Coumarin Anticoagulants Research Articles

Four-factor prothrombin complex concentrate (4F-PCC) is superior to three-factor prothrombin concentrate (3F-PCC) for reversal of coumarin anticoagulation

Four-factor prothrombin complex concentrate (4F-PCC) is superior to three-factor prothrombin concentrate (3F-PCC) for reversal of coumarin anticoagulation

Cardiovascular effects of coumarins besides their antioxidant activity.

Coumarins are a large group of substances, primarily of plant origin. Like their more intensively examined congeners flavonoids, many of them are antioxidants. Although such properties may be advantageous in cardiovascular diseases, it has been shown that coumarins exhibit direct effects on the cardiovascular system which are not based on antioxidant activity. The most common example is the well-known drug warfarin, a synthetic compound derived from natural dicoumarol. Moreover, other coumarins have been shown to possess antiplatelet and vasodilatory potential. Interestingly, the former effect may be mediated by the inhibition of various pathways leading to platelet aggregation, their differing effects on those pathways being due to structural differences between the various coumarins. Conversely, their vasodilatory potential is linked in the majority of cases to the inhibition of increases in intracellular calcium concentration in vascular smooth muscle cells, and in several coumarins also to NO-mediated vasodilatation. Available data on both activities are summarized in this review. At the end of this review, relevant data are provided from a few studies testing the in vivo effects of coumarins on major cardiovascular diseases; the clinical use of warfarin and other coumarin anticoagulants, as well as the limited data on the clinical use of coumarins in chronic venous insufficiency and the possible toxicological effects of coumarins.

What could be hidden behind acute respiratory failure causing emergency intubation?

This paper describes an uncommon case of acute respiratory failure in a patient who presented with low a haemoglobin rate and metabolic acidosis but with normal vital signs. He had a history of persistent atrial fibrillation, long-term therapy with coumarin anticoagulants and amiodarone, diabetes mellitus, and hypothyroidism. The patient was intubated due to severe acidosis, accumulation of lactic acid, and severe tachypnoea. During the investigation, and based on CT findings, it was thought that the patient had an upper gastrointestinal tumour. However, the results of the endoscopy were surprising. This paper outlines our comments, concerns and thoughts for an uncommon case which can present a potentially life-threatening situation for a patient. It also indicates the appropriate clinical and imaging investigation. Moreover, recommendations are given to enable a physician to offer the best possible services to a critically ill patient.

Skin response to epicutaneous application of anticoagulant rodenticide warfarin is characterized by differential time- and dose-dependent changes in cell activity

Context: Skin is the target of both acute and chronic exposure to warfarin, coumarin anticoagulant. Single exposure of rat skin to this agent induces early (24 h following epicutaneous administration) local response which might be part of inflammatory/reparatory homeostatic program or introduction to pathological events in exposed skin.Objective: To examine time-dependent changes in skin of rats exposed to epicutaneously applied warfarin.Materials and methods: The effect of low (10 μg) and high (100 μg) doses of warfarin on histologically evident changes of epidermis (epidermal thickness) and dermis (numbers of mesenchymal cells and dermal capillaries), skin cell proliferative activity (Ki67+ and PCNA+ cells) and apoptotic (TUNEL+) and necrotic (ultra structural appearance) cells was examined one, three and seven days after the application.Results: Both warfarin doses affected the majority of skin cell activity, but with differential time-course of skin epidermal and dermal cells state/activity. The occurrence of necrotic/apoptotic epidermal and dermal cells was noted the first day after the application and the activities which point to tissue reparation/remodeling were observed seven days after skin exposure to this agent.Discussion: The observed pattern of changes (early evidence of cell/tissue injury which was later followed by signs of cell activity characteristic for tissue reparation/remodeling) implied warfarin-induced toxicity in skin cells as stimulus for subsequent activities relevant for tissue homeostasis.Conclusion: The data presented provide new and additional information concerning skin responses to warfarin that gains access to this tissue.

Acenocoumarol in Thromoembolic Disorders

Thromboembolic disorders are common worldwide, frequently a leading cause of death. Judicial use of Anticoagulant plays an important role in the prevention and treatment of Venous and arterial thromboembolic diseases like deep vein thrombosis, pulmonary embolism, Stroke prevention in valvular and Non-valvular heart disease, and Acute coronary syndrome. Vitamin K antagonists, e.g., acenocoumerol and warfarin are commonly used as oral anticoagulants worldwide. The clinical use of oral anticoagulants has come a long way since their discovery over 50 years ago and Acenocoumarol is a coumarin derivative with pharmacological features closer to an ideal oral anticoagulant. Acenocoumarol is a drug with over 50 years of clinical experience and has been the subject of numerous clinical studies Acenocoumarol is prescribed once every day orally, as the anticoagulant is applied in various thromboembolic disorders. Amongst the coumarone, acenocoumarol is unique, with its rapid onset and offset of action and well documented efficacy and safety. Acenocoumarol has been shown to be superior to warfarin in maintaining INR stability within therapeutic range and efficacy. Despite the development of several new oral anticoagulants, coumarin anticoagulants remained unchallenged. Their efficacy has been established beyond doubt and they have long years of clinical experience. Forever 50 years since its discovery, acenocoumarol still continues to be widely used in India and various parts of the world.

Economic evaluation of a pharmacogenetic dosing algorithm for coumarin anticoagulants in The Netherlands.

To investigate the cost-effectiveness of a pharmacogenetic dosing algorithm versus a clinical dosing algorithm for coumarin anticoagulants in The Netherlands. A decision-analytic Markov model was used to analyze the cost-effectiveness of pharmacogenetic dosing of phenprocoumon and acenocoumarol versus clinical dosing. Pharmacogenetic dosing increased costs by €33 and quality-adjusted life-years (QALYs) by 0.001. The incremental cost-effectiveness ratios were €28,349 and €24,427 per QALY gained for phenprocoumon and acenocoumarol, respectively. At a willingness-to-pay threshold of €20,000 per QALY, the pharmacogenetic dosing algorithm was not likely to be cost effective compared with the clinical dosing algorithm. Pharmacogenetic dosing improves health only slightly when compared with clinical dosing. However, availability of low-cost genotyping would make it a cost-effective option.

Four-factor prothrombin complex concentrate (Beriplex® P/N) is superior to three-factor prothrombin complex concentrate for reversal of coumarin anticoagulation

The study was conducted as a head-to-head comparison of a four-factor prothrombin complex concentrate (4F-PCC) and two different three-factor PCCs (3F-PCC) for effective reversal of vitamin K antagonist (VKA)-induced anticoagulation using an established rat model of acute bleeding [1]. The 4F-PCC (containing the human coagulation factors II, VII, IX and X) is indicated for the urgent reversal of acquired coagulation factor deficiency induced by VKA therapy in adult patients with acute major bleeding. In contrast, the 3F-PCCs (containing factors II, IX, × and only minimal VII) are indicated for the prevention and control of hemorrhagic episodes in hemophilia B patients. Nevertheless, the use of 3F-PCC for correcting hemostasis following warfarin overdose has been discussed but the lack of factor VII in these 3F-PCC products has raised questions about efficacy.

Four-Factor Prothrombin Complex Concentrate (4F-PCC) Is Superior to Three-Factor Prothombin Comlex Concentrates (3F-PCC) for Reversal of Coumarin Anticoagulation

Due to its wide range of therapeutic indications approximately 2.5 million adults and children are currently receiving vitamin K antagonist (VKA) therapy in the US (Pengo et al., 2006). Bleeding is the major risk of anticoagulation, with an incidence of major hemorrhage in VKA-treated patients of 1.7-3.4% per year (Schulman et al., 2008). The 4-factor prothrombin complex concentrate (4F-PCC), which contains the human coagulation factors II, VII, IX and X together with the endogenous inhibitor proteins S and C, is indicated for the urgent reversal of acquired coagulation factor deficiency induced by VKA (e.g. warfarin or coumarin) therapy in adult patients with acute major bleeding. In contrast, the 3-factor prothrombin complex concentrates (3F-PCC), which contain factors II, IX, X and only minimal amounts of factor VII, are only indicated for the prevention and control of hemorrhagic episodes in hemophilia B patients. Nevertheless, the use of 3F-PCC for correcting hemostasis following warfarin overdose has been discussed (Imberti et al. 2011, Holland et al. 2009). However, the lack of factor VII in these 3F-PCC products has raised questions about efficacy in comparison to 4F-PCC (Sarode et al. 2012). To date, no studies have directly compared 3F-PCC vs. 4F-PCC regarding their efficacy for reversal of VKA anticoagulation.Therefore, this study was conducted as a head-to-head comparison of 4F-PCC and 3F-PCC for effective reversal of VKA (coumarin) induced anticoagulation using an established rat model of acute bleeding (Dickneite et al. 2007).Rats received an oral dose of 2.5 mg/kg phenprocoumon. At 15.75 hours post dosing, animals were treated with a single intravenous dose of saline, 4F-PCC (Beriplex® P/N, Kcentra®, CSL Behring) or 3F-PCC (Bebulin® VH and Profilnine® SD). Study endpoints included bleeding following tail clip, activated partial thromboplastin time (aPTT), and prothrombin time (PT). In addition, the plasma levels of vitamin K dependent coagulation factors were determined.Acute coumarin anticoagulation of rats induced a rise in median bleeding time by ≥2 fold from an average of 823 to 1800 seconds (max. observation period) compared to untreated animals. In parallel, PT and aPTT were prolonged from 8.9 to 29.9 seconds and 14.5 to 25.5 seconds, respectively. Treatment with 4F-PCC was able to fully and statistically significantly reverse bleeding, achieving average bleeding times of 676 seconds. In parallel, the elevation in PT was reversed to 15.1 seconds. In contrast, the 3F-PCCs were not or only partially able to reduce coumarin induced bleeding with average bleeding times of 1398 and 1708 seconds post treatment. This also correlated with inferior reductions in PT which achieved minimum levels of 23.8 and 29.5 seconds. There was no reduction in aPTT seen for any treatment option.In conclusion, this first direct comparison of 4F-PCC and 3F-PCCs for the reversal of VKA anticoagulation in a rat model of acute bleeding suggests that replenishment of all vitamin K-dependent coagulation factors including factor VII as achieved using a 4F-PCC may result in superior efficacy compared to the use of 3F-PCCs.ReferencesDickneite G: Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation.Thromb Res 119:643–651, 2007Holland L, Warkentin TE, Refaai M, et al. Suboptimal effect of three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic INR due to warfarin overdose. Transfusion 2009;49:1171–7.Imberti D, Barillari G, Biasioli C, et al. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 2011;9:148–55.Pengo V, Pegoraro C, Cucchini U, IIiceto S. The management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis 2006;21:73-7Sarode R, Matevosyan K, Bhagat R, Rutherford C, Madden C, Beshay JE. Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage.J Neurosurg 116:491–497, 2012Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: american college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;13:257S-98S DisclosuresHerzog:CSL Behring GmbH: Employment. Off Label Use: Non-clinical data on the use of 3F-PCC for reversal of VKA . Kaspereit:CSL Behring GmbH: Employment. Krege:CSL Behring GmbH: Employment. Niebl:CSL Behring GmbH: Employment. Schulte:CSL Behring GmbH: Employment. Dickneite:CSL Behring GmbH: Employment.

Use of coumarin anticoagulants and cerebral microbleeds in the general population.

It remains undetermined whether the use of coumarin anticoagulants associates with cerebral microbleeds in the general population. We investigated whether (1) coumarin use relates to higher prevalence and incidence of microbleeds, (2) microbleeds are more frequent in people with higher maximum international normalized ratios (INRs), and (3) among coumarin users, variability in INR associates with microbleed presence. From the population-based Rotterdam Study, 4945 participants aged ≥45 years were included in the cross-sectional analysis, and 3069 participants had follow-up brain MRI. Information on coumarin use was obtained from automated pharmacy records. Coumarin users were monitored, and INR values were measured in consecutive visits. Presence and location of microbleeds were rated on brain MRI. We investigated the association of coumarin use with microbleeds using multivariable logistic regression. Overall, 8.6% had used coumarin anticoagulants before the first MRI and 5.9% before follow-up MRI. The prevalence of microbleeds was 19.4%, and the incidence was 6.9% during a mean follow-up of 3.9 years (SD, 0.5). Compared with never users, coumarin users had a higher prevalence of deep or infratentorial microbleeds and a higher incidence of any microbleeds, although statistical significance was not reached in the latter. A higher maximum INR was associated with deep or infratentorial microbleeds. Among coumarin users, a greater variability in INR was associated with a higher prevalence of microbleeds. Coumarin use is associated with microbleeds. Associations were strongest for people with greater variability in INR.

Potential statin-drug interactions: prevalence and clinical significance.

BackgroundStatins are cholesterol-lowering drugs widely used for cardiovascular prevention. Although safe when used alone, in combination with other drugs the likelihood of adverse drug reactions increases significantly. The exposure of the Bulgarian population to coprescriptions leading to potential statin-drug interactions is currently unknown.ObjectiveThe aim of this study was to investigate the incidence of coprescriptions involving statins and to compare the exposure of outpatients and inpatients to potential statin-drug interactions.SettingA cardiology clinic of the teaching University hospital in Varna, Bulgaria.MethodThis observational retrospective study examined the medical records of hospitalized patients prescribed a statin in combination with potentially interacting drugs. Patients who entered the hospital with a statin coprescription (considered outpatients) were compared with those coprescribed a statin at discharge from hospital (considered inpatients). Potentially interacting drugs included inhibitors and inducers of cytochrome P450 (CYP) enzymes and drugs of narrow safety margin (coumarin anticoagulants, digitalis).Main outcome measureThe proportion of patients exposed to statin coprescriptions with potentially interacting drugs at hospital admission and discharge. Secondary outcome measures: laboratory evidence supporting possible statin-drug interactions.ResultsOut of 1641 hospitalized patients examined, 572 were prescribed a statin, either at hospital admission or discharge. Simvastatin was most commonly prescribed and simvastatin-drug coprescription predominated, especially at discharge. The exposure to all potential statin-drug interactions was similar at hospital admission (26.1%) and discharge (24.4%), as was the exposure to statin combinations with CYP inhibitors, 6.4% and 4%, correspondingly. Overall, more coprescriptions were generated, than were eliminated by hospital physicians. Amiodarone was the CYP inhibitor most frequently coprescribed. Of all interacting drugs acenocoumarol was the most commonly found, the proportions of statin-acenocoumarol coprescriptions being roughly the same at hospital entry (11.5%) and discharge (12.4%). In 7 patients out of 69 exposed to the combination, INR was found to be higher than 3, indicating a risk of over-anticoagulation.ConclusionsPotential statin-drug interactions are common. Although they do not differ between outpatient and inpatient settings, new hazardous coprescriptions are more frequently generated in hospital. Caution is required when acenocoumarol is coprescribed with statins, especially simvastatin.

PT005 Presence of thrombus in left atrium in patients with atrium fibrillation anticoagulated with coumarin anticoagulants versus dabigatran

O ST E R A B ST R A C T S theoretical and experimental studies, our group has shown that high bipolar electrogram Shannon entropy (ShEn) distinguishes the pivot and periphery of rotors. We hypothesised that ablation directed towards regions of high ShEn could slow or terminate AF. Objectives: The aim was to determine if directed ablation of regions of high ShEn would slow or terminate human persistent AF. Methods: The study enrolled 9 patients undergoing persistent AF ablation. (Left atrial diameter 45 6mm, LV ejection fraction 52 5%). Patients in spontaneous or induced AF were mapped with a 20-pole PentaRay catheter and NavX system. 8-second recordings of each mapped point were acquired, with endocardial contact verified by fluosocopy at each site. After mapping, mapped point electrophysiologic data and location data were exported to a PC where Shannon entropy (ShEn) was calculated for each mapped point. Points were ranked by entropy value, and colour-coded ShEn maps constructed. The top 10% of ShEn points were annotated on to the NavX map, and used to guide selection of regions for ablation. Ablation of pre-identified ShEn regions was performed after pulmonary vein antral isolation without CFAE or linear ablation. The study endpoints were: (i) AF cycle length change; and (ii) AF termination. Results: Mapping was able to be performed in all cases, with 621 26 points/pt acquired. AF termination occurred in 6/9 cases, with 3/9 cases requiring cardioversion. 5/9 cases showed AF termination co-localised with pre-specified regions of ShEn. In 3 of these cases, termination occurred at pre-specified regions of ShEn encountered during pulmonary vein antral isolation. In 2 cases,termination occurred at ShEn sites outside the pulmonary vein antra. Mean AFCL change post PV isolation was 11.8 13ms (p1⁄40.07), and AFCL change post-ShEn ablation was 29.1 26ms (p1⁄40.02). 6/9 cases remained in sinus rhythm at median follow-up 274 148 days . Sites of ShEn region termination included the base of LA appendage, right anterior wall, roof, posterior wall, and left superior PV ridge. Conclusion: The study demonstrates the feasibility of ablation of high ShEn regions, associated with termination of AF and/or AF cycle length slowing in selected AF patients, and requires further investigation in AF ablation. Disclosure of Interest: None Declared

Patients benefit from genetics-guided coumarin anticoagulant therapy.

Observational studies have overwhelmingly shown that variants in the genes CYP2C9 and VKORC1 are significant determinants of individual dose of coumarin anticoagulants needed to maintain a therapeutic international normalized ratio (INR).(1) Until recently, however, few randomized clinical trials had been performed relating to the use of genetic data to predict dosing. Three sucsh clinical trials have now reported their findings.

The Pharmacogenetics of Cardiovascular Drugs / FARMAKOGENETIKA KARDIOVASKULARNIH LEKOVA

Summary This article will primarily summarize the current knowledge of the pharmacogenetics of commonly used drugs for the cardiovascular system: oral anticoagulants, antiplatelet therapy and statins. Coumarin anticoagulants are widely used to treat and prevent thromboembolisms. Variations in the CYP2C9 and VKORC1 genes influence the pharmacodynamic response to coumarins. Genetic variation makes an important contribution to the variation in the response to clopidogrel, the most commonly prescribed antiplatelet treatment. Genetic polymorphisms in the CYP2C19 gene as in the paraoxonase 1 gene are associated with clopidogrel effectiveness and have shown an association with excess of ischemic events such as myocardial infarction and stent thrombosis, but also with serious threat of bleeding. Statin pharmacogenetics has the potential to improve the safety and effectiveness of lipid-lowering therapy by statins. Genetic variations in apolipoprotein E, cholesterol ester transfer protein, kinesin-like protein 6, statin transporter OATP1B1 etc. could partly explain the interindividual variation in statins therapeutic response and adverse reactions. Finally, we comment on the pharmacogenetics of other cardiovascular drugs that have been extensively studied, but for which data are conflicting or that have not yet seen clinical implementation. Based on the available data, it could be expected that in the future genome-tailored drug prescription and use of defined algorithms will contribute to the successful drug action, lowering the frequency of adverse events, and will have greater clinical relevance.

A comparative study of the molecular structure, lipophilicity, solubility, acidity, absorption and polar surface area of coumarinic anticoagulants and direct thrombin inhibitors

The methods of computational chemistry have been used to elucidate the molecular properties of coumarinic anticoagulants (acenocoumarol, phenprocoumon, warfarin and tecarfarin) and direct thrombin inhibitors (melagatran, dabigatran and their prodrug forms).

Safety of thrombolysis with IV rt-PA in patients with atrial fibrillation related ischemic strokes and prior subtherapeutic use of coumarinic anticoagulants

Background and purpose. There are conflicting data in the literature regarding the safety of intravenous thrombolysis in patients with ischemic strokes receiving prior treatment with vitamin K antagonists. We aimed to assess the safety, short term outcome and mortality after rt-PA administration in patients with atrial fibrillation related strokes and prior subtherapeutic use of vitamin K antagonists. Methods. The study included 210 patients with atrial fibrillation who received treatment with intravenous rt-PA for acute ischemic stroke. We compared the frequency of bleeding complications, including intracerebral hemorrhage of any type and symptomatic intracerebral hemorrhage in patients with and without preadmission acenocoumarol use. We also investigated whether there were differences regarding short term functional outcome (assessed with the modified Rankin score at three months after thrombolysis) and mortality rates between them. Results. 48 patients (22.8%) were receiving acenocoumarol before admission and had international normal ratio (INR) ≤ 1.7. In this group, the median INR value was 1.4 (IQR 1.3-1.6). Preadmission coumarinic anticoagulants use was neither associated with secondary intracerebral hemorrhage of any type (p = 0.9), nor with symptomatic intracerebral hemorrhage (p = 0.9). Moreover, no differences regarding short term stroke outcome (p = 0.86), and mortality (p = 0.56) were observed between patients with or without prior acenocoumarol use. Using logistic regression analysis NIHSS score was found to be the only independent predictor for both short term stroke outcome (OR = 0.82; 95% CI 0.77-0.87; p < 0.0001) and mortality (OR = 1.18; 95%CI 1.09-1.27; p < 0.0001). Chronic heart failure was a second independent predictor for mortality (OR = 3.66; 95%CI 1.41-9.5; p = 0.007). Blood pressure values of more than 185/110 mmHg during the first 24 hours after stroke onset were independently associated with the short term stroke outcome (OR 0.37; 95% CI 0.15-1.88; p = 0.02). Conclusion. In the present study the rates of intracranial hemorrhage and mortality following intravenous thrombolysis for atrial fibrillation related ischemic strokes were not different between the patients who were prior receiving subtherapeutic treatment with acenocoumarol and those who were not receiving coumarinic oral anticoagulants at all. As a result, the use of recombinant tissue plasminogen activator in this clinical setting seems to be safe. Further studies with larger number of patients and a prospective design are needed to confirm these findings.

Implication of novel CYP2C9*57 (p.Asn204His) variant in coumarin hypersensitivity

IntroductionPolymorphisms in CYP2C9 can vary the rate of metabolic clearance of oral anticoagulants, risking toxicity in patients. The present study focused on exploring the genetic etiology of idiopathic hyper sensitivity to coumarin anticoagulants in a patient who presented with multiple bleeding episodes and supra-elevated International Normalized Ratios. Materials and MethodsBidirectional gene sequencing of CYP2C9 and VKORC1 was carried out. Using allele-specific polymerase chain reaction, the identified novel variant was genotyped in 309 patients on anticoagulation therapy. The pharmacoproteomic significance of the novel genetic variant was elucidated by structural demonstration of binding of coumarin molecules within the mutant CYP2C9 204His protein model and in silico bioinformatic evolutionary analyses. Three-dimensional structure model of the mutant protein was constructed on the basis of the published X-ray crystal structure of human CYP2C9 protein (Protein Data Bank, 1R9O). ResultsThe patient was identified to have a novel heterozygous missense mutation in exon 4 of CYP2C9 gene (g.9172A>C; p.Asn204His; CYP2C9*57). The variant was absent in the 309 genotyped patients. In silico bioinformatic analyses indicated the variant to have a deleterious effect on the protein. Analysis of 3D structure model of the mutant protein revealed that the substituted His204 led to restricted binding of the coumarin drug within the binding site of CYP2C9 enzyme, thereby inhibiting its metabolic clearance and thus explaining the enhanced pharmacologic effect and bleeding in the patient. ConclusionsThe study elucidates the structurally deleterious role of the novel CYP2C9*57 missense mutation in coumarin toxicity.

Optimal dosing of warfarin and other coumarin anticoagulants: the role of genetic polymorphisms

Coumarin anticoagulants, which include warfarin, acenocoumarol and phenprocoumon, are among the most widely prescribed drugs worldwide. There is now a large body of published data showing that genotype for certain common polymorphisms in the genes encoding the target vitamin K epoxide reductase (G-1639A/C1173T) and the main metabolizing enzyme CYP2C9 (CYP2C9*2 and *3 alleles) are important determinants of the individual coumarin anticoagulant dose requirement. Additional less common polymorphisms in these genes together with polymorphisms in other genes relevant to blood coagulation such as the cytochrome P450 CYP4F2, gamma-glutamyl carboxylase, calumenin and cytochrome P450 oxidoreductase may also be significant predictors of dose, especially in ethnic groups such as Africans where there have been fewer genetic studies compared with European populations. Using relevant genotypes to calculate starting dose may improve safety during the initiation period. Various algorithms for dose calculation, which also take patient age and other characteristics into consideration, have been developed for all three widely used coumarin anticoagulants and are now being tested in ongoing large randomised clinical trials. One recently completed study has provided encouraging results suggesting that calculation of warfarin dose on the basis of individual patient genotype leads to few adverse events and a higher proportion of time within the therapeutic coagulation rate window, but these findings still need confirmation.

Genotyping ofCYP2C9andVKORC1in the Arabic Population of Al-Ahsa, Saudi Arabia

Polymorphisms in the genes encoding CYP2C9 enzyme and VKORC1 reductase significantly influence the dose variability of coumarinic oral anticoagulants (COAs). Substantial inter- and intraethnic variability exists in the frequencies of CYP2C9 ∗2 and ∗3 and VKORC1 –1639A alleles. However, the prevalence of CYP2C9 and VKORC1 genetic variants is less characterized in Arab populations. A total of 131 healthy adult subjects from the Al-Ahsa region of Saudi Arabia were genotyped for the CYP2C9 ∗2 and ∗3 and VKORC1 –1639G>A polymorphisms by PCR-RFLP method. The frequencies of the CYP2C9 ∗2 and ∗3 and VKORC1 –1639A alleles were 13.3%, 2.3%, and 42.4%, respectively, with no subjects carrying 2 defective alleles. The frequencies of the CYP2C9 ∗3 and VKORC1 –1639A alleles were significantly lower than those reported in different Arabian populations. None of the subjects with the VKORC1 –1639AA genotype were carriers of CYP2C9 ∗1/∗3 genotypes that lead to sensitivity to COAs therapy. The low frequency of the CYP2C9 ∗3 allele combined with the absence of subjects carrying 2 defective CYP2C9 alleles suggests that, in this specific population, pharmacogenetic COAs dosing may mostly rely upon VKORC1 genotyping.

Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model

One limitation of the direct thrombin inhibitor dabigatran is the lack of specific antidotes that allow acute bleeding events to be managed or urgent interventional procedures performed. Prothrombin complex concentrates (PCCs) have served as a standard treatment for the reversal of coumarin anticoagulation. This study was designed to determine in an animal model whether a PCC (Beriplex P/N) can effectively reverse the effects of dabigatran. An additional objective was to evaluate markers of dabigatran-associated bleeding diathesis. Anesthetized rabbits were treated with 0.4 mg kg(-1) dabigatran followed by PCC doses of 20, 35 or 50 IU kg(-1) or placebo. After a standardized kidney incision, volume of blood loss and time to hemostasis were determined. From an initial mean of 29 mL, blood loss progressively declined by 5.44 mL with a 95% confidence interval (CI) of 2.21-8.67 mL per 10 IU kg(-1) increment in PCC dose (P = 0.002). At a PCC dose of 50 IU kg(-1) blood loss was fully normalized. Increasing PCC doses shortened the median time to hemostasis from 20.0 to 5.7 min (P < 0.001). The rate of hemostasis was nearly trebled with each 10 IU kg(-1) increment in PCC dose (rate ratio, 2.89; CI, 1.64-5.09). In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran. Further investigation is warranted.

Right Atrial Thrombus as a Complication of Supraventricular Tachycardia Ablation Resolved by Anticoagulation

We present the case of a 40‐year‐old man who was found on routine echocardiography to have a right atrioventricular thrombus, 24 hours after succesful supraventricular trachycardia ablation he had undergone. With the patient being asymptomatic, coumarin anticoagulants were started, leading to complete clot resolution two weeks later. In this case, we stress the importance of routine echocardiography to identify thrombotic complications after ablation and we describe the course of a large right atrioventricular thrombus which was successfully treated with Vit K antagonists.