Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients

Virally inactivated, high-purity factor XI concentrates are available for treatment of patients with factor XI deficiency. However, preliminary experience indicates that some preparations may be thrombogenic. We evaluated whether a highly purified concentrate produced signs of activation of the coagulation cascade in two patients with severe factor XI deficiency infused before and after surgery. Signs of heightened enzymatic activity of the common pathway of coagulation (elevated plasma levels of prothrombin fragment 1 + 2 and fibrinopeptide A) developed in the early post-infusion period, accompanied by more delayed signs of fibrin formation with secondary hyperfibrinolysis (elevated D-dimer and plasmin-antiplasmin complex). These changes occurred in both patients, but were more severe in the older patient with breast cancer when she underwent surgery, being accompanied by fibrinogen and platelet consumption. There were no concomitant signs of heightened activity of the factor VII-tissue factor mechanism on the factor Xase complex (plasma levels of activated factor VII and of factor IX and X activation peptides did not increase). The observed changes in biochemical markers of coagulation activation indicate that concentrate infusions increased thrombin generation and activity and that such changes were magnified by malignancy and surgery. Because some factor XI concentrates may be thrombogenic, they should be used with caution, especially in patients with other risk factors for thrombosis.     

Moderation of hemophilia A phenotype by the factor V R506Q mutation

Although many examples of unrelated hemophilia A patients carrying identical point mutations in the factor VIII (FVIII) gene have been reported, the clinical phenotype is not always the same among patients sharing the same molecular defect. Possible explanations for this discrepancy include undetected additional mutations in the FVIII gene or coinheritance of mutations at other genetic loci that modulate FVIII function. We report molecular genetic analysis of potential modifying genes in two sets of unrelated patients carrying common FVIII missense mutations but exhibiting different levels of clinical severity. Both mutations (FVIII R1689C and R2209Q) are associated with severe hemophilia A in some patients and mild/moderate disease in others. The common von Willebrand disease type 2N mutation (R91Q) was excluded as a modifying factor in these groups of patients. However, analysis of the recently described factor V (FV) R506Q mutation (leading to activated protein C resistance) identified a correlation of inheritance of this defect with reduced hemophilia A severity. Two moderately affected hemophilia A patients, each with either of two FVIII gene mutations, were heterozygous for FV R506Q, whereas two severely affected patients and two moderately affected patients were homozygous normal at the FV locus. Our results suggest that coinheritance of the FV R506Q mutation may be an important determinant of clinical phenotype in hemophilia A and that modification of the protein C pathway may offer a new strategy for the treatment of FVIII deficiency.     

A 3-base pair deletion,c.9711_9713del,in DMD results in intellectual disability without muscular dystrophy

We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11–Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with β-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.     

Adrenocortical dysfunction in liver disease: a systematic review

In patients with cirrhosis, adrenal insufficiency (AI) is reported during sepsis and septic shock and is associated with increased mortality. Consequently, the term "hepato-adrenal syndrome" was proposed. Some studies have shown that AI is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation other than sepsis, such as bleeding and ascites. Moreover, other studies showed a high prevalence in liver transplant recipients immediately after, or some time after, liver transplantation. The effect of corticosteroid therapy in critically ill patients with liver disease has been evaluated in some studies, but the results remain controversial. The 250-μg adreno-cortico-tropic-hormone stimulation test to diagnose AI in critically ill adult patients is recommended by an international task force. However, in liver disease, there is no consensus on the appropriate tests and normal values to assess adrenal function; thus, standardization of normal ranges and methodology is needed. Serum total cortisol assays overestimate AI in patients with cirrhosis, so that direct free cortisol measurement or its surrogates may be useful measurements to define AI, but further studies are needed to clarify this. In addition, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented. This review evaluates published data regarding adrenal function in patients with liver disease, with a particular focus on the potential limitations of these studies as well as suggestions for future studies.     

The economic burden of preventable adverse drug reactions: a systematic review of observational studies

Introduction: Adverse drug reactions (ADRs) are an important cause of morbidity and mortality worldwide. They are associated with healthcare costs due to hospital admissions or prolonged length of stay, as well as additional interventions. The aim of this study was to conduct a systematic review of observational studies to evaluate the economic impact of preventable ADRs.

Areas covered: Published observational research investigating the cost of preventable ADRs in Western countries (limited to the USA and European countries).

Expert opinion: Several reviews have been carried out in the field of the ADR epidemiology but fewer reviews have investigated the economic impact of ADRs, and at the time of writing, none has focused on preventable ADRs. The reason why future research should focus on the costs of preventable ADRs is that both the costs and the negative clinical outcomes are preventable, and as such, are a key point of public health policy action. Nevertheless, the present review highlights an important and sobering limitation of published research on the cost of preventable ADRs, of which the major limitation is the heterogeneity in methods and in reporting which limit what can be known through the summarizing work of a systematic review.     

Complications of third molar surgery

This article addresses the incidence of specific complications and, where possible, offers a preventive or management strategy. Injuries of the inferior alveolar and lingual nerves are significant issues that are discussed separately in this text. Surgical removal of third molars is often associated with postoperative pain, swelling, and trismus. Factors thought to influence the incidence of complications after third molar removal include age, gender, medical history, oral contraceptives, presence of pericoronitis, poor oral hygiene, smoking, type of impaction, relationship of third molar to the inferior alveolar nerve, surgical time, surgical technique, surgeon experience, use of perioperative antibiotics, use of topical antiseptics, use of intra-socket medications, and anesthetic technique. Complications that are discussed further include alveolar osteitis, postoperative infection, hemorrhage, oro-antral communication, damage to adjacent teeth, displaced teeth, and fractures.