The coagulation system in endocrine disorders: A narrative review

Endocrine disorders can influence the haemostatic balance. Abnormal coagulation test results have been observed in patients with abnormal hormone levels. Also unprovoked bleeding or thrombotic events have been associated with endocrine disease. The aim of the present review is to summarise the available evidence on the influence of common endocrine disorders on the coagulation system, and their possible clinical implications. We focus on thyroid dysfunction, hyper- and hypocortisolism and growth hormone disturbances, while other endocrine disorders are only briefly discussed. In the published literature a clear bleeding diathesis has only been associated with overt hypothyroidism, mainly mediated by an acquired von Willebrand syndrome. A clinically relevant hypercoagulable state may be present in patients with hyperthyroidism, hypercortisolism or abnormal growth hormone levels, but adequate prospective clinical studies are lacking. Also effects of pheochromocytoma, hyperprolactinaemia and hyperaldosteronism on the coagulation system have been described. It is apparent that unprovoked bleeding and thrombotic episodes can be secondary to endocrine disorders.     

Approach to thromboelastography-based transfusion in cirrhosis: An alternative perspective on coagulation disorders

Viscoelastic tests, specifically thromboelastography and rotational thromboelastometry, are increasingly being used in the management of postoperative bleeding in surgical intensive care units (ICUs). However, life-threatening bleeds may complicate the clinical course of many patients admitted to medical ICUs, especially those with underlying liver dysfunction. Patients with cirrhosis have multiple coagulation abnormalities that can lead to bleeding or thrombotic complications. Compared to conventional coagulation tests, a comprehensive depiction of the coagulation process and point-of-care availability are advantages favoring these devices, which may aid physicians in making a rapid diagnosis and instituting early interventions. These tests may help predict bleeding and rationalize the use of blood products in these patients.     

阿司匹林与氯吡格雷预防或治疗缺血性脑卒中致出血并发症的系统评价

目的对阿司匹林与氯吡格雷预防或治疗缺血性脑卒中(IS)导致出血并发症风险进行评价。方法计算机检索Pub Med、EMBase、The Cochrane Library、CBM、CNKI、VIP和Wang Fang Data等数据库。检索自建库截止至2016年9月。搜集阿司匹林与氯吡格雷预防或治疗IS且产生出血并发症的随机对照试验(RCT)。由2位研究人员独立进行文献筛选、数据提取和质量评价后,采用Rev Man 5.2软件进行Meta分析。结果共纳入13个RCT,包括5204例患者。Meta分析结果显示:(1)预防IS时,阿司匹林相比氯吡格雷不增加皮肤黏膜、牙龈出血风险,但增加消化道出血风险;阿司匹林和氯吡格雷联用相比阿司匹林单用增加胃肠道反应。(2)治疗IS时,阿司匹林相比氯吡格雷不增加皮肤黏膜、牙龈、消化道出血风险,不增加胃肠道反应;阿司匹林和氯吡格雷联用相比阿司匹林单用亦不增加皮肤黏膜、牙龈、消化道、颅脑出血风险,不增加胃肠道反应。结论预防IS时,阿司匹林相比氯吡格雷会增加消化道出血风险,阿司匹林和氯吡格雷联用相比阿司匹林单用会增加胃肠道反应。     

Acute liver failure due to herpes simplex virus: diagnostic clues and potential role of plasmapheresis: A case report

Introduction:Acute liver failure (ALF) is a life-threatening condition that remains challenging for physicians despite several advances in supportive care. Etiologies vary worldwide, with herpes simplex virus (HSV) hepatitis representing less than 1% of cases. Despite its low incidence, ALF is a lethal cause of acute necrotizing hepatitis and has a high mortality. Early antiviral treatment is beneficial for survival and decreased liver transplantation necessity. However, plasmapheresis, despite its theoretical potential benefit, is scarcely reported.Patient concerns:A 25-year-old woman with no known disease presented with painful pharynx ulcers, increased transaminases and impaired liver function.Diagnosis:ALF due to a disseminated HSV-2 primary infection was diagnosed with a positive polymerase chain reaction for HSV-2 in the biopsied liver tissue and blood.Interventions:Empiric antiviral treatment was initiated. After clinical deterioration, plasmapheresis was also initiated.Outcomes:After 6 cycles of plasmapheresis and supportive care, the patient''s condition improved without undergoing liver transplantation.Conclusions:ALF is a life-threatening condition, and HSV as an etiology must be suspected based on background, clinical manifestation, and laboratory information. The potential role of plasmapheresis in HSV hepatitis should be considered.     

Lymphoma and other lymphoproliferative disorders in inflammatory bowel disease: A review

The lymphoproliferative disorders (LDs) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T, and NK cells. Inflammatory bowel disease (IBD)‐associated lymphomas are typically B‐cell LD, while T‐cell or Hodgkin's lymphomas are rare. In IBD patients not on immunosuppression, the risk of LD seems to be similar or slightly higher than the background population risk. Thiopurine therapy is associated with an increased risk: the relative risk is increased four‐ to sixfold and the absolute risk varies between 1 in 4000–5000 for those aged 20–29 to 1 in 300–400 in those over 70. It is difficult to quantify the risk of anti‐ tumor necrosis factor (TNF) therapy alone; however, it appears to be less than for thiopurines alone. There is particular concern regarding the development of post‐transplant‐like LD in those with latent epstein‐barr virus (EBV) infection exposed to immunosuppressives, the occurrence of hepatosplenic T cell lymphoma in patients treated with combination anti‐TNF and thiopurine therapy, and the development of hemophagocytic lymphohistiocytosis in those who acquire a primary EBV or other infections while on immunosuppressive medication. There are currently no guidelines for monitoring EBV (or other virus) status in patients on immunosuppression, although it could be used to monitor those who have a prior history of lymphoma and are about to start a thiopurine or anti‐TNF agent. In discussing the risks of lymphoproliferative disorders associated with agents used for the treatment of IBD, patients can often be reassured that the benefits of such therapy still outweigh the small, but real, risks.     

Reply to: diagnostic power of fecal calprotectin in inflammatory and functional intestinal disorders

Abstract

Objective. A retrospective clinical audit was carried out to identify whether relaxation of the sphincter of Oddi (SO) by botulinum toxin (BTX) injection can select patients with episodic functional post-cholecystectomy biliary pain who will benefit from endoscopic sphincterotomy. Patients and methods. Sixty-four patients complaining of functional post-cholecystectomy biliary pain with a frequency of at least four episodes per month had 100 units of BTX injected into their SO muscle in four aliquots. After review patients with a pain free interval following BTX injection of at least 4 weeks were offered biliary endoscopic sphincterotomy and their outcome assessed. Results. Of the 64 patients 46 (72%) had at least four pain free weeks after BTX therapy and 44 of these 46 patients (96%) went on to experience pain relief following endoscopic sphincterotomy. Of the 64 patients 41 had sphincter of Oddi manometry prior to BTX injection. Every patient with sphincter of Oddi hypertension defined by manometry and at least 4 weeks' pain relief following BTX (24) had pain relief following sphincterotomy. Fifteen (94%) of the 16 patients who did not undergo manometry but reported at least 4 weeks' pain relief after BTX had pain relief after sphincterotomy. Conclusion. Botulinum toxin relaxation of the SO may be a useful method of predicting the symptom response to endoscopic sphincterotomy in patients who have episodic functional biliary pain.     

A nine year retrospective analysis of resectable pancreatic cancer at the National Cancer Center Hospital in Tokyo: clues to diagnosis and diagnostic assessment.

A nine year retrospective survey was carried out at the National Cancer Center Hospital in order to define the diagnostic clues and most suitable diagnostic assessment in resectable pancreatic cancer patients. Forty six cases were detected (27 pancreatic head cancers, 19 pancreatic body and tail cancers). There were 8, 26, 3 and 9 cases of t1, t2, t3 and t4 tumour size cancers, respectively. Abdominal pain and/or discomfort and back pain were the most common initial symptoms and chief complaints. Jaundice was present only in pancreatic head cancer cases. Abnormal GTT and CA 19-9 were the biochemical tests most commonly found abnormal, irrespective of tumour size. ERCP followed by US and CT were the most accurate technical tests. The best care toward the awareness of the initial symptoms needs to be followed, as a first choice, by a proper biochemical (CA 19-9, GTT) and technical (US, ERCP, CT) assessment in the hope of identifying those patients whose prognosis might be improved by an early operation.     

A study to assess the immunogenicity, reactogenicity and safety of hepatitis A vaccine administered subcutaneously to patients with congenital coagulation disorders

Summary. The objective was to compare the immunogenicity, reactogenicity and safety of an inactivated hepatitis A vaccine administered subcutaneously to patients with congenital coagulation disorders. Subjects, 97 patients with congenital coagulation disorders (67 men aged > 16 and 30 children aged ≤ 16 years), received hepatitis A vaccine administered at 1440 ELISA (enzyme linked immunosorbent assay) units (ELU) to the adult group and at 720 ELU to the child group at 0 and 6 months by the subcutaneous route. The vaccine was well tolerated, with the incidence of adverse events decreasing with subsequent administration of vaccine. Overall, 90% of subjects seroconverted 1 month after the booster (95% confidence interval 76–97%), with 100% seroconversion occurring in the child group compared with 85% in the adult group. There was a corresponding progressive rise in geometric mean titres in each group and no significant difference in the geometric mean titres was found between the two groups. Of the subjects, 29% were HIV positive, 3% of children compared with 40% of adults. A lower rate of seroconversion was observed in subjects with low CD4 counts. Administration of two doses of an inactivated hepatitis A vaccine at 1440 ELU in adults and 720 ELU in children is safe and highly immunogenic when given by the subcutaneous route.     

Personalized medicine in functional gastrointestinal disorders:Understanding pathogenesis to increase diagnostic and treatment efficacy

There is overwhelming evidence that functional gastrointestinal disorders(FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms(UGI Sx). Among patients with UGI Sx, approximately equal proportions(25%) of patients have delayed gastric emptying(GE), reduced gastric accommodation(GA), both impaired GE and GA,or neither, presumably due to increased gastric or duodenal sensitivity.Treatments targeted to the underlying pathophysiology utilize prokinetics,gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia(with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome(IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2 D6, 2 C19 and 3 A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here;pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.     

Wnt5a: A player in the pathogenesis of atherosclerosis and other inflammatory disorders

Objective

The objective of this article is to review the current literature on Wnt5a and its signaling mechanism, along with its role in atherosclerosis. In addition, the significance of Wnt5a as a diagnostic marker and a potential therapeutic target is reviewed. Wnt5a, a secreted glycoprotein, belongs to a family of highly conserved proteins that regulate important processes such as cell fate specification, embryonic development, cell proliferation, migration, and differentiation in a variety of organisms. The complexity of Wnt5a signaling lies in the fact that Wnt5a can bind to different classes of frizzled receptors, receptor tyrosine kinase-like orphan receptor 2, as well as co-receptors such as low density lipoprotein receptor-related protein 5/6. Wnt5a signals primarily through the non-canonical pathway, where it mediates cell proliferation, adhesion, and movement. However, the role of Wnt5a in canonical signaling is still unresolved. Depending on the receptor availability, Wnt5a can serve to activate or inhibit the canonical Wnt signaling pathway. Due to the promiscuous nature of Wnt5a, it has been extremely difficult to fully understand its signaling mechanism. Wnt5a has recently emerged as a macrophage effector molecule that triggers inflammation. Perturbations in Wnt5a signaling have been reported in several inflammatory diseases, particularly in sepsis, rheumatoid arthritis, and atherosclerosis.

Conclusion

Both existing and emerging evidence suggests that the expression of Wnt5a is always up-regulated in these, and possibly other inflammatory disorders. This knowledge can be useful for targeting Wnt5a and/or its receptor and downstream signaling molecules for therapeutic intervention in inflammatory disorders.     

A clinical evaluation of the diagnostic usefulness of an early dermal reaction to tuberculin: a failure to distinguish between tuberculosis and other respiratory disease

An early (6-8 hour) reaction to RT23 tuberculin which was previously found to distinguish between patients with active tuberculosis and healthy tuberculin positive individuals failed to distinguish between such patients and those with other respiratory diseases. It also failed to distinguish between radiologically active and inactive cases of tuberculosis. Such early reactions were frequent among healthy hospital workers but not among other healthy subjects.     

Osmotic gradient ektacytometry: A valuable screening test for hereditary spherocytosis and other red blood cell membrane disorders

Introduction

New generation osmotic gradient ektacytometry has become a powerful procedure for measuring red blood cell deformability and therefore for the diagnosis of red blood cell membrane disorders. In this study, we aim to provide further support to the usefulness of osmotic gradient ektacytometry for the differential diagnosis of hereditary spherocytosis by measuring the optimal cutoff values of the parameters provided by this technique.

Methods

A total of 65 cases of hereditary spherocytosis, 7 hereditary elliptocytosis, 3 hereditary xerocytosis, and 171 normal controls were analyzed with osmotic gradient ektacytometry in addition to the routine red blood cell laboratory techniques. The most robust osmoscan parameters for hereditary spherocytosis diagnosis were determined using receiver operating characteristic curve analysis.

Results

The best diagnostic criteria for hereditary spherocytosis were the combination of decreased minimal elongation index up to 3% and increased minimal osmolality point up to 5.2% when compared to the mean of controls. Using this established criterion, osmotic gradient ektacytometry reported a sensitivity of 93.85% and a specificity of 98.38% for the diagnosis of hereditary spherocytosis.

Conclusion

Osmotic gradient ektacytometry is an effective diagnostic test for hereditary spherocytosis and enables its differential diagnosis with other red blood cell membrane diseases based on specific pathology profiles.     

Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan

Objectives: To determine the tentative diagnostic criteria and disease severity classification for Castleman disease (CD) and describe the clinical and pathologic features among human herpesvirus 8 (HHV-8) negative idiopathic multicentric CD (iMCD) in the Japanese population.

Methods: We established the working groups for the research of CD in Japan and had meetings to discuss and define the tentative diagnostic criteria and disease severity classification for CD. We subsequently analyzed 142 patients classified into iMCD by using the nationwide Japanese patient registry.

Results: We proposed the preliminary diagnostic criteria and disease severity classification for CD based on our discussion. In addition, we made a proposal for the disease activity score. We identified clinical and pathological features of patients with iMCD diagnosed by these diagnostic criteria. In the disease severity classification, 37, 33 and 30% patients were categorized into mild, moderate and severe diseases, respectively.

Conclusion: This is the first proposal for diagnosis and classification of CD by the Japanese group. Further studies are required to validate whether they can distinguish CD from other inflammatory diseases and to determine their sensitivity and specificity.