Associations between thrombophilic risk factors and determinants of atherosclerosis and inflammation in patients with non-arteritic anterior ischaemic optic neuropathy.

UNLABELLED: Non-arteritic anterior ischaemic optic neuropathy (NAION) is caused by ischaemia of the optic nerve head. The pathophysiology of NAION is unclear, and no proven effective treatment exists. PATIENTS, METHODS: We analyzed thrombophilic risk factors and determinants of atherosclerosis and inflammation in 109 consecutive patients and 109 age- and sex-matched volunteers using a case-control design. RESULTS: High levels of fibrinogen (>384 mg/dl; OR 3.2, p = 0.003), factors VIII:C (>183%; OR 2.6, p = 0.02), IX (>153%; OR 2.6, p = 0.026), XI (>142%; OR 3.4, p = 0.006), von Willebrand factor (activity >205%; OR 3.1, p = 0.005; antigen >194%; OR 3.5, p = 0.002), and triglycerides (>228 mg/dl; OR 2.8, p = 0.026), higher platelet counts (>294,000/µl; OR 2.5, p = 0.04), low levels of HDL cholesterol (<40 mg/dl; OR 2.7, p = 0.032), and an accelerated erythrocyte sedimentation rate (>20 mm/h; OR 4.4, p = 0.003) were associated with NAION. CONCLUSION: Our findings support the contention of a complex pathogenesis of NAION resulting from the coincidence of proatherogenic, prothrombotic and proinflammatory processes. The alterations described could be causative, side effects, or just coincidental findings.

[The ambivalence of progress - do we need a less-is-more strategy?**. **Extract from the programmtic opening speech delivered at the 59th Annual GTH Congress 2015]. / Die Ambivalenz des Fortschritts - ist weniger mehr?*. *Auszug aus der programmatischen Eröffnungsansprache zum 59. Jahreskongress der GTH 2015.

Economizing health care systems has led to industrialized hospitals. The consequences and side effects are substantial and rather promote costs explosion due to the dictated increase in cases and efficiency. Hence, position sensing and change in direction are required. Effective ways to find out of the current crisis are discussed.

Management of acquired haemophilia A.

Acquired haemophilia A (AHA) is caused by autoantibody inhibitors of coagulation factor VIII (FVIII : C). Recent onset of bleeds and isolated prolongation of the activated partial thromboplastin time (aPTT) are characteristic features of the disorder. Reduced FVIII : C activity and a detectable FVIII : C inhibitor in the Bethesda assay confirm the diagnosis. Patients should be referred to expert centres, whenever possible, and invasive procedures with a high risk of bleeding must be avoided, until haemostasis has been secured by adequate therapy. Bypassing agents capable of inducing sufficient thrombin formation in the presence of FVIII : C inhibitors are treatment of choice, including currently available recombinant factor VIIa (NovoSevenTM) and activated prothrombin complex concentrate (FEIBATM). These agents represent first line therapy to control acute or severe bleeds. To eradicate inhibitors, immunosuppressive treatment (IST) is indicated in patients with AHA. Glucocorticoids, cytotoxic agents and rituximab are most widely used. However, an ideal IST regimen has not been established so far. Adverse events of IST, including infections as the foremost cause death, are frequent complications in AHA.

[Pharmacological thromboprophylaxis in gynecology and obstetrics]. / Medikamentöse Thromboembolie-Prophylaxe in Gynäkologie und Geburtshilfe.

Venous thromboembolism (VTE) is associated with high morbidity and mortality. Therefore, effective methods for safe thromboprophylaxis remain an ongoing challenge in daily clinical practice. This is especially true for pregnant women and patients with gynaecological malignancies. Low-molecular weight heparins continue to be agents of choice for pharmacological thromboprophylaxis postoperatively, in pregnant patients at risk, and during the puerperium. However, these drugs can cause bleeds or heparin-induced thrombocytopenia (type II). Based on recent revisions of corresponding guidelines, this article provides an overview of the current state of pharmacological thromboprophylaxis and discusses prevailing problems and unresolved issues.

Rotation thromboelastography for the detection and characterization of lipoteichoid acid-induced activation of haemostasis in an in vitro sepsis model.

OBJECTIVES: In gram-positive sepsis, lipoteichoic acid (LTA) can induce alterations of haemostasis, potentially leading to disseminated intravascular coagulation. PATIENTS AND METHODS: Here, we demonstrate the effects of LTA on haemostasis in an in vitro model of gram-positive sepsis based on rotation thromboelastrography (ROTEM). RESULTS: In this model, LTA leads to time- and dose-dependent shortening of the clotting time (CT), whereas other ROTEM parameters are unaffected. Following heat shock simulation, the LTA effect was blunted with equal CTs in the presence and in the absence of LTA. In addition, the shortening of CT by LTA was inhibited by addition of the protein synthesis inhibitor. CONCLUSION: Our work demonstrates that the ROTEM system is capable of detecting the LTA effect on haemostasis and provides a sensitive in vitro tool for research into the links between gram-positive sepsis and coagulation.

Rotation thromboelastography (ROTEM) parameters are influenced by age, gender, and oral contraception.

Rotation thromboelastography (ROTEM) is a screening method that allows the rapid detection of plasma- and platelet-related haemostatic abnormalities. To use this procedure more efficiently, reference values depending on gender, age, and oral contraception are required. In this study, five cohorts of healthy subjects were examined by ROTEM upon activation of the extrinsic or intrinsic pathway of coagulation, or recalcification alone. The cohorts comprised male subjects below (1) and above (2) 45 years of age, female subjects below 45 years of age with (3) or without (4) oral contraception, and female subjects above 45 years (5) without hormone replacement therapy. A significant influence of gender, age, and oral contraception on parameters determined by ROTEM was observed. Thus, adjustment for age, gender, and oral contraception is required when ROTEM is used to screen for distinct abnormalities of haemostasis.

The impact and management of acquired platelet dysfunction.

Platelet function can be abnormally increased, as in association with acute vascular events, or defective, as in a variety of clinical settings. Acquired platelet dysfunction may occur at any age and range in severity from mild to life-threatening haemorrhages. Diagnostic work-up of platelet disorders requires meticulous evaluation of medical history, specifically of any drugs interfering with platelet function, careful clinical examination and a staged laboratory protocol to assess the underlying platelet defect(s). To identify hyperactive platelets ex vivo, costly procedures may be required using flow cytometry and distict epitope-specific monoclonal antibodies. Currently, this approach can be recommended for research purposes only. Drugs represent the most common cause of platelet dysfunction in our overmedicated society. While aspirin, clopigogrel (more recently also prasugrel) and integrin αIIbß3 (GPIIb-IIIa) receptor antagonists (abciximab, eptifibatide and tirofiban) are well-known prototypes of antiplatelet drugs, other widely used agents (e.g. nonsteroidal anti-inflammatory drugs, antibiotics, serotonin reuptake inhibitors and volume expanders) can also impair platelet function and thus cause or aggravate hemorrhages. Identification of individual patients with pre-existing hemostatic defects remains crucial (i) to prevent bleeding complications, (ii) to manage symptoms adequately, (iii) to minimize the risk from invasive procedures, and (iv) to avoid unnecassary exposure to blood products. Screening for platelet dysfunction can be performed by point-of-care testing followed by platelet aggregometry in response to various agonists. While mild bleeding episodes due to antiplatelet therapy can be managed by withdrawal of the drug(s), severe hemorrhages may require immediate platelet transfusions. Apart from that, the prohemostatic armamentarium is limited to desmopressin, antifibrinolytic agents, and recombinant factor VIIa.

Monitoring of antiplatelet therapy. Current limitations, challenges, and perspectives.

Screening of platelet function can be performed by point-of-care testing followed by platelet aggregometry in response to agonists such as collagen, adenosine diphosphate, epinephrine, and arachidonic acid. Despite in use for decades, this technique is not well standardized. Monitoring of antiplatelet therapy is increasingly applied in patients at high risk for re-thrombosis or bleeding. To assess pharmacological inhibition of platelet function, agonist-induced platelet aggregation, thromboxane B2 (TxB2) and vasodilator-stimulated protein phosphorylation (VASP) are being measured. While serum TxB2 levels of < 2 ng/ml reflect aspirin-induced inhibition of cyclo-oxygenase-1 activity with high sensitivity, VASP exhibits a wide variability upon treatment with clopidogrel or prasugrel. Multiple studies reveal an association between high residual platelet reactivity and adverse cardiovascular events in patients on antiplatelet therapy. However, despite the plethora of platelet function assays currently under investigation, their use in daily practice cannot be recommended. This is due to several reasons: (i) there is no consensus on the method and a respective cut-off value associated with clinical adverse outcome, and (ii) data demonstrating any benefit of tailored antiplatelet therapy and its monitoring (based on assessment of platelet functions) are still limited. Thus, appropriate identification of 'resistant' or 'poor responders' to antiplatelet agents remains challenging in clinical practice.

Clinical features and outcome of acquired haemophilia A. Interim analysis of the Düsseldorf study.

UNLABELLED: We have performed a monocenter study on 29 consecutive patients with acquired haemophilia A who were referred for diagnosis and treatment to the Düsseldorf Haemophilia Comprehensive Care Center between March 2001 and February 2010. PATIENTS, METHODS: 18 men (age: 44-86 years) and 11 women (age: 20-83 years). For laboratory evaluation, a standardized staged protocol of aPTT, FVIII:C activity and concentration, mixing studies with patient and normal plasma, and quantification of inhibitor titers (Bethesda assay) was used. Diagnostic work-up included elaborate examinations for any underlying disease. RESULTS: In 18 (62%) of the 29 patients with acquired haemophilia A, an underlying disorder was identified, including 9 patients with respiratory diseases (31%), 7 patients with autoimmune disorders (24%), one with malignancy, and one with postpartum state, while in 11 patients (38%) acquired haemophilia A remained idiopathic. Haemotherapy of bleeding, suppression or elimination of the inhibitor, and induction of immunotolerance to endogenous FVIII:C were performed according to a treatment algorithm. Predefined clinical endpoints were control of bleeding, eradication of the inhibitor, complete or partial remission (CR, PR), relapse, or early death (< or =30 days). Of the 29 patients in total, 22 individuals achieved CR (76%), three had PR, one relapsed, and three died within 30 days (one of acute myocardial infarction while on antihaemorrhagic treatment, one of sepsis while on immunosuppression due to active acquired haemophilia A, one of lung bleeding in association with pre-existing pulmonary sarcoidosis). CONCLUSION: This monocenter study demonstrates that control of life-threatening bleeding, eradication of the inhibitor, and induction of tolerance to endogenous FVIII have significantly improved the clinical outcome of acquired haemophilia A. Our data also suggest a shift in underlying disorders associated with acquired haemophilia A, whereby, in comparison to published studies, a relative increase in the proportion of patients with respiratory diseases is present.

Management of bleeding in patients using antithrombotic agents: prediction, prevention, protection and problem-oriented intervention.

Antiplatelet agents and anticoagulants are effective in the prevention and treatment of a variety of thrombotic disorders. Several clinical settings require more intense antithrombotic regimens. These can be provided by combining (i) two antiplatelet drugs, (ii) antiplatelet monotherapy with an anticoagulant, or (iii) anticoagulation with dual antiplatelet treatment (triple therapy). A major side effect of all antithrombotic regimens, however, is the induction of a bleeding diathesis. This is especially true in patients with preexisting haemostatic defects of any kind that may remain compensated, unless platelet function and/or coagulation are not inhibited pharmacologically. To address the dilemma of the "double-edged sword" between thrombosis and bleeding, several strategies are currently under study, including (i) identification of high-risk patients, (ii) stratification of patient subgroups, (iii) individualized decision making, and (iv) administration of "tailor-made" risk-adapted regimens. Nonetheless, prevention and protection from bleeding in patients using antithrombotic agents remain an enduring challenge. For high-risk patients on antiplatelet agents with urgent need of surgery, an algorithm is discussed that allows short-term interruption of oral antithrombotic therapy and i.v. administration of a GPIIb-IIIa receptor antagonist for bridging without increasing perioperative bleeding. When individual patients, using antiplatelet or anticoagulant agents, experience serious or even life-threatening haemorrhages, haemotherapy with platelet units or prothrombin complex concentrates remains an integral part of the clinical management.

Is there an overlap between sudden neurosensorial hearing loss and cardiovascular risk factors?

INTRODUCTION: Sudden sensorineural hearing loss (SSHL) has been proposed as a symptom of underlying vascular problems. The purpose of this work is to evaluate the genetic and acquired risk factors. METHODS: Ninety-nine patients were tested for the presence of common polymorphisms related to thrombophilia (prothrombin and factor V Leiden) in order to assess genetic risk factors, and several parameters classically associated with vascular disorders (cardiovascular events, brain stroke and antiphospholipid syndrome) were evaluated. Additional assessments of personal and familial history risk factors for vascular disorders were performed in each patient. RESULTS: Thrombophilia studies did not demonstrate statistically relevant differences between the patients and control group. However, lipidemia profile and directed personal and familial histories showed positive trends for SSHL. CONCLUSION: The lack of clear relationships between SSHL and other vascular risk factors suggests multicausality as a predominant disease profile. Although preliminary results point at a vascular involvement in SSHL, a long-term prospective study is necessary to demonstrate that SSHL represents an early vascular symptom.