Laboratory Measurement of the Anticoagulant Activity of the Non–Vitamin K Oral Anticoagulants

Background

Non–vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations.

Objectives

This study’s objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban.

Methods

We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2).

Results

We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R² = 0.92 to 0.99) and ecarin-based assays (R² = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R² = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification.

Conclusions

Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed.     

Impaired response or insufficient dosage?—Examining the potential causes of “inadequate response” to allopurinol in the treatment of gout

Objectives

Gout is one of the most common forms of arthritis. It is well established that urate-lowering therapy that aims for a serum urate less than at least 0.36 mmol/l (6 mg/dl) is required for the successful management of gout. Allopurinol, a xanthine oxidase (XO) inhibitor, is the most commonly used urate-lowering therapy. However, many patients fail to achieve the target serum urate on allopurinol; these patients can be considered to have “inadequate response” to allopurinol. Herein, we examine the potential mechanisms and implications of inadequate response to allopurinol.

Methods

The literature was reviewed for potential causes for failure to reach target serum urate in patients receiving allopurinol.

Results

The two most common causes of inadequate response to allopurinol are poor adherence and under-dosing of allopurinol. Adherent patients who fail to achieve target serum urate on standard doses of allopurinol form a group that could be considered to be “partially resistant” to allopurinol. There are four potential mechanisms for partial allopurinol resistance: decreased conversion of allopurinol to oxypurinol; increased renal excretion of oxypurinol; abnormality in XO structure and/or function such that oxypurinol is rendered less effective and/or drug interactions.

Conclusions

It is important to determine the reasons for failure to achieve treatment targets with allopurinol, particularly as newer agents become available. The knowledge of the mechanisms for inadequate response may help guide the clinician towards making a therapeutic choice that is more likely to result in achieving the serum urate target.     

Do we know the true mechanism of action of the DPP‐4 inhibitors?

The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti‐diabetic treatment aims to control glucose homeostasis as tightly as possible in order to reduce these complications. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a recent addition to the anti‐diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side‐effect profile and their low hypoglycaemia risk. The actions of DPP‐4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide, are known substrates, but other incretin‐independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP‐4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here.     

Covid-19, the thyroid and the pituitary — The real state of play

Thyroid and pituitary disorders linked to the coronavirus SARS-CoV-2, responsible for the COVID-19 epidemic, are mainly due to direct infection of the endocrine glands by the virus and to cell damage induced by the immune response. The two most frequent thyroid complications of COVID-19 are low T3 syndrome, or “non-thyroidal illness syndrome” (NTIS), and thyroiditis. Studies among in-patients with COVID-19 have shown that between one out of six and half of them have a low TSH level, related to NTIS and thyroiditis, respectively, sometimes found in the same patient. In NTIS, the decrease in free T3 concentration correlates with the severity of the infection and with a poor prognosis. Assessment of thyroid function in patients after a COVID-19 infection, shows normalization of thyroid function tests. Thyroiditis linked to COVID-19 can be divided into two groups, which probably differ in their pathophysiology. One is “destructive” thyroiditis occurring early in infection with SARS-CoV-2, with a severe form of COVID-19, usually observed in men. It is often asymptomatic and associated with lymphopenia. The other is subacute thyroiditis occurring, on average, one month after the COVID-19 episode, usually in clinically symptomatic women and associated with moderate hyperleukocytosis. Post-infection, one quarter to one third of patients remain hypothyroid. An Italian study demonstrated that low TSH in patients hospitalized for COVID-19 was associated with prolonged hospitalization and a higher mortality risk. Pituitary diseases associated with SARS-CoV-2 infection are much rarer and the causal relationship more difficult to ascertain. Several cases of pituitary apoplexy and diabetes insipidus during COVID-19 infection have been reported. Hyponatremia occurs in 20–50% of patients admitted to hospital for COVID-19. The prevalence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) amongst these hyponatremic cases is difficult to determine. These endocrine complications may influence the prognosis of infection with SARS-CoV-2. Although they rarely require specific treatment, it is important that endocrinologists recognize them to ensure appropriate management, particularly in the acute phase.     

Incretin concept revised: The origin of the insulinotropic function of glucagon‐like peptide‐1 – the gut,the islets or both?

Incretins comprise a pair of gut hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), which are secreted in response to food ingestion and enhance glucose‐dependent insulin secretion from pancreatic β‐cells. Immediately after secretion, GLP‐1 is degraded by dipeptidyl peptidase‐4 more rapidly than GIP, and circulating levels of biologically intact GLP‐1 are substantially lower than those of biologically intact GIP. Therefore, there has been a debate on how the gut‐derived GLP‐1 exerts insulinotropic actions. Recent publications have revealed two novel mechanisms by which GLP‐1 exerts insulinotropic actions: (i) the gut‐derived GLP‐1 activates receptors expressed in nodose ganglions, thereby potentiating glucose‐dependent insulin secretion through the vagus nerves; and (ii) the pancreatic α‐cell‐derived GLP‐1 activates receptors expressed in β‐cells in a paracrine manner. While the relative contributions of the two mechanisms under normal and pathological conditions remain unknown and mechanisms regulating GLP‐1 secretion from α‐cells need to be investigated, the available data strongly indicate that the effects of GLP‐1 on insulin secretion are far more complex than previously believed, and the classical incretin concept regarding GLP‐1 should be revised.     

Are T‐cell dysfunctions the other side of the moon in the pathogenesis of myelodysplastic syndromes?

Even though the pathogenesis of myelodysplastic syndromes (MDS) is dominated by an inefficient maturation of haematopoietic precursors, also immune mechanisms seem to play a crucial functional role. In this review, we will first describe the clinical and laboratory autoimmune manifestations often detectable in MDS patients. We will then focus on studies addressing the mechanisms of T-cell activation and their implications in the disease history. The potential impact of specific cell subsets, such as regulatory T-cells, Th17 cells and natural killer cells, will be also described. We will finally focus on potential therapeutic approaches based on immunomodulation, ranging from more classical immunosuppressive drugs to vaccination and transplantation strategies.     

Analysis of the 3′ Variable Region of the <Emphasis Type="Italic">cagA</Emphasis> Gene of <Emphasis Type="Italic">Helicobacter pylori</Emphasis> Isolated in Koreans

CagA protein of Helicobacter pylori is injected into epithelial cells, and it undergoes tyrosine phosphorylation, resulting in inducing cytoskeletal rearrangements. A few studies have suggested that the number of CagA tyrosine phosphorylation motifs (EPIYA) and subtypes of CagA were associated with gastric cancer. This study was performed to characterize the 3' variable regions of the cagA gene of H. pylori and to investigate whether or not there is any relationship between the diversities of cagA and the disease outcome in Korea. Seventy-nine patients (chronic gastritis, 15; duodenal ulcer, 27; benign gastric ulcer, 18; gastric cancer, 19) were enrolled. Biopsy specimens were taken from the antrum for H. pylori culture, and genomic DNA was extracted. PCR and DNA sequence analysis was carried out for the 3′ variable region of the cagA gene. Seventy-eight strains (98.8%) contained three EPIYA motifs and one strain (1.2%) isolated from a patient with duodenal ulcer contained four EPIYA motifs. Seventy-six strains (96.2%) were the East Asian type. In conclusion, there was no significant difference between the number of EPIYA motifs or CagA subtypes and various gastroduodenal diseases in Korea.     

Lack of association between the Pro<Subscript>12</Subscript>Ala polymorphism of the PPAR-γ2 gene and type 2 diabetes mellitus in the Qatari consanguineous population

Peroxisome proliferators-activated receptor γ (PPARγ) is a nuclear hormone receptor that serves as a master regulator for adipocytes-specific genes contributing to adipocytes differentiation, insulin sensitivity and lipid metabolism. The substitution of proline to alanine at codon 12 of the PPAR γ2 gene (Pro12Ala polymorphism) is most widely studied, and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Qatar ethnicity, however, there is no report about this polymorphism. The aim of this study was to estimate the allele frequency of the Pro₁₂Ala polymorphism of PPAR γ2 gene among Qatari population and investigate the association between this polymorphism and obesity or type 2 diabetes. This is a matched case–control study. It was carried out among diabetic patients and healthy subjects at the Primary Healthcare Clinics, and the survey was conducted from February 2003 to March 2006 in Qatari male and female nationals aged 35 to 60 years. The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI), and obesity. Their health status was assessed by medical conditions, family history, and blood pressure measurements. The allele frequency of Pro₁₂Ala polymorphism in PPAR γ2 gene among Qataris is lower than that in many Caucasian ethnic groups. No association is seen between the Pro₁₂Ala and type 2 Diabetes (0.055 vs 0.059, OR = 1.1311, P = 0.669). Nearly half of the diabetic type 2 patients (48.5%) were obese (BMI > 30) compared to nondiabetic subjects (29.8%) (P < 0.001). In this study, no association is seen between the Pro₁₂Ala polymorphism in PPAR γ2 gene and the type2 diabetes in Qatar.     

Does Nonresponse Bias the Results of Retrospective Surveys of End‐of‐Life Care?

OBJECTIVES: To evaluate the effect of nonresponse bias on reports of the quality of end‐of‐life care that older adults receive. DESIGN: Nationwide retrospective survey of end‐of‐life care. SETTING: Sixty‐two Veterans Affairs Medical Centers. PARTICIPANTS: Patients were eligible if they died in a participating facility. One family member per patient was selected from medical records and invited to participate. MEASUREMENTS: The telephone survey included 14 items describing important aspects of the patient's care in the last month of life. Scores (0–100) reflect the percentage of items for which the family member reported that the patient received the best possible care, and a global item defined the proportion of families who said the patient received “excellent” care. To examine the effect of nonresponse bias, a model was created to predict the likelihood of response based on patient and family characteristics; then this model was used to apply weights that were equivalent to the inverse of the probability of response for that individual. RESULTS: Interviews were completed with family members of 3,897 of 7,110 patients (55%). Once results were weighted to account for nonresponse bias, the change in mean individual scores was 2% of families reporting “excellent” care. Of the 62 facilities in the sample, the scores of only 19 facilities (31%) changed more than 1% in either direction, and only 10 (16%) changed more than 2%. CONCLUSION: Although nonresponse bias is a theoretical concern, it does not appear to have a significant effect on the facility‐level results of this retrospective family survey.     

Programming of the stress response: a fundamental mechanism underlying the long‐term effects of the fetal environment?

There is a large body of evidence which suggests that an adverse fetal environment results in a heightened biobehavioral response to stress, with increased activity of the classical mediators of the stress response, including the hypothalamic-pituitary adrenal axis and autonomic nervous system. Although this has been amply demonstrated in animal experiments, several recent studies suggest that the same processes operate in human populations and may have important consequences for health. The evidence suggests that an adverse early environment or markers of an adverse environment such as low birth weight are linked with long-term alterations in these neuroendocrine systems. However, these studies also demonstrate that there is a considerable degree of heterogeneity in the responses observed which appear to depend on a variety of factors such as the nature or timing of the adverse exposure as well as the gender of the offspring. The mediators of these classical neuroendocrine responses such as cortisol and catecholamines are biologically potent and may directly influence disease susceptibility by means of their effects on metabolism and the vasculature. However, lifelong changes in the set point of these neuroendocrine systems in response to the early environment may also direct the course of development during fetal life, infancy and childhood towards the generation of a phenotype adapted for the adult environment predicted by the clues available during fetal life. This has biological advantages if the actual adult environment turns out to be appropriate for the phenotype. However, ill health may occur if the phenotype is not well matched to the actual environment encountered in adult life.     

Clinical features of Behçet's disease in patients in the Sultanate of Oman; the significance of antiphospholipid antibodies?

The prevalence of symptoms in 34 Omani patients with Behcet's disease (BD) was: recurrent oral ulceration 100%, arthritis/arthralgia and genital ulceration 74% each, folliculitis 64%, neurological lesions 62%, retinal vasculitis 30%, iritis and hypopyon 26%, gastrointestinal lesions 12%, venous thrombosis and cardiovascular lesions 9% each, and pleuropulmonary lesions and epididymitis 6% each. Antiphospholipid (APL) antibodies (both anticardiolipin [ACAs] and anti-beta2 glycoprotein I [abeta2GPIs]) were present in 11/34 (32%) of the BD patients and in 54/73 (74%) of Omani patients with systemic lupus erythematosus (SLE) (chi2 = 21.2, P<0.001). In patients possessing APL antibodies, there was no significant difference in mean antibody levels between BD and SLE patients. IgM isotype antibodies, in the absence of IgG, were more prevalent in BD (5/11) than in SLE (10/54) patients (chi2 =3.8, P = 0.05). The frequency of organ involvement was similar in patients with and without APL antibodies (chi2 = 1.226, P > 0.05). This study fails to demonstrate a pathognomonic role for APL antibodies in BD.     

Measuring the impact of the <Emphasis Type="Italic">Voices of Survivors</Emphasis> program on health care workers’ attitudes toward survivors of intimate partner violence

BACKGROUND: Most continuing medical education programs on intimate partner violence (IPV) use an expert-driven approach and focus on changing knowledge and screening behaviors. The Voices of Survivors program aims to also improve attitudes and empathy. OBJECTIVES: To test the Attitudes Toward Survivors of IPV (ATSI) survey psychometrically. To assess the effectiveness of the Voices of Survivors program in changing health care workers' responsibility to assess for and counsel about IPV, respect for patient autonomy, empathy toward patients in abusive relationships, barriers, confidence, knowledge, and self-reported assessment behaviors. SETTING: Thirty-one unaffiliated primary care practices in Washington County, Ore. DESIGN: Comparison of ATSI survey results before and after a two-hour workshop including a 30-minute video and an advocate-led discussion. PARTICIPANTS: Convenience sample of primary care providers, medical support staff, and other clinic employees. Results: Two hundred and eighty-four health care workers participated in the training. Two hundred and sixty-seven (94%) completed workshop evaluations and 187 (66%) completed both pre- and postintervention surveys. Cronbach's alpha for all scales ranged from 0.68 to 0.92. Postintervention, participants' summary scores improved for responsibility to assess for IPV (3.96 vs 3.64; P<.0001), respect for patient autonomy (2.78 vs 2.41; P<.0001), empathy (3.24 vs. 2.99; P=.002), confidence (2.33 vs 2.07; P<.0001), knowledge (2.08 vs 1.64; P<.0001), and self-reported behaviors (3.08 vs 2.53; P=.0001). Barriers related to availability of resources and referrals also improved. CONCLUSIONS: The ATSI scales demonstrated good internal reliability and responsiveness to change in all domains except responsibility to counsel. The Voices of Survivors documentary, along with a workshop based on its companion guide, improved clinic employees' knowledge, attitudes, empathy, and self-reported assessment behaviors about IPV.     

PLATINO,a nine-year follow-up study of COPD in the city of S?o Paulo, Brazil: the problem of underdiagnosis

OBJECTIVE:

To determine the underdiagnosis rate in new COPD cases at the end of a nine-year follow-up period-in the study designated "Projeto Latino-Americano de Investigação em Obstrução Pulmonar" (PLATINO, Latin-American Pulmonary Obstruction Investigation Project)-and compare that with the underdiagnosis rate during the initial phase of the study, as well as to identify the clinical features exhibited by the subjects who were not diagnosed until the end of the follow-up phase.

METHODS:

The study population comprised the 1,000 residents of the city of São Paulo, Brazil, who took part in the PLATINO study. Of those, 613 participated in the follow-up phase, during which the subjects were assessed with the same instruments and equipment employed in the initial phase of the study. We used the chi-square test or the independent sample t-test to analyze the underdiagnosis rate and to identify the characteristics of the subjects who were not diagnosed until the end of the follow-up phase.

RESULTS:

The underdiagnosis rate for new COPD cases at the end of the nine-year follow-up period was 70.0%. The underdiagnosis rate during the follow-up phase was 17.5% lower than that reported for the initial phase of the study. The subjects who were not diagnosed until the end of the follow-up phase presented with fewer respiratory symptoms, better pulmonary function, and less severe disease than did those previously diagnosed with COPD.

CONCLUSIONS:

The underdiagnosis rate for new COPD cases was lower in the follow-up phase of the study than in the initial phase. The subjects who were not diagnosed until the end of the follow-up phase of the PLATINO study presented with the same clinical profile as did those who were not diagnosed in the initial phase. These findings underscore the need for spirometry in order to confirm the diagnosis of COPD and provide early intervention.