing for 2 hours at room temperature. On the contrary quick handling was most important for determination of PAI-1 antigen. In tubes anticoagulated with citrate no significant increase was found if the sample was prepared within 1 hour. EDTA was not suitable as anticoagulant mixture. Tubes containing the antiplatelet mixture CTAD could be used for determination of PAI activity, PAI antigen, vWF:Ag, FVII:Ag, t-PA activity and APTT. For measurement of PAI-1 antigen quick handling of blood anticoagulated with antiplatelet mixtures are preferable, and plasma treated in that manner could also be used to assay some hemostasis parameters.

Effects of metformin and metoprolol CR on hormones and fibrinolytic variables during a hyperinsulinemic, euglycemic clamp in man.

The aim of this study was to characterize the acute effect of euglycemic (glucose 5.2 +/- 0.6 mmol/l) hyperinsulinemia (mean 118 +/- 32 mU/l) on fibrinolytic variables, free fatty acids (FFA) and counterregulatory hormones. In addition, the effect of chronic treatment with metformin, an oral antidiabetic agent which enhances insulin action, and metoprolol CR, a relatively beta 1-selective adrenergic antagonist, was also evaluated. A randomized, double-blind, placebo-controlled, cross-over study including 18 non-obese men, aged 53 +/- 6 years, was performed. The investigations were performed after each treatment period of 6 weeks in both the postabsorptive state and during a euglycemic, hyperinsulinemic clamp. Compared to the postabsorptive state, plasminogen activator inhibitor (PAI-1) activity and antigen, tissue plasminogen activator (t-PA) antigen and FFA decreased (p < 0.001) after 120 min of euglycemic hyperinsulinemia. In addition, t-PA activity increased (p < 0.01) while blood levels of lipoprotein (a), catecholamines and cortisol remained unchanged. Growth hormone increased during the clamps and this was most pronounced after treatment with metoprolol CR. When the effect of treatment was compared, postabsorptive levels of C-peptide, FFA and t-PA antigen were lower after metformin than after the placebo period (p < 0.05). t-PA antigen also remained lower during the clamp after metformin treatment. No significant effects of metformin or metoprolol CR were seen on insulin-stimulated glucose uptake during the clamps or on postabsorptive levels of counterregulatory hormones, PAI-1 or Lp(a).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables.

The effects of oral and transdermal administration of estrogen replacement therapy (ERT) have been fairly well investigated regarding lipoprotein and carbohydrate metabolism, while the effects of different modes of estrogen administration on the haemostatic system have been less well studied. To delineate and compare the effects of perorally administered conjugated estrogens (CE) and transdermally administered estradiol (E2) in doses needed for hormone replacement therapy (HRT) on haemostasis parameters, 23 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (0.625 mg CE and 50 micrograms E2/24h) are the lowest which, with few exceptions, eliminate climacteric symptoms. Both CE and E2 increased factor VII:C, factor VII:Ag, and the prothrombin fragment1 + 2. The increase in factor VII:Ag, however, was significantly higher after treatment with CE. These changes were all towards a state of hypercoagulability. Furthermore, CE decreased plasminogen activator inhibitor (PAI) and the thrombin-antithrombin complexes (TAT), as well as antithrombin (ATIII).

Pre- and postoperative levels of antithrombin III with special reference to thromboembolism after total hip replacement.

A prospective study of antithrombin III, determined by electroimmunochemical assay or an amidolytical method, was carried out with special reference to thromboembolism after total hip replacement. Two hundred and seven patients were randomly allocated to thromboembolic prophylaxis with dextran 70 or low dose heparin combined with dihydroergotamine. Deep vein thrombosis determined by phlebography of the operated leg or pulmonary embolism diagnosed with perfusion/ventilation scintigraphy developed in 51% of the total material and did not differ significantly between the two groups of prophylaxis or between patients with a preoperative At III below normal and those with a normal value. The correlation between the two assay methods for At III was 0.61. An initial, postoperative decrease in At III was noted with a parallel fall in hematocrit and fibrinogen, later followed by an increase of the plasma proteins. It is concluded that the immediate postoperative decrease of At III is mostly due to hemodilution.

Sympathoadrenal activation and muscarinic receptor stimulation induce acute release of tissue-type plasminogen activator but not von Willebrand factor across the human forearm.

We have previously shown that both mental stress and administration of the muscarinic receptor agonist methacholine induce an acute release of tissue-type plasminogen activator (t-PA) across the human forearm. There are data indicating that the regulated acute release of t-PA from the endothelium is closely interrelated with release of von Willebrand factor (vWF). The aim of the present study was to simultaneously determine basal and stimulated in vivo release rates of t-PA and vWF in an intact human muscle vascular bed. Eighteen healthy young males were studied at rest and during 10 min of mental stress (forced arithmetic). A subsample of ten subjects also received a step-wise i.a. infusion of methacholine (0.1-0.8-4.0 microg/min). Forearm blood flow was determined by venous occlusion plethysmography and interconverted to forearm plasma flow (FPF) using individual hematocrits. Net release/uptake rates of t-PA and vWF were calculated as the product of the arteriovenous concentration gradient and FPF. At rest there was a net release of both t-PA antigen and activity. In contrast, there was no significant local net release of vWF antigen across the forearm. Net release rates of t-PA roughly doubled in response to the stress test (0.4 to 0.8 and 0.2 to 0.5 ng x min(-1) x 100 ml(-1) for t-PA antigen and activity, respectively, p <0.05 for both). Local administration of methacholine induced a more than 10-fold increase in the net release rates of t-PA (0.6 to 9.6 and 0.3 to 6.6 ng x min(-1) x 100 ml(-1) at the highest dose step for antigen and activity respectively, p <0.01 for both). In contrast, neither mental stress nor local administration of methacholine induced a significant net release of vWF antigen across the forearm. The results demonstrate that the processes of acute release of t-PA and vWF are not necessarily linked in vivo in man.

APC resistance and other haemostatic variables during pregnancy and puerperium.

Forty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type I and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

The acute effect of insulin on tissue plasminogen activator and plasminogen activator inhibitor in man.

The present study was performed to elucidate the acute effect of insulin on levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor of endothelial cell type (PAI-1). Nine middle-aged, non-obese and non-smoking men were studied during a hyperinsulinemic, euglycemic glucose clamp for 2 h. Plasma insulin level during the clamp averaged 84 +/- 12 mU/l and euglycemia was maintained at 4.9 +/- 0.6 mmol/l. The t-PA activity gradually increased (75% mean increase after 2 h, p less than 0.001) and the PAI-1 activity decreased (49% mean decrease after 2 h, p less than 0.001) during the clamp. t-PA activity decreased and PAI-1 activity increased after the insulin infusion was ceased, but they were still 48% higher and 38% lower, respectively, after 60 min. PAI-1 and t-PA activities were not affected by saline infusion for 2 h. Thus, acute changes in the insulin levels lead to rapid alterations in the fibrinolytic system even when euglycemia is maintained. These effects may be induced by insulin itself or by the concomitant activation of the sympatho-adrenal system during the euglycemic clamp.

The influence of a serine protease inhibitor, nafamostat mesilate, on plasma coagulation, and platelet activation during experimental Extracorporeal Life Support (ECLS).

INTRODUCTION: During extracorporeal circulation the contact between blood and the artificial surface of the circuit induces several changes in the hemostatic system. The objective of the present study was to assess the effect of a serine protease inhibitor--Nafamostat mesilate (FUT-175)--on coagulation and on platelets during experimental extracorporeal circulation. METHODS: Two identical Extra Corporeal Life Support (ECLS) circuits were primed with fresh, heparinized human blood and circulated for 24 h. FUT-175 was added to one of the paired circuits and the other was used as a control. The following FUT-175 concentrations were employed: (1) 7.1 mg/l/h, (2) 14.2 mg/l/h, (3) 14.2 mg/l/h + 85.5 mg given as an initial bolus, (4) 28.5 mg/l/h + 171 mg given as an initial bolus. Blood samples were collected from the circuits before the start of the perfusion and at 0.5, 1, 3, 12, and 24 h of perfusion, and analysed for platelet count, plasma betathromboglobulin (beta-TG), platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa expression, thrombin/antithrombin III complex (TAT), prothrombin fragment 1+2 (F1+2), fibrinogen, D-dimer, and plasminogen activator inhibitor 1 activity (PAI-1). RESULTS: Significantly higher platelet membrane GPIb expression and lower plasma beta-thromboglobulin levels were observed in the circuits holding FUT-175, suggesting a lower degree of platelet activation. Also, a reduced activation of the coagulation system was observed in the "FUT-circuits", as reflected by the levels of F1+2 and TAT, and the PAI-1 activity that was rapidly inactivated. CONCLUSION: FUT-175 reduces the activation of platelets and plasma coagulation in an in vitro ECLS model.

Hemostatic responses to mental stress during the menstrual cycle.

To study the effect of sex hormones on the hemostatic responses to stress, blood samples were collected before, during, and after 20 min of mental stress from 9 healthy, non-smoking female volunteers, examined in the follicular and luteal phase. Mental stress caused significant increases in heart rate, blood pressure, and plasma catecholamines. In addition, analysis of variance indicated significant changes of leukocyte count, hematocrit, fibrinogen, von Willebrand factor antigen, t-PA activity and antigen in response to the stress test. However, in contrast to a male group previously investigated, there were no significant changes in factor VII coagulant activity in either menstrual phase. Overall the responses were more pronounced in the luteal as compared to the follicular phase. The findings support the concept that both gender and physiological variations in female sex hormones may modulate hemostatic responses to psychosocial stress.

Antithrombin III molecular variants with defective binding to heparin or to serine proteases: evidence of two different abnormal patterns identified by crossed immunoelectrofocusing.

Molecular heterogeneity of antithrombin III (AT III) was investigated by a technique of crossed immunoelectrofocusing (CIEF) in plasma samples of patients from 16 families with AT III congenital defect, including 8 AT III molecular variants. The AT III CIEF pattern was normal in all the patients with AT III quantitative deficiency, showing a balanced decrease of all the peaks. Out of the 8 AT III variants investigated, 6 had an abnormal pattern: the three variants with defective binding to heparin (AT III Roma, AT III Barcelona, AT III Malmö) shared a similar abnormal pattern; three variants with defective binding to serine proteases (AT III Pescara, AT III Milano, AT III Tampere) had a common abnormal pattern clearly different from the first one, whereas the other two variants deficient in the inactivation of the serine proteases (AT III Chicago, AT III Milano 2) showed a normal pattern. The first type of pathological pattern (type Roma) was characterized by the presence of an abnormal peak overlapping the normal isoforms present at pH 4.8-4.6 and by an additional peak at pH 4.5. The second type of pattern (type Pescara) showed an additional peak at pH 4.5 and an abnormal quantitative distribution of the isoantithrombins all throughout the pH range (5.2-4.6). In order to separate the abnormal AT III fraction from the normal one, plasma of a patient with Roma defect and serum of a patient with Pescara defect were passed throughout an heparin-ultrogel column.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study of three low-molecular weight heparins (LMWH) and unfractionated heparin (UH) in healthy volunteers.

The levels of anti-IIa and anti-Xa activity, as reported in laboratory and clinical studies on low molecular weight heparin (LMWH) preparations, show a high degree of variability. This variation has been proposed as correlated to the variation in incidence of postoperative deep vein thrombosis (DVT) (8-30%) in different LMWH studies on comparable populations undergoing elective hip surgery. The aim of this study was to compare the ex vivo potency of Clexane (enoxaparin), Fragmin (dalteparin) and Logiparin (tinzaparin), applying the concept of bioequivalence, although unknown which activity/activities are best correlated to efficacy. Unfractionated heparin (UH) was included in the study as a reference drug. The drugs were studied with a cross-over technique in 12 healthy subjects and given subcutaneously in the doses recommended for orthopedic surgery. Blood samples were drawn each hour up to 10 h and at 12 h after administration. Anti-Xa and anti-IIa activities were measured using chromogenic substrate methods. The anti-Xa peak activity (Cmax) and the area under the curve (AUC) were highest for Clexane and Fragmin and lower for Logiparin and UH. Clexane and Fragmin were considered bioequivalent in anti-Xa activity. Regarding anti-IIa activity, no bioequivalence was found between the products. Fragmin was clearly different, with Cmax and AUC approximately twice as high as the other drugs. Whether the demonstrated differences in anti-Xa and anti-II activities are of any clinical significance remains unclear and can only be established by comparative clinical studies.

Changes of plasma coagulation and fibrinolysis in response to mental stress.

To study the effects of standardized mental stress (arithmetic and the Stroop color word test) on plasma coagulation and fibrinolysis, blood samples were obtained before, during, and after 20 minutes of mental stress from 10 healthy, non-smoking young males aged 22 to 30 years. Reactions were compared with those observed during physical exercise and infusion of adrenaline. Both von Willebrand factor antigen and factor VIII coagulant activity increased significantly in response to mental stress (95 +/- 28 vs 123 +/- 56%; p less than 0.05 and 125 +/- 54 vs 217 +/- 170%; p less than 0.05, respectively). There was also a significant increase of factor VII coagulant activity (86 +/- 31 vs 108 +/- 51%; p less than 0.05). Furthermore, mental stress caused an activation of the fibrinolytic system with an elevation of tissue plasminogen activator activity and tissue plasminogen activator antigen (0.80 +/- 0.48 vs 1.23 +/- 0.96 IU/ml; p = 0.076 and 4.38 +/- 1.87 vs 5.78 +/- 2.58 IU/ml; p less than 0.01). Fibrinogen concentration increased during stress (1.95 +/- 0.29 vs 2.11 +/- 0.27 g/l; p less than 0.05). Similar but more pronounced responses were observed during exercise and adrenaline infusion. Parallel to the increases in coagulation and fibrinolytic factors there were significant increases in heart rate, and systolic and diastolic blood pressure. It is concluded that mental stress has significant effects on plasma coagulation and fibrinolysis, and that it could thus affect important risk factors for cardiovascular disease.

Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults.

The syndrome of growth hormone deficiency (GHD) in adults is associated with premature atherosclerosis, increased cardiovascular mortality, abnormal lipoprotein patterns and abnormal body composition. We have previously shown that GH-deficient adults have increased concentrations of fibrinogen and plasminogen activator inhibitor (PAI-1) activity. The aim of the present investigation was to study coagulation and fibrinolysis in 17 patients with adult-onset GHD during two years of treatment with recombinant human GH (12 micrograms/kg body weight/day). The impact of the contemporary changes in metabolic variables and body composition on coagulation and fibrinolysis was studied. The patients received conventional thyroid, adrenal and gonadal hormone replacement therapy. PAI-1 activity, PAI-1 antigen and tissue plasminogen activator (t-PA) antigen levels decreased during the GH treatment period (p < 0.05). The decrease was more pronounced in patients with high pre-treatment levels of the different variables. alpha 2-antiplasmin decreased (p < 0.05), while plasminogen was unchanged during two years of GH treatment. Fibrinogen concentrations tended to decrease after two years of GH treatment (p = 0.06), while the coagulation factors VII and VIII were unchanged. von Willebrand factor demonstrated a transient decrease after 18 months of GH treatment. The coagulation inhibitor, protein C, decreased (p < 0.05), while antithrombin was unchanged. Fasting plasma insulin increased (p < 0.01), but blood glucose did not differ after two years of GH treatment. Serum high-density lipoprotein cholesterol, total cholesterol and triglycerides were unaltered. Body fat decreased during the initial GH treatment but was unaltered after two years, while lean body mass increased (p < 0.001) and the waist over hip circumference ratio tended to decrease (p = 0.06). In conclusion, PAI-1 activity, PAI-1 antigen and t-PA antigen decreased during long-term GH treatment. These changes may be a direct effect of GH itself or may be secondary to the favourable changes in body composition. It remains to be seen whether changes in these fibrinolytic variables during rhGH treatment reduces the cardiovascular risk in patients with GHD. The present results suggest that GH plays a role in the regulation of fibrinolysis.

Recombinant, B-domain deleted factor VIII (r-VIII SQ): pharmacokinetics and initial safety aspects in hemophilia A patients.

The pharmacokinetics of a second-generation recombinant B-domain deleted factor VIII (FVIII) preparation (r-VIII SQ) were studied in 36 patients with severe hemophilia A. In contrast to full-length recombinant FVIII, no albumin needs to be added to stabilize the final formulation of this B-domain deleted FVIII preparation. The in vivo recovery and half-life of r-VIII SQ were similar to those of plasma-derived (pd) FVIII (mean half-life of r-VIII SQ, 11.7 h). The volume of distribution and clearance were slightly, but significantly, higher for r-VIII SQ than for pdFVIII (p < 0.05). Peak plasma levels of FVIII were consistently related to the administered dose of r-VIII SQ (r = 0.94, p < 0.0001). The pharmacokinetic profile of r-VIII SQ remained essentially unchanged in a dose range of 25-100 IU/kg body weight and could be reproduced after repeated doses. r-VIII SQ was well tolerated. In conclusion, deletion of the B-domain of FVIII does not influence its in vivo pharmacokinetics.

Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1.

Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor -1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.