[Hemorrhagic disorders]. / Blutungsneigung.

Patients suffering from hemorrhagic disorders often present with only minimal bleeding during surgery or injuries. However, some patients have life-threatening bleeding. Simple screening tests can be used to find the cause of the bleeding: patient and family histories provide information on whether the bleeding tendency is hereditary or acquired. Clinical examination can reveal the bleeding type. Measurement of platelet count can be used to exclude thrombocytopenia. Coagulation tests, such as prothrombin time (PT, Quick) and activated partial thromboplastin time (aPTT) can supply initial information concerning deficiency states of coagulation factors. Bleeding time is often prolonged in patients suffering from von Willebrand disease, thrombocytopenia or thrombocytopathy. If--due to the results of these screening tests-further testing of particular coagulation factors or platelet function is needed, then patients should be referred to a centre specialized in blood coagulation.

[New anticoagulants. Characteristics, monitoring and management of bleeding]. / Neue Antithrombotika. Wirkprinzip, Monitoring und Blutungsmanagement.

Vitamin K antagonists and heparins have been standard anticoagulation drugs over the past decades. They are effective and safe but they have several drawbacks which has led to the development of new oral anticoagulants. Dabigatran etexilate is a specific oral thrombin inhibitor and rivaroxaban and apixaban are oral inhibitors of factor Xa. These agents produce a predictable anticoagulant response after fixed-dose administration so that routine coagulation monitoring is unnecessary. Currently, dabigatran etexilate, rivaroxaban and apixaban are licensed for thromboprophylaxis after elective total hip or knee replacement surgery. Since august 2011, dabigatran etexilate is licensed for patients with atrial fibrillation, rivaroxaban will follow. However, indications will be expanded e.g. for therapy of venous thromboembolism. It is important to be aware of the pharmacokinetic and pharmacodynamic profiles of these new agents. The drugs considerably influence the global test of coagulation thus making an interpretation of test results difficult. Currently, there is a lack of suitable coagulation tests to monitor anticoagulation in emergency cases, such as bleeding. Specific antidotes are not yet available.

Topical use of platelet-rich plasma to influence bone volume in maxillary augmentation: a prospective randomized trial.

BACKGROUND AND OBJECTIVES: The atrophic posterior maxilla often requires restoration of the alveolar ridge due to a lack of bone quantity and quality before dental implant placement. The aim of this study was to verify the hypothesis that platelet-rich plasma (PRP) has an influence on bone density in the maxilla after sinus floor elevation in combination with autologous cancellous bone from the iliac crest. Therefore, a randomized, prospective, controlled trial was set up in two centres. STUDY DESIGN AND METHODS: Fifty-three patients who underwent osteoplastic bone grafting for sinus floor elevation were included. The intervention group was treated with defined concentrations of PRP in addition to transplanted bone. Bone biopsy was performed 4 months after augmentation. Bone volume was then measured using the histomorphometric parameter bone volume. RESULTS: The histomorphometric evaluation of the biopsies did not indicate superiority of any of the treatments in terms of bone volume. CONCLUSION: Topical use of PRP did not improve maxillary bone volume either clinically relevant or statistically significant compared to that in conventionally treated patients. The use of PRP to support bone regeneration cannot be recommended as a standard method for maxillary augmentation.

Association of polymorphisms in the mannose-binding lectin gene and pulmonary morbidity in preterm infants.

Deficiency in the collectin mannose-binding lectin (MBL) increases the risk for pulmonary and systemic infections and its complications in children and adults. The aim of this prospective cohort study was to determine the genetic association of sequence variations within the MBL gene with systemic infections and pulmonary short- and long-term complications in preterm infants below 32 weeks gestational age (GA). Three single-nucleotide polymorphisms (SNPs) in the coding region and one SNP in the promotor region of MBL2 were genotyped by direct sequencing and with sequence-specific probes in 284 newborn infants <32 weeks GA. Clinical variables were comprehensively monitored. An association was found between two SNPs and the development of bronchopulmonary dysplasia (BPD), defined as persistent oxygen requirement at 36 weeks postmenstrual age, adjusting for covariates GA, grade of respiratory distress syndrome and days on mechanical ventilation (rs1800450 (exon 1 at codon 54, B variant): odds ratio dominant model (OR)=3.59, 95% confidence interval (CI)=1.62-7.98; rs7096206 (-221, X variant): OR=2.40, 95% CI=1.16-4.96). Haplotype analyses confirmed the association to BPD, and a single haplotype (frequency 56%) including all SNPs in their wild-type form showed a negative association with the development of BPD. We detected no association between the MBL gene variations and the development of early-onset infections or further pulmonary complications. Frequent variants of the MBL gene, leading to low MBL concentrations, are associated with the diagnosis of BPD in preterm infants. This provides a basis for potential therapeutic options and further genetic and proteomic analysis of the function of MBL in the resistance against pulmonary long-term complications in preterm infants.

Trapidil decreases the aggregation of platelets from heart transplant recipients ex vivo.

Heart transplant recipients show platelet hyperaggregability, which may be related to the incidence of graft vasculopathy. We investigated whether trapidil can inhibit the aggregation of platelets from these patients. Platelet count, mean platelet volume (MPV), and adenosine diphosphate (ADP)-induced platelet aggregation were determined in 18 heart transplant recipients and 12 healthy subjects. Additionally, platelet-rich plasma from the patients was incubated with trapidil or with saline, prior to measuring ADP-induced aggregation. The MPV was significantly greater in patients compared to controls (9.4+/-1.1 vs 8.5+/-0.7 fL; P=.01), and ADP-induced platelet aggregation was significantly increased in patients compared to controls (81.2%+/-13.1% vs 69.6%+/-16.2%; P=.04, respectively). The trapidil-treated samples showed significantly decreased platelet aggregation compared to the control samples (24.2%+/-12.6% vs 66.7%+/-11.7%; P<.001). Platelets from heart transplant recipients showed an increased MPV and increased ADP-induced aggregation. Trapidil effectively reduced the ADP-induced aggregation ex vivo.

Self-management of oral anticoagulation in nonvalvular atrial fibrillation (SMAAF study).

UNLABELLED: Most patients with atrial fibrillation are at risk of suffering thromboembolic events. This risk can be reduced by twothirds by efficient anticoagulation. This prospective multi-center trial investigated whether the quality of treatment can be improved by self-management in patients with atrial fibrillations (SMAAF Study) compared to conventional patient management by the family doctor. METHODS: Two thousand patients suitable for self-management were to be randomized into the two arms of the study. In the period of investigation from December 1999 to July 2001, only 202 patients (64.3+/-9.2 years, 69.3% men) consented to participate. The study was discontinued prematurely since the number of patients was too low. As a consequence, the group comparison is confined to the evaluation of the INR values measured using the two-tailed t test. RESULTS: Of the 202 patients included, 101 were assigned to the self-management group (64.6+/-9.6 years, 71.4% men) and 101 (64.1+/-8.9 years, 61.4% men, n.s.) were assigned to the group managed by the family doctor. The total number of INR measurements was 2 865. This comprised 2 072 measurements in patients under self-management and 793 in the family doctor group. The values were within the target range significantly more frequently (p=0.0061) in patients under self-management (67.8%) as compared to the family doctor group (58.5%). There was a trend with regard to the time within target range, but the difference was not significant (178.8+/-126 days as compared to 155.9+/-118.4 days). In the self-management group, there were two severe hemorrhages, and there was one thromboembolic event in the family doctor group. CONCLUSION: Management of oral anticoagulation by INR self-management in patients with atrial fibrillation is not inferior to conventional care.

[Background and evaluation plan of a study on self-management of anticoagulation in patients with non-valvular atrial fibrillation (SMAAF Study)]. / Hintergrund und Prüfplan der Studie zum Selbstmanagement der Antikoagulation bei Patienten mit nichtvalvulärem Vorhofflimmern (SMAAF-Studie).

The objective of this open, randomized, multicenter study is to investigate the benefits and economic efficiency of self-management of oral anticoagulation in patients with atrial fibrillation (SMAAF study) in comparison with a group of patients given conventional care by a general practitioner or specialist. Two thousand patients suitable for self-management will be assigned at random to either the self-management group or the control group. The numbers of thromboembolic and hemorrhagic complications requiring treatment during the 2-year follow-up period will be recorded as the primary end point. The secondary endpoint variables will be maintenance of the INR value in the individual target range, INR variance, the course of complications over time, and the cost efficiency of self-management compared with the routine procedures. The last of these parameters will include the diagnostic and/or therapeutic measures carried out, the duration of inpatient hospital treatment, and the social consequences (subsequent rehabilitation treatment, inability to work, forced retirement). The estimate of the required number of patients was based on the assumption that during long-term anticoagulant therapy within the framework of primary and secondary prevention 4% of patients with chronic non-valvular atrial fibrillation would have severe thromboembolic of hemorrhagic complications each year. Since this rate can be halved by self-management, a one-tailed chi 2-test of 80% power and a 5% significance threshold would require n = 997 patients per group. The results of the SMAAF study will establish the socioeconomic benefits of self-management in patients with non-valvular atrial fibrillation.

Coagulation alterations due to local fibrinolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) in patients with peripheral arterial occlusive disease.

PURPOSE: To determine the systemic effects of local fibrinolytic therapy with low-dose recombinant tissue-type plasminogen activator (rt-PA). METHODS: Ten patients received intrathrombal infusion of 20 mg rt-PA and heparin for local thrombolysis and had subsequent percutaneous transluminal angioplasty (PTA). Eight controls underwent PTA and received heparin alone. We measured t-PA, D-Dimer, and fibrinogen levels before, directly after, and 20, 40, and 60 min and 24 hr after therapy. RESULTS: In the thrombolysis group the t-PA level peaked immediately after infusion and then declined within 1 hr. D-Dimer increased and remained elevated, whereas in the control group only t-PA levels increased, and only after 24 hr. Fibrinogen remained within the normal range in both groups. Eight of ten patients in the thrombolysis group and seven of eight with PTA had clinical improvement after the procedure. CONCLUSIONS: The increase in D-Dimer in the rt-PA group indicates a good local fibrinolytic effect. The fact that fibrinogen levels remained unchanged indicates that there is a lack of systemic fibrinogenolysis.

Cyclosporine a inhibits tissue factor expression in monocytes/macrophages.

Accelerated coronary atherosclerosis in cardiac allografts is the major limiting factor for long-term survival after heart transplantation. There is growing evidence that activation of the coagulation mechanism is involved in the development of transplant atherosclerosis. Tissue factor (TF) expression by cells of the monocyte/macrophage system may represent an important mechanism underlying the fibrin deposition in the affected vessels. In the present study, we investigated the effect of cyclosporine A (CsA) on the lipopolysaccharide (LPS)-induced procoagulant activity (PCA) in human monocytes/macrophages. CsA exerted a dose-dependent inhibitory effect on LPS-induced monocyte/macrophage PCA, which was identified as TF activity based on functional and immunologic characterization. As shown by reverse transcriptase-polymerase chain reaction, CsA reduced the transcription of the TF gene in LPS-stimulated monocytes/macrophages. Electrophoretic mobility shift assay showed that CsA inhibited the LPS-induced activation of the nuclear factor kappa B (NF-kappa B). As shown by Western blot analysis, CsA treatment decreased the nuclear translocation of NF-kappa B, thereby suggesting the mechanism for the inhibitory effect of CsA on TF induction. Hence, a nonimmunologic effect of CsA may contribute to its successful use in transplant medicine.

[Endemic sprue: its first diagnosis based on bleeding complications]. / Einheimische Sprue: Erstdiagnose aufgrund von Blutungskomplikationen.

HISTORY AND CLINICAL FINDINGS: A 47-year-old man without previously known illness was admitted to hospital because of acute haematomas in the legs: the history revealed no cause. The pale-looking patient reported having large and foul-smelling stools once or twice daily. There were large haematomas and swellings on both legs. His general and nutritional state was reduced. "Bleeding of unknown origin" was suspected at this time. INVESTIGATIONS: Haemoglobin concentration was 5.6 g/dl, while iron was normal and ferritin reduced. Quick value was below 5%, activated partial thromboplastin time prolonged to 180 s. Vitamin A and E concentrations were reduced; coumarin derivatives were not demonstrated in blood. Abdominal ultrasonography showed clearly thickened intestinal walls. TREATMENT AND COURSE: Four units of erythrocyte concentrate were immediately administered, together with 2000 IU factors II, VII, X and anti-haemophilic factor B (PPSB), and 10 mg vitamin K intravenously. As intestinal malabsorption was suspected, a vitamin A absorption test was performed: it indicated malabsorption. Upper intestinal endoscopy showed coeliac disease, as did a biopsy. The patient's state quickly improved after he had been given vitamins A, D, E and K and put on a gluten-free diet. CONCLUSION: Coeliac disease can take a clinically unremarkable course for a long time and may finally become manifest through an isolated abnormality, such as bleeding.