intelligent use of anticoagulants.ppt
TRANSCRIPT
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Intelligent Use of
Anticoagulants
Murray L. Shames, M.D.
Assistant Professor of Surgery andRadiology
Division of Vascular and Endovascular
Surgery
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Outline
Available anticoagulants Surgical prophylaxis DVT and pulmonary embolus
Atrial fibrillation Perioperative management of patients on
chronic anticoagulation Arterial thromboembolism
Cerebral Visceral Extremity
Anticoagulation in pregnancy
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The Coagulation Cascade
X
Xa+
Va + Ca++
Intrinsic system
XIIXIIaXI IX
Xia
IXa+
VIIa+
Ca++
Extrinsic system
Injury
Tissuethromboplastin
+
VII
Prothrombin Thrombin
Fibrinogen Fibrin
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Available anticoagulants
Unfractionated heparin
Low Molecular Weight Heparins
Oral Anti-coagulants Alternative agents
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Unfractionated Heparin-Mechanism of Action
Binds anti-thrombin III 1:1
Inactivates thrombin and F Xa
Secondary effect on F V
Effects not first order kinetics
Effective after subcutaneousand intravenousadministration
Short half life (90 min)
Reversed with protamine(1mg per 100 U circulatingheparin)
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Unfractionated Heparin-Limitations
Significant protein binding
Response is unpredictable (closemonitoring required)
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Unfractionated Heparin-Dosing
Loading 80-100 U/ kg IV
Then IV infusion at 18 U/kg/hr
Normogram available for mosthospitals
Therapeutic range 1.5-2.5 X control PTT
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Unfractionated Heparin-Complications
Major bleeding complications 0-7%
HIT 1-5%
Osteoporosis Alopecia
Hypoadrenalism
Anaphylaxis
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HeparinInducedThrombocytopenia
Incidence 1-5%
Can occur with all methods ofadministration
No known risk factors
Increased incidence with Bovine
preparations Dx- plt count < 100-150 000/uL
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HeparinInducedThrombocytopenia I
HIT I Heparin induced platelet aggregation
Platelet sequestration and consumption
Mild Thrombocytopenia in first few days of therapy
Plt count usually > 100 000/uL
Asymptomatic
Resolves spontaneously without d/c heparin
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HeparinInducedThrombocytopenia II
HIT II (HITT) Immunologically mediated
Ab to Heparin-PF 4 complex
More severe but less common 5-7 days after initiating Tx
PLT
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HeparinInducedThrombocytopenia II
Thrombotic events arterial and venous
Associated skin necrosis
Global amnesia Prosthetic valve thrombosis
29% mortality and 21% amputation rate
H i I d d
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HeparinInducedThrombocytopenia
Treatment Withdrawal of ALL heparin and heparin
products Plasmapheresis - anecdotal success
Further treatment should await confirmationof Dx Start anti-platelet therapy ? LMWH
Thrombin inhibitors Ancrod Conversion to Warfarin
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Available Anticoagulants
Unfractionated heparin
Low Molecular Weight Heparins
Oral Anti-coagulants Alternative agents
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Characteristics of UFH andLMWH Chains
Molecular weight (daltons)10,000 15,000 20,0005,000
5,400
Anti-Xa Anti-IIa and anti-XaResistant to PF4 Sensitivity to PF4Little non-specific binding Non-specific bindingInhibition of thrombin generation Less inhibition thrombin generation
Hirsh J, Levine MN. Blood. 1992; 79: 1-17.
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Low Molecular Weight Heparins
Effect through AT IIIInhibits Factor XaMore predictable
anticoagulant responseLonger half-lifeBetter bioavailability atlow dosesRenal clearanceLower incidence of HITNo need to monitor PTT
in most cases
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FDA-Approved Indications (May 2001)for Available LMWHs
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Advantages of LMWH OverUFH
Less platelet activation
Less vascular permeability
Smaller size
Increased release of TFPIfrom vascular endothelium
Less plasma protein binding
Less interaction with PF4
Less osteoclast activation
Less binding to VWF Stimulates megakaryopoiesis
Less thrombin, growth factorproduction
May limit tumor movement intointravascular space
More potent anti-angiogenesis
activity More potent anticoagulant and
anti-cancer activity Predictable PK, safety, once daily
dosing Lower incidence of HIT
Less osteoporosis with long termuse
Less bleeding May attenuate chemotherapy -
induced thrombocytopenia
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Low Molecular Weight Heparins-Dosing
1mg/kg q12H
Can monitor anti-factor Xa levels
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Available Anticoagulants
Unfractionated heparin
Low Molecular Weight Heparins
Oral Anti-coagulants Alternative agents
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Oral Anticoagulation-Mechanism of Action
Inhibition of Vitamin K-dependantcoagulation factors II, VII, IX, X
Inhibition of Vitamin K- dependantcarboxylation of Protein C and S
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Oral Anticoagulation-Limitations
May create initial hypercoaguable state
3-5 days for anticoagulant effect
3-5 days to reverse effects Reversed rapidly by FFP
Can reduce time of reversal with
supplemental Vit K (10mg IV or 3-5mg PO)
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Oral Anticoagulation-Complications
Hemorrhage
Skin necrosis
Protein C deficiency
Malignancy
Teratogenic
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Oral Anticoagulation- Dosing
Loading 5mg PO QD
Adjust daily dose to reach goal INR
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Available Anticoagulants
Unfractionated heparin
Low Molecular Weight Heparins
Oral Anti-coagulants Alternative agents
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Alternative Anticoagulants
Danaproid
Thrombin Inhibitors
Hirudin
Lepirudin
Argatroban
Ancrod
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Alternative Anticoagulants-Danaproid
Heparinoid
Mixture heparin-like glycosaminoglycans andchondroitins
Anti-factor Xa and anti-factor IIa activity Can be used in patients with HIT
Approved for DVT prophylaxis
Longer duration than UF heparin
Measure by anti-factor Xa levels
Weight based dosing
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Alternative Anticoagulants-Thrombin Inhibitors
Hirudin
Protein isolated from salivary gland ofleech
Irreversible binding to thrombin
High incidence of bleeding complications
Monitor by PTT and ACT
Substitute for heparin in patients with HIT Efective DVT prophylaxis
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Alternative Anticoagulants-Thrombin Inhibitors
Lepirudin
Recombinant Hirudidn derivative
Reduced mortality and morbidity in HIT
patients
Renally excreted
Dosing - 0.4mg/kg IV loading and
0.15mg/kg maintenance Monitor PTT
Therapeutic range: 1.52.5 X normal
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Alternative Anticoagulants-Thrombin Inhibitors
Argatroban
Competitive thrombin inhibitor
Univalent thrombin inhibitor (less
specificity and affinity)
Short plasma life- no adj. for RF
2ug/kg/min IV
Monitor by PTT or ACT (2-3.5 X baseline)
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Alternative Anticoagulants-Ancrod
Venom of Malaysian Pit Viper
Defibrinating agent
Converts fibrinogen to soluble aggregate
removed by plasmin and RES Increases FDPaugments anticagulant
effect
Indirect micro-fibrinolytic by increasing TPArelease
Monitor fibrin levels
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Venous Thromboembolism
Virchows Triad
Stasis
Intimal injury Activation of coagulation
(hypercoaguable state)
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Venous Thrombosis-Epidemiology
Venous thromboembolism is the 3rd mostcommon vascular disease in the UnitedStates
Mortality and morbidity associated with VTEis enormous
Average cost per admission in the US:
PE = $12,595
DVT = $9,337
Additional long-term costs of morbidity > 75% ofinitial therapy costs
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Venous Thrombosis-Rationale for Prophylaxis
Clinically silentdisease High prevalence in hospitalized patients Dire consequences of missed DVT
First manifestation may be fatal PE Most deaths within 30 min of acute event Long term morbidity from post-phlebitic
syndrome
Wide variations in practice of physicians
Only 1/3 of at risk patients receive adequateprophylaxis 58% of fatal PE patients not prophylaxed in spite
of risk factors
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Venous Thrombosis-Risk Factors
Obesity Varicose Veins Cardiac dysfunction Indwelling vascular
catheter IBD Nephrotic syndrome Pregnancy or estrogen
use
Advanced age Prolonged immobility Stroke or Paralysis Previous VTE
Cancer and itstreatment Major Surgery
esp. abdomen,pelvis, and lower
extremities Trauma
esp. fractures ofpelvis, hip, or leg
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Surgical Prophylaxis-Low Risk Patient
Risk Factors
Age under 40 yearsMinor surgeryNo other risk factors
Event rate
Calf DVT 2.0%Proximal DVT 0.4%Clinical PE 0.2%Fatal PE 0.002%
Recommended Regimens
No specific measuresAggressive mobilization
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Surgical Prophylaxis-Moderate Risk Patient
Risk Factors Major surgery in
patients with additional
risk factors Non-major surgery in
patients 40-60 with noadditional risk factors
Major surgery inpatients < 40 with noadditional risk factors
Event Rates
Calf DVT 10-20%
Proximal DVT 2-4%
Clinical PE 1-2% Fatal PE 0.1-0.4%
Recommended RegimensLMWH
Low dose UFHElastic stockings
Intermittent Pneumatic Compression
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Surgical Prophylaxis-High Risk Patient
Risk Factors
Non-major surgeryin patients > 60 or
additional riskfactors
Major surgery inpatient < 40 oradditional riskfactors
Event Rate
Calf DVT 20-40%
Proximal DVT 4-8%
Clinical PE 2-4%
Fatal PE 0.4-1.0%
Recommended Regimen
LMWH
Low dose UFH q8h
IPC
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Surgical Prophylaxis-Highest Risk Patient
Risk Factors Major surgery in
patients > 40 plus
prior VTE, cancer,hypercoaguablestate
Hip or knee
arthroplasty Major trauma
Spinal cord injury
Event Rate Calf DVT 40-80%
Proximal DVT 10-20%
Clinical PE 4-10% Fatal PE 0.2-5.0%
Recommended Regimen
LMWH
Oral Anticoagulants
IPC/ES + LMWH/LDUFH
Adjustable dose UFH
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LMWH vs. UFH
In Acute Treatment of VTE
In Favor of LMWH In Favor of UFH
0.0 1 20.25 0.5 0.75 1.5 0.751.25
Venous Thromboembolism
Pulmonary Embolism
Major Bleeding
Thrombocytopenia
Total Mortality
Minor Bleeding
Pooled Relative Risk
Dolovich L, et al. Arch Intern Med. 2000:160:181-187.
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LMWH: Fewer Deaths
Meta-Analysis: N=3,566
LMWH UFH PMortality 5.1% 6.7% 0.02
Overall 30% mortality reduction from:Recurrent Thromboembolism, Bleeding,and Cancer
Gould, et al. Ann Intern Med. 1999; 130: 800-9.
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Study DesignEnoxaparin
sodium 1mg/kgq12h SC
Adjusted-doseheparininfusion
Documentedacute, proximalDVT without PE
Warfarin therapyinitiated on 2nd day
Warfarin 90 dayspost randomization
Clinicalendpoints
Clinicalendpoints
Outpatient Treatment of DVTEnoxaparin q12h vs. Heparin
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Embolic Event
Total VTE*DVT onlyProximal DVTPE
13 (5.3)11 (4.5)10 (4.0)2 (0.8)
17 (6.7)14 (5.5)12 (4.7)3(1.2)
Enoxaparin sodiumn=247 (%)
Heparinn=254 (%)
Outpatient Treatment of DVTEnoxaparin q12h vs. HeparinResults: Recurrences of Thromboembolism
* VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/orpulmonary embolism [PE]).
95% CI = -5.6 to 2.7. Two died during the study.
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Treatment Group & Event
Enoxaparin sodium (n=5)Soft-tissue hematoma of hip 6 2.7 27Abdominal-wall hematoma 7 2.7 55Abdominal-wall hematoma 7 3.2 40Subdural hematoma 5 3.4 40Hematemesis
6 2.4 40Heparin (n=3)Hematuria 2 1.3 64Gastrointestinal bleeding 3 3.0 88Hematemesis 1 2.7 64
Study Day INR*
* International Normalized Ratio. P= 0.50. Patient had cancer and associated thrombocytopenia due to chemotherapy and radiation.
Outpatient Treatment of DVTEnoxaparin q12h vs. Heparin
Results: Episodes of Major Bleeding
aPTT(sec)
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Atrial Fibrillation
Most common arrythmia in adults
Responsible for 15% CVA
Better survival with combined ratecontrol and anticoagulation
IV heparin/ LMWH + coumadin
Administer anticoagulation before and3 - 4 weeks after cardioversion
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Atrial Fibrillation
Age
< 65
>65-75
Any
Risk FactorsFor Stroke*
None
None
1 or more
*Mitral stenosis, HTN, previous TIA or stroke, CHF, LV
dysfunction, or age > 75
Therapy
ASA or none
ASA or Warfarin
Warfarin
Perioperative Management Of
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Perioperative Management OfPatients on Chronic
AnticoagulationPatients at low risk
VTE adequatelt treated for > 3 months, no
predisposing factors Nonvalvular A. Fib without embolic events
Most bioprosthetic and mechanical heart
valves without thromboembolism
Perioperative Management Of
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Perioperative Management OfPatients on Chronic
AnticoagulationRecommendations
Hold warfarin 4 days before surgery Recheck PT day of surgery
Resume warfarin on post-op day 2
Perioperative Management Of
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Perioperative Management OfPatients on Chronic
AnticoagulationPatients at intermediate risk Venous or arterial embolism
In 2nd
to 3rd
month of Tx, no predisposingfactors
Recurrent VTE tx for 12 months
Valvular heart disease, A. Fib,prosthetic heart valve with distant h/oembolism
Perioperative Management Of
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Perioperative Management OfPatients on Chronic
AnticoagulationRecommendations
Hold warfarin 4 days before surgery Prophylactic SC UFH or LMWH pre-op
Recheck PT day of surgery
Continue prophylaxis in peri-operative period Restart warfarin at pre-operative dose on
post-op day 2
Stop heparin when INR > 2
Perioperative Management Of
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Perioperative Management OfPatients on Chronic
AnticoagulationPatients at highest risk Venous thromboembolism with specific
circumstances (consider IVC filter) Onset within last month
Idiopathic, last 6 months
Recurrent VTE, within last 12 months
Documented hypercoaguable state
Recent embolism from A. Fib, prosthetic ordiseased heart valve
Acute arterial embolism within 1 month
Perioperative Management Of
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Perioperative Management OfPatients on Chronic
AnticoagulationRecommendations
Hold warfarin 4 days prior to surgery
Begin IV heparin or SC LMWH 2 days prior tosurgery
Recheck PT day of surgery
Hold heparin 6-12 hrs before surgery
Resume heparin 12 hours after surgery ifadequate hemostasis
Resume warfarin on post-op day 2
D/C heparin when INR > 2
A t i l Th b b li
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Arterial Thromboembolism-Goals of Therapy
Prevent recurrent thrombosis or embolism
Adequate anticoagulation reduces in-
hospital recurrence from 31% to 9% Decrease mortality from 25% to 4%
Does result in increased woundcomplications (without major bleeding
episodes) UFH first choice in therapy
Increased flexibility in monitoring and control
A t i l Th b b li
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Arterial Thromboembolism-Extremity
Patient with
suspected ALI
History
PEDoppler
HEPARIN
Diagnosis confirmed
Arterial Thromboembolism
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Arterial Thromboembolism-Extremity
IV HEPARIN5000 u bolus
Titrate to PTT 60-80 sec
Protection against clot propagation
Prevent embolus
Arterial Thromboembolism
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Arterial Thromboembolism -Cerebral
No benefit to anticoagulation in completed
stroke
May benefit stroke-in-progress if < 25 hrsand submaximal
Need to eliminate other causes of
neurologic deterioration
Arterial Thromboembolism
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Arterial Thromboembolism -Cerebral
Cardioembolic stroke
Risk of recurrence 10-20% within 2-4 weeks
Evaluate for cardiac source (13-34%)
No clear consensus
Cerebral embolism study group
Anticoagulation in normotensive patients with
small moderate strokes after 24 hrs
Larger strokes after 5-7 days
Recommendations
IV heparin without loading dose
Start Warfarin after 24 hrs
INR 2.0-3.0
Long-term therapy in patients with AtrialFibrillation
Arterial Thromboembolism
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Arterial Thromboembolism-Visceral
Acute mesenteric ischemia
Embolic
Thrombotic
Non-occlusive
Venous thrombosis
Arterial Thromboembolism
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Arterial Thromboembolism-Visceral
Diagnosis requires high index of suspicion
Angiography diagnostic
Treatment
Initiate IV heparin at time of diagnosis (bolus
and titrate to PTT 60-80 sec)
Thrombolysis if no evidence of peritonitis
Surgical thrombectomy/revascularization withbowel resection
Arterial Thromboembolism
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Arterial Thromboembolism-Visceral
Non-occlusive mesenteric ischemia
Multi-system organ failure, low-flow states,and visceral vasoconstriction
Rarely exists without severe cardiacdysfunction
Abdominal pain75%
Arterial Thromboembolism
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Arterial Thromboembolism-Visceral
Arteriography demonstrate mesenteric arterial
spasm
Reversible with intra-arterial papaverine infusion
or other vasodilating agents Adjunctive use of IV heparin recommended
Arterial Thromboembolism
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Arterial Thromboembolism-Visceral
Venous thrombosis Hypercoaguable state
Intraabdominal infection or inflammation
Asymptomatic state to catastrophic illness Generalized abdominal pain out of proportion to physical
exam
Diagnosis by CT, angiography
Treatment
Rigorous resuscitation IV heparin anticoagulation (PTT 60-80)
Surgical exploration for peritonitis
Long-term therapy with warfarin (life-time if hypercoaguablestate identified)
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Anticoagulation in Pregnancy
Sixfold risk of venous thrombembolism
PE most common cause of maternal
mortality in US
Gravid uterus compressing Vena Cava
Pregnancy related hypercoagulability
(increase II, VII, VIII, X)
Decreased fibrinolytic activity and AT III
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Anticoagulation in Pregnancy
Coumadin during first trimester associated
with specific malformations in > 25% of
births
Fetal Warfarin Syndrome (nasalhypoplasia, stippled epiphyses)
Increase CNS anomalies if used during
other time during pregnancy
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Anticoagulation in Pregnancy
Drugs with molecular weight < 1000
daltons pass through placental
membranes
Fetus has already low levels of Vit-Kdependant factors- further depleted by
warfarin effect
Anticoagulation in Pregnancy
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Anticoagulation in Pregnancy-Recommendations
Initiate anticoagulation with intravenous heparin
Continue Tx with subcutaneous heparin orLMWH
Continue Tx through delivery and post-partumperiod
After delivery coumadin for 6 months
Prophylaxis (LMWH) recommended during
subsequent pregnancy Acute iliofemoral DVT consider thrombectomy
or vena Caval filter placement
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