Lori-Ann Linkins

Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. METHODS The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C). CONCLUSIONS Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.

Use of different D-dimer levels to exclude venous thromboembolism depending on clinical pretest probability

Summary.  Currently, the same d‐dimer cut‐off point is used to define a positive result for all patients with suspected venous thromboembolism, regardless of their pretest probability. However, use of a relatively high d‐dimer cut‐off point (lower sensitivity) for those with a low clinical pretest probability, and a low d‐dimer cut‐off point (higher sensitivity) for those with a high clinical pretest probability, may be preferable. To determine if using three different d‐dimer cut‐off points according to low, moderate or high clinical pretest probability has greater utility for exclusion of venous thromboembolism than using the same single d‐dimer cut‐off point in all patients. Data from a previously published study of 571 patients was used to identify the highest d‐dimer cut‐off point with a negative predictive value of at least 98% for the subgroup of patients with low and high pretest probability. The d‐dimer cut‐off point for those with moderate clinical pretest probability remained unchanged [0.5 fibrinogen equivalent units (FEU) µg mL−1]. Accuracy of d‐dimer testing for venous thromboembolism using three cut‐off points vs. one cut‐off point was than determined. d‐dimer cut‐off points of 0.2 and 2.1 FEU µg mL−1 were selected for the high and low pretest probability groups, respectively. When three pretest probability‐specific cut‐off points were used instead of the previously determined single d‐dimer cut‐off point (0.5 FEU µg mL−1), sensitivity and negative predictive value were unchanged (95 and 98%, respectively), but specificity increased from 44.7 to 60.4% (P < 0.001). This resulted in exclusion of venous thromboembolism in 80 additional patients. Use of three pretest probability‐specific d‐dimer cut‐off points rather than a single d‐dimer cut‐off point for all patients, has the potential to increase the utility of d‐dimer testing for the diagnosis of venous thromboembolism.

In vitro comparison of the effect of heparin, enoxaparin and fondaparinux on tests of coagulation.

Low-molecular weight heparin (LMWH) is increasingly used in place of unfractionated heparin (UFH) in patients with unstable angina, and phase II clinical trials using fondaparinux for this indication are underway. Because unstable angina patients often require urgent percutaneous coronary interventions (PCI) or aortocoronary bypass surgery, a point-of-care test is needed to monitor the anticoagulant effect of these agents. The activated clotting time (ACT) and activated partial thromboplastin time (aPTT) are the tests most often used to monitor heparin. The purpose of this in vitro study was to determine whether the ACT or the aPTT can be used to monitor the anticoagulant effect of low-molecular weight heparin and fondaparinux. The ACT and aPTT were measured after heparin, enoxaparin or fondaparinux was added to the blood of healthy volunteers, in doses with equivalent inhibitory activity against activated factor X (factor Xa). To mimic the clinical scenario where an unstable angina patient, who has already received enoxaparin, is urgently taken for PCI or bypass surgery, the ACT was determined after heparin was added to blood containing clinically relevant doses of enoxaparin. We determined that enoxaparin produced significantly less prolongation of both the ACT and the aPTT than heparin, whereas fondaparinux had no effect on either of these tests. Addition of enoxaparin to heparin-containing plasma did not prolong the ACT beyond that produced by heparin alone. The ACT and aPTT therefore cannot be used to monitor low-molecular weight heparin or fondaparinux, highlighting the need for a point-of-care anti-factor Xa assay.

Beyond heparin and warfarin: the new generation of anticoagulants

Heparin and warfarin are widely used for the prevention and treatment of venous and arterial thromboembolism. Although effective, both agents have important limitations; for example, both drugs must be monitored, which is inconvenient for patients and for physicians. Heparin requires parenteral administration and can cause heparin-induced thrombocytopenia, an immune-mediated process that can lead to life-threatening thrombosis. Warfarin also has its limitations. Due to its slow onset of action, warfarin must be overlapped with heparin (or another rapidly acting anticoagulant) when treating patients with established thrombosis or who are at high risk for thrombosis. Warfarin dosing is variable because its activity is influenced by dietary intake of vitamin K, genetic polymorphisms in enzymes that are involved in its metabolism and numerous drug–drug interactions that promote or reduce its activity. New anticoagulants have been developed to overcome these problems. Building on a better understanding of coagulation pathways, advances in structure-based drug design and information derived from natural anticoagulants isolated from hematophagous organisms, most of the new anticoagulants target specific coagulation enzymes. Focussing on drugs that have at least completed Phase II evaluation, this article briefly reviews the coagulation pathways and its natural regulators; outlines the limitations of existing anticoagulants and identifies the opportunities for new ones; highlights the properties of selected new anticoagulants; describes the clinical trial results with these agents; and provides a perspective on their potential strengths and weaknesses.

Non‐necrotizing heparin‐induced skin lesions and the 4T’s score

See also Schindewolf M, Kroll H, Ackermann H, Garbaraviciene J, Kaufmann R, Boehncke W‐H, Ludwig RJ, Lindhoff‐Last E. Heparin‐induced non‐necrotizing skin lesions: rarely associated with heparin‐induced thrombocytopenia. This issue, pp 1486–91.

Selective d-Dimer Testing for Diagnosis of a First Suspected Episode of Deep Venous Thrombosis: A Randomized Trial

BACKGROUND D-Dimer testing is sensitive but not specific for diagnosing deep venous thrombosis (DVT). Changing the use of testing and the threshold level for a positive test result on the basis of risk for DVT might improve the tradeoff between sensitivity and specificity and reduce the need for testing. OBJECTIVE To determine whether using a selective D-dimer testing strategy based on clinical pretest probability (C-PTP) for DVT is safe and reduces diagnostic testing compared with using a single D-dimer threshold for all patients. DESIGN Randomized, multicenter, controlled trial. Patients were allocated using a central automated system. Ultrasonographers and study adjudicators but not other study personnel were blinded to trial allocation. (ClinicalTrials.gov: NCT00157677) SETTING 5 Canadian hospitals. PATIENTS Consecutive symptomatic patients with a first episode of suspected DVT. INTERVENTION Selective testing (n = 860), defined as D-dimer testing for outpatients with low or moderate C-PTP (DVT excluded at D-dimer levels <1.0 µg/mL [low C-PTP] or <0.5 µg/mL [moderate C-PTP]) and venous ultrasonography without D-dimer testing for outpatients with high C-PTP and inpatients, or uniform testing (n = 863), defined as D-dimer testing for all participants (DVT excluded at D-dimer levels <0.5 µg/mL). MEASUREMENTS The proportion of patients not diagnosed with DVT during initial testing who had symptomatic venous thromboembolism during 3-month follow-up and the proportion of patients undergoing D-dimer testing and ultrasonography. RESULTS The incidence of symptomatic venous thromboembolism at 3 months was 0.5% in both study groups (difference, 0.0 percentage point [95% CI, -0.8 to 0.8 percentage points]). Selective testing reduced the proportion of patients who required D-dimer testing by 21.8 percentage points (CI, 19.1 to 24.8 percentage points). It reduced the proportion who required ultrasonography by 7.6 percentage points (CI, 2.9 to 12.2 percentage points) overall and by 21.0 percentage points (CI, 14.2 to 27.6 percentage points) in outpatients with low C-PTP. LIMITATION Results may not be generalizable to all D-dimer assays or patients with previous DVT, study personnel were not blinded, and the trial was stopped prematurely. CONCLUSION A selective D-dimer testing strategy seems as safe as and more efficient than having everyone undergo D-dimer testing when diagnosing a first episode of suspected DVT. PRIMARY FUNDING SOURCE Heart and Stroke Foundation of Ontario.

Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study

Rapid exclusion of heparin-induced thrombocytopenia (HIT) is needed to determine which patients can continue to receive heparin. In this prospective management study, 526 participants had a 4Ts score, rapid particle gel immunoassay (platelet factor 4/heparin [PF4/H]-PaGIA), and serotonin-release assay (SRA) performed. While awaiting SRA results, participants with a low 4Ts score (irrespective of PF4/H-PaGIA result) or intermediate 4Ts score plus a negative PF4/H-PaGIA result received prophylactic doses of danaparoid or fondaparinux; all others received therapeutic doses of nonheparin anticoagulants. The primary outcome was the frequency of management failures defined as HIT-positive participants with a low 4Ts score (irrespective of PF4/H-PaGIA result) or intermediate 4Ts score plus negative PF4/H-PaGIA result. Six participants (1.1%; 95% confidence interval [CI], 0.2-2.1%) were management failures. A negative PF4/H-PaGIA result reduced the pretest probability of HIT from 1.9% to 0% (95% CI, 0-1.3%), 6.7% to 0% (95% CI, 0-2.7%), and 36.6% to 0% (95% CI, 0-14.3%) in the low, intermediate, and high score groups, respectively. A positive PF4/H-PaGIA result increased the probability of HIT in the low score group to 15.4% (95% CI, 5.9-30.5). Thus, a low or intermediate 4Ts score plus negative PaGIA result excluded HIT, whereas any other combination of results justified the use of alternative anticoagulants until HIT could be excluded. This trial was registered at www.clinicaltrials.gov as #NCT00489437.

The Approach to Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) bound to heparin. HIT is an intense hypercoagulability state (increased thrombin generation in vivo) that is complicated more often by venous thromboembolism (deep vein thrombosis, pulmonary embolism) than by arterial thrombosis. HIT is a risk factor for coumarin-induced microthrombosis, particularly affecting acral regions of limbs with deep vein thrombosis (venous limb gangrene). Coumarins (e.g., warfarin) are therefore contraindicated during the acute (thrombocytopenic) phase of HIT. Venous thromboembolism can occur early during an episode of HIT, sometimes even before HIT-associated platelet count declines become clear. Recognition of HIT may be facilitated through the use of a clinical scoring system, the 4Ts ( Thrombocytopenia, Thrombosis, Timing, and o Ther explanations). Anti-PF4/polyanion enzyme-immunoassays (EIAs) and washed platelet activation assays readily detect HIT antibodies, and thus have high diagnostic sensitivity; however, only the platelet activation assays have high diagnostic specificity, suggesting that HIT is likely to be overdiagnosed in settings where EIAs are used exclusively for diagnosis. Treatment of HIT emphasizes substitution of heparin with an alternative nonheparin anticoagulant, such as a direct thrombin inhibitor (lepirudin, argatroban), or an indirect (antithrombin-mediated) inhibitor of factor Xa (danaparoid, fondaparinux?).

Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy

Summary.  Background: Rate of major bleeding is generally accepted as a good measure of the risks associated with anticoagulant therapy, but this may not be true if the proportion of major bleeds with the most serious consequences differs according to the indication for anticoagulant therapy. Objective: To determine whether the indication for long‐term oral anticoagulant therapy influences the proportion of major bleeds that are intracranial and fatal. Patients/Methods: Two authors abstracted intracranial and fatal bleeds from randomized trials of patients who received anticoagulant therapy for a minimum of 6 months for atrial fibrillation, ischemic heart disease, venous thromboembolism, prosthetic heart valves and ischemic stroke. Results: There were 877 major bleeds among 23 518 patients in 39 studies. The proportion of bleeds that were intracranial was significantly higher in patients with ischemic stroke (36%; 95% CI, 22–52%; P = 0.02) compared with patients with venous thromboembolism (10%; 95% CI, 5–20%). The difference in the proportion of bleeds that were intracranial among atrial fibrillation, ischemic heart disease, venous thromboembolism and prosthetic heart valves was not statistically significant; however, the estimates varied from 10% to 27%. The proportion of bleeds that were fatal did not differ significantly according to indication, but varied from 8% to 20%. For all indications for anticoagulation, intracranial bleeds were much more likely to be fatal than extracranial major bleeds (44% vs. 4% overall). Conclusions: In current practise, the indication for oral anticoagulant therapy has limited influence on the proportion of major bleeds that are intracranial or fatal.

Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis

Recommendations for management of cancer‐related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low‐quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies.