Factor VII deficiency: defining the clinical picture and optimizing therapeutic options

Summary. Factor VII (FVII) deficiency is the most frequent among rare congenital bleeding disorders, accounting for one symptomatic individual per 500 000 population, apparently without any racial/ethnic predilection. FVII deficiency prevalence in the general population is probably higher because of the presence of asymptomatic and poorly symptomatic individuals. In accordance with the role of FVII as part of the initiating complex of the extrinsic coagulation pathway, laboratory diagnosis is easy, because FVII deficiency is the only congenital bleeding disorder characterized by isolated prolonged prothrombin time. Molecular diagnosis is available, and a broad spectrum of mutations has been characterized in the FVII gene, which is located in chromosome 13. Clinical manifestations are heterogeneous, ranging from severe life‐threatening haemorrhages, such as cerebral, gastrointestinal, and joint haemorrhages, to miscellaneous minor bleeding. The main clinical features in our database (International Registry on Congenital FVII Deficiency database, n = 515) are as follows: (i) the absence of a clear‐cut and consistent correlation between bleeding symptoms and FVII clotting levels; (ii) an excess of symptomatic women compared with men; (iii) frequent surgery‐related bleeding, which is often a diagnostic tool in previously asymptomatic individuals. Several therapeutic options are possible, including plasma‐derived and recombinant products, but therapeutic schedules, optimal dosages, and administration times still have to be precisely defined, and clinical studies, including online registries such as the Seven Treatment Evaluation Registry, are actually ongoing to achieve in a better manner a safe, rational and standardized substitution treatment for this congenital disorder.     

IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach

Mutations in the IL-2-inducible T-cell kinase gene have recently been shown to cause an autosomal recessive fatal Epstein Barr virus (EBV) associated lymphoproliferation. We report 3 cases from a single family who presented with EBV-positive B-cell proliferation diagnosed as Hodgkin's lymphoma. Single nucleotide polymorphism array-based genome-wide linkage analysis revealed IL-2-inducible T-cell kinase as a candidate gene for this disorder. All 3 patients harbored the same novel homozygous nonsense mutation C1764G which causes a premature stop-codon in the kinase domain. All cases were initially treated with chemotherapy. One patient remains in durable remission, the second patient subsequently developed severe hemophagocytic lymphohistiocytosis with multi-organ failure and died, and the third patient underwent a successful allogeneic bone marrow transplantation. IL-2-inducible T-cell kinase deficiency underlies a new primary immune deficiency which may account for part of the spectrum of Epstein Barr virus related lymphoproliferative disorders which can be successfully corrected by bone marrow transplantation.     

Factor X deficiency and pregnancy: preconception counselling and therapeutic options

Women with factor X deficiency (FXD) who want to become pregnant face uncertain risks to themselves and to an unborn infant from haemorrhagic complications during pregnancy and at parturition. Women with FXD may also experience difficulty achieving pregnancy secondary to haemorrhagic symptoms of the reproductive organs. Case reports describe differences in bleeding phenotypes and pregnancy outcomes that are not easily correlated with prepregnancy bleeding symptoms or factor X levels. The aim of this article is to identify factors for consideration and information to assist the physician in counselling women with FXD who want to become pregnant, and to offer guidelines for management where appropriate. We identified cases of pregnancy among women with FXD and their outcomes from the literature; 15 women with 24 pregnancies were identified and 18 were successful. The women in this small cohort did not have an increased rate of spontaneous abortion, (8.3% vs. 13.5% in the general US population) but did have a 2.5-fold increased risk of preterm labour (37.5% vs. 12.2% in the general US population). The role of prophylaxis to control reproductive haemorrhagic symptoms, including haemorrhagic complications of pregnancy has not yet been defined, but use of prophylaxis may allow more women to be able to attempt pregnancy. Women who had access to a tertiary care centre with a multidisciplinary team including an obstetrician with high-risk obstetric training, a haematologist, a perinatologist, and access to a reference laboratory and blood bank were able in most cases to successfully deliver healthy, term infants.     

Sporadic cases of Legionnaires' disease: the expanding clinical spectrum.

An analysis of seven sporadic cases of Legionnaires' disease confirmed clinical features recorded during epidemics and identified aspects of the illness either unreported or not emphasized. Four patients had central nervous system abnormalities. Mental status changes included somnolence, obtundation, delirium, disorientation, and confusion. Three patients experienced visual hallucinations, and one patient without pneumonia had a grand mal seizure with residual memory deficit. Two patients had disseminated intravascular coagulation with thrombocytopenia, elevated split fibrin products, and prolonged partial thromboplastin and prothrombin times. Four patients had severe hypoxia; one patient had an exudative pleuritis. One patient whose treatment included erythromycin had radiologic improvement of his pneumonia despite deteriorating ventilatory function that led to death. The concept of Legionnaires' disease as a severe, diagnostically perplexing pneumonic illness is valid but too narrow. The emerging spectrum is that of a multisystem disease that, besides the lungs, often involves the central nervous system and can be accompanied by disseminated intravascular coagulation.     

Understanding the spectrum of haemophagocytic lymphohistiocytosis: update on diagnostic challenges and therapeutic options

The cytokine storm syndrome ‘haemophagocytic lymphohistiocytosis’ (HLH) is an under‐recognized hyperinflammatory disorder, causing high morbidity and mortality risk in children and adults. It can be subdivided into a primary, genetic form and a secondary, acquired form that complicates diverse infections, malignancies and autoimmune or autoinflammatory disorders. Both subtypes present with the same spectrum of non‐specific symptoms, making accurate diagnosis and rapid treatment initiation challenging. In the last decade, increased awareness and international collaborative efforts fuelled a marked progress in diagnostic protocols and novel treatment strategies for HLH and new diagnostic guidelines are being tailored to specific secondary HLH subtypes. Therapy is gradually shifting its focus from overall immunosuppression towards targeting specific cytokines, cell types or signalling pathways underlying pathophysiology. Nevertheless, continued research efforts remain indispensable to customize therapy to individual patient needs.     

Gamma heavy chain disease--an expanding clinical and laboratory spectrum

In this review we consider the expanded clinical and laboratory spectrum of gamma heavy chain disease based on 25 reported cases, and we describe an additional patient with several unique features. These features included the youth of the patient (age 18), rapidity of his course (death occurring within five weeks of clinical onset) and bone involvement with hypercalcemia. The patient's serum and urine contained a gamma heavy chain fragment of unusually fast electrophoretic mobility belonging to the gamma G4 subclass. This gamma heavy chain protein was found to be a noncovalently linked dimer lacking interchain disulfide linkages. The structural features of other gamma heavy chain proteins were reviewed and compared with those in our case.     

Abdominal Aortic dissections: anatomic and clinical features and therapeutic options

Isolated abdominal aortic dissections are rare events. Their anatomic and clinical features are different from those of atherosclerotic aneurysms. We report 4 cases of isolated abdominal aortic dissection that were successfully treated with surgical or endovascular intervention. The anatomic and clinical features and a review of the literature are also presented.     

Diabesity: therapeutic options

A pathogenic relationship exists between type 2 diabetes and obesity. Over the last decade, the escalation in diabetes cases has paralleled the rapid increase in obesity rates, constituting a global health crisis. Environmental risk factors attributed to the global increase in obesity include the consumption of high‐calorie, high‐fat foods and inadequate physical activity. Obese individuals may also have a genetic predisposition for obesity. Both diabetes and obesity confer an elevated risk of developing a range of complications and comorbidities, including cardiovascular disease, hypertension and stroke, which can complicate disease management. This review examines the aetiology of the linkages between diabetes and obesity and the range of available therapies. Recent clinical evidence substantiating the efficacy and safety of incretin‐based antidiabetic therapies is analysed, in addition to data on antiobesity therapeutic strategies, such as antiobesity agents, behaviour modification and bariatric surgery. Glucose control is often accompanied by weight‐neutral or modest weight reduction effects with DPP‐4 inhibitor treatment (sitagliptin, vildagliptin, saxagliptin) and weight loss with GLP‐1 receptor agonist therapy (exenatide, liraglutide). Studies of antiobesity agents including orlistat, sibutramine and rimonabant have shown attrition rates of 30–40%, and the long‐term effects of these agents remain unknown. Bariatric surgical procedures commonly performed are laparoscopic adjustable banding of the stomach and the Roux‐en‐Y gastric bypass, and have produced type 2 diabetes remission rates of up to 73%. Therapeutic strategies that integrate glycaemic control and weight loss will assume greater importance as the prevalence of diabetes and obesity increase.     

Paradoxical embolism: clinical presentation, diagnostic strategies, and therapeutic options

Thirty cases of paradoxical embolism are reviewed to consolidate clinical presentations and common predisposing factors. The presence of patent foramen ovale in the great majority of these patients in association with maneuvers that transiently elevate right atrial pressure is emphasized in relation to the pathophysiology of the disorder. Contrast echocardiography with provocative maneuvers such as Valsalva and cough are discussed and treatment options highlighted. The underdiagnosis of paradoxical embolism is discussed, and its potential importance in other more common vascular diseases addressed.     

Red cell pyruvate kinase deficiency: molecular and clinical aspects

Red cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of the glycolytic pathway causing hereditary non-spherocytic haemolytic anaemia. The degree of haemolysis varies widely, ranging from very mild or fully compensated forms, to life-threatening neonatal anaemia and jaundice necessitating exchange transfusions. Erythrocyte PK is synthesized under the control of the PK-LR gene located on chromosome 1. To date, more than 150 different mutations in the PK-LR gene have been associated with PK deficiency. First attempts to delineate the biochemical and clinical consequences of the molecular defect were mainly based on the observation of the few homozygous patients and on the analysis of the three-dimensional structure of the enzyme. More recently, the comparison of the recombinant mutants of human red cell PK with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.     

Novel insulins: expanding options in diabetes management

Management of type 1 and type 2 diabetes mellitus with intensive insulin therapy usually includes an intermediate- or long-acting basal component for between-meal and nocturnal glycemic control, together with preprandial bolus injections of a short-acting insulin for control of meal-stimulated increases in serum glucose levels. Although the ideal basal/bolus insulin combination has yet to be found, recent developments may provide safer and more effective options. Two new short-acting semisynthetic analogs--insulin lispro and insulin aspart--can be administered as preprandial bolus injections closer to mealtime than regular human insulin, thereby synchronizing insulin administration and food absorption. In clinical trials, postprandial increases in blood glucose levels were significantly less after treatment with insulin lispro or insulin aspart than with premeal regular insulin. Because of their short duration of action, a slightly greater basal insulin supply may be needed when insulin lispro or insulin aspart is used. Inhalation devices for aerosolized regular human insulin offer another alternative to premeal subcutaneous bolus injections. Inhaled insulin is absorbed more rapidly than subcutaneous regular insulin and may therefore be given closer to mealtime. For basal therapy, insulin glargine, a new long-acting analog, is absorbed more slowly after subcutaneous administration than are conventional neutral protamine Hagedorn (NPH) and ultralente insulin, and has a relatively flat metabolic effect. Clinical trials indicate that insulin glargine is at least as effective as NPH insulin and ultralente insulin, and is associated with a reduced risk of nocturnal hypoglycemia. Other long-acting analogs, such as fatty acid acylated insulins, have been tested in animal models and are being evaluated in clinical studies.     

Eosinophilic fasciitis: clinical spectrum and therapeutic response in 52 cases

The clinical course of 52 cases with eosinophilic fasciitis observed at the Mayo Clinic has been described. Cutaneous changes included pitting edema, peau d'orange, and induration, and may affect virtually any body surface area. In addition, localized morphea was present in 15 cases. Arthritis was observed in 21 patients; 29 patients had flexion contractures and 12 had carpal tunnel syndrome. Associated hematologic diseases were found in five patients; thrombocytopenia in two, myeloproliferative disorder in one, myelomonocytic leukemia in one, and chronic lymphocytic leukemia in one. Peripheral blood eosinophilia was noted in 33 of 52 patients, hypergammaglobulinemia was noted in 17 of 49, and elevated sedimentation rate was noted in 15 of 52. Nonspecific EMG changes were seen in 11 of 15 patients. None had clinical involvement of the kidneys, lungs, or heart. No significant association between any HLA-A, -B, or -DR and eosinophilic fasciitis was seen. Prednisone and hydroxychloroquine seemed equally beneficial in treatment; however, some cases showed spontaneous recovery, making evaluation of therapeutic efficacy difficult. Relapses occurred in some cases.     

Foot tendinopathies in rheumatic diseases: etiopathogenesis, clinical manifestations and therapeutic options

Damage to the mutual and delicate articular relationships of the foot may lead to functional failure. A painful foot can be the heralding sign of inflammatory, metabolic or degenerative rheumatic disease that may cause severe disability if left untreated. Healthy tendons are brilliant white in colour, are fibroelastic in texture and can withstand huge mechanical loads. Pathological tendons are characterised by changes in cellular function, rupture of collagen bundles, increased production of the proteoglycan-water matrix and neurovascular proliferation. According to the underlying disease, tendinopathies may present with pain of variable duration and intensity and with functional impairment, or they may be an asymptomatic finding on imaging techniques. Pain is the most common presenting symptom in the inflammatory rheumatic diseases of the ankle and the foot and usually precedes ultrasound or radiographic changes; pain results from inflammatory changes of the synovia and soft tissue structures including bursae, tendons, fascias and peripheral nerves. The management of tendinopathies in inflammatory and non-inflammatory rheumatic patients includes “articular economy,” pharmacological treatment, foot orthotics, cryotherapy, instrumental physiotherapy, rehabilitation and physical. This review highlights the differences between tendinopathies occurring in non-inflammatory rheumatic disorders compared to those appearing in the course of inflammatory rheumatic disorders and defines a conservative management framework that non-rheumatologists (orthopaedic surgeons) and rheumatologists could adhere for the management of foot tendinopathies.     

Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency

3-Phosphoglycerate dehydrogenase (3-PGDH) deficiency is considered to be a rare cause of congenital microcephaly, infantile onset of intractable seizures and severe psychomotor retardation. Here, we report for the first time a very mild form of genetically confirmed 3-PGDH deficiency in two siblings with juvenile onset of absence seizures and mild developmental delay. Amino acid analysis showed serine values in CSF and plasma identical to what is observed in the severe infantile form. Both patients responded favourably to relatively low dosages of serine supplementation with cessation of seizures, normalisation of their EEG abnormalities and improvement of well-being and behaviour. These cases illustrate that 3-PGDH deficiency can present with mild symptoms and should be considered as a treatable disorder in the differential diagnosis of mild developmental delay and seizures. Synopsis: we present a novel mild phenotype in patients with 3-PGDH deficiency.     

Hypertension and diabetes: new therapeutic options

The treatment of high-risk hypertensive patients with diabetes presents clinicians with challenges and opportunities. The coexistence of hypertension and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications. Perhaps most important among these is the increased risk of cardiovascular events in this patient population, an observation that can be best appreciated by the increased number of deaths attributed to cardiovascular-related diseases in diabetic patients aged 45 to 65 years. Consequently, aggressive therapy in this population offers the promise of significantly reducing excess cardiovascular deaths. Despite this opportunity for reducing mortality in these high-risk patients, several challenges to treatment remain. While aggressive blood pressure reduction has been documented to reduce the rate of events in these patients, questions remain as to the level to which blood pressure should be reduced. The recent guidelines from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure emphasized the importance of treating patients with hypertension and diabetes as if they already have target organ damage. Low blood pressure targets of 130/85 mm Hg, with an optimal goal of 120/80 mm Hg, can reduce the risk of events in hypertensive patients with diabetes, regardless of the pharmacological means used. However, there are physiologic and clinical rationale for renin angiotensin system blockade, with angiotensin-converting enzyme inhibition as the preferential therapy in these patients. In this regard, preliminary data with the new class of angiotensin II receptor blockers suggest that these agents may offer benefits equivalent to those observed with angiotensin-converting enzyme inhibitors while offering better tolerance.     

Prehypertension: Underlying pathology and therapeutic options

Prehypertension(PHTN) is a global major health risk that subjects individuals to double the risk of cardiovascular disease(CVD) independent of progression to overt hypertension. Its prevalence rate varies considerably from country to country ranging between 21.9% and 52%. Many hypotheses are proposed to explain the underlying pathophysiology of PHTN. The most notable of these implicate the renin-angiotensin system(RAS) and vascular endothelium. However, other processes that involve reactive oxygen species, the inflammatory cytokines, prostglandins and C-reactive protein as well as the autonomic and central nervous systems are also suggested. Drugs affecting RAS have been shown to produce beneficial effects in prehypertensives though such was not unequivocal. On the other hand, drugs such as β-adrenoceptor blocking agents were not shown to be useful. Leading clinical guidelines suggest using dietary and lifestyle modifications as a first line interventional strategy to curb the progress of PHTN; however, other clinically respected views call for using drugs. This review provides an overview of the poten-tial pathophysiological processes associated with PHTN, abridges current intervention strategies and suggests investigating the value of using the "Polypill" in prehypertensive subjects to ascertain its potential in delaying(or preventing) CVD associated with raised blood pressure in the presence of other risk factors.     

Liver transplantation in the 21st century: expanding the donor options

Over the past decade, use of ECD organs for OLT has allowed many transplant programs to afford patients access to an otherwise scarce resource and to maintain center volume. Although overall posttransplant outcomes are inferior to results with optimal, whole-liver grafts, aggressive utilization of ECD and DCD organs significantly lowers median wait-times for OLT, MELD score at OLT, and death while awaiting transplantation. It is incumbent on the transplant community to provide continued scrutiny of the many factors involved in ECD organ utilization, evaluate the degree of risk and benefit such allografts may impart on particular recipients, and thereby provide suitable “matching” to maximize favorable outcomes. Transplant caregivers need to provide patients with evidence-based care decisions, be good stewards of a scarce resource, and maintain threshold survival results for their programs. This requires balancing the urgency with which a transplant is needed and the utility of such a transplant. There is a clear necessity to pursue additional donor research to improve use of these marginal grafts and assess interventions that enhance the safety of ECD livers.