A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors

The presence of inhibitory antibodies to clotting factors complicates the treatment of bleeding in haemophilia patients. For patients with high-titre inhibitors, bypassing agents are essential to haemostatic management. To determine optimal treatment practices, an international panel of physicians convened to develop a systematic treatment approach for problem bleeds (i.e. bleeds that are unresponsive to initial therapy with a single agent within a reasonable amount of time) in haemophilia patients with inhibitors. AIM: The goal of this panel was to develop a consensus algorithm that would aid physicians in considering a variety of treatment approaches to optimize patient care by preventing extensive therapy with inadequate treatments that may lead to suboptimal patient outcomes and unnecessary costs. METHODS: Consensus opinions were analyzed for clinical preferences at different time periods, depending on patient response to treatment. Decision-making points were defined based on the type of bleed: every 8-12 h for the first 24 h, then every 24 h thereafter for limb-threatening bleeds; every 2-4 h for 2-7 days for life-threatening bleeds. RESULTS: The resultant consensus guidelines provide a generalized methodology to guide the treatment of problem bleeds in patients with severe haemophilia A and inhibitors, and emphasize changing treatment at the first sign of an inadequate haemostatic response. The treatment algorithms apply to both paediatric and adult patients, although the differences between the two groups were reviewed. CONCLUSION: These guidelines are focused on optimising the timing of treatment decisions, which may lead to faster responses and improved outcomes.     

Platelet activation with massive formation of thromboxane A2 during and after cardiopulmonary resuscitation

Objective: Hypoxia and ischemia cause endothelial cell damage with consequent platelet activation. The hypothesis that human cardiac arrest accelerates platelet activation and the formation of prostanoids was tested. Design: Prospective, observational cohort study. Setting: Emergency Department and general Intensive Care Unit in a city hospital. Interventions: Basic and advanced life support. Patients and participants: Forty-seven out-of-hospital cardiac arrest patients. The patients were classified into two groups, those who were resuscitated (n=18) and those who died (n=29). Measurements and results: Serial levels of platelet aggregation, thromboxane B₂ (TXB₂), 11-dehydro-TXB₂ and 6-keto-prostaglandin F₁ alpha (6-keto-PGF₁ alpha) were measured. The results of measurements and demographic data were compared between the groups. Platelet counts decreased at the end of cardiopulmonary resuscitation (CPR), the decrease of the platelet counts showed statistical significance especially in the patients who died (p<0.001). Platelet aggregation induced by adenosine diphosphate, epinephrine and collagen decreased to the lower limits of normal during and after CPR. Although high values of TXB₂ and 11-dehydro-TXB₂ continued throughout the study period in the resuscitated patients, 6-keto-PGF₁ alpha decreased to the normal range (22.7±3.6 pg·ml^–1, p<0.05) at 24 h after arrival at the Emergency Department. Conclusions: Platelet activation with the massive formation of thromboxane A₂ (TXA₂) occurs in patients with out-of-hospital cardiac arrest. Successful resuscitation is not associated with the balanced production of PGI₂ against the TXA₂ formation. Received: 15 February 1996 Accepted: 2 September 1996     

Dual antiplatelet therapy unmasks distinct platelet reactivity in patients with coronary artery disease

Summary. Background: Platelet‐induced thrombosis is a major risk factor for recurrent ischemic events, although platelet function in patients with cardiovascular disease taking aspirin and clopidogrel is very poorly characterized. The aim of this study was to assess platelet reactivity in patients with cardiovascular disease taking aspirin and clopidogrel. Methods: We developed a rapid assay to measure platelet aggregation in response to arachidonic acid, collagen, adenosine diphosphate (ADP), epinephrine and thrombin receptor activating peptide (TRAP) in 80 healthy volunteers. We then recruited 200 consecutive patients from outpatient clinics and the cardiac catheterization laboratory and tested platelet function. Platelet aggregation induced by epinephrine is a marker of global platelet reactivity. We tested platelet function in 146 patients compliant with antiplatelet therapy. Platelet aggregation to epinephrine was divided into quartiles. The platelet response to the other agonists was analysed based on the response to epinephrine. Results: Platelet reactivity increased significantly across the quartiles in response to epinephrine in healthy volunteers and patients (P < 0.0001). A significant increase in response across quartiles was seen with all agonists in healthy volunteers (P < 0.001). In contrast, a significant increase in response across quartiles was only seen with ADP in patients (P < 0.0001). Hypertension, smoking and diabetes were significantly associated with increasing platelet reactivity to epinephrine (P < 0.05). Conclusion: This study shows that platelet response differs between healthy volunteers and patients on dual antiplatelet therapy. In patients with cardiovascular disease, dual antiplatelet therapy unmasks a distinct type of platelet reactivity in response to epinephrine and ADP but not other agonists.     

Type IIB von Willebrand disease: a paradox explains how von Willebrand factor works

Summary.  Type IIB is a variant form of von Willebrand disease in which a structural abnormality of von Willebrand factor (VWF) causes enhanced binding to the platelet glycoprotein Ib receptor. As a consequence of this functional alteration, there is a decrease in the concentration of the largest VWF multimers in plasma, and the platelet count may be episodically decreased as a consequence of microaggregation. The net result is an apparent paradox, since the presence of a hyperfunctional adhesive molecule in blood causes a bleeding tendency. Here I recall how my colleagues and I managed to understand what goes on in these patients.     

Upstream Effect for Atrial Fibrillation: Still a Dilemma?

Atrial fibrillation is the most common arrhythmia in clinical practice. Ion channel blocking agents are often characterized by limited long-term efficacy and several side effects. In addition, ablative invasive procedures are neither easily accessible nor always efficacious. The "upstream therapy," which includes angiotensin-converting enzyme inhibitors, aldosterone receptor antagonists, statins, glucocorticoids, and ω-3 poly-unsaturated fatty acids, targets arrhythmia substrate, influencing atrial structural and electrical remodeling that play an essential role in atrial fibrillation induction and maintenance. The mechanisms involved and the most important clinical evidence regarding the upstream therapy influence on atrial fibrillation are presented in this review. Some open questions are also proposed.     

Invited review: Frontotemporal dementia caused by microtubule‐associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging

Hereditary frontotemporal dementia associated with mutations in the microtubule‐associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms.     

Dehydro-β-proline Containing α4β1 Integrin Antagonists: Stereochemical Recognition in Ligand–Receptor Interplay

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Diagnosis and Treatment of Patients with Thyroid Cancer

Background

Thyroid cancer is the most common malignancy of the endocrine system, representing 3.8% of all new cancer cases in the United States and is the ninth most common cancer overall. The American Cancer Society estimates that 62,450 people in the United States will be diagnosed with thyroid cancer in 2015, and 1950 deaths will result from the disease.

Objective

To review the current approach to the diagnosis and treatment of patients with thyroid cancer.

Discussion

Over the past 3 decades, there has been a dramatic increase in the number of people diagnosed with thyroid cancer, which may be attributable to the wide use of imaging studies, including ultrasounds, computed tomography, magnetic resonance imaging, and positron emission tomography scans that incidentally detect thyroid nodules. Thyroid cancer is divided into several main types, with papillary thyroid cancer being the most common. The treatment options for patients with thyroid cancer include the surgical removal of the entire thyroid gland (total thyroidectomy), radioactive iodine therapy, and molecular-targeted therapies with tyrosine kinase inhibitors. This article summarizes the diagnosis and treatment of thyroid cancer, with recommendations from the American Thyroid Association regarding thyroid nodules and differentiated thyroid cancer. Recently approved drugs and treatment trends are also explored.

Conclusion

The prognosis and treatment of thyroid cancer depend on the tumor type and its stage at the time of diagnosis. Many thyroid cancers remain stable, microscopic, and indolent. The increasing treatment options for patients with thyroid cancer, including therapies that were recently approved by the US Food and Drug Administration, have kept the mortality rate from this malignancy low, despite the increase in its incidence. Early diagnosis and appropriate treatment can improve prognosis and reduce mortality.     

骨髓增殖性肿瘤治疗进展:第56届美国血液学会年会报道

近年对bcr-abl阴性的骨髓增殖性肿瘤的发病机制、诊断、风险分层及治疗等方面的研究取得了长足进展,文章就2014年第56届美国血液学会(ASH)年会上关于bcr-abl阴性的骨髓增殖性肿瘤治疗进展等内容作一介绍.