Anticoagulants and Blood

Educational Objectives

The goal of this program is to improve prevention and treatment of perioperative deep venous thrombosis (DVT) and the practice of blood transfusion. After hearing and assimilating this program, the clinician will be better able to:

1.   Use appropriate pharmacologic and mechanical measures to prevent DVT in clinical practice.

2.   Recognize the indications for extended DVT prophylaxis.

3.   Describe the pros and cons of the most promising new anticoagulants, including oral thrombin inhibitors and factor Xa inhibitors.

4.   List and discuss the major causes of transfusion-related mortality.

5.   Determine whether a patient needs a transfusion and, if so, the best management strategy for that patient.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose. Dr. Pendleton presents information that is related to off-label use of medication.

Acknowledgements

Dr. Pendleton spoke at the 37th Annual Phoenix Surgical Symposium, held February 11-14, 2009, in Phoenix, AZ, and sponsored by the Phoenix Surgical Society. Dr. Diebel was recorded at the Detroit Trauma Symposium, held No­vember 6-7, 2008, in Detroit, MI, and sponsored by the Detroit Receiving Hospital and Wayne State University School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

An Update on DVT/PE Prophylaxis

Robert C. Pendleton, MD, Associate Professor of Medicine and Director, University Thrombosis Service, Uni­versity of Utah School of Medicine, Salt Lake City

Background: Institute of Medicine 1999 report, “To Err is Human,” key catalyst behind national quality improve­ment (QI) movement; venous thromboembolism (VTE) kills more Americans annually than AIDS, breast cancer, and motor vehicle fatalities combined; »60% of all VTE events linked to hospitalization or surgery, when inter­vention possible; surrogate end points include asymptomatic clots in large proximal veins of thigh, as well as symptomatic events; without prophylaxis, 5% to 10% of surgery patients develop deep venous thrombosis (DVT)

Controversies: is emphasizing DVT prevention justifiable, when 80% of all VTE asymptomatic, with no effect on patient outcomes? of patients who die of pulmonary embolism (PE), »70% have no premorbid symptoms; best data from other countries suggest that 10% of all hospital deaths related to fatal PE

Routine QI prevention measures: shown to improve patient outcomes in VTE; example  —  electronic alert system used at Brigham and Women’s Hospital (Boston, MA) decreased clinical VTE events by 40% over 1- to 3-mo follow-up; American College of Chest Physicians (ACCP) now recommends that hospitals have formal strategies for routine prevention of DVT; however, clinical practice often does not follow practice guidelines; national reg­ulatory bodies striving to hold clinicians accountable

Surgical Care Improvement Project (SCIP): joint effort by Joint Commission (JC), National Quality Forum (NQF), and Centers for Medicare and Medicaid Services (CMS) to define best practices, including DVT prevention; hos­pitals now required to report percentage of patients with recommended prophylaxis ordered, and percentage of surgery patients who receive prophylaxis £24 hr before surgery and 24 hr after surgery; patients and payors can examine individual hospitals’ practices online

Best practices defined SCIP: most general-surgery patients assumed to have intermediate risk; preferred strategy pharmacologic prophylaxis; mechanical prophylaxis indicated for patients at high risk for bleeding; orthopedic surgery or trauma patients considered higher risk, and therefore more aggressive pharmacologic approach indi­cated; opinion that pharmacologic prophylaxis leads to better outcomes in VTE and lower mortality (however, evidence supporting that view becoming dated); recent meta-analysis of bleeding risk associated with pharmaco­logic prophylaxis showed only modest increase in average risk (each patient should be considered individually)

Stratification of regimens recommended by ACCP: not recommended  —  aspirin (associated with risk; no evidence of efficacy); moderate recommendation  —  unfractionated heparin administered bid; recommended as proactive strategy for patients with some bleeding risk; for patients with lower bleeding risk, more aggressive heparin strat­egies or low molecular weight (LMW) heparin recommended

Precaution with routine pharmacologic prophylaxis: neuroaxial anesthesia  —  includes deep peripheral nerve blocks; do not insert or withdraw needles during peak anticoagulant activity; instead, insert or withdraw needle at nadir of anticoagulant activity (before next scheduled dose)

Mechanical prophylaxis (pneumatic compression): efficacy 60%; questions regarding applications in everyday practice (eg, knee-high devices sufficient, or thigh-high devices necessary?); compliance biggest drawback; rates of use in routine practice,  »50%; clinicians who prefer mechanical compression must ensure that nurses apply it as prescribed; ACCP guidelines recommend mechanical prophylaxis primarily for patients at high risk for bleed­ing, or as adjunct to pharmacologic prophylaxis for very high-risk patients; pharmacologic prophylaxis still rec­ommended for most surgical patients

Prophylaxis associated with laparoscopic surgery: VTE uncommon (event rate <2%) in this patient population; therefore, ACCP guidelines recommend no prophylaxis other than early ambulation; exceptions  —  patients with active cancer, previous DVT or PE, or who have undergone long or complicated procedure; recommendations similar to those for open surgery; consider combining modalities for patients at highest risk for VTE

Duration of prophylaxis: especially important for patients undergoing orthopedic surgery; 75% of all symptomatic DVT and PE events in post-joint replacement patients occur after hospital discharge (mean, day 17 after hip ar­throplasty, and day 7 after knee replacement surgey); extending prophylaxis through postoperative day 28 to 35 “highly effective”; prolonged prophylaxis now standard of care in this population

Patients undergoing abdominopelvic cancer surgery: consider extended prophylaxis, especially if patients at high risk (eg, elderly, with prolonged immobility); patients undergoing general abdominal surgery also benefit from extended (28 days) prophylaxis

New Anticoagulants on the Horizon: Is a Change Upon Us?

Dr. Pendleton

Background: warfarin and heparin used for >50 yr; coagulation system (and alterations to it) complicated; consists of intrinsic and extrinsic systems that culminate in final common pathway leading to fibrin formation

Actions of new anticoagulants (in phase III trials): direct inhibition of factor Xa and thrombin; however, complexity of coagulation system means targeting just one area carries high risk for unintended or off-target effects

Oral thrombin inhibitors: block ability of thrombin to convert fibrinogen to clot-bound fibrin; thrombin also in­volved in clot stabilization, platelet activation, thrombin inhibition (through feedback loop), and inflammation, raising potential for impact on many other effects; negatives of heparin  —  works through antithrombin; therefore, cannot reach clot-bound fibrin to prevent further clot propagation, which limits its efficacy

Dabigatran: currently approved in Canada and some European countries; peak activity occurs within »1 hr; half-life 12 to 17 hr; mostly eliminated through kidneys

Ximelagatran: proven efficacy in patients with myocardial infarction and atrial fibrillation; effective for secondary PE and DVT prevention, and acute VTE treatment; good risk-benefit profile; however, 5% to 10% of patients de­veloped significant hepatotoxicity, prompting Food and Drug Administration (FDA) to reject US application, de­spite previous European approval; orthopedic trials also raised questions about efficacy, risk for cardiovascular events, and methodologic problems

Orthopedic surgery patients: first subjects in almost all trials of new anticoagulants, due to high risk for clots; in these studies, dabigatran as safe and effective as LMW heparin in preventing VTE events and mortality; dabiga­tran approved in Europe and Canada; however, North American trials could not show noninferiority to LMW heparin, so more data needed for US approval

Factor Xa inhibitors: factor Xa upstream from thrombin, at key amplification point in coagulation cascade; fondaparinux (Arixtra)  —  mechanism of action similar to that of LMW heparin (indirect inhibition of factor Xa through antithrombin); cleared by kidneys; FDA-approved for prevention and treatment of VTE]; idraparinux  —  subcutaneous indirect factor Xa inhibitor administered once per week; half-life £130 hr; could present problem for patients requiring urgent surgery; in early phase III trials, associated with high risk for acute PE; in phase III trial of patients with atrial fibrillation, idraparinux associated with nearly double risk for major bleeding compli­cations; antidote now available to reverse effect if necessary, but speaker remains skeptical

Oral factor Xa inhibitors: work on free-floating factor Xa and as part of prothrombinase complex; rivaroxaban and apixaban furthest along in development; half-lives range from 5 to 9 hr (rivaroxaban) to 12 hr (apixaban); both inhibitors have rapid onset of action, high degree of bioavailability, and multiple routes of excretion (benefit for patients with renal insufficiency or liver dysfunction); both have wide therapeutic window, with few drug-drug interactions; no drug-food interactions, and no off-target effects yet identified; effect dose-dependent; apixaban shows trend for greater efficacy than enoxaparin or warfarin in orthopedic surgery patients; in low doses, apixa­ban at least as safe as enoxaparin or warfarin (associated with fewer bleeding events); however, cost-effective noninferiority of apixaban difficult to prove; rivaroxaban under review at FDA; more effective than enoxaparin in reducing VTE in patients undergoing knee or hip replacement, with no difference in bleeding complications; however, dose of enoxaparin used in trials 40 mg/day, rather than standard North American dose of 30 mg bid

There Will Be (Bad) Blood

Lawrence N. Diebel, MD, Professor of Surgery, Wayne State University School of Medicine, and Chief of SICU, Harper University Hospital, Detroit, MI

Current risks of allogeneic blood transfusion: unrecognized or unexpected transfusion-related deaths likely in­crease total and long-term mortality rates

Causes of transfusion-related mortality (in descending order): transfusion-related acute lung injury (TRALI); con­tamination of blood or blood products; blood type mismatching

Transfusion-related lung injury: often unreported; involves plasma component found even in red blood cells (RBCs)

Contamination: bacterial or viral

Blood type mismatching: fatal in »10% of cases; accounts for ³16 deaths/yr in United States; other clinically rele­vant problems include allergic or anaphylactic reactions, development of alloantibodies to RBC antigens, and possible development of transfusion-associated graft-versus-host disease

Transfusion-related problems: blood banks inefficient method for storing blood; often, too much blood donated too late to help anyone; excess discarded; suggests need for blood substitutes (eg, hemoglobin-based oxygen carrier [HBOC]; Polyheme); shelf-life of RBCs 42 days; >90% of donated blood utilized; restrictions on donor eligibility increasing; transfused patients at risk for transfusion-related immune system modulation (TRIM); true benefits of RBC transfusion unknown; TRIM associated with increased risk for cancer recurrence, perioperative infection, and multiple organ failure; causes include “passenger” white blood cells (WBCs; indicates role for leukoreduction of transfused RBCs), and patient factors such as endothelial activation (particular concern with trauma patients); risk may be increased if RBCs stored for lengthy period; RBC storage lesion  —  occurs on day 1; associated with rapid loss of nitric oxide, which affects ability of blood to deliver oxygen through microcirculation; also associated with transfusion-associated lung injury and lipid-induced priming of polymorphonuclear leukocytes, and febrile transfu­sion reactions

Transfusions after trauma: associated with increased risk for multiple organ failure and mortality; longer length of stay; risk for systemic inflammatory response syndrome (SIRS) or acute respiratory distress syndrome (ARDS); increased risk for infectious complications; mitigating factors  —  use of “old” blood or transfusing >6 U within first 12 hr amplifies drawbacks; transfusion associated with increased risk for infection (evidence of linear corre­lation between number of units transfused and incidence of infection); according to a meta-analysis, risk for post­transfusion infection highest in trauma patients; transfusion of blood products independent risk factor for transfusion-associated pneumonia (risk increases with number of units transfused); age of blood corresponds to risk for multiple organ failure and major infections

Leukoreduction: associated with RBC loss; expensive ($35/U); does not decrease mortality or lung injury among trauma patients; associated with decreased incidence of infection, especially when >6 U of RBCs transfused; risk for RBC adhesion to endothelium increases over time; overall, speaker considers it worth extra $35; benefits of leukoreduction decrease when patient given old blood (stored >14 days); RBC washing time-consuming, with lit­tle benefit

Hemoglobin-based oxygen carrier: speaker coauthor of study of 712 patients at multiple trauma centers; median transport time from trauma scene to medical center, 26 min; 1 U of HBOC increases hemoglobin by 1 g/dL; com­pared to patients receiving standard care, no difference in mortality at day 1 or day 30; conclusion  —  HBOC use­ful when blood needed but not available; confounding factors included short transport time; flawed definition of shock (systolic blood pressure <90 mm Hg; 50% of control group received no blood); no difference in myocar­dial events between groups

Microcirculation: oxygen exchange probably occurs at capillary-venule level and possibly capillary-arteriole level; changes associated with blood loss during trauma include changes in functional capillary perfusion, interactions between WBCs and endothelium, and conformational changes in RBCs; perfusion of “new” blood (stored <21 days) had salutary impact on Shugoshin-like protein 2 (SGOL2); older blood did not have that effect; suggests that older blood does not traverse capillaries as well as new blood, although HBOC has been shown to improve microcirculatory blood flow

Patient management: administer blood if patient bleeding heavily; when bleeding controlled, consider comorbidi­ties, age of patient, cardiac status, hemodynamic stability, and degree of pulmonary disease (if any); if patient has cardiac disease, use lower threshold for transfusing blood; restrict transfusions in hemodynamically stable pa­tients; leukoreduction “can’t hurt, might help”; restrict use of old blood in massively transfused patients; consider HBOC if blood not available

Suggested Reading

Dentali F et al: Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 147:523, 2007; Geerts WH et al: Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133(6 Suppl):381S, 2008; Geerts WH et al: Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126(3 Suppl):338S, 2004; Marik PE, Corwin HL: Efficacy of red blood cell transfusion in the critically ill: a systematic review of the liter­ature. Crit Care Med 36: 2667, 2008; Snyder CW et al: The relationship of blood product ratio to mortality: survival benefit or sur­vival bias? J Trauma 66:358, 2009; Stinnett JM et al: Venous thromboembolism prophylaxis in medically ill patients and the development of strategies to improve prophylaxis rates. Am J Hematol 78:167, 2005; Urbankova J et al: Intermittent pneumatic compression and deep vein thrombosis prevention. A meta-anlysis in postoperative patients. Thromb Haemost 94:1181, 2005; Wein­berg JA et al: Age of transfused blood: an independent predictor of mortality despite universal leukoreduction. J Trauma 65:279, 2008; Weinberg JA et al: Transfusions in the less severely injured: does age of transfused blood affect outcomes? J Trauma 65:794, 2008; Weitz JI et al: New anticoagulant drugs: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126(3 Suppl):265S, 2004; Weitz JI et al: New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133(6 Suppl):234S, 2008.