[Pregnancy in women with congenital bleeding disorder]. / Gravidita u pacientek s vrozenou krvácivou chorobou.

THE AIM OF THE STUDY: To highlight the risks associated with pregnancy at women with von Willebrand´s disease or hemophilia. Introduce the rules of multidisciplinary prenatal and peripartal care to minimalize these risks. The article is accompanied by case report where maladministration led to fatal consequences for the newborn. DESIGN: Review and case report.Seatings: Department Obstetric and Gynecology UJEP and Masaryk´s Hospital Ústí n/Labem, Institute Haematology and Blood Transfer Prague, Children´s Haemato-onkology Clinic University Hospital Prague Motol.Coclusions: The pregnancy in both above-mentioned diseases is risky. The close multidisciplinary collaboration is required.

Safety of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors: overall rFVIIa exposure and intervals following high (>240 µg kg⁻¹) rFVIIa doses across clinical trials and registries.

Recombinant activated factor VII (rFVIIa) is indicated for treatment of bleeding in congenital haemophilia with inhibitors (CHwI) using 90 µg kg(-1) every 2-3 h (EU and US) or a single 270 µg kg(-1) dose (EU only) with ~90% efficacy reported for both regimens. Dosing of rFVIIa varies, and home treatment makes assessment of frequency of doses >90 µg kg(-1), the intervals before additional treatment, and the risk for thromboembolic events (TEs) more difficult. This post hoc analysis assessed the safety and distribution of rFVIIa dosing in CHwI and the impact of >240 µg kg(-1) dosing on subsequent bypassing agent (BPA) dosing interval and frequency. Data regarding on-demand or prophylactic rFVIIa dosing, TE incidence and subsequent BPA dosing after high rFVIIa doses were compiled from multiple sources incorporating safety surveillance. A total of 61 734 rFVIIa doses were reported in 481 patients treated for 3947 bleeds and for 43 135 prophylaxis days. Over half (52%) exceeded 120 µg kg(-1), 37% exceeded 160 µg kg(-1) and 15% exceeded 240 µg kg(-1). Subsequent doses of BPA(s) were administered after 38% of initial and 49% of any rFVIIa dose >240 µg kg(-1), and were most frequently administered ≥24 h after initial (40%) or any (53%) doses >240 µg kg(-1). No TEs were reported. The findings of this analysis show that rFVIIa doses >90 µg kg(-1) are utilized for 'real-world' treatment of children and adults. When additional BPA was administered following an rFVIIa dose >240 µg kg(-1), reported intervals were prolonged, often ≥24 h. No safety issues were identified in the 61,734 doses analysed.

[Thrombophilic mutation by women with serious pregnancy complications]. / Výskyt trombofilních mutací zen se závaznými tehotenskými komplikacemi.

OBJECTIVE: The purpose of this study was to determine whether maternal or fetal genotype frequencies of the inherited thrombophilic gene mutation (F V Leiden, F II) are altered in adverse pregnancy outcomes - severe preeclampsia, IUGR, abruption of placenta and stillbirth. DESIGN OF THE STUDY: Retrospective study. SETTING: Department of Gynecology and Obstetrics of the Teaching Hospital and the 2nd Medical Faculty of the Charles University in Prague. METHODS: We studied 232 women who had pregnancy complications. All women were tested postpartum for mutation of factor V Leiden and G20210A prothrombine gene. At the same time were tested the newborns of those women. RESULTS: In the group of women with preeklampsia (n=141) we have demonstrated 5 women with mutation encoding for F V, 5 women with mutation encoding for F II and 1 combination of both. In the group of IUGR 2 women with mutation F V, 1 with mutation F II a 1 combination of both were found. In women after stillbirth occure two mutation of F V, one mutation of F II and one combination of both. In the group with abruptio of placenta was 1 case of mutation F V and 3 cases of mutation F II. When we tested a newborn we found 4 cases of mutation F V and 3 cases of F II in the group with preeclampsia, 4 cases of mutation F V 3 cases od mutation of F II in the group with IUGR, no case in the group with abruptio of placenta and 1 case in a death fetus. There was no assotiation between any severe pregnancy complications and any of the maternal or fetal inherited thrombophilia. CONCLUSION: Factor V Leiden and prothrombin gene mutations did not seem play a significant role in adverse pregnancy outcome in our population.

[Does the asymptomatic carriage of FV Leiden and FII prothrombin in heterozygous configuration represent the increased risk of thrombembolic complications during pregnancy, childbirth and postpartum?]. / Predstavuje asymptomatické nosicství mutace FV Leiden a FII protrombin v heterozygotní. Konfiguraci zvýsené riziko trombembolických komplikací v prubehu tehotenství, porodu a sestinedelí?

OBJECTIVE: To evaluate the course of pregnancy and puerperium in asymptomatic carriers of FV Leiden and FII prothrombin mutation in heterozygous configuration in terms of risk of thrombembolic disease and late pregnancy complications. To evaluate whether global prophylactic LMWH administration already during pregnancy has brought some benefit to these women. TYPE OF STUDY: Prospective study. METHODS: From June 2007 to June 2011, we monitored the incidence of thrombembolic events (TED) and severe late pregnancy complications in 473 asymptomatic carriers of FV Leiden and FII prothrombin mutation in heterozygous configuration. We also compared the ongoing changes of commonly clinically available hemocoagulation tests. In selected women, we added to coagulation tests a thrombin generation test (TGA) and thrombin-antithrombin test (TAT). In 253 women (Group A), preventive LMWH application was introduced already during pregnancy. In 220 women (Group B), the application of LMWH was commenced as late as on the delivery day. In both groups application of LMWH continued during the puerperium. RESULTS: The incidence of TED in the whole group of carriers of thrombophylic mutations accounted for 0.19%. The incidence of severe late pregnancy complications was very low - 3%. Medians of the monitored parameters of the hemocoagulation in compared groups and 'healthy' controls did not show statistically significant differences at any stage of pregnancy, labor or end of puerperium, with the exception of the results of TAT test at the end of puerperium. CONCLUSIONS: No direct causal relationship has been established between asymptomatic carriage of Leiden and prothrombin mutation in heterozygous configuration and the occurrence of severe late pregnancy complications. These types of mutation represent only a slightly increased risk in terms of development of thrombophylic events. General LMWH prophylaxis during pregnancy is not indicated. However, individual careful monitoring of hemocoagulation changes and early detection of associated transient situations potentiating risk of thrombembolic events is desirable. Statistically significant differences in the TAT results between group A and B at the end of puerperium revealed that the recommended extended LMWH prophylaxis until the end of puerperium was not followed by a number of women who started the prophylaxis on the date of labor.

[Thrombotic thrombocytopenic purpura in pregnancy. Case report]. / Trombotická trombocytopenická purpura v tehotenství. Kazuistika.

OBJECTIVE: Description of case of patient with rare thrombotic thrombocytopenic purpura in pregnancy. SUBJECT: Case report. SETTING: Department of Gynecology and Obstetrics, Charles University and University Hospital Motol, Prague. CONCLUSION: Thrombotic thrombocytopenic purpura (TTP) is a rare and substantial disorder characterized with combination of microangiopathic haemolytic anemia, consumption trombocytopenia and symptoms of organs dysfunction--especially kidneys and neurological deficiency. It's caused by production of microthrombi affecting small blood vessels. These palatelets-rich microtrombi are formed due to deficiency of the enzyme ADAMTS13--metalloprotease which is responsible for cleaving of ultralarge multimers of von Willebrand factor into smaller units. In our case report we describe patient with TTP in pregnancy. Therapy with corticosteroids and immunoglobulines was not effective, improvement of thrombocytopenia appeared after plasmapheresis (total count 14). The delivery was induced at term without complications. Target examination confirmed diagnosis of secondary TTP.

[Prolonged prophylaxis of thromboembolic events in colorectal malignancy resections]. / Prodlouzená profylaxe tromboembolismu pri resekci kolorekta pro malignitu.

Patients indicated for surgery for malignancies are at significantly increased risk of thromboembolic complications (TEN), compared to other surgery patients. The higher risk of TEN occurs during hospitalization, as well as during the follow up outpatinet care. The authors describe correlation between organ malignancies-surgical procedures and TEN. At the end of their work, the authors present current guidlines for extended TEN prophylaxis after oncosurgical procedures.

Single-dose (270 microg kg(-1)) recombinant activated factor VII for the treatment and prevention of bleeds in haemophilia A patients with inhibitors: experience from seven European haemophilia centres.

Several studies have suggested that recombinant factor VIIa (rFVIIa) is effective and safe at doses >90 microg kg(-1). In March 2007, the European Medicines Agency approved the use of single-dose rFVIIa 270 microg kg(-1) for the treatment of mild-to-moderate bleeds in haemophilia patients with inhibitors. The aim of this study was to describe the use of single-dose rFVIIa in a real-life setting. In November 2007, seven haemophilia specialists from five European countries convened to share and discuss their experiences with the single-dose rFVIIa regimen within haemophilia A. Case histories of eight patients were discussed in this retrospective study. Six adult and two paediatric patients (age range, 19 months-40 years) were treated with single-dose rFVIIa for a variety of target-joint bleeding, other bleeds and bleeding prevention. Treatment was successful in all the eight cases, with most patients requiring one dose to achieve bleeding resolution. No thrombotic or other safety concerns were raised by single-dose rFVIIa treatment. All patients and physicians preferred single-dose rFVIIa treatment to multiple injections; key benefits of single-dose rFVIIa treatment reported by patients and physicians included improved quality of life, greater convenience and ease of administration, improved compliance, faster control of bleeding, less injection-related pain and faster pain relief. In the patients reported here, single-dose rFVIIa 270 microg kg(-1) appears to be an effective and safe haemostatic treatment that improves the quality of life and convenience of treatment for patients. Such treatment might be of particular benefit for patients with difficult venous access or needle phobia.

Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HemoRec registry data from the Czech Republic.

Identifying haemophilia patients with inhibitors for clinical trials is difficult due to the limited number of patients available. Registries are therefore being established as an additional means of data collection. The aim of this study was to investigate the effect of different recombinant activated factor VII (rFVIIa; NovoSeven dose ranges and dosing schedules on the incidence of re-bleeding in haemophilia patients with inhibitors. In this retrospective, uncontrolled study, data on the bleeding patterns of adult haemophilia patients with high responding inhibitors were analysed. Only data from the Czech Republic, obtained by the HemoRec registry, were used. This study analysed 'real-life' clinical data and focused on the collection of the same parameters in different patients: time from bleeding onset to first injection, effect of first injection, number of re-bleedings, total number of injections and total amount of haemostatic drug used. Fifteen patients met the inclusion criteria and were included into the study (128 bleeding episodes). Patients treated within 2 h of bleeding onset experienced less re-bleeding than patients treated after 2 h of bleeding onset (5.2% vs. 13.7%, respectively). In addition, patients who were treated after 2 h of bleeding onset experienced fewer re-bleedings when high-dose rFVIIa was used (15.8% and 0%; <120 microg kg(-1) and >250 microg kg(-1), respectively). Initial high-dose rFVIIa was also associated with a decline in total rFVIIa consumption. This registry has provided a unique insight into the bleeding patterns of inhibitor patients, highlighting the importance of early treatment initiation and appropriate starting dose.

Paediatric haemophilia with inhibitors: existing management options, treatment gaps and unmet needs.

Development of inhibitors is a severe complication of haemophilia posing many management challenges. While a long-term goal in inhibitor patients is eradication of inhibitors through immune tolerance induction, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) are essential for control of bleeding episodes. Paediatric patients with haemophilia and inhibitors are at particular risk of recurrent haemarthroses, and management of these patients should seek to avoid joint damage and support the child's full social and physical development. Current options for management of bleeding complications include on-demand treatment of acute bleeding episodes, secondary prophylaxis to avoid recurrent bleeds and surgery to treat affected joints. There is also a rationale for adopting prophylactic approaches to prevent bleeding in inhibitor patients, allowing this group similar opportunities for protection against arthropathy development as are given to non-inhibitor patients. This paper, based on a roundtable meeting of haematology experts at the first Zürich Haemophilia Forum in May 2008, reviews the current evidence supporting more intense and prophylactic approaches to manage bleeding risk in paediatric haemophilia patients with inhibitors, and highlights the need for investigations of primary prophylaxis in this vulnerable patient group, to support best long-term outcome.

Thrombophilia and pulmonary endarterectomy.

UNLABELLED: In the present study, we compared groups of patients with and without thrombophilia, who underwent pulmonary endarterectomy (PEA), definitive treatment for chronic pulmonary hypertension resulting from thromboembolic disease. METHODS AND PATIENTS: Between September 2004 and June 2007, we operated 54 patients with CTEPH. We divided our patients into three groups. Group I patients, had one or more signs of serious thrombophilia (15 patients), Group II patients, had no signs of thrombophilia (23 patients without thrombophilia and without Methylenetetrahydrofolate Reductase (MTHFR)), and Group III patients with MTHFR (16 patients with MTHFR only, without any serious thrombophilia). RESULTS: After the surgery, there was a statistically considerable improvement of hemodynamic parameters (mPA, CI, PVR) in all groups, without a statistical difference between the groups. Comparison of all these groups showed more complications in-group I (thrombophilia), in particular reperfusion oedema, pericardial effusion, and renal insufficiency. Within one month, there was a considerable improvement or normalisation of haemodynamic parameters, an increase in walking distance at the six-minute walking test, and NYHA classification with no significant difference between the three groups. CONCLUSIONS: Early hemodynamic results of patients with thrombophilia after PEA, were comparable to the results of patients without thrombophilia, when we looked at both clinical and hemodynamic improvements. We did not find any differences when we looked at the results between Group II and Group III (MTHF), when we considered the number and type of complications. Patients with thrombophilia in Group I had statistically higher morbidity, especially when it came to a higher number of reperfusion oedema, pericardial effusion, and renal insufficiency.

The influence of intrinsic coagulation pathway on blood platelets activation by oxidized cellulose.

Oxidized cellulose is an effective hemostat that works naturally to aid in blood coagulation. The mechanism of its action is not very well understood. Little effect on blood coagulation, but a pronounce decrease in platelet count has been reported upon the addition of the oxidized cellulose to the whole blood. As a marker of platelet activation and aggregation we used serotonin release reaction and turbidity changes in time. We found that oxidized cellulose did not activate washed platelets reconstituted in plasma-free medium or plasma-free medium with fibrinogen; no reduction of platelet count was observed. Serotonin release in platelet-rich plasma incubated with oxidized cellulose started in the range from 5 to 10 min. Serotonin release from platelets reconstituted in plasma deficient in either coagulation factor V, VIII, IX, or XII was delayed. Blood platelets activation by oxidized cellulose requires calcium ions present in dispersion of oxidized cellulose. Factor XIII deficiency had no influence on blood platelets activation by oxidized cellulose. Our results clearly indicate the significance of intrinsic coagulation pathway activation on blood platelets activation by oxidized cellulose and so indirectly on the hemostyptic effect of oxidized cellulose.

The role of tissue factor in thrombosis and hemostasis.

The tissue factor (TF) is one of the most important regulators of arterial thrombosis. Because arterial thrombosis is the pathophysiologic background of acute coronary syndrome, the possible impact of blocking the arterial thrombosis on its onset is a challenging problem. The investigations of TF brought a new concept of "cell-based coagulation model" which highlighted the question of blood-borne TF as a source of TF in circulating blood. In this review we summarize essential information on the pathophysiology, molecular structure, expression and distribution of TF and we propose a novel concept of blood-borne TF, suggesting the possibilities of inhibition of the coagulation cascade with newly synthetized drugs.

[Intrahepatic cholestasis in pregnancy--guidelines of treatment]. / Intrahepatická cholestáza tehotných--doporucené postupy lécby, vedení tehotenství a porodu.

OBJECTIVE: The introduction of the guidelines of treatment of intrahepatic cholestasis of pregnancy (ICP) into the clinical praxis. METHODS: The procedures were elaborated on the basis of meta-analysis of published trials engaging in this tissue and based on results authors' randomised prospective study. RESULTS: The guidelines for treatment of ICP introduce the assessment of serum values of bile acids in diagnostics as the most important indicator of foetal hazard. They introduce the ursodeoxycholic acid as the standard in the treatment of ICP. The concentration of moderate and severe cases into the perinatology centres is recommended. In general, the termination of pregnancy after reaching the safety maturity of the fetus is recomanded.

[Ursodeoxycholic acid, S-adenosyl-L-methionine and their combinations in the treatment of gestational intrahepatic cholestasis (ICP)]. / Kyselina ursodeoxycholová, S-adenosyl-L-metionin a jejich kombinace v lécbe tehotenské intrahepatálnfí cholestázy (ICP).

UNLABELLED: SEATING: Department of Obstet. Gynecol., 2nd Medical School Charles University and Teaching Hospital Motol, Prague, Institute of Haematology and Blood Transfusion Prague, Department of Clin. Bioch. General Teaching Hospital and 1st Medical School, Charles University Prague, Czech Republic. AIM OF THE STUDY: To compare the efficacy of the monotherapy with ursodeoxycholic acid and S- adenosyl-L-methione with combined effect of both drugs in the treatment in pregnant women with intrahepatic cholestasis of pregnancy. METHODOLOGY: All women with singleton pregnancy at <36 weeks of gestation with moderate or severe form of ICP during January 1999 to June 2005 were enrolled. All were randomly assigned oral ursodeoxycholic acid (UDCA) 3 x 250 mg daily or 500mg S-adenosyl-L-methione (SAMe) twice daily in slow running infusion for twelve days ongoing oral 500 mg twice daily until delivery. Haematological and biochemical parameters were evaluated every week. Intensive monitoring of the fetus with cardiotocography and utrasound were accompanied. RESULTS: Of the 78 women enrolled, 25 received SAMe and 26 UDCA monotherapy. 27 women received combined therapy with both drugs. At enrolment, gestational age, duration of therapy, parity and biochemical characteristics were similar in the groups. All types of therapy improve the pruritus. The combined therapy and the monotherapy with UDCA led to improving of the serum concentrations of bile acids, asparate aminotranspherase, alanine aminotranspherase compared with monotherapy with SAMe. The differencies were statisticaly significant (p>0.01). The combined therapy led to quicker decrease of serum concentrations of bile acids and transaminases compared with UDCA monotherapy, however the results are only of borderline statistical significance. Gestational age at the time of labor and rate of prematurity were similar in all groups. No adverse effects were noted on the fetuses or neonates with either therapy. CONCLUSIONS: Ursodeoxycholic acid is effective in improving the biochemical parametres during the treatment of ICP. There is probably the synergistic effect with S adenosyl-L-methione. Whether the successful treatment influence the conditions of the fetus is not clear. The good perinatal outocome is probably more due to the precise monitoring of the intrauterine well-being of the fetus.

[Hematological aspects of gestational cholestatic hepatosis (ICP)]. / Hematologické aspekty tehotenské cholestatické hepatózy (ICP).

AIM OF THE STUDY: To assess the changes of hemocoagulative parametres induced by ICP from the view of posssible affection of the hemostasis. SEATING: Department of Obstet. Gynecol. 2nd Medical School Charles University and Teaching Hospital Motol, Prague, Institute of Haematology and Blood Transfusion Prague. METHODOLOGY: 20 blood samples of the pregnant with severe signs of ICP underwent the precise hemocoagulative analysis. The control group was composed from 12 women with physiological course of pregnancy comparable in terms of gestational week, age and parity. RESULTS: The routine hemocoagulative tests did show any statistical significant difference between both groups of examined women. The statisticaly significant elevation was found in women with ICP in factor VIII (fVIII:C), vWf and in the serum levels of fibrinogen. The elevated levels of fibrinogen did not influence the function of platelets and even the analysis of fibrinogen itself did not show any significant differences. Clinically assessed peripartal blood loss did not deviate from average of loss during the spontaneous labor of healthy women. CONCLUSIONS: The changes in hemocoagulative parametres in patients with ICP do not increase the risk of thromboembolic events during pregnancy and labor. We also did not approve the risk of the higher peripartal blood loss in these patinets.

[Hereditary form of thrombotic thrombocytopenic purpura]. / Vrozená forma trombotickté trombocytopenické purpury.

BACKGROUND: Thrombotic thrombocytopenic purpura is characterized by microvascular platelet clumping resulting in thrombocytopenia, microangiopathic hemolysis, neurological abnormality, and renal dysfunction. Similar manifestations also occur in patients with the hemolytic uremic syndrome or other types of disorders. Recent studies demonstrate that severe deficiency of the von Willebrand factor cleaving metalloprotease, ADAMTS 13, causes thrombotic thrombocytopenic purpura. Aim of our study was to characterize gene defects causing inherited type of disease. METHODS AND RESULTS: We investigated nine patients with recurrent type of disease with familiar origin and twelve relatives. Samples were taken in a remission of disease. We measured activity of ADAMTS13 (vWF-CP) with modified method of the quantitative immunoblotting of degraded vWF multimers. Mutation screening was carried out by sequencing all 29 exons and flanking intron regions of the ADAMTS13 gene. Five distinct mutations were found. Three of them are novel. CONCLUSIONS: Mutation analysis of the ADAMTS 13 gene brought interesting results in eight patients. We found a one single base frameshift insertion, 4143insA in 8 of 9 unrelated individuals. This investigation represents an advantage in the differential diagnosis of disease since the thrombotic thrombocytopenic purpura phenotype in childhood can be variable and rapid detection of mutation is helpful for the recurrence prevention.

Tissue factor, tissue factor pathway inhibitor and cytoadhesive molecules in patients with an acute coronary syndrome.

The tissue factor plays a crucial role in initiating blood coagulation after plaque rupture in patients with acute coronary syndrome. It is abundant in atherosclerotic plaques. Moreover, P-selectin, some cytokines, endotoxin and immune complexes can stimulate monocytes and induce the tissue factor expression on their surface. The aim of the study was to compare plasma levels of the tissue factor, tissue factor pathway inhibitor, P-selectin, E-selectin and ICAM-1 in patients with acute myocardial infarction, unstable angina pectoris, stable coronary artery disease and normal control subjects. In addition, plasma levels of the tissue factor, tissue factor pathway inhibitor, P-selectin, E-selectin and ICAM-1 were measured in the blood withdrawn from the coronary sinus in a subgroup of patients with unstable angina pectoris and stable coronary artery disease in which the difference between concentrations in the coronary sinus and systemic blood was calculated. A significant increase in tissue factor pathway inhibitor plasma levels was detected in patients with acute myocardial infarction (373.3+/-135.1 ng/ml, p<0.01) and unstable angina pectoris (119.6+/-86.9 ng/ml, p<0.05) in contrast to the patients with stable coronary artery disease (46.3+/-37.5 ng/ml) and normal subjects (45.1+/-14.3 ng/ml). The plasma levels of tissue factor pathway inhibitor were significantly increased both in the coronary sinus and systemic blood in the patients with unstable angina pectoris. There was only a non-significant trend to higher plasma levels of the tissue factor in patients with acute myocardial infarction and unstable angina pectoris as compared to the patients with stable coronary artery disease and normal subjects, the values being 129.1+/-30.2 pg/ml, 130.5+/-57.8 pg/ml, 120.2+/-45.1 pg/ml and 124.9+/-31.8 pg/ml, respectively. Plasma levels of soluble P-selectin was only slightly, but non-significantly higher in patients with unstable angina pectoris and stable coronary artery disease (184.2+/-85.4 ng/ml and 201.6+/-67.9 ng/ml, respectively) than in patients with the acute myocardial infarction (157.4+/-88.4 ng/ml) or normal subjects (151.4+/-47.1 ng/ml). The difference in plasma levels of soluble ICAM-1 between the blood withdrawn from the coronary sinus and systemic circulation correlated significantly with the corresponding difference in plasma levels of soluble P-selectin and E-selectin. In conclusion, the tissue factor and the tissue factor pathway inhibitor play a crucial role in the initiation of arterial thrombosis. The tissue factor pathway inhibitor levels are increased both in the systemic blood and in the coronary sinus of patients with the acute coronary syndrome.