Ayesha Zia

Thromboelastography identifies children with rare bleeding disorders and predicts bleeding phenotype.

Rare bleeding disorders (RBDs) comprise 3–5% of all congenital bleeding disorders. They can evade typical coagulation screening tests and there is a poor correlation between laboratory results and bleeding phenotype. Thromboelastography (TEG) measures coagulation globally in whole blood samples. The aims of this study were to evaluate the utility of TEG as an adjunct to the routine screening tests employed for the diagnosis of RBDs and to correlate TEG results with the bleeding phenotype in RBDs. TEG parameters and clot kinetics were compared to bleeding phenotypes (asymptomatic, mild, moderate and severe) in 26 RBD patients and 30 normal controls. Clot kinetics correlated strongly with RBDs and with the severity of bleeding phenotype with mean maximum rate of thrombus generation (MRTG) 15.4 mm min−1 in controls vs. 6.0 in RBDs (P < 0.0001, Wilcoxin). The mean MRTG was 7.7 in mildly symptomatic, 5.5 in moderately symptomatic and 4.1 in severely symptomatic patients (P < 0.0001, Kruskal–Wallis). Disorders that are often missed by conventional screening tests, dysfibrinogenaemia and platelet disorders displayed a distinctive TEG curve with markedly decreased maximum amplitude (MA) and low MRTG values. Factor XIII and PAI deficient patients displayed increased fibrinolysis in addition to low MRTGs. All patients with RBDs, but none of the normal controls, had abnormal clot kinetics suggesting that TEG may be an effective screening test for RBDs.

Developing a multidisciplinary Young Women's Blood Disorders Program: a single‐centre approach with guidance for other centres

Bleeding from the reproductive tract in women is a natural event, generally occurring with menstruation and childbirth. Women with an underlying bleeding disorder may experience heavy menstrual bleeding (HMB) and thereby, unacceptable blood loss. Up to 20% of US women with abnormal uterine bleeding and a normal gynaecological exam may have an underlying bleeding disorder corresponding to almost 2–3 million American women. These females face many obstacles in achieving optimum medical care for their problems. A haematologist may not evaluate these women as they are treated symptomatically. Recognition of an underlying bleeding disorder is not straightforward and many come to attention after serious bleeding events. Although mortality from HMB is uncommon, the true burden of HMB is its impact on health‐related quality of life. To address these issues, women with HMB require a comprehensive approach to their care.

Challenges of diagnosing and managing the adolescent with heavy menstrual bleeding

Unpredictable, prolonged or heavy menstrual bleeding (HMB) may be expected for many adolescents soon after menarche. A decade of clinical experience and research has now established firmly that bleeding disorders (BD) are common in adolescents with HMB. Despite these advances, many questions remain, and several aspects of the diagnosis and management of BDs in adolescents are not supported by rigorous clinical trials. In this overview, four major areas will be discussed. First, we will discuss the frequency of BDs in young women with HMB. Up to 20% of older females with HMB are thought to have an underlying BD. Estimates from retrospective studies in adolescents suggest a prevalence that varies anywhere from 10 to 62%. Prospective studies with uniform hemostatic evaluation are needed to answer this question definitively. Second, we will review existing tools that help screen and diagnose adolescents with HMB with an underlying BD. Although identification of an underlying BD in older women with HMB is relatively straight forward, uncertainties remain for adolescents. Heavy menstrual bleeding in this age group may have different pathophysiological underpinnings than those in older women and may often be disregarded as anovulatory. There is an urgent need to develop novel tools, and evaluate existing diagnostic strategies in adolescents. Third, we will discuss the optimal medical management of HMB in young adolescents. As direct evidence is largely lacking, these areas are also subject to extrapolation from older women. Lastly, an important area- prediction, and management of future bleeding in those adolescents who are diagnosed with a mild BD-will be discussed. Throughout, areas of controversy and opportunities for further research are highlighted.

Glutathione Depletion, Pentose Phosphate Pathway Activation, and Hemolysis in Erythrocytes Protecting Cancer Cells from Vitamin C-induced Oxidative Stress

The discovery that oxidized vitamin C, dehydroascorbate (DHA), can induce oxidative stress and cell death in cancer cells has rekindled interest in the use of high dose vitamin C (VC) as a cancer therapy. However, high dose VC has shown limited efficacy in clinical trials, possibly due to the decreased bioavailability of oral VC. Because human erythrocytes express high levels of Glut1, take up DHA, and reduce it to VC, we tested how erythrocytes might impact high dose VC therapies. Cancer cells are protected from VC-mediated cell death when co-cultured with physiologically relevant numbers of erythrocytes. Pharmacological doses of VC induce oxidative stress, GSH depletion, and increased glucose flux through the oxidative pentose phosphate pathway (PPP) in erythrocytes. Incubation of erythrocytes with VC induced hemolysis, which was exacerbated in erythrocytes from glucose-6-phosphate dehydrogenase (G6PD) patients and rescued by antioxidants. Thus, erythrocytes protect cancer cells from VC-induced oxidative stress and undergo hemolysis in vitro, despite activation of the PPP. These results have implications on the use of high dose VC in ongoing clinical trials and highlight the importance of the PPP in the response to oxidative stress.

Hypercoagulability in adolescent girls on oral contraceptives‐global coagulation profile and estrogen receptor polymorphisms

Oral contraceptive (OCP) induced changes on coagulation are complex with high inter‐individual variability. The precise reason for differences in this variability is unknown. We hypothesized that global coagulation assays better delineate these changes and variability in hypercoagulability may be the result of differences in estrogen metabolism and thrombophilia. Fifty‐two adolescents initiating OCPs were prospectively enrolled; 33 subjects completed the study. Samples were analyzed prior to and after OCPs for procoagulant and anticoagulant factor activities and thrombin generation (TG) +/‐thrombomodulin. Participants were genotyped for common thrombophilia and estrogen receptor‐α (ESR‐α) single nucleotide polymorphisms (SNPs). SNP genotypes were compared to coagulation parameters; TG parameters and differences pre and post OCPs were examined. At baseline, a striking finding was elevated FVIII levels. FVL was absent in all and F2 G20210A was present in one participant. The ESR‐α polymorphism was present in heterozygous state in 59% and homozygous state in 21% participants. There were no differences in VWF levels and FVIII: C after being on OCPs. Protein S levels decreased with OCPs. Sixty percent of participants showed evidence of hypercoagulability on TG testing on OCPs. Higher thrombin peak and endogenous thrombin potential (ETP) were seen on TG after OCPs. With thrombomodulin, ETP and thrombin peak did not decrease after OCPs, signifying ‘thrombomodulin resistance’. We demonstrated that OCPs induce a state of “variable” hypercoagulability in adolescents, predominantly through the protein S pathway. Genetic and nongenetic factors may account for the variable increase in hypercoagulability. Further research is needed to understand this. Am. J. Hematol. 90:725–731, 2015.

Emergency department visits in children with hemophilia

The pediatric emergency department (ED) management of bleeding and other complications of hemophilia constitutes an increasingly important component of hemophilia therapy. This retrospective study examined the overall ED use by children with hemophilia in a single center, with a particular aim to investigate visits related to injury or bleeding, and those related to blood stream infection in patients with a central venous catheter (CVC).

Hereditary Intrinsic Factor Deficiency in Chaldeans

Juvenile vitamin B(12) or cobalamin (Cbl) deficiency is notoriously difficult to explain due to numerous acquired and inherited causes. The consequences of insufficient Cbl are megaloblastic anemia, nutrient malabsorption, and neurological problems. The treatment is straightforward with parenteral Cbl supplementation that resolves most health issues without an urgent need to clarify their cause. Aside from being clinically unsatisfying, failing to elucidate the basis of Cbl deficiency means important information regarding recurrence risk is not available to the individual if the cause is contagious or inherited. Acquired causes have largely disappeared in the Modern World because they were mostly due to parasites or malnutrition. Today, perhaps the most common causes of juvenile Cbl deficiency are Imerslund-Gräsbeck syndrome and inherited intrinsic factor deficiency (IFD). Three genes are involved and genetic testing is complicated and not widely available. We used self-identified ancestry to accelerate and confirm the genetic diagnosis of IFD in three families of Chaldean origin. A founder mutation limited to Chaldeans from Iraq in the intrinsic factor gene GIF was identified as the cause. World events reshape the genetic structure of populations and inherited diseases in many ways. In this case, all the patients were diagnosed in the USA among recent immigrants from a single region. While IFD itself is not restricted to one kind of people, certain mutations are limited in their range but migrations relocate them along with their host population. As a result, self-identified ancestry as a stratifying characteristic should perhaps be considered in diagnostic strategies for rare genetic disorders.

Global coagulation assays: a clinical perspective

An ideal coagulation assay is one which has an ability to capture and characterize phenotypic variability, is clinically useful in both diagnostic and therapeutic monitoring across a broad hemostatic range, is predictive of clinical endpoints, has established reference ranges and is validated and endorsed by regulatory agencies. Plasma based clotting assays, such as activated partial thromboplastin time (APTT) and prothrombin time (PT), are commonly employed to detect aberrations in the coagulation cascade. While these are considered the ‘gold standard’, they only assess the initiation of clot formation, when only 3–5 % of thrombin has been generated. Sufficient clot formation is a continuous process and is better studied by global coagulation assay, as thrombin generation is dependent on several key players in the coagulation cascade, including, but not limited to cellular elements, platelets, fibrin polymerization and the components in the fibrinolytic cascade. Global coagulation assays

Utility of a screening tool for haemostatic defects in a multicentre cohort of adolescents with heavy menstrual bleeding

Heavy menstrual bleeding (HMB) may be expected for many adolescents after menarche. Accurate assessment of HMB, a key component in the diagnosis of a haemostatic defect (HD), is a well‐recognized challenge.

Rivaroxaban dose adjustment using thrombin generation in severe congenital protein C deficiency and warfarin-induced skin necrosis

Key Points Rivaroxaban was efficacious and safe in a child with protein C deficiency to prevent the recurrence of skin necrosis or venous thrombosis. The dosage of direct oral anticoagulants in children with thrombophilia is unclear; a thrombin generation assay may be useful to adjust it.