How to manage patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia is a rare systemic autosomal dominantly inherited disorder of the fibrovascular tissue with a wide variety of clinical manifestations. Diagnosis is based on the clinical Curaçao criteria or molecular genetic testing. Dilated vessels can develop into telangiectases or larger vascular malformations in various organs, calling for an interdisciplinary approach. Epistaxis and gastrointestinal bleeding can result from these vascular defects. Various conservative and interventional treatments have been described for these conditions. However, no optimal therapy exists. Treatment can become especially difficult due to progressive anaemia or when anticoagulant or anti-thrombotic therapy becomes necessary. Screening for pulmonary arteriovenous malformations (PAVM) should be performed in all confirmed and suspected patients. Treatment by percutaneous transcatheter embolotherapy and antibiotic prophylaxis is normally effective for PAVM. Cerebral or hepatic vascular malformations and rare manifestations need to be evaluated on a case-by-case basis to determine the best course of action for treatment.

Treatment of epistaxis in hereditary hemorrhagic telangiectasia with tranexamic acid - a double-blind placebo-controlled cross-over phase IIIB study.

INTRODUCTION: Epistaxis is the most frequent manifestation in hereditary hemorrhagic telangiectasia, in which no optimal treatment exists. It can lead to severe anemia and reduced quality of life. Positive effects of tranexamic acid, an antifibrinolytic drug, have been reported on epistaxis related to this disorder. We sought to evaluate the efficacy of treating nosebleeds in hereditary hemorrhagic telangiectasia with tranexamic acid. MATERIALS AND METHODS: In a randomized, double-blind, placebo controlled, cross-over phase IIIB study, 1 gram of tranexamic acid or placebo was given orally 3 times daily for 3 months for a total of 6 months. RESULTS: 22 patients were included in the intention-to-treat analysis. Hemoglobin levels, the primary outcome measure, did not change significantly (p=0.33). The secondary outcome measure was epistaxis score and patients reported a statistically significant reduction in nosebleeds, equaling a clinically relevant 54% diminution (p=0.0031), as compared to the placebo period. No severe side effects were observed. CONCLUSION: Tranexamic acid reduces epistaxis in patients with hereditary hemorrhagic telangiectasia. (Clinical trial registration numbers: BfArM 141 CHC 9008-001 and ClinicalTrials.gov NCT01031992).

Variables influencing Multiplate(TM) whole blood impedance platelet aggregometry and turbidimetric platelet aggregation in healthy individuals.

We investigated the relationship between impedance platelet aggregometry (IPA) as measured by the Multiplate system and turbidimetric platelet aggregation (TPA) induced by ADP, arachidonic acid (AA), and collagen; blood cell counts; platelet function analyzer (PFA-100) closure times (CT), and von Willebrand factor (VWF) in 120 well-characterized healthy individuals. Pre-analytical and analytical conditions were standardized comprehensively. Analytical reliability of IPA and TPA and the influence of pre-analytical variables on assay results were also examined. IPA and TPA did not change significantly between 0.5 and 5 hours after blood collection when samples were stored at room temperature. TPA and IPA showed significantly greater intra-assay imprecision than respective TPA induced by the same agonists. Intra-individual variation did not differ significantly between IPA and TPA. The lower limits of reference range (2.5th percentiles) of AAIPA, ADPIPA and collagen IPA determined AM were 37, 20 and 40 AU, respectively. ADPIPA showed significantly lower maximum aggregation values than AAIPA and collagen IPA (P < 0.0001). There were no significant differences in any parameter between males and females. No significant differences between blood group 0 and non-0 individuals were noted with respect to IPA and TPA. IPA did not change significantly during the day. In contrast, TPA measured PM was significantly lower than corresponding values determined a.m. (p < 0.0001). CEPI-CT, CADP-CT and leukocyte counts increased significantly from a.m. to p.m. (P = 0.008 and P > 0.0001, respectively). Donors had significantly greater IPA induced by any agonist than non-donors (P-values < 0.0001, 0.0001 and 0.001, respectively), whereas TPA was not significantly different between donors and non-donors. IPA did not correlate significantly with TPA nor with PFA-100 CT. ADPIPA and collagen IPA correlated significantly with platelet count. TPA was not associated with platelet count. An inverse significant correlation was observed between TPA induced by any agonist and leukocyte count, whereas leukocyte count did not influence IPA. CEPI-CT and CADP-CT correlated significantly with VWF:CBA and with each other but not with TPA. We concluded that IPA and TPA measure different aspects of platelet function. IPA results reflect interactions between platelets, red and white cells, while TPA does not. This explains discrepancies in associations of IPA and TPA with cell counts, time of day and blood donation. The clinical significance of IPA determined using the Multiplate device remains to be determined in studies on patients with platelet dysfunction and under treatment with antiplatelet agents.

Variables influencing Platelet Function Analyzer-100 closure times in healthy individuals.

We investigated the relationship between platelet function analyzer (PFA-100) closure times (CT) and bleeding time (BT), platelet aggregation (PA) induced by ADP, arachidonic acid, and collagen, blood cell counts, and von Willebrand factor (VWF) in 120 well-characterised healthy individuals. Pre-analytical and analytical conditions were standardised comprehensively. In a substantial number of cases the differences between duplicate measurements exceeded 15%. The reference range (5th and 95th percentiles) for CT with the collagen/epinephrine (CEPI) and the collagen/ADP (CADP) cartridge was 93-223 s and 64-117 s respectively. Re-examination of 11 individuals with CEPI-CT above the 95th percentile revealed considerable batch-to-batch variation of CEPI-CT. Males had significantly longer CADP than females (P = 0.002). CEPI and CADP-CT measured pm were significantly longer than corresponding values determined am (P = 0.003 and P < 0.0001 respectively). Blood group O was associated with greater CEPI and CADP-CT and lower VWF levels compared with non-O blood groups (P = 0.008, P = 0.0003 and P < 0.0001 respectively). Linear regression analysis revealed association between CEPI-CT, CADP-CT and VWF (P < 0.0001), but no relationship was found between CT and BT or between CT and PA. We conclude that VWF plasma levels modulate PFA-100 CT to a greater extent than platelet function. Establishment of reliable reference ranges and careful standardisation of pre-analytical and analytical conditions is a prerequisite for obtaining reliable PFA-100 results. Duplicate measurements are necessary.

New molecular defects in the gamma subdomain of fibrinogen D-domain in four cases of (hypo)dysfibrinogenemia: fibrinogen variants Hannover VI, Homburg VII, Stuttgart and Suhl.

Four new molecular abnormalities in the gamma subdomain of the D domain elucidated in three unrelated thrombophilic patients and in one asymptomatic case of hypofibrinogenemia are reported: fibrinogen Suhl, gamma 326, Cys-->Tyr, fibrinogen Hannover VI, gamma 336 Met-->Ile, fibrinogen Stuttgart, gamma 345, Asn-->Asp and fibrinogen Homburg VII, gamma 354,Tyr-->Cys. In all cases, fibrin polymerization in plasma is impaired. In the case of fibrinogen Suhl, there was a normalization of fibrin polymerization in plasma at higher Ca(2+) concentration. The protective effect of Ca(2+) on plasmic degradation of fibrinogen was incomplete with all three variants. The fibrinogen molecules in variants Homburg VII and Suhl contain covalently bound albumin. Fibrin clot structure was abnormal in case of variant Homburg VII, with finer and more branched fibers forming a less porous clot. Experimental data indicate possible effects of the molecular abnormalities on Ca(2+)-binding, D-E interaction and lateral association of protofibrils.

On the prophylactic and therapeutic use of danaparoid sodium (Orgaran) in patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a rare but dangerous complication of heparin prophylaxis or treatment. The present laboratory tests to measure heparin-associated antibodies are not specific. The diagnosis of HIT mainly depends on the decrease in platelet count and on clinical symptoms. To evaluate clinical outcome, bleeding complications and platelet counts were evaluated in 45 patients with HIT type II (HIT II) treated prophylactically (subcutaneous injections) or therapeutically (intravenous infusion) with danaparoid. Group I included 24 patients with HIT II without thromboembolic complications who received danaparoid twice daily subcutaneously (10 IU/kg) for a mean of 16 days. Group II included 21 patients with thromboembolic complications. They were treated with intravenous danaparoid (2.6 IU/kg/h +/- 1.1) for a mean of 17 days. During subcutaneous prophylaxis, mean anti-Xa levels of 0.2 U/mL and during intravenous treatment, mean anti-Xa levels of 0.4 U/mL were reached. No deaths, amputations, or serious bleeding complications occurred, and no new thromboses were observed in both patient groups. Treatment with danaparoid led to a fast normalization of the platelet counts. This normalization occurred earlier and the concentration of platelets was higher in patients treated with intravenous doses. Danaparoid with subsequent vitamin K-antagonist treatment effectively prevents thromboembolic complications in patients with HIT.

Effect of high power ultrasound on endothelial cells--an in vitro study of the endothelium--hemostasis interaction.

OBJECTIVE: The goal of this study was to develop an in vitro model system in which the hemostatic effects of high power ultrasound applied to the outer surface of blood vessels during tumor dissection can be simulated and measured. METHODS: Monolayers of endothelial cells (HUVEC, ATCC) in cell culture plates were sonicated with an ultrasound dissector (SONOCA II, Soering) at a frequency of 23.5 kHz. The dissector was equipped with a cooling circuit. The cell cultures were exposed to 2 minutes of continuous ultrasound with intensities of 10, 50, or 100 W/cm(2). To differentiate between heat and sound effects, selected monolayers were warmed for 2 minutes. Finally, the cell cultures were stained with trypan blue to assess for cell death due to membrane disruption. Cytomorphological alterations and changes in the concentration of coagulation parameters in the cell culture medium were evaluated. RESULTS: The cytomorphological alterations were found to depend on ultrasound intensity. They included detachment of single endothelial cells, cell cluster formation and cytoplasmic cavitation. Disruption of the cell membrane integrity was infrequently observed. Of 14 screened coagulation parameters, thromboxane B(2) (TXB(2)), prostaglandin F(1alpha) (PGF(1alpha)), plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin (TM), and thrombospondin (TSP) were found to be ultrasound sensitive. TXB(2) concentrations in the medium increased beginning at low ultrasound intensities (p < 0.01) and were independent of temperature. PGF(1alpha) concentrations peaked at high ultrasound intensities (p < 0.05), and heat alone produced a significant increase in concentration (p < 0.05). At high intensities, the ratio of TXB(2) to PGF(1alpha) shifted in favour of PGF(1alpha). PAI-1 was most strongly secreted at low ultrasound intensities (p < 0.01), and heat resulted in a decrease of concentration (p < 0.05). TM and TSP concentrations correlated strongly and reached a non significant peak at low intensities. CONCLUSION: The results demonstrate that during sonication of endothelial cells in vitro, coagulation parameters are released from distant undamaged cells. HUVEC-cells exhibit a differential hemostaseological response at different ultrasound intensities, and the response is also influenced by heat. Additionally, massive morphological damage can be induced at the endothelium.

In vitro hemocompatibility testing of biomaterials according to the ISO 10993-4.

The development of synthetic materials, textured polymers and metals and their increasing use in medicine make research of biomaterials' hemocompatibility very relevant. Problems arise from the polymorphism and diversity of the different materials, the static and dynamic test models and the patients' individual biologic factors. First, methods, models, tests as well as preanalytical factors have to be standardized according to the current knowledge in medicine laid down in the ISO 10993 part 4. The routine controls used in clinical chemistry and hematology have to be performed. Information about normal ranges (mean value, standard deviation, 95% confidence interval) should be provided. Tests have to be performed within a minimal delay of usually 2 h since some properties of blood change rapidly following collection. Various conditions (depending on the wall shear rate) were simulated within the centrifugation system and a Chandler system. Qualities and aspects of hemocompatibility such as platelet activation, oxidative burst, hemolysis, fibrinolysis, fibrin formation, generation of thrombin, contact activation, and complement activation were analysed and the results were entered non-dimensionally into a non-dimensional score system, where 0 points stand for the best and 65 points for the worst evaluation. We found a good correlation between the total score and contact activation, thrombin generation and leukocyte activation in a low shear stress system and a good correlation between the total score and thrombin generation, hemolysis and platelet activation in the high shear stress system. Further on the effect of additives and sterilization procedures can be measured. The concepts presented underline the relevance/importance of an efficient diagnostic approach to hemocompatibility that takes account of clinical and socio-economic concerns.