THROMBOEMBOLISM: IDENTIFYING AND PREVENTING DISASTER
From the University of California, Davis, School of Medicine’s Symposium on Clinical Pharmacology 2006
Richard E. White, MD, Professor and Chief, Division of General Medicine, Medical Director, Anticoagulation
Service, Department of Internal Medicine, University of California, Davis, School of Medicine
| Introduction: prudent venous thromboembolism (VTE) prophylaxis requires comparing risk for thrombosis with
risk for hemorrhage; challenges—know some risk factors for thrombosis, but know little about their interaction;
know almost nothing about highly complex cases with multiple risk factors; currently, use only 2 doses of heparin
or low molecular weight heparin (LMWH) for prophylaxis (same in patients who weigh 80-400 lb or 20-100 yr of
age); no validated tools to predict perioperative bleeding
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| Risk factors: cancer, especially adenocarcinoma, leukemia, and lymphoma; patients with advanced-stage cancer at
increased risk; surgical patients at high risk postoperatively, especially patients with trauma, immobility, and inflammation;
orthopedic patients undergoing lower extremity surgery and neurosurgical patients at high risk;
trauma, especially to lower extremity or pelvis; immobility, before admission or in hospital, increases risk for VTE;
age increases risk because of coexisting comorbidity and stasis; obesity increases risk for VTE (obese patients have
higher C-reactive protein [in pro-inflammatory state]; risk increases as body mass index [BMI] increases); previous
episode of deep venous thrombosis (DVT) associated with very high risk
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| Incidence of VTE: epidemiologic study—20% to 30% of patients have idiopathic thromboembolic events; ≈8% of patients
have serious medical issues (eg, heart failure, nephrotic syndrome, lupus); ≈15% of events occur during hospitalization;
5% occur within 2 wk of hospital discharge (20% in surgical patients, 5% in trauma patients, small number
occur in pregnancy); ≈20% of patients have malignancy; age—incidence of VTE decreases in men after 75 to 84 yr
of age, but continues to increase in women; surgical procedure—study looked at incidence of VTE events in surgical
patients without cancer during hospitalization and within 3 mo after discharge; 2.5% incidence in patients who had total
hip arthroplasty (15% of patients had VTE on venography; 1 in 5 symptomatic) and 1.8% occurred after hospital
discharge; recommend extended prophylaxis up to 6 wk after discharge; incidence 2.3% in patients who underwent
invasive neurosurgery (most occurred after hospital discharge); substantial number of DVT events occur after hospital
discharge in all surgical patients; looked at incidence in patients undergoing surgery for cancer; patients with bladder
cancer, especially metastatic cancer, at very high risk (incidence of DVT 3.7% and 2% after discharge); percutaneous
nephrostomy associated with high incidence; incidence of VTE in patients with cancer almost double that of patients
without cancer; risk—increases with age; identical in males and females; slightly higher in blacks; slightly lower in
Latinos; 50% lower in Asians; almost double in people with malignancy; 6-fold increase in patients with previous
VTE event; duration of prophylaxis—study compared patients who had total hip replacement to patients who had total
knee replacement; incidence after total hip replacement continues to rise until 2 to 3 mo after surgery; incidence after
total knee replacement decreases after 1 mo; 90% of VTE events occur after discharge
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| Other risk factors: inherent risk factors—thrombophilic genetic factors associated with risk for VTE; include factor
V Leiden, prothrombin gene mutation, protein C and protein S deficiency, antithrombin (AT) deficiency, and factor
VIII; usually coupled with another risk factor, eg, air travel, trauma, immobilization, oral contraceptives; patients
with 2 defects have higher incidence; acquired risk factors—antiphospholipid antibody syndrome related to lupus;
screening—not necessary; 10% of people have one defect; 85% of people with factor V Leiden never have blood
clot; novel risk factors—extended air travel, extended immobility, especially patients in nursing homes; patients
with medical diseases with increased inflammatory response, eg, inflammatory bowel disease (IBD), sepsis or infections,
or connective tissue diseases
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| Incidence of VTE in hospitalized medical patients: study looked at incidence of VTE within 3 mo of discharge in
patients with serious medical conditions; sepsis associated with 2.1% of cases, connective tissue disease 2.1%,
acute renal failure 1.7%, and hyperosmolar state 1.7%; HIV has high incidence; fair number of VTE events occur
after hospital discharge; incidence associated with connective tissue disease increases after hospital discharge; patients
with sepsis remain at risk for 2 mo after discharge; hyperosmolar state associated with increased risk for 1 to
2 mo postdischarge
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| Anticoagulant prophylaxis: assessment—perform in patients at risk for VTE; no valid assessment tool available;
assess surgical and medical patients for risk of thrombosis and bleeding; institute evidenced-based prophylaxis in
all patients in hospital; consider extended prophylaxis in highest-risk patients; risk stratification—assume all
but healthiest patients need prophylaxis, unless patient at high risk for bleeding; for surgical patients, follow evidence-based
guidelines; for medical patients, institute prophylaxis, except in fully ambulatory patients or patients
expected to stay in hospital <48 hr without risk for bleeding; risk factors for bleeding—severe anemia,
chronic renal failure, thrombocytopenia, previous history of bleeding, cirrhosis with liver dysfunction, alcoholism,
concomitant use of acetylsalicyclic acid and clopidogrel, risk for falls, and severe systolic hypertension;
study looked at risk factors for bleeding in patients with atrial fibrillation; risk factors include hepatic or renal
disease, ethanol abuse, malignancy, older age, reduced platelet count or function, hypertension, anemia, genetic
factors, excessive risk for falls, and stroke (“hemorrhage” mnemonic device); controversial issues—right dose
of heparin or LMWH; usefulness of sequential compression devices (SCD) and thromboembolic deterrent (TED)
stockings alone; right duration of prophylaxis (evidence suggests risk extends over considerable period of time);
prophylaxis studies funded by pharmaceutical firms and do not use hard end points; need randomized trials with
hard outcomes (eg, clinical VTE events 3 mo after surgery); Safety Study of Fondapatinux Sodium to Prevent Venus
Thromboembolic Events (APOLLO) study—compared 2.5 mg of fondaparinux (Arixtra) with SCD to SCD
alone in general surgical patients; decreased incidence of proximal DVT and overall incidence of VTE in patients
on fondaparinux and SCD compared to SCD alone; 2 patients in fondaparinux group and 4 in SCD group
had symptoms; bleeding occurred in 15 patients in fondaparinux group and in 4 patients treated with SCD alone;
risk for pulmonary embolization (PE) and acute death may outweigh risk for bleeding from treatment with
fondaparinux; guidelines—no prophylaxis in low-risk patients (incidence of VTE <1%); includes patients <40
yr of age, those undergoing short surgery, and ambulatory medical patients; in moderate-risk patients (incidence
of VTE 1%-2%), recommend subcutaneous heparin prophylaxis 5000 IU bid (5000 tid or 7500 bid in larger patient)
or LMWH (dalteparin 5000 IU or enoxaparin 40 mg or tinzaparin 75 IU/kg); moderate-risk group includes
patients >40 yr of age, those undergoing major surgery, most medical patients; SCD approved for use in gynecologic
or urologic patients; recommend higher dose of LMWH or adjusted dose of warfarin in high-risk patients
(>2% incidence of VTE); high-risk group includes patients undergoing total hip or total knee replacement or surgery
to repair hip fracture, neurosurgical patients, or patients with active cancer; recommend extended duration
for total hip replacement and SCD in neurosurgical patients
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 | Factor Xa inhibitors: fondaparinux—given subcutaneously; half-life 17 hr; can give recombinant factor VIIa to induce
thrombosis (costly); idraparinux—half-life 80 hr; also pentasaccharide; given by subcutaneous injection;
can give once weekly for anticoagulation; razaxaban—looked at in total knee replacement; incidence of VTE on
venography 8.6%, compared to 15.8% in group taking enoxaparin; low rate of bleeding associated with 25-mg
tablet; BAY 59-7939—oral anti-Xa inhibitor; dose–ranging trials showed incidence of VTE 12% to 18%, compared
with enoxaparin 17%; bleeding incidence increased with dose, especially doses >10 mg; odiparcil—oral drug
with half-life 4 hr; inhibits assembly of intact proteoglycans on cell surface; increases release of chondroitin and
dermatan sulfate; lower incidence of VTE
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| Perioperative management: bridging in patients on warfarin—assess risk for thrombosis; high-risk patients get
full dose of LMWH (eg, patient with atrial fibrillation and congestive heart failure [CHF] with previous episode of
stroke, patient with older mitral valve prosthesis and CHF); estimate postoperative risk for bleeding; delay heparin
until risk acceptable in high-risk patient; in patients at low risk for thrombosis, stop warfarin, place patient on VTE
prophylaxis regimen and restart warfarin postoperatively; in high-risk patients, stop warfarin, start on full-dose
LMWH (with last dose 24 hr before surgery), and reinstitute warfarin postoperatively after risk reduced; can consider
lower dose of heparin in high-risk patient; patients with mitral mechanical valves, older aortic mechanical
valves, atrial fibrillation, history of cerebrovascular accident (CVA), DVT event in past month, hypercoagulable
state with recent thrombosis, underlying cancer, or history of life-threatening clot considered high risk; patients
with newer aortic mechanical valves, atrial fibrillation without multiple risk factors for CVA, and DVT treated for
>1 mo considered low risk; rebound hypercoagulability—risk for thromboembolism after discontinuation of oral
anticoagulants probably increases compared to steady-state risk of patient off oral anticoagulants, however none
exists; surgery causes activation of coagulation factors; bridging in patients with atrial fibrillation—need to treat
270 patients with more intense LMWH therapy to prevent one stroke; patient who had DVT within last month at
highest risk; recommend discontinuation of warfarin 24 hr before surgery, then reinstitute prophylaxis when safe in
highest-risk patient; consider placing filter postoperatively in patients who cannot be anticoagulated; study of 216
patients with mechanical heart valves or atrial fibrillation; participants bridged using dalteparin; 2 CVAs occurred
in 2 patients and major bleeding occurred in 15 patients
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| Perioperative strategies: in low-risk patient—can stop warfarin, perform surgery, place patient on DVT prophylaxis
postoperatively, then continue patient on warfarin; can discontinue anticoagulation in low-risk patient; partial
anticoagulation—withhold warfarin preoperatively; give patient warfarin or low to moderate dose LMWH (30 mg
q12 hr or 40 mg/day) after surgery; consider 15,000 U daily unfractionated heparin if high risk or 5000 IU q12 hr if
lower risk; risk for major bleeding—incidence ≈2% after medical procedure and 2% to 4% with full-dose LMWH
after surgery; incidence of bleeding higher than risk for stroke, but thromboembolic stroke associated with high
mortality and severe disability
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| LMWH and heparin-induced thrombocytopenia (HIT): obtain platelet count at onset of hospitalization and on
day 3 and 5; HIT usually occurs by about day 5; monitor platelet count every other day for 2 days after day 5; very
rare in medical patients given subcutaneous regular heparin
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| Postoperative anticoagulation: patients who undergo total hip or knee replacements get warfarin for at least 1 mo;
other high-risk patients, if switched over to warfarin, maintained in anticoagulation clinic
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| Idiopathic DVT: genetic defect occurs in half of patients who had DVT; speaker does not treat either group differently;
other half of patients have genetic defect not characterized yet; recurrence rate same in either group
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Educational Objectives
| The goal of this program is to educate the listener on the identification, prevention, and treatment of thromboembolism.
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss the challenges in planning for prudent thromboembolism prophylaxis.
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| 2. Identify patients at risk for venous thromboembolism.
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| 3. Describe the different types of risk factors for thromboembolism.
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| 4. List the emerging factor Xa inhibitors.
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| 5. Discuss the perioperative management of patients on warfarin.
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Discussed on This Program
Dabigatran etexilate [Rendix] (investigational)
Dalteparin sodium [Fragmin]
Enoxaparin sodium [Lovenox]
Fondaparinux sodium [Arixtra]
Heparin sodium injection
Idraparinux sodium (investigational)
Low molecular weight heparins (LMWHs)—dalteparin [Fragmin], enoxaparin [Lovenox], tinzaparin [Innohep]
Odiparcil (investigational)
Razaxaban (investigational)
Warfarin sodium [Coumadin]
Suggested Reading
Alcalay A et al: Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival.J Clin
Oncol. 24:1112, 2006; Dager WE et al: Tinzaparin in outpatients with pulmonary embolism or deep vein thrombosis.
Ann Pharmacother. 39:1182, 2005; Hull RD et al: Extended-duration thromboprophylaxis in acutely ill medical
patients with recent reduced mobility: Methodology for the EXCLAIM study. J Thromb Thrombolysis. 22:31, 2006;
Jones T et al: Venous thromboembolism after spinal cord injury: incidence, time course, and associated risk factors
in 16,240 adults and children. Arch Phys Med Rehabil. 86:2240, 2005; Kamali F et al:The future prospects of pharmacogenetics
in oral anticoagulation therapy. Br J Clin Pharmacol. 61:746, 2006 Wheeler A: Venous thromboembolism
in medically ill patients: identifying risk and strategies for prevention. Clin Cornerstone. 7:23, 2005; White
RH et al: Incidence of venous thromboembolism in the year before the diagnosis of cancer in 528,693 adults. Arch
Intern Med. 165:1782, 2005; White RH et al: Effect of ethnicity and gender on the incidence of venous thromboembolism
in a diverse population in California in 1996. J Thromb Haemost. 93:298, 2005; White RH et al: Effect of age
on the incidence of venous thromboembolism after major surgery. Thromb Haemost. 2:1327, 2004; White RH et
al:Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb
Haemost. 90:446, 2003; White RH: The epidemiology of venous thromboembolism. Circulation. 107:I4, 2003;
White RH et al: Risk factors for venous thromboembolism after total hip and knee replacement surgery. Curr Opin
Pulm Med.8:365, 2002.
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. White is a consultant for Boehringer-Ingelheim Pharmaceuticals and for Agenix Limited.
Dr. White was recorded April 21-23, 2006, in Napa Valley, CA, at Clinical Pharmacology 2006: Drug Therapy Management
, sponsored by the University of California, Davis, School of Medicine. The Audio-Digest Foundation thanks
Dr. White and the sponsor for their cooperation in the production of this program.
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