Drug-induced Bleeding Research Articles

Association Between NAD(P)H Quinone Oxidoreductase 1 (NQO1) Gene Methylation/Expression and Bleeding Incidence Among an Iranian Population Undergoing Warfarin Therapy.

Increased bleeding tendency is a common and challenging complication of warfarin therapy which results in extensive pharmacogenomic studies in order to develop a personalized dosing approach and minimize the risk of related side effects. Here we aimed to explore the potential role of NQO1 gene expression in warfarin response in a group of Iranian patients. We also evaluated the NQO1 promoter methylation and its association with mRNA expression. A total of 87 patients on warfarin therapy including 34 cases with drug-induced bleeding events and 53 matched controls without bleedings were included in the study. The expression of NQO1 was examined by real-time q-PCR and the methylation status of its promoter region was analyzed using methyQESD technique. There was a significant association between the reduced NQO1 gene expression and susceptibility to bleeding before (OR = 1.92, 95% CI = 1.23-3.00, p = 0.004) and following adjustment for hypertriglyceridemia (OR = 2.22, 95% CI = 1.33-3.69, p = 0.002). Furthermore, a medium negative correlation was observed between NQO1 expression and its promoter methylation (r = - 0.382, p = 0.001). The lower expression of NQO1 which partly arises from increased methylation of promoter region, may predispose warfarin treated patients to bleeding events.

Coming full circle: The potential utility of real-world evidence to discern predictions from a physiologically based pharmacokinetic model.

Today real word data (RWD) are playing a greater role in informing health care decisions. A physiologically based pharmacokinetic model (PBPK) and observed exposure-risk relationship predicted an increased bleeding risk induced by rivaroxaban (RXB) in patients with mild to moderate chronic kidney disease (CKD) taking concomitant medications that are combined Pgp-CYP3A inhibitors. In this commentary, we explore the potential use of RWD to assess the clinical consequence of this complex drug-drug interaction predicted from PBPK. This is a retrospective, case control, pilot study using a RWD dataset of 896,728 patients with mild to moderate chronic kidney disease and rivaroxaban use that was refined based upon combined Pgp-CYP3A inhibitor exposure and report of drug-induced bleeding (DIB). The odds ratio of patients with mild to moderate chronic kidney disease taking rivaroxaban with or without concurrent Pgp-CYP3A inhibitor use having a DIB was calculated. The odds ratio for DIB was 2.04 (CI95 1.82, 2.3; p<0.001) suggesting an approximate doubling of bleeding risk which is consistent with the rivaroxaban exposure changes predicted by the published PBPK model and observed exposure-risk relationship. This exploratory analysis demonstrated the potential utility of RWD to assess model-based predictions as part of a drugs life cycle management.

Evaluation of risk stratification and adherence to venous thromboembolism prophylaxis among hospitalized obstetric women: Retrospective case file review at East Jeddah Hospital during 2018-2019.

BACKGROUND:Venous thromboembolism (VTE) is associated with substantial mortality as well as morbidity and is largely preventable among hospitalized obstetric women. However, thromboprophylaxis is underutilized in most hospitalized patients.OBJECTIVES:To evaluate VTE risk and adherence to local thromboprophylaxis protocol among hospitalized pre- and postnatal women.METHODS:This retrospective study was conducted at East Jeddah Hospital, Jeddah, Saudi Arabia, in 2020. The electronic record database of the hospitalized pregnant Saudi women during the years 2018 and 2019 was reviewed. Based on the local hospital protocol, the risk stratification was reassessed by researchers, and the hospital adherence to the prophylaxis was reviewed separately for antenatal and postnatal women.RESULTS:One thousand and ninety-five electronic records (539 antenatal and 556 postnatal) were reviewed. The postnatal group showed a significantly higher risk compared with an antenatal group (62.2% vs. 11.7%) (P = 0.000). There was a highly significant difference between risk categories assessment by the physicians and the researchers in both groups (P = 0.000). Thromboprophylaxis was overutilized in the low risk (5% heparin and 41.4% heparin and mechanical devices for antenatal and 17.08% heparin and 6.1% heparin and a mechanical device for the postnatal group) and underutilized in intermediate groups (50% no prophylaxis in antenatal and 51.5% mechanical devices in the postnatal group). There was less adherence to documentation in postnatal as compared to antenatal group (83.6% vs. 95%, P = 0.000) for risk documentation and 85.3% versus 91.5% for physician signature (P = 0.001). Thromboprophylaxis was ordered for 21.3% of antenatal (12.2 heparin, 3.5% mechanical, and 5.6% both) and 23.7% of postnatal patients (16.5 heparin, 2% mechanical, and 5.2% both). There were no reported VTE events or bleeding complications.CONCLUSION:There was a considerable VTE risk among hospitalized obstetric patients which peaked during the postnatal period. Physicians showed good compliance to local VTE protocol with no reported VTE events or drug-induced bleeding. However, the implementation of prophylaxis is associated with both under and overutilization. There is a need for increasing the physicians’ awareness of optimizing VTE risk assessment and documentation for hospitalized obstetric patients.

A cell-based high-throughput screen identifies drugs that cause bleeding disorders by off-targeting the vitamin K cycle

AbstractDrug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended bleeding of obvious cause are relatively easy to control. However, the mechanisms of most drug-induced bleeding disorders are poorly understood, which makes intervention more difficult. As most bleeding disorders are associated with the dysfunction of coagulation factors, we adapted our recently established cell-based assay to identify drugs that affect the biosynthesis of active vitamin K–dependent (VKD) coagulation factors with possible adverse off-target results. The National Institutes of Health (NIH) Clinical Collection (NCC) library containing 727 drugs was screened, and 9 drugs were identified, including the most commonly prescribed anticoagulant warfarin. Bleeding complications associated with most of these drugs have been clinically reported, but the pathogenic mechanisms remain unclear. Further characterization of the 9 top-hit drugs on the inhibition of VKD carboxylation suggests that warfarin, lansoprazole, and nitazoxanide mainly target vitamin K epoxide reductase (VKOR), whereas idebenone, clofazimine, and AM404 mainly target vitamin K reductase (VKR) in vitamin K redox cycling. The other 3 drugs mainly affect vitamin K availability within the cells. The molecular mechanisms underlying the inactivation of VKOR and VKR by these drugs are clarified. Results from both cell-based and animal model studies suggest that the anticoagulation effect of drugs that target VKOR, but not VKR, can be rescued by the administration of vitamin K. These findings provide insights into the prevention and management of drug-induced bleeding disorders. The established cell-based, high-throughput screening approach provides a powerful tool for identifying new vitamin K antagonists that function as anticoagulants.

Progress in the development of antiplatelet agents: Focus on the targeted molecular pathway from bench to clinic.

Antiplatelet drugs serve as a first-line antithrombotic therapy for the management of acute ischemic events and the prevention of secondary complications in vascular diseases. Numerous antiplatelet therapies have been developed; however, currently available agents are still associated with inadequate efficacy, risk of bleeding, and variability in individual response. Understanding the mechanisms of platelet involvement in thrombosis and the clinical development process of antiplatelet agents is critical for the discovery of novel agents. The functions of platelets in thrombosis are regulated by two major mechanisms: the interaction between surface receptors and their ligands, and the downstream intracellular signaling pathways. Recently, most of the progress made in antiplatelet drug development has been achieved with P2Y receptor antagonists. Additionally, the usage of GP IIb/IIIa receptor antagonists has decreased, because it is associated with a higher risk of bleeding and thrombocytopenia. Agents targeting other platelet surface receptors such as PARs, TP receptor, EP3 receptor, GPIb-IX-V receptor, P-selectin, as well as intracellular signaling factors, such as PI3Kβ, have been evaluated in an attempt to develop the next generation of antiplatelet drugs, reduce or eliminate interpatient variability of drug efficacy and significantly lower the risk of drug-induced bleeding. The aim of this review is to describe the pathways of platelet activation in thrombosis, and summarize the development process of antiplatelet agents, as well as the preclinical and clinical evaluations performed on these agents.

Clot Retention: Our Experiences with a Simple New Technique of Evacuation with a Thoracic Catheter.

Introduction: Clot retention in the urinary bladder is a very common health problem in surgical and nonsurgical cases and clot retention treatment is quite costly.Objectives: The aim of this retrospective study was to describe an alternative technique for removing tenacious and chronic clots by using a thoracic catheter technique.Materials and methods: Between January 2011 and June 2018, a total of 27 patients of clot retention were treated under local anesthesia with the thoracic catheter technique.Results: Twenty-seven patients with a mean age of 58 years (range 45-70) were included. The etiologies of bladder clots included surgical causes and nonsurgical causes. Of the surgical causes, the most common cause was post-transurethral resection of the prostate (TURP). The nonsurgical causes were upper tract bleeding, drug-induced bleeding, post-traumatic bleeding, and haematochyluria. It was found that the thoracic catheter technique was simple and easily adoptable, with no training required.Conclusions: Clot retention in the urinary bladder is a very common problem in surgical and nonsurgical cases. Our technique is a simple, safe, fast, and effective option of clot removal from the urinary bladder and it doesn’t require any added cost.

Usefulness of multiple electrode aggregometry as a screening tool for bleeding disorders in a pediatric hospital

Platelet function testing is a cornerstone in the diagnostic investigation of patients with a bleeding history. Multiple electrode aggregometry (MEA) has been shown to detect von Willebrand disease (VWD), platelet function disorders, and drug-induced bleeding disorders. However, there are few studies supporting its successful use in children. We have implemented and used MEA over 3 years in our hemostasis laboratory in order to study its usefulness to supplement and expedite diagnosis. This is a retrospective, single-center, cohort study of 109 hospitalized children who underwent a laboratory investigation of hemostasis and either had a reported bleeding history or an abnormal bleeding episode. Plasmatic coagulation testing, blood counts, plasmatic von Willebrand testing, platelet function analyzer (PFA-100), and impedance aggregometry (MEA) were performed in all children. Light transmission aggregometry testing was performed as needed. In 41 cases (37.6%), a working diagnosis was made; a primary hemostatic disorder was detected in 35 children (VWD (n = 16), platelet disorder (n = 15), and valproic acid therapy-induced bleeding disorder (n = 3), acetylsalicylic acid-related bleeding (n = 1). In patients diagnosed with VWD, MEA ristocetin-induced platelet aggregation test (RISTO) high test revealed abnormally low aggregation in six patients (43.8%); whereas in patients diagnosed with a platelet function disorder, abnormally low values were found by MEA in only three children (20%). Three of the four children with laboratory evidence of drug-induced platelet dysfunction had abnormalities on MEA. There were no cases in which an abnormal MEA result was used to make a previously undetermined diagnosis. Retrospectively, MEA has demonstrated limited additional diagnostic value beyond standard laboratory testing for detecting defects of primary hemostasis in children.

Personalizing Health Care—Is This the Right Time for Warfarin?

Personalizing Health Care—Is This the Right Time for Warfarin?

Drug-induced bleeding after nonsurgical interventions

Drug-induced bleeding after nonsurgical interventions

Why we need a national registry in interventional cardiology

Percutaneous coronary intervention (PCI) is increasingly used in the management of acute coronary syndromes and refractory angina, and technical advances such as drug-eluting stents (DES) and potent antithrombotic therapies (such as clopidogrel and glycoprotein IIb/IIIa inhibitors) have been heralded as improving long-term outcomes. Offsetting these advances has been: considerable concern about the safety of DES in regard to late stent thrombosis and antithrombotic drug-induced bleeding; the rising use of PCI and DES in clinical situations where evidence of efficacy is lacking; preferential use of PCI in low-risk populations; and limited cost-effectiveness data comparing PCI with other treatments. There are few contemporary data in Australia on the efficacy, safety and costs of PCI--as used in everyday clinical practice--that matches clinical outcomes with baseline patient characteristics, indications for intervention, coronary anatomy, procedural technique, co-interventions and site of care. A national registry that prospectively collects standardised data on processes and outcomes of PCI is warranted. This would ensure safe and appropriate evidence-based use of limited resources in an era of expanding use of PCI in clinical circumstances not tested in randomised trials.

Developing Indicators of Inpatient Adverse Drug Events Through Nonlinear Analysis Using Administrative Data

Because of uniform availability, hospital administrative data are appealing for surveillance of adverse drug events (ADEs). Expert-generated surveillance rules that rely on the presence of International Classification of Diseases, 9th Revision Clinical Modification (ICD-9-CM) codes have limited accuracy. Rules based on nonlinear associations among all types of available administrative data may be more accurate. By applying hierarchically optimal classification tree analysis (HOCTA) to administrative data, derive and validate surveillance rules for bleeding/anticoagulation problems and delirium/psychosis. Retrospective cohort design. A random sample of 3987 admissions drawn from all 41 Utah acute-care hospitals in 2001 and 2003. Professional nurse reviewers identified ADEs using implicit chart review. Pharmacists assigned Medical Dictionary for Regulatory Activities codes to ADE descriptions for identification of clinical groups of events. Hospitals provided patient demographic, admission, and ICD9-CM data. Incidence proportions were 0.8% for drug-induced bleeding/anticoagulation problems and 1.0% for drug-induced delirium/psychosis. The model for bleeding had very good discrimination and sensitivity at 0.87 and 86% and fair positive predictive value (PPV) at 12%. The model for delirium had excellent sensitivity at 94%, good discrimination at 0.83, but low PPV at 3%. Poisoning and adverse event codes designed for the targeted ADEs had low sensitivities and, when forced in, degraded model accuracy. Hierarchically optimal classification tree analysis is a promising method for rapidly developing clinically meaningful surveillance rules for administrative data. The resultant model for drug-induced bleeding and anticoagulation problems may be useful for retrospective ADE screening and rate estimation.

Antidote-mediated control of an anticoagulant aptamer in vivo

Patient safety and treatment outcome could be improved if physicians could rapidly control the activity of therapeutic agents in their patients. Antidote control is the safest way to regulate drug activity, because unlike rapidly clearing drugs, control of the drug activity is independent of underlying patient physiology and co-morbidities. Until recently, however, there was no general method to discover antidote-controlled drugs. Here we demonstrate that the activity and side effects of a specific class of drugs, called aptamers, can be controlled by matched antidotes in vivo. The drug, an anticoagulant aptamer, systemically induces anticoagulation in pigs and inhibits thrombosis in murine models. The antidote rapidly reverses anticoagulation engendered by the drug, and prevents drug-induced bleeding in surgically challenged animals. These results demonstrate that rationally designed drug-antidote pairs can be generated to provide control over drug activities in animals.

DDAVP is not a panacea for children with bleeding disorders.

DDAVP is not a panacea for children with bleeding disorders.

Do NSAIDs prevent colorectal cancer?

There is increasing evidence to suggest that acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer. This observation is supported by animal studies that show fewer tumours per animal and fewer animals with tumours after administration of several different NSAIDs. Studies in humans consistently support this hypothesis. Intervention data from familial adenomatosis coli establish that the process of human colonic adenoma polyp formation is affected. Supportive evidence comes from 21 of 23 human studies - both case-control and cohort. The reduced risk has been found in men and women, for cancers of the colon and the rectum and for the use of both ASA and the other NSAIDs. Earlier detection of lesions as a result of drug-induced bleeding does not seem to account for these findings. The molecular mechanisms responsible for the chemopreventive action of this class of drugs is not completely established. Protection may affect several pathways, including cell cycle arrest and induction of apoptosis. Because of the consistency of epidemiological, clinical and experimental data, there is no need for further placebo trials. At the same time, there is a need to establish the dose, duration and frequency of use required for cancer-preventive activity.

Desmopressin (DDAVP) in bleeding disorders of childhood.

As in adults, desmopressin (DDAVP) can be used in children for prophylaxis of bleeding and to stop bleeding in many hereditary and acquired bleeding disorders. DDAVP is the treatment of choice in children with mild hemophilia and type 1 von Willebrand's disease (vWD). It is effective in some variants of vWD and in many patients with platelet function defects. It reduces the bleeding diathesis of children with uremia and drug-induced bleeding complications. In any case, a test dose of DDAVP has to be given to the patient to predict the hemostatic effect before relying on this drug for treatment. The response can be measured by shortening of the bleeding time (BT) and of partial thromboplastin time (PTT), indicating a rise of Factor (F) VIII or von Willebrand factor (vWF). Side effects such as facial flushing, transient headache, increased pulse rate, and drop in systolic blood pressure are mild and transient. They can be minimized when the dose is not exceeding 0.3 microg/kg body weight, and the infusion lasts at least 20 to 30 minutes. The strong antidiuretic action of DDAVP has some potential problems that are negligible in adults and older children when water intake is restricted. In infants and small children under the age of 18 months, however, DDAVP should be used with caution and with close surveillance in order to prevent water intoxication and electrolyte imbalance. The danger is increased when the patients receive parenteral fluid substitution. The advantages of DDAVP include the reduction in the use of plasma factor concentrates, thereby minimizing the danger of immunological or infectious complications, as well as the considerable reduction of costs realized by treatment with this form of medication. Fortunately, it can be applied successfully in the most frequent hereditary bleeding disorder, namely vWD type 1.

Review of clinical experience of desmopressin in patients with congenital and acquired bleeding disorders.

This paper discusses clinical experience of the use of desmopressin in patients with either congenital or acquired bleeding disorders. The bleeding disorders reviewed herein are haemophilia A, von Willebrand's disease and platelet function disorders (congenital bleeding disorders); uraemia, liver cirrhosis and drug-induced bleeding (acquired bleeding disorders).

Current Status of Gastric Proton Pump Inhibitors in the Treatment of Acid-Peptic Disease

Proton pump inhibitors represent an important advance in the treatment of acid-peptic disease. Omeprazole, the prototype of the drug class, produces a profound and sustained degree of gastric acid suppression. Recent studies confirm earlier reports that omeprazole 20 mg/d is generally more effective than standard histamine2 receptor antagonist (H2RA) dosage regimens in treating duodenal ulcer (DU), gastric ulcer (GU), and erosive esophagitis. Omeprazole tends to accelerate DU and GU healing, especially during the first 2 weeks of treatment, and also accelerates mucosal healing in patients with all grades of esophagitis. Omeprazole is the drug of choice for treating patients with large or refractory ulcers, severe or refractory erosive esophagitis, Barrett's esophagus, and Zollinger-Ellison syndrome. Maintenance therapy with omeprazole seems to reduce ulcer recurrence and esophagitis, but optimal treatment regimens must be established. Dual therapy with omeprazole and amoxicillin shows encouraging results in eradicating Helicobacter pylori, reducing duodenal ulcer recurrence rates, and altering the natural history of peptic ulcer disease. Further studies are required to determine the efficacy of omeprazole in preventing nonsteroidal anti-inflammatory drug-induced ulcers and stress-related mucosal bleeding, and in treating upper gastrointestinal bleeding. Omeprazole is well-tolerated in the majority of patients receiving either short-term or long-term treatment. The type and frequency of adverse effects are similar to those reported with the H2RAs. There is no evidence to support genotoxicity or hypergastrinemia-induced enterochromaffin-like cell carcinoid of the stomach in patients receiving omeprazole treatment for more than 5 years. Omeprazole interacts selectively with hepatic P-450 and may potentially interact with phenytoin, warfarin, or diazepam. Pharmacoeconomic studies suggest that treatment with omeprazole provides a significant cost-savings over the H2RAs in patients with moderate to severe erosive esophagitis and possibly in patients with DU. Lansoprazole, a newly developed proton pump inhibitor, seems to offer no clear advantage over omeprazole.

Antimicrobial activity, pharmacokinetics, therapeutic indications and adverse reactions of ceftazidime.

Ceftazidime is an aminothiazolyl cephalosporin with potent activity against gram-negative bacteria including multiresistant strains of Pseudomonas aeruginosa. It has limited activity against gram-negative anaerobes, is less active against some gram-positive cocci than other newer beta-lactam compounds and is inactive against Streptococcus faecalis and methicillin-resistant Staphylococcus aureus. Ceftazidime is stable against common plasmid and chromosomally mediated beta-lactamase produced by Enterobacteriaceae and Pseudomonas sp. Its pharmacokinetic properties are similar to those of moxalactam and ceftizoxime, and it has a half-life of 1.9 hours. Excretion is by glomerular filtration. It is not metabolized. Ceftazidime penetrates into most body tissue and fluids, including cerebrospinal fluid, and produces therapeutic levels against most of the pathogenic gram-negative bacteria, including P. aeruginosa. Ceftazidime accumulates during renal failure, but is removed by hemodialysis and peritoneal dialysis. As a single agent it has been shown effectively to treat meningitis; urinary tract infections; gram-negative pneumonia; bone, joint and skin infections; and obstetric and gynecologic infections due to susceptible organisms. When combined with an agent that is effective against gram-positive organisms, it is also beneficial in the treatment of infections in seriously ill neonates. Different investigators have used ceftazidime alone or in combination with other agents in the successful treatment of infections in immunosuppressed patients. Adverse reactions have been few and are mostly reversible laboratory findings. The effects of ceftazidime on prothrombin synthesis and platelet function have been minimal, and no drug-induced clinical bleeding has been reported.

Drug-induced bleeding

Drug-induced bleeding disorders can be categorized according to the manner in which they embarrass hemostasis. Thus, there are drugs which: (1) are themselves anticoagulants, (2) potentiate the action of simultaneously administered anticoagulants, (3) when discontinued induce bleeding diatheses among patients who continue to receive anticoagulants, (4) inhibit the functional activity of platelets, (5) decrease the number of circulating platelets, and (6) cause increased vascular fragility. The drugs in each category are tabulated and briefly discussed.

Drug-induced bleeding.

Drug-induced bleeding disorders can be categorized according to the manner in which they embarrass hemostasis. Thus, there are drugs which: (1) are themselves anticoagulants, (2) potentiate the action of simultaneously administered anticoagulants, (3) when discontinued induce bleeding diatheses among patients who continue to receive anticoagulants, (4) inhibit the functional activity of platelets, (5) decrease the number of circulating platelets, and (6) cause increased vascular fragility. The drugs in each category are tabulated and briefly discussed.