The prothrombin time/international normalized ratio (PT/INR) Line: derivation of local INR with commercial thromboplastins and coagulometers--two independent studies

The WHO scheme for prothrombin time (PT) standardization has been limited in application, because of its difficulties in implementation, particularly the need for mandatory manual PT testing and for local provision of thromboplastin international reference preparations (IRP).

Intracranial Hemorrhage, Outcome, and Mortality After Intra-Arterial Therapy for Acute Ischemic Stroke in Patients Under Oral Anticoagulants

Use of intravenous tissue-type plasminogen activator (IV tPA) for acute ischemic stroke is restricted to patients with an international normalized ratio (INR) less than 1.7. However, a recent study showed increased risk of symptomatic intracranial hemorrhage after IV tPA use in patients with oral anticoagulants (OAC) even with an INR less than 1.7. The present study assessed the risk of symptomatic intracranial hemorrhage, clinical outcome, and mortality after intra-arterial therapy (IAT) in patients with and without previous use of OAC.

[Liver transplantation - when and for whom it should be performed]

During the past two decades, orthotopic liver transplantation (OLT) emerged to the treatment of choice for patients with end-stage liver disease. In Switzerland, about 100 liver transplantations are performed every year, while the shortage of cadaveric organs considerably outmatches the demand. Common indications for OLT include cirrhosis due to alcoholic liver disease or chronic viral hepatitis related to hepatitis B or C, and hepatocellular carcinoma. With the advent of the new allocation policy in Switzerland in 2007, patients listed for OLT are mainly stratified based on the Model of End-stage Liver Disease (MELD) score. Using a patient's laboratory values for serum bilirubin, serum creatinin, and the international normalized ratio for prothrombin time (INR), the MELD score accurately predicts three-month mortality among patients on the waiting list. Compared to the pre-MELD era, patients with significantly higher MELD scores undergo transplantation which leads in turn to more complications and higher costs yet with a comparable outcome. Timely referral of potential candidates to a transplant center is crucial since thorough evaluation to rule out contraindications such as uncontrolled infection, extrahepatic malignancy or advanced cardiopulmonary disease is essential. Taken together, every patient presenting with acute liver failure, decompensated cirrhosis or suspected hepatocellular carcinoma should be evaluated in a center with liver transplantation capability.

Relation of psychological distress to the INR in Patients with venous thromboembolism with and without oral anticoagulant therapy

Psychological distress might affect the international normalized ratio (INR), but effects might vary depending on oral anticoagulant (OAC) therapy.

Treatment of acute ischaemic stroke with thrombolysis or thrombectomy in patients receiving anti-thrombotic treatment

Systemic thrombolysis with alteplase is the only approved medical treatment for patients with acute ischaemic stroke. Thrombectomy is also increasingly used to treat proximal occlusions of the cerebral arteries, but has not shown superiority over systemic thrombolysis with alteplase. Many patients with acute ischaemic stroke are pretreated with antiplatelet or anticoagulant drugs, which can increase the bleeding risk of thrombolysis or thrombectomy. Pretreatment with aspirin monotherapy increases the bleeding risk of alteplase in both observational and randomised trials with no effect on clinical outcome, and the risk of intracerebral haemorrhage is increased with the combination of aspirin and clopidogrel. Antiplatelet drugs should not be given in the first 24 h after alteplase treatment. Data from pooled randomised trials and a large observational study show that thrombolysis can probably be done safely in patients given vitamin-K antagonists if the international normalised ratio is less than 1·7, although bleeding risk is slightly raised. Almost no data are available for the safety of alteplase in patients with atrial fibrillation who have been given novel oral anticoagulants (NOAC) for stroke prevention. Some coagulation parameters could help to identify patients treated with NOAC who might be eligible for thrombolysis. Thrombectomy can be done in patients given antiplatelets and probably in those given anticoagulants; however, conclusions about anticoagulants are based on findings from observational studies with small patient numbers.

Reasons to withhold intra-arterial thrombolysis in clinical practice

BACKGROUND: In selected stroke centers intra-arterial thrombolysis (IAT) is used for the treatment of acute stroke patients presenting within 6 hours of symptom onset. However, data about eligibility of acute stroke patients for IAT in clinical practice are very scarce. METHODS: We collected prospectively data on indications advising for or against IAT of 230 consecutive stroke patients in a tertiary stroke center. RESULTS: 76 patients (33.0%) presented within 3 hours, 69 (30%) between 3 and 6 hours of symptom onset and 85 (37%) later than 6 hours. Arteriography was performed in 71 patients (31%) and IAT in 46 (20%). In 11 patients no or only peripheral branch occlusions were seen on arteriography and therefore IAT was not performed. In 9 patients the ICA was occluded and barred IAT and in five anatomical or technical difficulties made IAT impossible. 72 patients presenting within 6 hours did not undergo arteriography and thrombolysis, mostly because of mild (n = 44) or rapidly improving neurological deficits (n = 13). Other reasons to withhold IAT were CT and/or clinical findings suggesting lacunar stroke due to small vessel occlusion (n = 7), limiting comorbidty (n = 7) and baseline international normalized ratio > 1.7 (n = 1). CONCLUSIONS: A third of the patients underwent diagnostic arteriography and one fifth received IAT. The most important reasons to withhold thrombolysis were presentation beyond the 6 hours time window and mild or rapidly improving symptoms.

Safety of inferior vena cava filter retrieval in anticoagulated patients

PURPOSES: To evaluate the safety of inferior vena cava (IVC) filter retrieval in therapeutically anticoagulated patients in comparison to prophylactically or not therapeutically anticoagulated patients with respect to retrieval-related hemorrhagic complications. MATERIALS AND METHODS: This was a retrospective study of 115 consecutive attempted IVC filter retrievals in 110 patients. Filter retrievals were stratified as performed in patients who were therapeutically anticoagulated (group 1), prophylactically anticoagulated (group 2), or not therapeutically anticoagulated (group 3). The collected data included anticoagulant and antiplatelet medications (type, form and duration of administration, dosage) at the time of retrieval. Phone interviews and chart review was performed for the international normalized ratio (INR), activated partial thromboplastin time, platelet count, infusion of blood products, and retrieval-related hemorrhagic complications. RESULTS: Group 1 included 65 attempted filter retrievals in 61 therapeutically anticoagulated patients by measured INR or dosing when receiving low-molecular-weight heparin (LMWH). Four retrievals were not successful. In patients receiving oral anticoagulation, the median INR was 2.35 (range, 2 to 8). Group 2 comprised 23 successful filter retrievals in 22 patients receiving a prophylactic dose of LMWH. Group 3 included 27 attempted filter retrievals in 27 patients not receiving therapeutic anticoagulation. Six retrievals were not successful. Five patients were receiving oral anticoagulation with a subtherapeutic INR (median, 1.49; range, 1.16 to 1.69). No anticoagulation medication was administered in 22 patients. In none of the groups were hemorrhagic complications related to the retrieval procedures identified. CONCLUSIONS: These results suggest that retrieval of vena cava filters in anticoagulated patients is safe. Interruption or reversal of anticoagulation for the retrieval of vena cava filters is not indicated.

Thrombophilic risk factors in patients with cranial and spinal dural arteriovenous fistulae

OBJECTIVE: Numerous studies have reported the technical aspects and results of surgical and/or endovascular treatment of cranial dural arteriovenous fistulae (cDAVF) and spinal dural arteriovenous fistulae (sDAVF). Only a few of them have addressed the question of thrombophilic conditions, which may be relevant as pathogenetic factors or can increase the risk for venous thromboembolic events. Therefore, the objective of this study is to compare thrombophilic risk factors in patients with cDAVF and sDAVF with no history of trauma. METHODS: A total of 43 patients (25 with cDAVF and 18 with sDAVF) were included in this study. Blood samples were analyzed for G20210A mutation of the prothrombin gene and factor V Leiden mutation. In all patients, prothrombin time, international normalized ratio, fibrinogen, antithrombin, protein C and S activity, von Willebrand factor antigen, ristocetin cofactor activity, D-dimer, coagulation factor VIII activity, and tissue factor pathway inhibitor were determined. Screening was performed for the occurrence of lupus antiphospholipid and cardiolipin antibodies. RESULTS: The prevalence of G20210A mutation of the prothrombin gene was significantly higher in patients with cDAVF (n = 6) compared with patients with sDAVF (n = 0; P < 0.05, Fisher's exact test). A factor V Leiden mutation was found in 3 patients with sDAVF and in 1 patient with cDAVF (P = 0.29, Fisher's exact test). No significant difference was found for other parameters, except for fibrinogen, but decreased protein C activity was more frequent in patients with cDAVF compared with patients with sDAVF (4 versus 1). Decreased protein S activity was encountered in 3 patients (2 with sDAVF and 1 with cDAVF). Cardiolipin antibodies were found in 2 patients with cDAVF but in none with sDAVF, whereas only 1 patient with sDAVF had lupus antiphospholipid antibodies. CONCLUSION: In both groups of patients with dural arteriovenous fistulae, genetic thrombophilic abnormalities occurred in a higher percentage than in the general population. The differences of the genetic abnormalities may be involved in different pathophysiological mechanism(s) in the development of these distinct neurovascular entities.

Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: a prospective cohort study

INTRODUCTION: The inflammatory response to an invading pathogen in sepsis leads to complex alterations in hemostasis by dysregulation of procoagulant and anticoagulant factors. Recent treatment options to correct these abnormalities in patients with sepsis and organ dysfunction have yielded conflicting results. Using thromboelastometry (ROTEM(R)), we assessed the course of hemostatic alterations in patients with sepsis and related these alterations to the severity of organ dysfunction. METHODS: This prospective cohort study included 30 consecutive critically ill patients with sepsis admitted to a 30-bed multidisciplinary intensive care unit (ICU). Hemostasis was analyzed with routine clotting tests as well as thromboelastometry every 12 hours for the first 48 hours, and at discharge from the ICU. Organ dysfunction was quantified using the Sequential Organ Failure Assessment (SOFA) score. RESULTS: Simplified Acute Physiology Score II and SOFA scores at ICU admission were 52 +/- 15 and 9 +/- 4, respectively. During the ICU stay the clotting time decreased from 65 +/- 8 seconds to 57 +/- 5 seconds (P = 0.021) and clot formation time (CFT) from 97 +/- 63 seconds to 63 +/- 31 seconds (P = 0.017), whereas maximal clot firmness (MCF) increased from 62 +/- 11 mm to 67 +/- 9 mm (P = 0.035). Classification by SOFA score revealed that CFT was slower (P = 0.017) and MCF weaker (P = 0.005) in patients with more severe organ failure (SOFA >or= 10, CFT 125 +/- 76 seconds, and MCF 57 +/- 11 mm) as compared with patients who had lower SOFA scores (SOFA <10, CFT 69 +/- 27, and MCF 68 +/- 8). Along with increasing coagulation factor activity, the initially increased International Normalized Ratio (INR) and prolonged activated partial thromboplastin time (aPTT) corrected over time. CONCLUSIONS: Key variables of ROTEM(R) remained within the reference ranges during the phase of critical illness in this cohort of patients with severe sepsis and septic shock without bleeding complications. Improved organ dysfunction upon discharge from the ICU was associated with shortened coagulation time, accelerated clot formation, and increased firmness of the formed blood clot when compared with values on admission. With increased severity of illness, changes of ROTEM(R) variables were more pronounced.

Major bleeding risk in anticoagulated patients receiving concomitant antiplatelet therapy: a prospective study

INTRODUCTION Current literature suggesting a higher bleeding risk during combination therapy compared to oral anticoagulation alone is primarily based on retrospective studies or specific populations. We aimed to prospectively evaluate whether unselected medical patients on oral anticoagulation have an increased risk of bleeding when on concomitant antiplatelet therapy. MATERIAL AND METHODS We prospectively studied consecutive adult medical patients who were discharged on oral anticoagulants between 01/2008 and 03/2009 from a Swiss university hospital. The primary outcome was the time to a first major bleed on oral anticoagulation within 12 months, adjusted for age, international normalized ratio target, number of medications, and history of myocardial infarction and major bleeding. RESULTS Among the 515 included anticoagulated patients, the incidence rate of a first major bleed was 8.2 per 100 patient-years. Overall, 161 patients (31.3%) were on both anticoagulant and antiplatelet therapy, and these patients had a similar incidence rate of major bleeding compared to patients on oral anticoagulation alone (7.6 vs. 8.4 per 100 patient-years, P=0.81). In a multivariate analysis, the association of concomitant antiplatelet therapy with the risk of major bleeding was not statistically significant (hazard ratio 0.89, 95% confidence interval, 0.37-2.10). CONCLUSIONS The risk of bleeding in patients receiving oral anticoagulants combined with antiplatelet therapy was similar to patients receiving oral anticoagulants alone, suggesting that the incremental bleeding risk of combination therapy might not be clinically significant.

Anticoagulation in primary care - a cross sectional study in 14 heterogeneous countries

Background: New oral anticoagulants (NOACs) are predicted to become the new standard treatment for stroke prevention in patients with atrial fibrillation, and may replace vitamin K antagonists (VKAs). NOACs are prescribed less than expected, even though they do not require international normalised ratio (INR) monitoring. In this study we assessed methods for INR monitoring after the introduction of NOACs a in heterogeneous sample of countries. Methods: We asked representatives of the Vasco da Gama Movement, a network of junior and future gen- eral practitioners (GPs) in Europe, and WONCA, the World Organization of Family Doctors, to describe the way INR is monitored in their respective countries. Results: Representatives of 14 countries responded. In most countries, the INR is monitored by GPs; in some countries, these patients are treated by other specialists or in specialised anticoagulation centres. In only a few countries, anticoagulated patients monitor the INR themselves. Conclusion: Our study showed several strategies for managing anticoagulation in different countries. In most countries, the INR is monitored by GPs. These consultations offer opportunities to address other is- sues, such as blood pressure control or medication adherence. These factors may be considered when de- ciding to switch patients from VKAs to NOACs.

Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation

Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.

The adherence to initial processes of care in elderly patients with acute venous thromboembolism.

BACKGROUND We aimed to assess whether elderly patients with acute venous thromboembolism (VTE) receive recommended initial processes of care and to identify predictors of process adherence. METHODS We prospectively studied in- and outpatients aged ≥65 years with acute symptomatic VTE in a multicenter cohort study from nine Swiss university- and non-university hospitals between September 2009 and March 2011. We systematically assessed whether initial processes of care, which are recommended by the 2008 American College of Chest Physicians guidelines, were performed in each patient. We used multivariable logistic models to identify patient factors independently associated with process adherence. RESULTS Our cohort comprised 950 patients (mean age 76 years). Of these, 86% (645/750) received parenteral anticoagulation for ≥5 days, 54% (405/750) had oral anticoagulation started on the first treatment day, and 37% (274/750) had an international normalized ratio (INR) ≥2 for ≥24 hours before parenteral anticoagulation was discontinued. Overall, 35% (53/153) of patients with cancer received low-molecular-weight heparin monotherapy and 72% (304/423) of patients with symptomatic deep vein thrombosis were prescribed compression stockings. In multivariate analyses, symptomatic pulmonary embolism, hospital-acquired VTE, and concomitant antiplatelet therapy were associated with a significantly lower anticoagulation-related process adherence. CONCLUSIONS Adherence to several recommended processes of care was suboptimal in elderly patients with VTE. Quality of care interventions should particularly focus on processes with low adherence, such as the prescription of continued low-molecular-weight heparin therapy in patients with cancer and the achievement of an INR ≥2 for ≥24 hours before parenteral anticoagulants are stopped.

VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children

BACKGROUND Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. PROCEDURE Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. RESULTS With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. CONCLUSIONS This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.

Safety of Prasugrel Loading Doses in Patients Pre-Loaded With Clopidogrel in the Setting of Primary Percutaneous Coronary Intervention: Results of a Nonrandomized Observational Study.

OBJECTIVES The aim of this study was to assess the safety of the concurrent administration of a clopidogrel and prasugrel loading dose in patients undergoing primary percutaneous coronary intervention. BACKGROUND Prasugrel is one of the preferred P2Y12 platelet receptor antagonists for ST-segment elevation myocardial infarction patients. The use of prasugrel was evaluated clinically in clopidogrel-naive patients. METHODS Between September 2009 and October 2012, a total of 2,023 STEMI patients were enrolled in the COMFORTABLE (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI]) and the SPUM-ACS (Inflammation and Acute Coronary Syndromes) studies. Patients receiving a prasugrel loading dose were divided into 2 groups: 1) clopidogrel and a subsequent prasugrel loading dose; and 2) a prasugrel loading dose. The primary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding in hospital at 30 days. RESULTS Of 2,023 patients undergoing primary percutaneous coronary intervention, 427 (21.1%) received clopidogrel and a subsequent prasugrel loading dose, 447 (22.1%) received a prasugrel loading dose alone, and the remaining received clopidogrel only. At 30 days, the primary safety endpoint was observed in 1.9% of those receiving clopidogrel and a subsequent prasugrel loading dose and 3.4% of those receiving a prasugrel loading dose alone (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.25 to 1.30, p = 0.18). The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) bleeding score tended to be higher in prasugrel-treated patients (p = 0.076). The primary safety endpoint results, however, remained unchanged after adjustment for these differences (clopidogrel and a subsequent prasugrel loading dose vs. prasugrel only; HR: 0.54 [95% CI: 0.23 to 1.27], p = 0.16). No differences in the composite of cardiac death, myocardial infarction, or stroke were observed at 30 days (adjusted HR: 0.66, 95% CI: 0.27 to 1.62, p = 0.36). CONCLUSIONS This observational, nonrandomized study of ST-segment elevation myocardial infarction patients suggests that the administration of a loading dose of prasugrel in patients pre-treated with a loading dose of clopidogrel is not associated with an excess of major bleeding events. (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI] [COMFORTABLE]; NCT00962416; and Inflammation and Acute Coronary Syndromes [SPUM-ACS]; NCT01000701).