Temporarily Reversing Warfarin With Low-Dose 4-Factor Prothrombin Complex Concentrate in Left Ventricular Assist Device Patients Undergoing an Invasive Procedure.

BACKGROUND: American Association for Thoracic Surgery and The International Society for Heart and Lung Transplantation (AATS/ISHLT) guidelines recommend warfarin in patients with continuous-flow left ventricular assist devices (LVADs) to reduce the risk of device thrombosis and systemic embolization. Left ventricular assist device patients often undergo elective and emergent procedures that require interrupted anticoagulation. Data and experience vary on the optimal strategy to rapidly reverse warfarin in LVAD patients when an emergent procedure is planned. OBJECTIVE: The purpose of this study was to describe the use of 4-factor prothrombin complex concentrate (PCC4) for warfarin reversal in patients with LVADs undergoing elective and emergent procedures. METHODS: This retrospective, single-center, cohort review describes the use of PCC4 in patients with LVADs who require warfarin reversal for elective or emergent procedures. The primary outcome was a composite incidence of pump thrombosis, venous thromboembolism, and ischemic stroke within 30 days of PCC4 administration. RESULTS: In total, 14 patients received 17 administrations of PCC4. One patient received 3 administrations, and 1 other patient received 2 administrations during separate encounters. The median dose was 500 units or 6.6 units/kg (range = 4.2-14.1 units/kg). Of the PCC4 administrations, 82% (14/17) were for low bleed risk procedures and 76% (13/17) were for elective procedures. There were no cases of pump thrombosis, venous thromboembolism, or stroke within 30 days of the procedure. CONCLUSIONS AND RELEVANCE: Low-dose PCC4 appears to be a safe and effective temporary reversal strategy for patients with LVADs undergoing low-bleed risk elective procedures.

Positive Patient Postoperative Outcomes with Pharmacotherapy: A Narrative Review including Perioperative-Specialty Pharmacist Interviews.

The influence of pharmacotherapy regimens on surgical patient outcomes is increasingly appreciated in the era of enhanced recovery protocols and institutional focus on reducing postoperative complications. Specifics related to medication selection, dosing, frequency of administration, and duration of therapy are evolving to optimize pharmacotherapeutic regimens for many enhanced recovery protocolized elements. This review provides a summary of recent pharmacotherapeutic strategies, including those configured within electronic health record (EHR) applications and functionalities, that are associated with the minimization of the frequency and severity of postoperative complications (POCs), shortened hospital length of stay (LOS), reduced readmission rates, and cost or revenue impacts. Further, it will highlight preventive pharmacotherapy regimens that are correlated with improved patient preparation, especially those related to surgical site infection (SSI), venous thromboembolism (VTE), nausea and vomiting (PONV), postoperative ileus (POI), and emergence delirium (PoD) as well as less commonly encountered POCs such as acute kidney injury (AKI) and atrial fibrillation (AF). The importance of interprofessional collaboration in all periprocedural phases, focusing on medication management through shared responsibilities for drug therapy outcomes, will be emphasized. Finally, examples of collaborative care through shared mental models of drug stewardship and non-medical practice agreements to improve operative throughput, reduce operative stress, and increase patient satisfaction are illustrated.

Executive Summary: Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline.

BACKGROUND: The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug. METHODS: Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines. RESULTS: A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures. CONCLUSIONS: Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management questions.

Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline.

BACKGROUND: The American College of Chest Physicians Clinical Practice Guideline on the Perioperative Management of Antithrombotic Therapy addresses 43 Patients-Interventions-Comparators-Outcomes (PICO) questions related to the perioperative management of patients who are receiving long-term oral anticoagulant or antiplatelet therapy and require an elective surgery/procedure. This guideline is separated into four broad categories, encompassing the management of patients who are receiving: (1) a vitamin K antagonist (VKA), mainly warfarin; (2) if receiving a VKA, the use of perioperative heparin bridging, typically with a low-molecular-weight heparin; (3) a direct oral anticoagulant (DOAC); and (4) an antiplatelet drug. METHODS: Strong or conditional practice recommendations are generated based on high, moderate, low, and very low certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology for clinical practice guidelines. RESULTS: A multidisciplinary panel generated 44 guideline recommendations for the perioperative management of VKAs, heparin bridging, DOACs, and antiplatelet drugs, of which two are strong recommendations: (1) against the use of heparin bridging in patients with atrial fibrillation; and (2) continuation of VKA therapy in patients having a pacemaker or internal cardiac defibrillator implantation. There are separate recommendations on the perioperative management of patients who are undergoing minor procedures, comprising dental, dermatologic, ophthalmologic, pacemaker/internal cardiac defibrillator implantation, and GI (endoscopic) procedures. CONCLUSIONS: Substantial new evidence has emerged since the 2012 iteration of these guidelines, especially to inform best practices for the perioperative management of patients who are receiving a VKA and may require heparin bridging, for the perioperative management of patients who are receiving a DOAC, and for patients who are receiving one or more antiplatelet drugs. Despite this new knowledge, uncertainty remains as to best practices for the majority of perioperative management questions.

Bridging with Tirofiban during Oral Antiplatelet Interruption: A Single-Center Case Series Analysis Including Patients on Hemodialysis.

INTRODUCTION: Patients requiring an interruption in dual-antiplatelet therapy (DAPT) within 6 months of cardiac stenting are at risk for thrombotic events. Bridging with short-acting intravenous antiplatelet agents has been proposed to minimize the risk of thrombotic and hemorrhagic complications. METHODS: This retrospective analysis of a tirofiban bridging strategy did not use an initial bolus loading dose. Tirofiban infusions were initiated 24-48 hours after the last oral antiplatelet dose at a rate of 0.1 µg/kg/min (or 0.05 µg/kg/min if renal dysfunction) and continued until 4-8 hours before surgery or until DAPT could be resumed. Coprimary end points were occurrence of major adverse cardiac events (MACE) and bleeding. RESULTS: Twenty patients requiring DAPT interruption within 6 months of cardiac stenting for either a surgical procedure or who were unable to take any medications by mouth were included. The median time from stent implantation to DAPT interruption was 33 days (range 3-146 days). Two patients experienced a MACE during their hospital stay. No major bleeding events occurred; minor bleeding occurred in four patients during tirofiban therapy. Five patients in this analysis had end-stage renal disease requiring hemodialysis. Of these patients, no MACE or major bleeding events occurred. CONCLUSIONS: This analysis observed that a tirofiban bridging strategy without an initial bolus loading dose has comparable efficacy and safety as previously published reports. A tirofiban infusion without bolus dosing may be a safe option for antiplatelet bridging in patients with a recent cardiac stent implant to prevent stent thrombosis.

Reversing the anticoagulation effects of dabigatran.

The standard of care for oral anticoagulation therapy has primarily been warfarin, which is limited by its indirect mechanism-of-action, variable kinetics, tolerability, and routine monitoring concerns. The direct-acting oral anticoagulants (DOACs) have predictable pharmacokinetics and pharmacodynamics, and improved safety and efficacy compared to warfarin for the prevention of stroke in patients with nonvalvular atrial fibrillation and prevention or management of venous thromboembolism. Consequential bleeding is a concern with all anticoagulants. Vitamin K is not a rapid reversal agent for warfarin; rather it facilitates synthesis of new vitamin K-dependent clotting factors, which can take longer than 24 h. Other nonspecific agents, including recombinant activated factor VII, three- and four-factor prothrombin complex concentrates (PCC), and activated PCC or Factor Eight Inhibitor Bypassing Activity (FEIBA®), are options based on clinical need. Specific agents to quickly reverse the effects of DOACs have been under development, and idarucizumab, a monoclonal antibody fragment that rapidly binds dabigatran, has been approved for clinical use in cases of dabigatran-related life-threatening bleeding, or if a dabigatran-treated patient needs emergency surgery or an invasive procedure. Idarucizumab specifically and rapidly reverses dabigatran-induced anticoagulation as measured by established coagulation assays. However, this does not guarantee complete hemostasis, especially if a patient has underlying comorbidities such as renal or liver disease, or has experienced recent trauma that requires urgent surgery. In these cases, concomitant supportive therapy and/or administration of concentrated clotting factors may be considered. Emerging data from ongoing trials and clinical experience will further inform providers regarding optimal approaches for anticoagulation reversal.

Developing a management plan for oral anticoagulant reversal.

PURPOSE: To describe a process for prompt evaluation and management- including reversal of the effects of warfarin and target-specific oral anticoagulants-of patients with or at high risk for bleeding during oral anticoagulant therapy or when such therapy is interrupted for an urgent invasive procedure or surgery. SUMMARY: The use of pharmacologic interventions for anticoagulant reversal may depend on the measured level of anticoagulation, time since the last anticoagulant dose, target level of coagulation, reliability of laboratory tests of coagulation, severity of or risk for bleeding, the agents' mechanism of action and pharmacokinetics, and pharmacodynamics of the reversal agent. The patient's age, weight, renal function, comorbid conditions, and other drug therapy, as well as the risk for thromboembolism and other adverse effects of the reversal therapies, also enter into therapeutic decisions. Hemodialysis may be used to remove the direct thrombin (factor IIa) inhibitor dabigatran and reverse its anticoagulant effects. Limited experience with clotting factor concentrates suggests that activated prothrombin complex concentrate may be useful for reversing the anticoagulant effects of dabigatran. The activity of oral factor Xa inhibitors (i.e., rivaroxaban and apixaban) is higher up the common pathway of the coagulation cascade and thus may be easier to reverse than that of direct thrombin inhibitors. Additional clinical experience is needed to identify the optimal reversal agents, dosage, and impact on thrombosis or bleeding outcomes for both classes of agents. CONCLUSION: A comprehensive plan individualized to each agent should be developed to promptly reverse the effects of oral anticoagulants and optimize outcomes in patients with bleeding or an urgent need for surgery.

Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study.

BACKGROUND: Patients receiving the direct thrombin inhibitor dabigatran may have selected anticoagulation assays performed as part of routine care. The effect of dabigatran on the international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen requires clarification. OBJECTIVE: To describe the effect of dabigatran on selected assays in North America and the United Kingdom. METHODS: Pooled normal plasma enriched with dabigatran at concentrations of 25, 50, 75, 100, 125, 150, 200, 300, 400, and 500 ng/mL were sent blinded to 19 centers in the US, the UK, and Canada to assess the effect of dabigatran on routine coagulation screening tests, the INR, aPTT, TT, and fibrinogen. RESULTS: Data were returned from 16 centers. For effects on INR, Neoplastine CI Plus and Simplastin HTF were the most sensitive and Thromborel S the least sensitive to increasing dabigatran concentrations. For the aPTT, all reagents demonstrated decreasing sensitivity to increasing dabigatran concentrations. Measured fibrinogen either demonstrated no change or factitious decrease with increasing dabigatran concentrations. Commercial TT methods were very sensitive to low concentrations of dabigatran, with 9 of 10 reporting sites exceeding test limits at dabigatran concentrations of 100 ng/mL. CONCLUSIONS: The INR, aPTT, and TT rise as dabigatran concentrations increase. Both the INR and aPTT increase in a linear pattern with marginal slopes, creating challenges in using these assays as reliable means for assessing the amount of dabigatran present. The commercial TT assay is very sensitive at low concentrations of dabigatran. Fibrinogen test results may be either unaffected or lower in the presence of dabigatran.

Bivalirudin for anticoagulation during hypothermic cardiopulmonary bypass and recombinant factor VIIa for iatrogenic coagulopathy.

OBJECTIVE: To describe management of anticoagulation with a decreased dose requirement of bivalirudin during cardiopulmonary bypass using deep hypothermic circulatory arrest (DHCA) and the reversal of the ensuing coagulopathy with recombinant factor VIIa (rFVIIa). CASE SUMMARY: A 48-year-old male developed chest pain, hypertension, and an aortic aneurysm requiring urgent surgical repair. At the time of surgery, the patient reported an allergy to heparin, so bivalirudin was used for anticoagulation (1 mg/kg loading dose, followed by intermittent infusions of 1.25-2.5 mg/kg/h over the 5 hours of cardiopulmonary bypass). When the cooling process was initiated, bivalirudin was stopped in anticipation of loss of the clotting cascade function and potential slowing of drug elimination. Bivalirudin was restarted for 45 minutes during the rewarming period because of concern for potential clot formation in the bypass circuit with recovery of hemostasis; it was again stopped due to the patient's activated clotting time (ACT) of 504 seconds. Despite this measure, diffuse and severe coagulopathy was observed upon rewarming, with ACTs longer than 999 seconds. Although multiple blood products were administered, visualization of a clot in the surgical field was not notable. A total dose of rFVIIa 20 µg/kg was administered, resulting in visual clot formation within 4 minutes. On postsurgical day 6, bilateral asymptomatic distal deep vein thromboses were noted on imaging; on postsurgical day 8, fondaparinux 2.5 mg subcutaneously was administered daily to prevent clot extension. The patient was discharged on postoperative day 23 with no acute issues and no further anticoagulants. DISCUSSION: Alternative anticoagulation agents such as bivalirudin are used in patients who have an allergy or contraindication to heparin. We propose that prolonged coagulopathy after the induction of hypothermia is due to decreased clotting cascade function as well as slowing of protease activity resulting in decreased bivalirudin elimination. We observed a positive response to low-dose rFVIIa, which could be due to activation of the extrinsic pathway and/or a thrombin burst, resulting in hemostasis. Currently, there is limited evidence supporting reversal of direct thrombin inhibitors with rFVIIa. CONCLUSIONS: In the setting of DHCA, bivalirudin should be used cautiously, with frequent monitoring of the ACTs and potential cessation of the infusion in anticipation of prolonged drug effect with subsequent potential coagulopathy. If coagulopathy ensues, use of low-dose rFVIIa may be an option to initiate hemostasis. When using rFVIIa, it is important to consider the risk of thrombosis and monitor patients accordingly.

Clinical and management challenges in preventing venous thromboembolism in health systems: a case-based panel discussion.

PURPOSE: To illustrate clinical and management issues in the prevention of venous thromboembolism (VTE) in health systems. SUMMARY: Lack of evidence to guide the choice among available anticoagulants and the dosing, timing of initiation, and duration of therapy for VTE prevention in certain clinical situations can present challenges for clinicians. Patient characteristics such as the presence of obesity, epidural catheters, renal impairment, or heparin- induced thrombocytopenia complicate the decision-making process. The introduction of new anticoagulants may overcome some of the clinical challenges associated with VTE prophylaxis, but determining whether to add new agents to the formulary and restrict their use may pose management challenges. The safety, effectiveness, ease of use, and cost of new agents compared with older agents already on the formulary are primary considerations. CONCLUSION: An understanding of the clinical and management issues involved in preventing VTE is needed to improve the use of anticoagulants and reduce the incidence of VTE in health systems.

Issues in assessing and reducing the risk for venous thromboembolism.

PURPOSE: To describe issues and challenges associated with venous thromboembolism (VTE) risk assessment and the use of drug therapies for VTE prophylaxis. SUMMARY: Patients at risk for VTE are a heterogeneous group. Systems for scoring VTE risk have been developed to identify patients who warrant prophylaxis, but most risk-scoring systems are complex and have not been validated. The optimal drug therapies and dosing strategies for reducing VTE risk are not well defined for many clinical situations, despite the availability of evidence-based guidelines from authoritative sources. Patient characteristics can influence the agent selected, dosing, timing of initiation, and duration of drug therapy. Individualized approaches to prophylaxis in patients undergoing major orthopedic surgery should take into account the presence of severe renal impairment, critical illness, morbid obesity, epidural catheters, and history of heparin-induced thrombocytopenia. To provide safe, effective VTE prophylaxis, clinicians, including health-system pharmacists, should collaborate in developing management plans tailored to patients' needs. CONCLUSION: Preventing VTE is a challenge that can be addressed by gaining an understanding of the issues involved in patient assessment and prophylactic drug therapy and using a team approach to optimize patient outcomes.

Considerations for drug dosing post coronary artery bypass graft surgery.

Acute physiologic changes after bypass graft surgery may temporarily result in reduced drug elimination and dosing requirements for the desired effect. Substantially lower doses for drugs such as the direct thrombin inhibitor argatroban may need to be considered when initiating therapy soon after surgery if the therapeutic window is narrow and impaired liver, kidney, or cardiac function is present. Initial dosing approaches, with follow-up infusion rate adjustments and allowances for the extended time needed to establish and maintain an activated partial thromboplastin time value in the target ratio range, also need to consider the risk of thrombosis or bleeding complications. The duration of reduced dosing may depend on several variables, and, as systems recover, the dosage may need to be adjusted upwards. Retrospective analysis for identifying heparin-induced thrombocytopenia may be difficult in situations where other causes of thrombocytopenia are present, suggesting that posttest scoring methods also be considered to confirm its presence until better, validated methods become available.

Systemic anticoagulant prophylaxis for central catheter-associated venous thrombosis in cancer patients.

OBJECTIVE: To review the literature regarding the incidence of thrombosis in cancer patients with central venous catheters (CVCs) and weigh the evidence supporting thromboprophylaxis in this patient population. DATA SOURCES: Clinical literature was identified by searching MEDLINE (1966-February 2007) using the key search terms malignancy, cancer, catheters, prophylaxis, thrombosis, and central venous catheters. STUDY SELECTION AND DATA EXTRACTION: An evaluation of retrospective and prospective clinical trials that studied the use of systemic anticoagulants (eg, warfarin, heparin, and low-molecular-weight heparin [LMWH]) to prevent thrombosis with CVCs was performed. Different patient populations, including those manifesting with solid tumor or hematologic malignancy and those undergoing hematopoietic stem cell transplant, were evaluated for this review. DATA SYNTHESIS: Thrombosis associated with CVCs is a common complication in cancer patients. Most CVC thrombosis will occur within 30 days after placement, with a majority within 8 days. The incidence may depend on the type of CVC and location of the catheter tip. Despite recommendations against the use of systemic anticoagulation for prophylaxis against CVC thrombosis, a potential role continues to be explored in selected settings. Several variables are noted between published clinical trials, making any comparisons difficult to determine whether any benefit exists. Generally, the use of mini-dose warfarin, LMWH, or low-dose unfractionated heparin did not consistently reach significance in reporting a reduction in CVC thrombosis. CONCLUSIONS: Available data do not support the routine use of anticoagulants for thromboprophylaxis to prevent CVC-related thrombosis. However, several inconsistencies can be found in the studies done to date. More studies are needed to identify subsets of cancer patients who are at higher risk of developing CVC thrombosis and may benefit from prophylactic systemic anticoagulation.

Heparin-induced thrombocytopenia: treatment options and special considerations.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse effect that typically manifests several days after the start of heparin therapy, although both rapid- and delayed-onset HIT have been described. Its most serious complication is thrombosis. Although not all patients develop thrombosis, it can be life threatening. The risk of developing HIT is related to many factors, including the type of heparin product administered, route of administration, duration of therapy, patient population, and previous exposure to heparin. The diagnosis of HIT is typically based on clinical presentation, exposure to heparin, and presence of thrombocytopenia with or without thrombosis. Antigen and activation laboratory assays are available to support the diagnosis of HIT. However, because of the limited sensitivity and specificity of these assays, bedside probability scales for HIT were developed. When HIT is suspected, prompt cessation of all heparin therapy is necessary, along with initiation of alternative anticoagulant therapy. Two direct thrombin inhibitors--argatroban and lepirudin--are approved for the management of HIT in the United States, and bivalirudin is approved for use in patients with HIT who are undergoing percutaneous coronary intervention. Other agents, although not approved to manage HIT, have also been used; however, their role in therapy requires further evaluation. A comprehensive HIT management strategy involves the evaluation of numerous factors. Many patients, including those undergoing coronary artery bypass surgery, those with acute coronary syndromes, those with hepatic or renal insufficiency, and children, require special attention. Clinicians must become familiar with the available information on this serious adverse effect and its treatment so that optimum patient management strategies may be formulated.

Choosing the appropriate antithrombotic agent for the prevention and treatment of VTE: a case-based approach.

OBJECTIVE: To review the risk of venous thromboembolism (VTE) in various patient populations and evaluate the agents available for the prevention and treatment of VTE using a case-based approach. DATA SOURCES: A MEDLINE search (1995-July 2006) was conducted to identify relevant literature. Additional references were reviewed from selected articles. STUDY SELECTION AND DATA EXTRACTION: Articles related to the prevention of VTE in orthopedic surgery, general surgery, and medically ill patients, as well as the treatment of VTE, were reviewed. DATA SYNTHESIS: Pharmacologic options for the prevention and treatment of VTE include warfarin, unfractionated heparin (UFH), low-molecular-weight heparins (LMWH), and fondaparinux. Current guidelines support the use of warfarin, LMWH, or fondaparinux for VTE prophylaxis following lower limb major orthopedic surgery. For VTE prophylaxis in hospitalized medical patients or patients undergoing general surgery, use of UFH and LMWH is supported; however, recent data on fondaparinux suggest that it is also effective in these patient populations. The use of UFH or LMWH (both in conjunction with warfarin) for treatment of acute deep venous thrombosis or nonmassive pulmonary embolism is recommended. Recent data suggest that fondaparinux (in conjunction with warfarin) is also effective for the treatment of VTE. A variety of pharmacokinetic, pharmacodynamic, and pharmacoeconomic factors differentiate each agent for the various indications. CONCLUSIONS: Currently, a "one-size-fits-all" anticoagulant is not available for treatment of VTE. A variety of patient factors, including type of surgery, medical indication, thrombotic risk factors, bleeding risk, history of heparin-induced thrombocytopenia, and a variety of comorbid conditions can affect the safety, efficacy, and selection of appropriate VTE therapy.

Tinzaparin in outpatients with pulmonary embolism or deep vein thrombosis.

BACKGROUND: The low-molecular-weight heparins (LMWHs) have been shown to be effective in the outpatient treatment of deep vein thrombosis (DVT). Data regarding outpatient use of any LMWH in pulmonary embolism (PE) or tinzaparin in DVT while transitioning therapy to a vitamin K antagonist are limited. OBJECTIVE: To determine the safety and efficacy of tinzaparin in patients with either DVT or PE being transitioned to warfarin during LMWH therapy in the outpatient setting. METHODS: All patients who were treated with at least one outpatient dose of tinzaparin for venous thromboembolism (VTE) were identified. Charts of all patients followed within the University of California Davis healthcare system were reviewed. The incidence of bleeding and recurrent thromboembolism over a minimum of the first 4 weeks to a maximum of 12 weeks after initiating anticoagulation was assessed. RESULTS: A total of 178 patients with acute VTE were treated with tinzaparin, and outcomes could be determined in 140 cases. Forty-seven percent of these patients had objectively documented PE. Only one (0.7%) case of recurrent VTE was observed. Major bleeding was documented in 5 (3.6%) and minor bleeding in 8 (5.8%) patients. Two bleeding events, both major, occurred during tinzaparin therapy. CONCLUSIONS: Outpatient use of tinzaparin during transition to warfarin therapy in the treatment of VTE, including PE, appears to be feasible in patients who are judged candidates for home therapy.

Special considerations with fondaparinux therapy: heparin-induced thrombocytopenia and wound healing.

Multiple options for anticoagulation therapy are now available, placing an additional responsibility on health care workers for choosing the optimal therapy for each patient. The heparins carry a risk of heparin-induced thrombocytopenia (HIT), an immune-mediated reaction to heparin that may lead to pulmonary embolism and death. Fondaparinux, a new, synthetic pentasaccharide, binds to antithrombin III and potentiates antithrombin III's inhibition of factor Xa. Fondaparinux does not bind to platelet factor 4 and thus is theoretically unable to cause immunoallergic HIT. Unlike low-molecular-weight heparins, fondaparinux does not cross-react in vitro with sera from patients with clinical cases of HIT. These findings suggest that fondaparinux would not lead to formation of HIT antibodies and would not provoke clinical thrombosis in patients who had HIT antibodies because of previous exposure to heparins. To date, no cases of immunoallergic HIT have been associated with fondaparinux use in clinical trials. Anecdotal evidence suggests that fondaparinux eventually may prove to be valuable for preventing and treating thrombosis in patients with HIT. The effect of anticoagulants on wound healing is another consideration when choosing a thromboprophylactic strategy after major surgery. There is evidence that thrombin plays a role in wound healing, but fondaparinux is too small to enable antithrombin III to inhibit thrombin. Thus, fondaparinux may be less likely than a low-molecular-weight heparin to interfere with wound healing.

Argatroban therapy for antithrombin deficiency and mesenteric thrombosis: case report and review of the literature.

Antithrombin deficiency is a hypercoagulable state that can increase the risk for thrombosis, especially in the presence of other procoagulant triggers. Unfractionated heparin and low-molecular-weight heparins may not provide effective anticoagulation since they require antithrombin for activity. Direct thrombin inhibitors, however, work independently of antithrombin. A 21-year-old man with a history of heavy alcohol consumption had thrombosis of the superior mesenteric vein. Infusion with unfractionated heparin was started, and despite repeated boluses and increases to 21 U/kg/hour, the maximum activated partial thromboplastin time reached was 39 seconds. The unfractionated heparin was discontinued, and the direct thrombin inhibitor argatroban was infused at rates of 0.4-0.5 microg/kg/minute. Over the course of several weeks, the patient had numerous operations to remove and repair necrotic bowel. When no further surgery was anticipated, warfarin therapy was started; the argatroban infusion was discontinued when the patient reached the therapeutic target international normalized ratio with warfarin. No recurrent thrombosis or major bleeding occurred. Direct thrombin inhibitors, such as argatroban, seem to be suitable alternatives for acute anticoagulation in patients with antithrombin deficiency.

Low-molecular-weight heparin-induced thrombocytopenia in a child.

OBJECTIVE: To report a case of probable acute venous thrombosis caused by heparin-induced thrombocytopenia (HIT) in a pediatric patient with a normal platelet count after prolonged enoxaparin therapy. CASE SUMMARY: An 11-year-old African American female with Crohn's disease developed extensive vena cava thrombosis. Her deep vein thrombosis (DVT) was treated with intravenous unfractionated heparin followed by extended outpatient warfarin therapy. Four months later, the warfarin was stopped and subcutaneous enoxaparin 1.5 mg/kg once daily was substituted prior to an elective colonoscopy. She was readmitted 6 weeks later with acute DVT with a platelet count of 233 x 10(3)/mm3, significantly lower than the count of 550-700 x 10(3)/mm3 5 months previously and the count of 433 x 10(3)/mm3 3 months earlier. An enzyme-linked immunosorbent assay for heparin-platelet factor 4 antibodies was strongly positive and a d-dimer was elevated at 2.9 mg/L (normal <1.5). She was treated with lepirudin followed by warfarin when repeat d-dimer on day 3 was normal. An ultrasound at that time showed no clot extension, and the platelet count had risen to >300 x 10(3)/mm3. Over the next 4 months, there was no further thrombosis. DISCUSSION: HIT appears to be rare in the pediatric population, and only a few cases treated with a direct thrombin inhibitor have been reported. This is the first case report to our knowledge of a pediatric patient developing HIT secondary to enoxaparin. An interesting feature of this case is the development of HIT in the face of a normal platelet count, which is rare but has been reported in adults. CONCLUSIONS: Pediatric patients receiving low-molecular-weight heparin are still at risk for developing HIT. Treatment of HIT should involve the initial use of a direct thrombin inhibitor to manage thrombosis until the platelet count returns to higher values. Once the platelet count returns, warfarin can be used for long-term thrombosis management.

Pharmacotherapy of heparin- induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a life-and-limb threatening condition that is associated with the development of antibodies that activate platelets and the coagulation system in the presence of unfractionated heparin or low molecular weight heparin. The binding of antibody to heparin-PF-4 complexes can activate platelets, leading to an acute, often catastrophic, thrombotic diathesis. The most common laboratory finding is the development of thrombocytopenia 5 or more days after beginning heparin treatment, which occur in up to 1 - 5% of patients exposed to heparin, depending on type of heparin and indication for anticoagulation. The onset of thrombocytopenia can be immediate or delayed for several weeks after the exposure to heparin. Approximately 50 - 60% of patients who develop HIT manifest acute venous or arterial thrombosis and a significant percentage of these patients die or develop vascular gangrene of a limb that requires amputation. Given the severe sequelae associated with HIT, recognition and immediate medical management is essential. Treatment of a patient with HIT is complex, as there are several different anticoagulants now available which have been shown to be useful. Optimal management depends on each patient's individual clinical manifestations, as well as the need for ongoing anticoagulation therapy. No single agent or treatment approach can be considered to be 'standard practice' as very few clinical trials have been completed, compare different treatment options. The use of warfarin alone in a patient with HIT, must be avoided in order to avoid the possibility of further activating coagulation, which may hasten the development of venous limb gangrene. There are several different tests available that detect HIT antibodies and each has different sensitivity and specificity for HIT. In this review we discuss the epidemiology and natural history of HIT, risk factors associated with the development of HIT and the clinical and laboratory tests that aid in the diagnosis and treatment. Special emphasis is given to addressing the management of HIT in special populations, particularly patients with renal or liver disease, acute coronary syndromes, pregnancy, paediatrics and patients who require cardiopulmonary bypass surgery.