BLOOD ISSUES
| ANTICOAGULATION MANAGEMENT OF SPECIAL POPULATIONS —Robert C. Pendleton, MD, Assistant Professor
of Medicine, University of Utah Medical Center, Salt Lake City
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| Parenteral anticoagulants: 3 primary classes—unfractionated heparin (UFH), low molecular weight heparin
(LMWH), and pentasaccharides (eg, fondaparinux); exert anticoagulant activity through, and have ability to potentiate,
antithrombin; antithrombin inactivates enzymes involved in coagulation and has anti-10a activity
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| Newer agents: ie, LMWH and pentasaccharides; more specifically stimulate antithrombin anti-factor Xa activity; associated
with increased subcutaneous bioavailability, compared to UFH; half-life of UFH 1 to 2 hr, LMWH 4 hr, and pentasaccharides
17 hr; LMWH and pentasaccharides processed through renal system; provide weight-based dosing for treatment
or fixed dosing for prophylaxis, with predictable anticoagulant activity, allowing for once-daily or bid dosing without
monitoring in most patients; prolonged use associated with decreased incidence of osteoporosis and heparin-induced
thrombocytopenia (HIT), compared to UFH; slight clinical advantage over UFH in treating patients with venous thromboembolism
(VTE) and acute coronary syndromes (ACS); safer and more convenient to use for prophylaxis in patients at
high risk for VTE; allow outpatient management of deep venous thrombosis (DVT); LMWH allows outpatient “bridging”
management; LMWH preferred method for most indications; monitoring—consider in obese patient and patient with renal
impairment; College of American Pathologists recommends monitoring chromogenic anti-factor Xa activity with
LMWH; measure peak activity dose 4 hr after dose; useful in morbid obesity, renal failure, pregnancy, and during prolonged
use; target peak anti-factor Xa levels for prophylactic dosing (0.1 to 0.2 IU/mL) and for treatment dosing (1.0 to 2.0
IU/mL [once-daily dosing] or 0.6 to 1.0 IU/mL [bid dosing]
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| Obese patient: treatment dosing—study looked at weight-based dosing of LMWH in obese patients; use of total body
weight in calculating dose associated with best clinical outcome; study looked at pharmacokinetics of single treatment
dose of LMWH in morbidly obese patients (weight up to 144 kg) compared to normal weight controls; pharmacokinetic
curves of anti-factor Xa activity almost identical; study showed no apparent cumulative effect of repeated dosing of LMWH
in obese patients treated for VTE; subgroup analysis of data from Thrombolysis in Myocardial Infarction (TIMI) 11B and
Efficacy and Safety of Enoxaparin in Non-Q Wave Coronary Events (ESSENCE) trials showed enoxaparin slightly more effective
than UFH in nonobese and obese patients with ACS in reducing death, myocardial infarction (MI), and urgent revascularization;
fewer cases of major hemorrhage in obese patients given LMWH; incidence of bleeding same with LMWH
and UFH; fondaparinux—Matisse studies in obese patients; compared fondaparinux to enoxaparin in treatment of
DVT, and fondaparinux to UFH in treatment of PE; fondaparinux did not increase incidence of major bleeding or lose
clinical efficacy in obese patients; prophylaxis—study looking at LMWH in obese surgical patients showed that as body
weight increases, anti-factor Xa exposure with fixed dose of LMWH decreases; Prospective Evaluation of Dalteparin Efficacy
for Prevention of VTE in Immobilized Patients Trial (PREVENT) found that as body weight increases, efficacy of
dalteparin decreased, compared to placebo; efficacy of fixed dose of dalteparin same as placebo in patients with body
mass index (BMI) >40; study looking at enoxaparin 40 mg once daily in patients undergoing orthopedic surgery; patients
with BMI >32 have 2-fold increase in venographic DVT rate; studies suggest these agents lose clinical efficacy at certain
body weight; speaker recommends using weight-based prophylactic dosing up to total body weight of 170 kg to achieve
predictable anticoagulant activity in obese patients (correlates to enoxaparin dose of 0.5 mg/kg once daily); study looking
at prophylactic dosing of LMWH in patients undergoing bariatric surgery found 40-mg dose of enoxaparin q12h in combination
with mechanical devices and early ambulation resulted in decrease in rate of VTE from 5.4% to 0.6%; therapeutic
indications—dose of LMWH based on actual body weight with no cap; consider monitoring anti-factor Xa activity
in patients >150 kg; fondaparinux effective, but consider alternative method of anticoagulation in patients >125 kg; prophylactic
indications—adjust dose in obese patients( >125 kg) or increase dose interval
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| Patients with renal impairment: fondaparinux—contraindicated because of 17-hr half-life and renal elimination;
LMWH—consider use in some patients; pharmacology of LMWH means that as renal function declines, half-life increases;
2- to 3-fold increase in elimination half-life in renally impaired patients; study looked at treatment dose of LMWH compared
to UFH in ACS patients with and without impaired renal function (creatinine clearance 25 mL/min); renally impaired
patients exhibited higher rates of ischemic events; LMWH associated with increased clinical efficacy, compared to UFH in
all patients irrespective of renal impairment; patients with renal dysfunction had higher rates of major bleeding, whether
they received UFH or LMWH; study used different doses of enoxaparin in patients with severe or moderately impaired renal
function or normal renal function and found decreasing dosage (based on severity of renal impairment) resulted in similar
levels of anti-factor Xa activity; recommend two thirds of normal dose in patients with severe renal dysfunction to achieve
same outcome; study looking at repeated dosing to prevent VTE found that patients with severe renal impairment (creatinine
clearance <30 mL/min) had increased exposure to enoxaparin, resulting in 35% increase in anti-factor Xa activity and 2.5-
fold increase in elimination half-life; studies looking at prophylactic doses of LMWH in patients with mild-to-moderate renal
impairment (creatinine clearance 30-90 mL/min) found no increased risk for bleeding; dose adjustment appears unnecessary
in patients with mild-to-moderate dysfunction; recommendations—use UFH for therapeutic indications; for
prophylactic indications, no dose adjustment necessary in patients with creatinine clearance >30 mL/min; consider using
UFH and mechanical devices or enoxaparin 30 mg once daily in patients with creatinine clearance <30 mL/min
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| THE COAGULOPATHIC PATIENT: USING SYSTEMIC AND LOCAL HEMOSTATIC AGENTS —Kenji Inaba, MD,
Assistant Professor of Surgery, Division of Trauma and Surgical Critical Care, Keck School of Medicine of the University
of Southern California, Los Angeles
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 | Liquids: fibrin-based products—differ in storage methods and duration (eg, Tisseel stored long-term and requires time
to reconstitute; Crosseal stored in refrigerator, has shorter shelf-life but quick reconstitution); contain fibrinogen and
thrombin; some products contain cross-linking agents or plasmin inhibitors; majority of products designed for use on
soft-tissue surfaces and solid organs; effective as hemostatic agent in solid organs; non-fibrin–based products—BioGlue
newest liquid hemostatic agent; contains bovine albumin and glutaraldehyde; Food and Drug Administration
(FDA)-approved for hemostasis and in large-vessel repair; stored at room temperature, and no preparation time required;
may use liquid products in combination with fibers
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| Fibers: most plant-derived, cellulose-based products, eg, Surgicel; rely on contact activation of coagulation cascade for
effectiveness; associated with low risk for infection and possibly bacteriostatic properties
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| Bandages: eg, Hemcon; variety of shapes and sizes; all products chitosan-based multilamellar bandages with adhesive
and absorptive properties; stored at room temperature; good tissue adherence and mechanical sealing; FDA-approved
for external use; studies show greater efficacy, bleeding control
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| Granules (eg, QuikClot): contains granular zeolite or volcanic rock; FDA-approved for external use; rapidly absorbs water
and concentrates clotting components in blood at injury site; inexpensive; study in porcine model shows efficacy in
creating hemostasis at site of complex groin injury; exothermic reaction created when product applied to soft tissues;
study recorded temperatures in excess of 100° C at site of application (can cause organ or tissue damage); recommend
use sparingly, apply directly to area of injury, and keep area as dry as possible; after arresting hemorrhage or during
second-look laparotomy, brush out excess granules and flood area with water for heat dissipation
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| TRANSFUSION THERAPY WITH RECOMBINANT FACTOR VII a—Dr. Inaba
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| Recombinant factor VIIa (rFVIIa): current indications—treatment of bleeding episodes in hemophilia A or B
with inhibitors to factor VIII or factor IX; prevention of bleeding in surgical interventions or invasive procedures in hemophilia
A or B with inhibitors to factor VIII or factor IX; treatment of bleeding episodes in patients with congenital
factor VII deficiency; prevention of bleeding in surgical interventions or invasive procedures in patients with congenital
factor VII deficiency
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| Indications in trauma patients: consider in hypothermic, coagulopathic, and acidotic patients to help with diffuse nonsurgical
bleeding; when used as adjunctive therapy for bleeding control in severely injured trauma patients with blunt and
penetrating injuries, study showed statistically significant decrease in transfusion of red blood cells (RBCs) and decrease
in number of patients receiving massive transfusion (>20 units) at 48 hr; no change in number of thromboembolic
adverse events; survival advantage unknown; single dose of rFVIIa costs >$7000, and complete dosing regimen
costs $30,000
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| HEPARIN-INDUCED THROMBOCYTOPENIA: WHAT THE SURGEON NEEDS TO KNOW —Erika R. Ketteler,
MD, Assistant Professor of Vascular Surgery, University of New Mexico Health Sciences Center, Albuquerque
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| Heparin-induced thrombocytopenia (HIT): type 1—occurs in 10% of patients; mild decrease in platelets (rarely
<100,000 platelets/µL); usually dissipates in 2 days; not related to immunologic function; type 2—“white clot syndrome”;
IgG-mediated; associated with ≥50% drop from baseline platelet count; characteristics—prothrombotic state;
thrombus can occur in venous and/or arterial system (50% of patients develop both); 33% of patients develop HIT within
10 days if untreated; patients can develop central necrosis of skin; 10% to 20% of patients need limb amputation; death
can occur in 20% to 30% of patients; residual effects can include stroke, MI, and PE; morbidity and mortality rates—
complications occurred in up to 78% of patients; mortality rate 20%; when thrombosis first sign of HIT, complication
rate 52% and mortality rate 21%
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| Epidemiology: HIT not rare; 33% of all hospitalized patients receive heparin; 8% develop HIT antibody; 1% get full-
blown HIT; 120,000 cases of HIT occur each year, with 8200 deaths (6.8%); 3% to 5% of cases occur with UFH, 0.5% of
cases occur after injection with LMWH, after catheter flushed, or after placement of coated catheter; HIT can occur after
single exposure to heparin; can occur in surgical, intensive care unit (ICU), vascular surgery, cardiothoracic, and orthopedic
patients; lack of awareness of HIT can lead to underdiagnosis; platelet monitoring key to diagnosis
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| Treatment: discontinue if patient develops antibodies; HIT can take minutes, hours, days, weeks, or months to develop;
50% of patients develop thrombus within 10 days; 5% of patients experience sudden death from MI or PE; cessation of heparin
can exacerbate new thrombi (treat “thrombotic storm”); provide patient with antithrombin inhibitor; do not wait for
test to confirm clinical diagnosis; new complications can develop at rate of 6% per day in untreated patient; key time to diagnose
HIT 4 to 10 days after heparin delivery; keep index of suspicion high in patient with rapidly decreasing platelet
count who has received heparin before; warfarin—do not start warfarin after heparin cessation; exacerbates prothrombosis
and can result in venous gangrene and central skin necrosis; inferior vena cava (IVC) filter—HIT not contraindication
for anticoagulation; cases reported in literature that involve IVC occlusion, resulting in venous gangrene; avoid IVC
filters in patient with HIT; consult hematologist— to rule out other etiologies for severe drop in platelet count (eg, sepsis,
graft material, pseudothrombocytopenia) and to help interpret confirmatory laboratory tests; functional tests include
heparin-induced platelet antibody (HIPA) and serotonin release assay (SRA); specific tests include enzyme-linked immunosorbent
assay (ELISA); also important from medicolegal perspective; to help manage thrombin inhibitors (can prolong
international normalized ratio [INR]) and can make warfarin dosing challenging); start warfarin when platelets ≥150,000
(consider 5-day overlap between warfarin and thrombin inhibitors); thrombin inhibitors include lepirudin (contraindicated
in patients with renal impairment) and argatroban (contraindicated in patients with liver dysfunction); hematologist can
provide other treatment options if thrombin inhibitors fail or if patient still having complications; after therapy—platelet
level rebounds; antibody disappears in 2 to 3 mo; patient should take warfarin for 2 to 3 mo; can consider heparin in future
if titers low (requires close observation)
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| Prevention: determine whether patient has received heparin in past; limit heparin to 5 days; avoid heparin flushes; use
warfarin early (except if patient had HIT; initiate oral anticoagulation at start of heparin treatment); use LMWH when
possible
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Educational Objectives
| The goal of this activity is to provide a greater understanding of the following: managing anticoagulation in special populations,
using local hemostatic agents in the coagulopathic patient, transfusion therapy with recombinant factor VIIa (rFVIIa),
and heparin-induced thrombocytopenia (HIT). After hearing and assimilating this program, the clinician will be better able
to:
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| 1. Discuss treatment dosing of parenteral anticoagulants in morbidly obese and renally impaired patients.
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| 2. Describe prophylactic dosing of parenteral anticoagulants in morbidly obese and renally impaired patients.
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| 3. List the types of local hemostatics available for the coagulopathic patient.
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| 4. State the indications for transfusion therapy with rFVIIa.
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| 5. Evaluate a patient for HIT.
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Suggested Reading
Bauer KA et al: New anticoagulants. Hematology Am Soc Hematol Educ Program 450, 2006; Bjorses K et al:
Various local hemostatic agents with different modes of action; an in vivo comparative randomized vascular surgical experimental
study. Eur J Vasc Endovasc Surg Nov 27, 2006; Creekmore FM et al: Incidence and economic implications
of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism. Pharmacotherapy
26:1438, 2006; George-Phillips KL et al: Use of low-molecular-weight heparin to bridge therapy in obese patients
and in patients with renal dysfunction. Pharmacotherapy 26:1479, 2006; Hamad GG et al: Enoxaparin for
thromboprophylaxis in morbidly obese patients undergoing bariatric surgery: findings of the prophylaxis against VTE outcomes
in bariatric surgery patients receiving enoxaparin (PROBE) study. Obes Surg 15:1368, 2005; Napolitano LM et
al: Heparin-induced thrombocytopenia in the critical care setting: diagnosis and management. Crit Care Med 34:2898,
2006; Rizoli SB et al: Recombinant Activated Coagulation Factor VII and Bleeding Trauma Patients. J Trauma
61:1419, 2006; Rondina MT et al: The treatment of venous thromboembolism in special populations. Thromb Res Jul
28, 2006; Spinler SA et al: ESSENCE and TIMI 11B Investigators. Safety and efficacy of unfractionated heparin versus
enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI
11B studies. Am Heart J 146:33, 2003; Warkentin TE: Think of HIT. Hematology Am Soc Hematol Educ Program
408, 2006; Warkentin TE et al: Testing for heparin-induced thrombocytopenia antibodies. Transfus Med Rev 20:259,
2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Pendleton is on the Speakers’ Bureaus at GlaxoSmithKline and Sanofi-Aventis.
Dr. Pendleton was recorded January 25-28, 2006, in Scottsdale, AZ, at the 34th Annual Phoenix Surgical Symposium,
sponsored by the Phoenix Surgical Society and Banner Health. Dr. Inaba was recorded May 22-23, 2006, in Pasadena,
CA, at the 13th Annual USC Trauma/Critical Care Symposium, sponsored by the Division of Trauma/Critical
Care and the Office of Continuing Medical Education at the Keck School of Medicine, University of Southern California,
and the Institute of Continuing Education for Nurses, Department of Nursing, Los Angeles County USC Medical
Center. Dr. Ketteler was recorded September 6-8, 2006, in Albuquerque, NM, at Current Concepts in General
Surgery and Trauma Update, sponsored by the University of New Mexico Health Sciences Center, Department of
Surgery and Office of Continuing Medical Education. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
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