COAGULATION UPDATE: MEDICAL AND SURGICAL PERSPECTIVES
| A PRACTICAL APPROACH TO PERIPROCEDURAL ANTICOAGULATION —Robert C. Pendleton, MD, Assistant
Professor of Medicine, University of Utah Medical Center, Salt Lake City
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| Estimating thromboembolic risk: main indications for anticoagulation (AC) therapy— atrial fibrillation (AF);
mechanical heart valves; venous thromboembolism (TE); annualized recurrent risk for TE in patients off AC
therapy—for patients with AF, 1% to 18%; for patients with mechanical heart valves, 9% to 91%; for patients with
venous TE, 1% to 40%; difficult to translate annualized risk into daily risk; considerations—70% of patients who suffer
perioperative embolic stroke die or have major neurologic deficit; mortality 15% for patients who suffer valve thrombosis
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| Risk for TE in patients with AF: patients with AF in setting of valvular heart disease or mitral stenosis have significantly
increased stroke risk; clinical features associated with increased stroke risk—previous stroke or transient ischemic
attack (TIA); heart failure, old age, hypertension, and diabetes increase stroke risk but probably not factors during
perioperative period
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| Risk for TE in patients with mechanical heart valves: high risk for TE—patients with valve in mitral valve
position, older-generation valve, or recent embolic event; more aggressive periprocedural AC therapy indicated; low
risk—patients with new-generation aortic valve and no other risk factors for TE; aggressive periprocedural AC therapy
not required; patients on warfarin for deep venous thrombosis (DVT) or pulmonary embolism—important to consider
length of time since index event; for patients <1 mo from original event, risk for recurrence 40% in 1 mo off AC
therapy (risk compounded by surgical risk and other risk factors); for patients >3 mo from original event, risk for recurrence
low and routine DVT prevention methods sufficient
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| Postoperative risk for bleeding: for patients on therapeutic unfractionated heparin (UFH) after major surgery, daily
risk for major bleeding event 1.5%; risk dependent on type of procedure and hemostasis during surgery
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| Procedural risk for bleeding: low-risk surgery—dental procedures; skin excisions; endoscopic procedures with biopsies;
arthrocentesis; cataract surgery; risk low enough that, according to most consensus panels, interruption of AC
therapy not necessary; high-risk surgery—neurosurgery, genitourinary, cardiothoracic, major vascular, renal biopsy,
and bowel polypectomy have higher risk than major abdominal, major orthopedic, and laparoscopic surgery
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| Patient-specific risk for bleeding: old age; renal insufficiency; severe thrombocytopenia; concomitant antiplatelet
therapy; steroid use; worsening liver function
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| Management strategy for patients at low risk: for patients undergoing procedures with extremely low bleeding
risk (eg, incisional skin biopsy), no interruption of AC therapy indicated; if concerned about bleeding, withhold 1 to 2
doses of warfarin and allow international normalized ratio (INR) to drop; for patients undergoing procedure with higher
risk for bleeding (eg, prostatectomy) who have low risk for TE (eg, AF with well-controlled hypertension), interruption
of AC therapy alone indicated
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| Withholding warfarin: for routine surgeries, preoperative INR goal <1.5; if patient’s normal INR goal 2.0 to 3.0, withhold
4 to 5 doses of warfarin; check INR 24 hr preoperatively, and if not near goal, give low dose of oral vitamin K
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| Bridging therapy: studies—2 single-arm cohort studies using preoperative low molecular weight heparin (LMWH)
and postoperative LMWH dose dependent on bleeding risk; strategy—withhold warfarin; begin LMWH and give last
dose morning before surgery (avoids neuraxial anesthesia); ensure INR <1.5; resume warfarin evening of surgery if surgery
successful and hemostasis achieved; 1 day postoperatively, dependent on surgery success and bleeding risk, either
no LMWH/UFH or judgment call on prophylactic vs treatment LMWH/UFH; success of bridging therapy—very few
patients who receive periprocedural bridging therapy have thromboembolic or major bleeding complication; no surgeries
canceled secondary to excessive AC therapy; average time to being back on AC therapy 4.5 days; LMWH vs UFH—
LMWH preferred modality for periprocedural bridging therapy due to cost savings and convenience; neuraxial
anesthesia—for treatment dosing, spinal needle should not be placed until 24 hr after last dose of treatment LMWH; resume
AC therapy 2 hr after catheter removed
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| Management strategy for patients at high risk: for patients at high risk for TE (eg, patients with mechanical mitral
valve), accept increased risk for bleeding and institute aggressive periprocedural AC therapy; for patients with moderate
risk (eg, patients with AF), bleeding concerns may outweigh stroke concerns and less aggressive AC therapy
indicated; strategy—withhold warfarin preoperatively and bridge with LMWH (bleeding not concern preoperatively);
for patients with AF (similar concerns for bleeding and stroke), prophylactic dosing of LMWH indicated postoperatively;
for patients with mechanical mitral valves, aggressive therapeutic AC therapy within 24 to 48 hr indicated
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| THE “MUST KNOWS” OF HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)—Dr. Pendleton
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| Type I (non–immune-mediated) HIT: little clinical significance; mild reduction in platelet count; not immune-mediated;
has no negative impact on clinical outcome
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| Type II (immune-mediated) HIT: clinically important; typical pattern of onset; causes moderate to severe reduction in
platelet count; antibody-mediated; high risk for thrombosis; note—for rest of summary, HIT refers to type II (immune-mediated)
HIT
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| Development of HIT: heparin complexes with platelet factor 4 (PF4; endogenous); complex of heparin and PF4 antigenic
and leads to formation of antibodies; if titer high enough and targeted at right antigenic site, antibodies can lead to
marked platelet activation, in turn leading to thrombocytopenia and creation of prothrombotic state with marked thrombin
generation (type II HIT is thrombosis disorder, not bleeding disorder); thrombocytopenia defined by reduction of
50% in baseline platelet count; 60% of patients who develop thrombocytopenia have thrombotic complication; serologic
testing not helpful unless it confirms presence of clinical syndrome
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| Risk for disease occurrence: Warkentin et al (1995)—patients undergoing orthopedic surgery randomized to UFH
or LMWH (300 in each group); diagnosis of HIT made if patient fits case criteria, ie, reduction of 50% in platelet count
without alternative explanation and positive serology; 3% of patients in UFH group developed clinically overt HIT, compared
to no patients in LMWH group; of patients who developed HIT, 89% developed thrombotic complication
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| Typical-onset HIT: 65% of patients follow logical course, ie, following exposure to heparin, antibodies develop over
number of days, and antibodies have sufficient platelet activation to result in thrombocytopenia; platelet count declines
typically 5 to 14 days after exposure; nadir platelet count occurs 7 to 14 days after exposure
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| Rapid-onset HIT: clinical course involves exposure to heparin and, despite no ongoing heparin exposure, production of antibodies
due to immune stimulation from index event; on re-exposure to heparin, HIT occurs within hours; patients appear
septic
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| Delayed-onset HIT: 5% of HIT presentations; clinical onset occurs up to 7 days after discontinuation of heparin due to
ongoing platelet activation from circulating antibodies despite absence of ongoing heparin exposure; much more common
with UFH than LMWH; clinical pearl—for patient receiving heparin for DVT prophylaxis who returns within 7
days of discharge with DVT or pulmonary emboli, check platelet count before initiating anticoagulant therapy because
may be delayed-onset HIT
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 | Types of thrombotic events: thrombotic event precedes drop in platelet count in 10% of patients; venous thrombosis—
75% of cases; life-threatening arterial thrombosis—10% to 20% of cases; eg, peripheral ischemia leading to limb
amputation (5%-10%), MI, stroke
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| Clinical features: heparin plaques (hematomas) at injection site (tend to be painful; precursor to development of HIT antibodies);
heparin can cause skin necrosis, eg, sometimes seen with warfarin use in patients with protein C deficiency;
catastrophic acute systemic reaction
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| Laboratory tests for HIT: serologic testing overdiagnoses HIT; laboratory studies (eg, serotonin release and platelet
aggregation assays, PF4 enzyme-linked immunosorbent assay) should be considered as confirmatory; HIT is clinical diagnosis
confirmed by laboratory studies
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| Management of HIT: pitfalls—despite not causing HIT very often, LMWHs contraindicated in established HIT; unless
patient overtly bleeding, platelet transfusions contraindicated (likely to promote thrombotic event); high risk for
thrombosis persists despite discontinuation of heparin; unopposed warfarin therapy contraindicated in patients with HIT;
if only action discontinuation of heparin, 53% of patients have thrombotic event within 30 days; clinical pearl—in most
cases, manage isolated HIT even without established thrombosis with alternative therapeutic anticoagulant
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| Argatroban and lepirudin: direct thrombin inhibitors approved by Food and Drug Administration (FDA); require continuous
intravenous infusion; lepirudin cleared renally, argatroban cleared hepatically; short half-life; monitored using activated
partial thromboplastin time (aPTT; target 1.5-2.5 times control value); argatroban—number needed to treat (NNT) 10;
acceptable major bleeding event rate; transition to warfarin— in patients taking concomitant warfarin and argatroban,
argatroban can be stopped once INR >4; recheck INR in 4 to 6 hr and if below target range, reinstitute argatroban, increase
warfarin, and recheck next day; lepirudin—renal clearance poses difficulty in many acutely ill hospitalized patients;
many patients develop antilepirudin antibodies, making dosing difficult; favorable clinical efficacy; approximately
2-fold higher risk for bleeding than argatroban
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| Fondaparinux: does not appear to cause antibody formation or have in vitro cross-reactivity to HIT antibodies
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| Warfarin: cannot be initiated unopposed in patients with HIT because of risk for warfarin-induced venous limb gangrene
(microvascular thrombotic process); warfarin should not be initiated until patient on parenteral anticoagulant and platelet
count recovering
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| Reinstitution of heparin: re-exposure to heparin soon after resolution of HIT associated with high risk for recurrence;
HIT antibodies tend to disappear within 3 mo of discontinuation; once antibodies cleared, risk for HIT no higher than patients
with no history of HIT
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| NEW AGENTS FOR TREATING COAGULOPATHY —Robert C. Mackersie, MD, Professor of Surgery, University of
California, San Francisco, School of Medicine
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| Reversal of warfarin-induced coagulopathy: for elective surgery, reversal typically involved withdrawal of warfarin;
vitamin K used for more urgent cases; fresh frozen plasma (FFP) mainstay treatment but time-consuming (4-8 hr)
and large volumes needed for elderly patients
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Prothrombin Complex Concentrates (PCCs)
| Introduction: evidence that warfarin-induced coagulopathy can be reversed in minutes; lyophilized concentrates that
need to be reconstituted by pharmacist; in general, contain vitamin K-dependent factors (most contain high concentrations
of factor IX); some preparations contain heparin and antithrombin to reduce potential for thrombogenicity
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| Efficacy of PCCs: clinical study—PCCs vs FFP; PCCs associated with rapid reversal of INR in 10 min and good clinical
response; study—in 42 patients on warfarin, PCCs associated with rapid reversal of INR and no thromboembolic
events; study—in brain-injury patients, factor IX concentrate associated with fast correction of INR (10-15 min) but
fewer complications in FFP group
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| Application of PCCs: speaker uses PCCs principally for elderly patients typically with AF and taking warfarin who develop
traumatic brain injury; in these patients, mortality rate 4.5- to 5-fold higher than nonanticoagulated patients
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| Summary: well-demonstrated efficacy for rapid reversal of INR; heat-treated, so minimal viral risk; no apparent risk for
thromboembolic events; expensive; indications— life-threatening hemorrhage in anticoagulated patients; high-risk,
time-sensitive emergent operations
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Recombinant Factor VIIa
| Introduction: approved by FDA for treatment of hemophilia A and B; used off-label for cardiac transplant surgery and
coagulopathic bleeding in trauma patients
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| Mechanism of action: trypsin-like serine protease that complexes with tissue factor at site of injury; induces hemostasis
in absence of factor VIII and IX; activates factor X without tissue factor and binds to activated platelets and induces
intense thrombin burst at site of injury; enhances local coagulation by increasing cross-linkage and forming tighter clot
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| Characteristics: seems to be cleared more rapidly in children (pediatric population not well studied); fairly resistant to
primary fibrinolysis; does not work in acidic environments, ie, pH <7.25; half-life 2.7 hr; appears to be effective for management
of warfarin-induced coagulopathy, but more expensive than PCCs
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| Dosage: single dose 30 µg/kg; recommended range 60 to 120 µg/kg; most studies use 90 µg/kg as initial dose
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| Potential adverse effects: concern over thromboembolic complications and disseminated intravascular coagulation
(DIC); initial hypothesis suggested recombinant factor VIIa may cause microvascular thrombosis, leading to acute respiratory
distress syndrome (ARDS)
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| Literature: study (2002)—in 19 trauma patients, recombinant factor VIIa reduced prothrombin time (PT) and PTT and
decreased subsequent transfusion rate; survival 68%; study (2005)—retrospective study of 315 nonhemophiliac patients
who received recombinant factor VIIa; INR reduced in treatment groups; thromboembolic event rate 9.8%
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Educational Objectives
| The goal of this activity is to educate the listener about issues in coagulation. After hearing and assimilating this program,
the clinician will be better able to:
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| 1. Utilize periprocedural anticoagulation to minimize the risk for major bleeding and thromboembolic events.
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| 2. Identify patients for whom bridging anticoagulation therapy is indicated.
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| 3. Review the clinical features of heparin-induced thrombocytopenia (HIT).
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| 4. Manage patients with HIT.
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| 5. Discuss new agents for managing coagulopathy.
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Suggested Reading
Ansell J et al: The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic
and Thrombolytic Therapy. Chest 126:204S, 2004; Cartmill M et al: Prothrombin complex concentrate for
oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 14:458, 2000; Douketis JD: Perioperative anticoagulation
management in patients who are receiving oral anticoagulant therapy: a practical guide for clinicians. Thromb
Res 108:3, 2002; Douketis JD et al: Low-molecular-weight heparin as bridging anticoagulation during interruption of
warfarin: assessment of a standardized periprocedural anticoagulation regimen. Arch Intern Med 164:1319, 2004; Gala B
et al: Benefits of recombinant activated factor VII in complicated liver transplantation. Transplant Proc 37:3919, 2005;
Garcia DA et al: Perioperative anticoagulation for patients with mechanical heart valves: a survey of current practice. J
Thromb Thrombolysis 18:199, 2004; Haas T et al: Successful reversal of deleterious coagulopathy by recombinant factor
VIIa. Anesth Analg 100:54, 2005; Joshi AV et al: Pharmacoeconomic analysis of recombinant factor VIIa versus
APCC in the treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors. Curr Med Res Opin 22:23,
2006; Lewis BE et al: Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced
thrombocytopenia. Chest 129:1407, 2006; Lubenow N et al: Lepirudin in patients with heparin-induced
thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3.
J Thromb Haemost 3:2428, 2005; Pendleton R et al: Argatroban dosing of patients with heparin-induced thrombocytopenia
and an elevated aPTT due to antiphospholipid antibody syndrome. Ann Pharmacother 40:972, 2006; Roitberg B
et al: Human recombinant factor VII for emergency reversal of coagulopathy in neurosurgical patients: a retrospective
comparative study. Neurosurgery 57:832, 2005; Spyropoulos AC et al: A disease management protocol for outpatient
perioperative bridge therapy with enoxaparin in patients requiring temporary interruption of long-term oral anticoagulation.
Pharmacotherapy 24:649, 2004; Warkentin TE: Heparin-induced thrombocytopenia: pathogenesis and management.
Br J Haematol 121:535, 2003; Warkentin TE, Greinacher A: Heparin-induced thrombocytopenia: recognition,
treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:311S,
2004.
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. For this issue, the following
has been reported: Dr. Pendleton is on the Speakers’ Bureaus for GlaxoSmithKline and Sanofi-Aventis.
Dr. Pendleton spoke at the 34th Annual Phoenix Surgical Symposium presented January 25-28, 2006, by Banner Health
and the Phoenix Surgical Society, and held in Scottsdale, AZ. Dr. Mackersie spoke at the Postgraduate Course in General
Surgery presented March 23-25, 2006, by the University of California, San Francisco, School of Medicine, and held in San
Francisco, CA. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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