Emergency care of patients receiving non-vitamin K antagonist oral anticoagulants.

Non-vitamin K antagonist oral anticoagulants (NOACs), which inhibit thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban, edoxaban) have been introduced in several clinical indications. Although NOACs have a favourable benefit-risk profile and can be used without routine laboratory monitoring, they are associated-as any anticoagulant-with a risk of bleeding. In addition, treatment may need to be interrupted in patients who need surgery or other procedures. The objective of this article, developed by a multidisciplinary panel of experts in thrombosis and haemostasis, is to provide an update on the management of NOAC-treated patients who experience a bleeding episode or require an urgent procedure. Recent advances in the development of targeted reversal agents are expected to help streamline the management of NOAC-treated patients in whom rapid reversal of anticoagulation is required.

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.

Long-term anticoagulant therapy in patients with coronary artery disease.

Secondary prevention of coronary events in coronary artery disease (CAD) patients with aspirin is generally accepted because of ease of administration, predictable safety, and proven efficacy. The use of long-term anticoagulant therapy with heparins, vitamin-K antagonists (VKAs), or thrombin inhibitors is, however, more controversial. During the last 40 years, several trials have been conducted in order to evaluate the role of anticoagulant therapy in patients with CAD as a protection against subsequent death and thrombo-embolic complications. The conducted trials are heterogeneous in many ways, concerning comparative medications, patient populations, endpoints and follow-up, which makes a standardized recommendation on the basis of these studies difficult. This review is an overview of the largest and best studies on this topic and discusses the scientific background for a possible use of VKA or an alternative anticoagulant treatment in CAD patients, looking at both the beneficial effects and the risk of bleeding.

Venous thromboembolism in the medically ill patient: a call to action.

The risk of venous thromboembolism (VTE) in medical patients is generally underestimated. However, recent studies including two large double-blind placebo-controlled trials, the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilised Patients trial (PREVENT) and prophylaxis in MEDical patients with ENOXaparin, study show that low-molecular-weight heparins (LMWHs) provide effective thromboprophylaxis for medical patients at risk from VTE without increasing the risk of bleeding. In PREVENT the significant 45%, reduction in VTE among patients receiving dalteparin 5000 IU once daily for 14 days was attributed entirely to a reduction in clinically relevant VTE. The recently published guidelines for the prevention and treatment of VTE, issued by the American College of Chest Physicians, recommend prophylaxis with LMWHs (or low-dose unfractionated heparin) in acutely ill medical patients with risk factors for VTE (grade 1A). Current evidence should encourage the more widespread adoption of thromboprophylaxis in at-risk medical patients, and thus reduce the number of preventable deaths and complications due to VTE.

Primary and secondary prophylaxis of venous thromboembolism with low-molecular-weight heparins: prolonged thromboprophylaxis, an alternative to vitamin K antagonists.

Low-molecular-weight heparins (LMWHs) are used widely in the treatment and prevention of venous thromboembolism (VTE). The LMWHs dalteparin and enoxaparin reduce the rate of VTE by at least 50% if administered for 4-5 weeks following major orthopedic surgery, compared with in-hospital prophylaxis for 7-15 days. Meta-analyses have confirmed that the size of the reduction is similar for both clinical and asymptomatic VTE. Vitamin K antagonists (VKAs) have been shown to be associated with significantly higher bleeding rates compared with LMWH when used as prolonged prophylaxis against VTE following major orthopedic surgery. Patients with cancer are a recognized group at high risk of VTE, and those undergoing major surgery for their malignancy are at particular risk. Evidence from clinical trials is amassing to show that prolonged prophylaxis with LMWH (dalteparin, enoxaparin) in these patients can significantly reduce the rate of postoperative VTE. In cancer patients with acute VTE, the traditional approach is to initiate acute treatment with unfractionated heparin or LMWH followed by long-term treatment with VKA to prevent recurrence. However, clinical trial data have confirmed that the LMWH dalteparin, when administered for 6 months, is significantly more effective than VKA in preventing recurrence, cutting the rate of VTE by 52% without increasing the risk of bleeding. A new and intriguing area of interest is whether LMWH can enhance survival in patients with cancer. Preliminary data suggest that a biological effect of LMWH may act to prolong survival in patients with cancer.

A rare cause of steatohepatitis.

We present a rare case of steatohepatitis due to neutral lipid storage disorder in a 1.5-year-old male presenting with intermittent fever, hepatomegaly and dark-coloured urine. On examination, there was ichthyosis involving both the limbs. Liver biopsy showed steatohepatitis. The peripheral blood smear revealed fat vacuoles in the cytoplasm of leucocytes, characteristic of the Dorfman-Chanarin syndrome. Awareness of this condition helps in prompt diagnosis and avoids unnecessary further investigations.

Low-molecular-weight heparins: weeks or months instead of days of treatment.

Low-molecular-weight heparins (LMWHs) have been used for more than a decade in the prophylaxis and treatment of venous thromboembolism and recently in coronary artery disease. During the past few years, the duration of treatment has been increased in several pathologic conditions. A number of clinical studies provided evidence that the duration of prophylaxis after hip replacement should be prolonged up to 35 days after surgery. Several clinical trials concluded that LMWHs provide an effective and safe alternative to oral anticoagulants in the secondary prevention of deep vein thrombosis. A recent trial showed that extended dalteparin treatment is useful for protection against further complications while patients are waiting for invasive procedures. Finally, LMWHs seem to be safe during pregnancy.

A critical review of clinical trials for low-molecular-weight heparin therapy in unstable coronary artery disease.

Unstable angina and non-ST-segment elevation myocardial infarction (MI) are collectively referred to as unstable coronary artery disease (UCAD). They are conditions that share a common pathophysiology and represent frequently encountered, potentially life-threatening clinical manifestations of advanced atherosclerosis. Therefore, treatment of UCAD is a major focus for practicing clinicians, and although pharmacologic agents have been developed that impact on patient outcome, recent data suggest that a further reduction in ischemic complications is possible. Acute-phase treatment with aspirin is associated with a significant reduction in death and nonfatal MI in patients with UCAD. This benefit is enhanced by the addition of unfractionated heparin (UFH) to the treatment strategy; however, UFH requires careful monitoring and titration. In contrast, low-molecular-weight heparins (LMWHs), produced by chemical or enzymatic depolymerization of UFH, yield a predictable and consistent pharmacokinetic profile and anticoagulant response, making them an attractive treatment alternative to UFH in patients with UCAD. The optimal duration of treatment with LMWH is an important question influenced by the observation that reactivation of coagulation occurs following the early and abrupt discontinuation of heparin treatment. Early trials, such as FRISC and FRIC, demonstrated the benefit of acute therapy with dalteparin sodium; however, the results of extended treatment with dalteparin were inconclusive. The extended phase of these studies included relatively low-risk patients, and a once-daily, relatively low-dose strategy was employed. The findings derived from the FRISC II trial, which used a twice-daily dose of dalteparin, suggest a benefit for at least 60 days with extended treatment in high-risk patients with UCAD. Although an early-invasive treatment strategy is particularly beneficial, patients in whom early revascularization is not possible should be considered for extended treatment with dalteparin for up to 45 days, especially those awaiting percutaneous coronary intervention. Extended treatment with dalteparin therefore provides a protective "bridge" to enhance the outcome of patients with UCAD awaiting revascularization.

Evaluation of principal components analysis with high-performance liquid chromatography and photodiode array detection for the forensic differentiation of ballpoint pen inks.

Inks from seven black and eight blue ballpoint pens were separated by a high-performance liquid chromatography (HPLC) method utilizing a photodiode array detection (PDA). A classifier flowchart was designed for the chromatographic data based on the presence or absence of certain peaks at different wavelengths to qualitatively discriminate between the inks. The same data were quantitatively classified by principal components analysis (PCA) to estimate the separation between a pair of classes of ink samples. It was found that the black ballpoint pen inks were discriminated satisfactorily utilizing two-dimensional data of the peak areas and retention times at the optimum wavelengths. The blue pens were discriminated by analyzing the chromatographic data at four different wavelengths simultaneously with a cross-validated PCA. The results of this study indicated that HPLC-PDA coupled with chemometrics could make a powerful discriminating tool for the forensic chemist, especially when analyzing extensive and/or complex data.

Critical appraisal of current antithrombotic trials in patients undergoing total hip replacement.

Patients undergoing total hip replacement are at high risk of developing venous thromboembolism. The 6th ACCP Consensus Conference on Antithrombotic Therapy identified two effective prophylactic methods; low molecular weight heparins (LMWH) and oral anticoagulants. However, two key issues remain controversial. The relative efficacy and safety of prophylaxis initiated pre operatively and post operatively and the optimum duration of prophylaxis. Clinical practice has diverged in North America and Europe as to the appropriate time to administer prophylaxis. This treatment is given pre-operatively in Europe and post-operatively in North America. A number of recent studies have demonstrated that an effective antithrombotic agent administered either immediately before or after surgery may be more effective than current practice. The use of LMWH for extended thromboprophylaxis is supported by convincing data. Clinical trials have demonstrated a significant benefit of pentasaccharide in the prevention of venous thromboembolism in major orthopaedic surgery. A direct thrombin inhibitor given sc. followed by oral administration was found to be as effective and safe as LMWH for the prophylaxis of deep vein thrombosis (DVT) following major hip or knee surgery.

[Follow-up of the treatment by direct thrombin inhibitors: activated partial thromboplastin time or ecarin clotting time]. / Surveillance du traitement par les inhibiteurs directs de la thrombine: temps de céphaline avec activateur ou temps d'écarine.

The clinical use of the direct inhibitors of thrombin requires a reliable test to monitor the treatment and to predict the hemorragic risk. The activated partial thromboplastin time (APTT) is the most common test used to monitor treatment with unfractionated heparin. Thus APTT has been first chosen to follow patients treated with direct thrombin inhibitors, but studies have shown that it was probably not the most appropriate test. Indeed, APTT values were not well correlated with the dose administered and were dependent on the type of the thrombin inhibitor used and on the APTT reagent. The ecarin clotting time (ECT), which converts prothrombin into meizothrombin has been then tested and seemed to be a better test. In vitro studies have shown a good correlation between ECT and the different concentrations of thrombin inhibitors. Furthermore, the ECT in contrast to APTT is not sensitive to heparin or oral anticoagulant and interindividual variations are low with ECT. ECT which is a reliable test and is easy to perform seems to be a more appropriate test to monitor treatment with direct thrombin inhibitors but further studies are needed to validate its use in a clinical setting.

Acute and prolonged treatment with low-molecular-weight heparin therapy in patients with unstable coronary artery disease.

Unstable angina and non-ST-segment elevation myocardial infarction (MI) are known as unstable coronary artery disease (UCAD). They are syndromes that share a common pathobiology and represent a frequently encountered and potentially life-threatening medical condition. Acute-phase treatment with aspirin is associated with a significant reduction in death and non-fatal MI in patients with UCAD. This benefit is enhanced by the addition of unfractionated heparin (UFH) to the treatment strategy; however, UFH requires careful monitoring and titration. In contrast, low-molecular-weight heparins (LMWHs), produced by chemical or enzymatic depolymerization of UFH, yield a predictable and consistent pharmacokinetic profile and anticoagulant response making them an attractive alternative treatment to UFH in patients with UCAD. In several studies, acute-phase treatment with LMWH has been shown to be at least as effective and safe as UFH. The optimal duration of treatment with LMWH is an important question that has been influenced by the observation that reactivation of coagulation occurs following the early and abrupt discontinuation of heparin treatment. In early trials, such as FRISC (Fragmin during instability in coronary artery disease) and FRIC (Fragmin in unstable coronary artery disease), the results of extended treatment were inconclusive; however, the trial populations included patients of relatively low risk and used a once-daily dosing regimen. In the TIMI 11B (Thrombolysis in myocardial infarction) extended treatment beyond the few days of acute treatment with enoxaparin did not add to the beneficial LMWH effect, but in this study 40% of the high-risk patients did not continue on extended treatment. The findings derived from the FRISC II trial, which used a twice-daily dose of dalteparin sodium, suggest a benefit for up to 45 days with extended treatment in high-risk UCAD patients. Although an early invasive treatment strategy is particularly beneficial, patients in whom early revascularization is not possible should be considered for extended treatment with dalteparin sodium awaiting percutaneous coronary intervention.

Efficacy of a modified Ultra Fast Papanicolaou (UFP) stain for breast aspirates.

The chief limitation of Ultra Fast Papanicolaou (UFP) stain, suggested by Yang and Alvarez (1995), is that, Richard Allan Haematoxylin (RA-H) and Richard Allan Cytostain (RA-C), used in the staining procedure are not universally available. It has not been established so far, whether, changes in the reagents and their proportions depending on the local availability, influence the performance of the stain. The objective of this study was to assess the feasibility and applicability of a modified UFP stain to suit our local laboratory supplies of chemical dyes, as applied to the permanent smears prepared from Fine Needle Aspiration (FNA) of breast lumps. In the present study, smears from FNA from 100 breast lumps were stained by the modified UFP stain. The modification consisted of following two changes: use of Gill's Haematoxylin instead of RAH and omission of Orange G from cytostain. Eighty Six breast aspirates were adequate for interpretation. Smears showed transparent cells with crisp nuclear features, equal to and even better than the conventional Papanicolaou stain, in a blood free background. There was an increase in total staining time by 40 seconds. We recommend the use of this modified UFP stain, only if similar reagents are being used in other laboratories. Otherwise situation specific modifications may be needed. If the UFP stain is to be used for tissues where the chances of cytoplasmic keratinization are negligible, then the use of Orange G component of the stain may become redundant.

Efficacy of fine needle capillary sampling in the diagnosis of stage III and IV cervical carcinoma.

OBJECTIVE: To test the sensitivity of fine needle capillary sampling (FNCS) as compared to scrape cytology in cervical carcinoma, stage III and IV, and to study the quality of material obtained by FNCS. STUDY DESIGN: Prospective. In 48 cases of cervical carcinoma, clinically stage III and IV, FNCS was done along with scrape cytology. The results were compared, considering histopathology as the gold standard. The quality of material obtained by both methods was compared using the parameters background, cellularity and cellular preservation. RESULTS: FNCS had a sensitivity of 87.5% as against 62.5% for scrape cytology. Material obtained by FNCS had a cleaner background and better cellularity and morphologic preservation. CONCLUSION: FNCS is superior to scrape cytology for the diagnosis of stage III and IV cervical carcinoma.

Evaluation of fine needle capillary sampling in superficial and deep-seated lesions. An analysis of 670 cases.

OBJECTIVE: To study the efficacy and merits of a simplified cytologic technique of fine needle capillary (FNC) sampling in 670 cases. STUDY DESIGN: FNC sampling was tested on a consecutive series of 600 superficial palpable masses and 70 deep-seated lesions during the period January 1993-September 1993. Among superficial masses, sampling was done on 380 lymph nodes, 88 breast lesions, 56 thyroids, 12 salivary glands and 64 miscellaneous sites. Fifty-five lung lesions were sampled using 8 computed tomography, while 15 abdominal masses were sampled using ultrasonography. Cell samples were assessed as diagnostically adequate or inadequate. RESULTS: The diagnostic adequacy in lymph node, breast and thyroid lesions was 95%, 91.07% and 90.09%, respectively. The diagnostic adequacy for deep-seated lesions was 91.42%. CONCLUSION: The procedure gives a better perception of tumor consistency and control of the hand. FNC resulted in a high yield of good-quality material with retention of cellular architecture. It is recommended that the operator become familiar with the macroscopic slide appearance of a cellular smear. Doubts persist with respect to fibrotic and cystic lesions.