Body mass index best predicts recovery of recombinant factor VIII in underweight to obese patients with severe haemophilia A

Background Factor VIII (FVIII) products are usually dosed according to body weight (BW). This may lead to under- or over-dosing in underweight or obese patients, respectively. Objective This article evaluates the pharmacokinetics (PK) of recombinant FVIII concentrate, particularly recovery, in relation to body mass index (BMI) and other body composition descriptors. Materials and Methods Thirty-five previously treated adults with severe haemophilia A from five BMI categories (underweight, normal, overweight, obese class I and II/III) were included. PK was evaluated after 50 IU per kilogram of BW single-dose recombinant FVIII (turoctocog alfa). The body composition variable was based on measurements of weight, height, bioimpedance analysis, and dual-energy X-ray absorptiometry. A dosing model was derived to achieve similar peak FVIII activity levels across BMI categories. Results A statistically significant positive association between BMI and C30min, IR30min, and AUC0–inf was observed; CL and Vss showed a significant negative association with BMI; t½ was independent of BMI and other parameters. The dosing model introduced a correction factor ‘M’ for each BMI category, based on linear regression analysis of C30min against BMI, which ranged from 0.55 for underweight to 0.39 for obese class II/III. This model achieved similar peak FVIII activity levels across BMI categories, estimating an average dose adjustment of þ243.3 IU (underweight) to –1,489.6 IU (obese class II/III) to achieve similar C30min. Conclusion BMI appears to be the best predictor of recombinant FVIII recovery; however, PK endpoints were also dependent on other body composition variables. The model demonstrated that dosing can be adjusted for individual BMI to achieve better FVIII predictability across BMI categoriesThis work was funded by Novo Nordisk A/S (Bagsværd, Denmark)

Pathogenesis of vascular complications in Cushing's syndrome

AbstrAct chronic exposure to high glucocorticoid levels in cushing's syndrome (cs) is often associated with alterations in the hemostatic system and the expression of prothrombotic phenotypes. Increased frequency of both atherothrombotic and venous thromboembolic events (VtE) has been reported in patients with cs. In general, cardiovascular complications in these patients cause a five-fold increase in mortality compared to the normal population. Although numerous abnormalities in the hemostatic system have been detected in patients with cs, the underlying mechanisms of the prothrombotic state are not fully elucidated. High levels of factor VIII and von Willebrand factor, with evidence of enhanced thrombin generation and decreased fibrinolytic activity, have been documented in several studies. However, it is not clear to what extent these changes contribute to the shift of hemostatic balance towards the hypercoagulable state and expression of thrombophilic phenotypes. thrombosis is usually a multicausal disease, and all three components of the so-called Virchow triad, namely 1) vascular abnormalities and endothelial dysfunction, 2) hypercoagulability and 3) stasis, may play a variable role in the pathogenesis of the prothrombotic state in cs patients. Larger studies are needed to establish strategies for prevention of cardiovascular complications in patients with cushing's syndrome

Slow Dynamic Slope method in internal combustion engine benchmarking

Enlarged engine control complexity made the full-factorial steady-state testing approach extremely time consuming and hardly applicable under actual industry demands. Slow dynamic slope (SDS) method is one of many approaches with a potential for considerable testing time savings, with its own benefits and drawbacks. This paper puts in focus SDS approach and evaluates its applicability, potentials and accuracy for fast estimation of engine steady-state maps. The presented research is based on an extensive experiment conducted on a small passenger car compresion ignition engine. Being the method that uses quasi-stationary sweeping of the engine, SDS test cycle durations in the range from 120-600 seconds are used in order to test the method and draw conclusions on its applicability. It is shown that well shaped SDS testing cycle can provide a rather good estimate of the steady-state operating points very quickly, with a negligible or very small loss of accuracy. The analysis is conducted both on fast responding variables and those that are heavily influenced by process inertia. This led to some suggestions on how to form a criterion for the SDS gathered data quality evaluation and SDS testing cycle correction

Obstetric and gynecological intervention in women with Bernard-Soulier syndrome: Report of two cases

Introduction. Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder characterized by giant platelets thrombocytopenia e prolonged bleeding timee frequent hemorrhages with considerable morbidity. Data on the outcome of pregnancy and gynecological intervention in BSS are rare and there are no general therapeutic recommendations. Cases Outline. We report two cases of BSS. In the first case a 29-year-old patient with BSS was admitted in 8 weeks of gestation. The diagnosis of BSS was made on the basis of prolonged bleeding time, giant-platelets thrombocytopenia, and absent ristocetin-induced platelet aggregation. In 38 week of gestation Cesarean section, with platelets transfusion preparation, was performed. Obstetric intervention passed without complication. Postoperative course was complicated with a three-week vaginal bleeding resistant to platelet transfusion. Neonate platelet count was normal. Our second case was a 28-year-old patient with BSS, hospitalized for ovarial tumor surgery. The patient was prepared for the intervention with platelets transfusion. The surgery was uncomplicated, but on the second postoperative day a massive vaginal bleeding, resistant to the platelet transfusion, developed. Bleeding control was achieved with activated recombinant factor VII. Twelve hours the patient developed later hypertensive crisis with epileptic seizure due to subarachnoid hemorrhage. Therapy was continued with platelet transfusion, antihypertensive and antiedema drugs. PH examination of tumor tissue showed hemorrhagic ovarial cyst. Conclusion. Obstretic and gynecological intervention in women with BSS may be associated with a life-threatening bleeding thus requiring a multidisciplinary approach with adequate preparation. Because of the limited data in the literature, it is not possible to provide firm management recommendations and each case should be managed individually

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with severe factor XII deficiency

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited adult-onset microangiopathy caused by missense mutations in the Notch3gene on chromosome 19. However, common vascular risk factors may additionally modify clinical expression and progression of the disease. The role of various prothrombotic factors has also been implied. We report a case of a middle-aged man with typical clinical, neuroimaging and histological features of CADASIL, but with notably prolonged activated partial thromboplastin time. Hematological investigations revealed severe clotting Factor XII deficiency. This case illustrates that the occurrence of vascular risk factors should not be overlooked in patients with CADASIL

The C20068T gene variant in the 3` end of the prothrombin gene and recurrent pregnancy loss: A pilot study

Recurrent pregnancy loss (RPL) is a health problem affecting up to 5% of women of reproductive age. Several thrombophilic risk factors might contribute to RPL. To investigate relationship between a novel C20068T gene variant in the 3' end of prothrombin gene and RPL, we tested 153 women with RPL and 111 controls for the presence of this gene variant. In patients, we have detected four heterozygous (2.61%) and no homozygous carriers. In controls, no carriers were detected. Our results indicate higher prevalence of C20068T gene variant in women with RPL but this difference was not statistically significant. However, in patients who suffered 5 or more RPL, frequency of C20068T gene variant was significantly increased compared to controls (12.5% vs. 0%, P = 0.02). This is the first study which points out a possible role of C20068T gene variant in etiology of RPL, but larger studies should be carried out to confirm our findings

Procarboxypeptidase U (TAFI) contributes to the risk of thrombosis in patients with hereditary thrombophilia

Introduction: It is considered that high plasma levels of procarboxypeptidase U (proCPU or TAFI) can promote the development of thrombosis, but data comparing proCPU levels in thrombophilia carriers and healthy subjects are rather scarce. Moreover, the results of previous studies on the risk of thrombosis related to high proCPU concentration in this population were not consistent. Although the 325 polymorphism, of proCPU has a significant effect on the CPU half-life, it's influence on the risk of thrombosis or spontaneous pregnancy loss in carriers of hereditary thrombophilia is not clear. Materials and Methods: The study population consisted of 144 thrombophilic patients (94 heterozygous and 10 homozygous carriers of FV Leiden, 26 heterozygous carriers of the prothrombin G20210A variation and 14 double carriers of FV Leiden and FII variation) and 69 healthy controls. Results: The results show that patients with inherited thrombophilia have a tendency toward lower mean proCPU plasma levels compared to healthy controls, however, this difference was only significant in carriers of FII G20210A (p = 0.014). A higher frequency of the most stable Ile325Ile proCPU was seen among carriers of I'll G20210A mutation compared to the control group (19% vs 7%; p = 0.186). In the second part of the study proCPU as a risk factor for thrombosis was evaluated. In heterozygous carriers of FV Leiden or FII G20210A high levels of proCPU conferred to an almost 4-fold increased risk for spontaneous onset thrombosis. The more stable Ile325Ile proCPU seems to impose a higher risk for clinical manifestation of the thrombophilic condition. Finally, a significant positive correlation between F1 + 2 and proCPU concentration was seen. Conclusion: The increased risk of thrombosis in thrombophilia patients is not only ascribable to an increased thrombin generation, but also high levels of proCPU and the presence of the 325Ile genotype tip the balance towards thrombotic tendency even further

Pregnancy complicated with deficiency of antithrombin: Review of current literature

Antithrombin deficiency, although the rarest thrombophilia, carries the highest risk of thromboembolism. This risk is increased especially for pregnant women due to physiological coagulation changes in pregnancy. Therefore, in cases of positive personal and/or family history of thromboembolic events as well as recurrent pregnancy loss women should be tested for antithrombin deficiency. Antithrombin deficiency is caused by numerous mutations of serpin peptidase inhibitor clade C 1 gene (SERPINC) and is classified according to antithrombin plasma activity and antigen levels into Type I (quantitative defect) and Type II (qualitative defect). Complications during pregnancy can be divided into those regarding the mother and those concerning the fetus. The main clinical manifestation of antithrombin deficiency regarding the mother is thromboembolism occurring spontaneously or recurrently during pregnancy. Numerous major gestational complications such as miscarriage, intrauterine growth restriction or fetal death, placental abruption, preeclampsia and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome can be linked to antithrombin deficiency. Close monitoring with early and adequate prophylaxis and treatment nowadays can mostly assure the positive pregnancy outcome for both mother and child. Prophylaxis/therapy with both low molecular weight heparin and antithrombin concentrate should start as soon as pregnancy is planned or at least as early as possible in pregnancy and continue until the end of the puerperium