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THROMBOPHILIA DVT PROPHYLAXIS VTE MANAGEMENT DR. ASHISH Moderator: DR. MEERA KHARBANDA www.anaesthesia.co.inwww.anaesthesia.co.in anaesthesia.co.in@gmail.comanaesthesia.co.in@gmail.com

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Thrombophilia Thrombophilia - propensity for thrombotic events Most often manifests clinically in form of venous thrombosis (frequently DVT of lower extremity) Thrombophilia may result from inherited or acquired conditions

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Heritable cause of thrombophilia Decreased anti thrombotic proteins Hereditary antithrombin deficiency Hereditary protein c deficiency Hereditary protein s deficiency

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Heritable cause of thrombophilia Due to increased prothrombotic proteins Factor V Leiden genetic polymorphism Prothrombin G20210A genetic polymorphism

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Acquired causes of thrombophilia Myeloproliferative disorders Malignancies Pregnancy & OCP use Nephrotic syndrome patients Antiphospholipid antibodies

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Hypercoagulable States and Risk for Perioperative Thrombosis High Risk Heparin-induced thrombocytopenia (HIT) Antithrombin deficiency Protein C deficiency Protein S deficiency Antiphospholipid antibody syndrome

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Hypercoagulable States and Risk for Perioperative Thrombosis Moderate risk Factor V Leiden genetic polymorphism Prothrombin G20210A genetic polymorphism Hyperhomocysteinemia Dysfibrinogenemia Postoperative prothrombotic state Malignancy Immobilization

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Random screening of asymptomatic patients for thrombotic risk has not proved cost effective or clinically efficacious Careful history focusing on prior thrombotic events, family H/O thrombosis, & concurrent drug therapy offers greater predictive value than random screening.

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Common Inherited Thrombotic Disorders Factor V Leiden(=activated protein C resistance) Point mutation of factor V gene Results in impaired inactivation of factor V by activated protein C Factor V leiden stays active in circulation > N, fostering increased thrombin generation Heterozygosity: 5x ~ 7x risk of VTE Homozygosity: 80x risk of VTE

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Prothrombin gene G20210A mutation Prothrombin gene mutation: nucleotide position 20210: G A Elevated prothrombin levels and activity Increased risk of venous thrombosis Rare in Asians & Africans

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Protein C deficiency Synthesis in the liver; Vit-K dependent Inactivate factor and factor . It needs a cofactor: protein S Protein C def. l/t overabundance of thrombin Risk of thrombosis if warfarin therapy started in absence of protective anticoagulation by heparin

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Protein S deficiency Synthesis in hepatocytes & megakaryocytes Vit-K dependent Cofactor of activated protein C(APC) Protein C have shorter half life than Protein S

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Antithrombin deficiency Antithrombin (AT, also called AT III) defense against clot formation in healthy vessels or at the perimeter of a site of active bleeding Autosomal dominant trait Heterozygosity: 20x risk of VTE Homozygosity: Not compatible with life

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In absence of coexisting precipitating conditions, absolute thrombotic risk secondary to heritable thrombophilia proves limited. In the presence of family history or test abnormality suggesting thrombophilia with no h/o thrombosis, risks a/w long-term preventive anticoagulation may outweigh potential benefits.

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After a thrombotic complication, however, these patients most often are managed with life-long anticoagulation.

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Acquired thrombophilia- Antiphospholipid Syndrome Autoimmune disorder ch/by venous and/or arterial thromboses, recurrent pregnancy loss. 2 0 to autoimmune disorders such as SLE or RA, or occur in isolation. Mild prolongation of aPTT & + testing for lupus anticoagulant or anticardiolipin antibodies.

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Acquired thrombophilia- Antiphospholipid Syndrome No increased bleeding risk but risk of thrombosis. Isolated prolongation of an aPTT in preoperative patient consider - antiphospholipid syndrome. Risk of recurrent thrombosis - life-long anticoagulation.

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HIT Autoimmune-mediated drug reaction - 5% of pt. receiving heparin therapy. Heparin AT complex also binds to platelet factor 4 & some pt. develop - Heparin- induced ab. that can cross react with this platelet binding site to produce platelet clumping and subsequent thrombocytopenia Can be triggered by low dose heparin as well as therapeutic dose heparin

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MALIGNANCY Adenocarcinomas of pancreas, colon, stomach, & ovaries. Pathogenesis - release of procoagulant factor(s) by tumor, which directly activate factor X, endothelial damage by tumor invasion, and blood stasis. Lab: No abnormalities or some combination of thrombocytosis, elevation of the fibrinogen level, and low-grade DIC.

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Pregnancy and OCP Use Incidence - 1 in 1500 pregnancies Risk of PE highest during 3rd trimester & immediate postpartum period Antithrombin IIIdeficient women high risk - anticoagulated throughout pregnancy. Factor V Leiden and the prothrombin G20201A mutation a/w less risk. Women with one of these inherited traits not anticoagulated unless h/o PE or recurrent DVT

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Pregnancy and OCP Use Since low-dose estrogen OCP introduction - incidence decreased. Women - smoke, h/o migraine headaches, inherited hypercoagulable defect at increased risk (30-fold) of venous thrombosis, PE, & cerebrovascular thrombosis.

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Nephrotic Syndrome Patients Risk of thromboembolic disease including renal vein thrombosis. D/t N levels of other coagulation factors. Hyperlipidemia and hypoalbuminemia - also possible etiologic factors

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Perioperative venous thromboembolism Without prophylaxis, incidence of DVT 14% in gynaecological surgery 22% in neurosurgery, 26% in abdominal surgery, 4560% in orthopaedic surgery.

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Agency for health care research and quality have issued report stating that : Prophylaxis for venous thromboembolism is single most important measure for ensuring patient safety in hospitalized patients

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Patients at risk for VTE Surgery : major surgery: abdominal, gynecologic,urologic, orthopedic, neurosurgery, cancer related surgery Trauma : multisystem trauma, spinal cord injury, spinal #, # of hip and pelvis Malignancy : any malignanacy, risk higher during chemo & radiotherapy Acute medical illness: stroke, acute MI, heart failure,neuromuscular weakness syndrome(GBS)

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Patients at risk for VTE Patient specific risk factor: H/o VTE, Obesity, increasing age > 40yr, hypercoagulable state( estrogen therapy) ICU related factors: prolonged mechanical ventilation, neuromuscular paralysis(drug induced), CVC, severe sepsis, consumptive coagulopathy, HIT

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Risk assessment model (RAM) from the ACCP Low risk Uncomplicated minor surgery in patients

Risk assessment model (RAM) from the ACCP Moderate risk factor Major and minor surgery in pt. 4060 yr with no clinical risk factors Major surgery in pt. 30 min Other risk factor : cancer, obesity, h/o VTE, estrogen t/t, hypercoagulable state

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Risk assessment model (RAM) from the ACCP High risk Major surgery in patients >40 yr who have additional risk factors Major surgery : performed under GA and last > 30 min Other risk factor : cancer, obesity, h/o VTE, estrogen t/t, hypercoagulable state

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Risk assessment model (RAM) from the ACCP Very high risk Major surgery in pt. >40 yr plus previous VTE or malignant disease or hypercoagulable state Elective major orthopaedic surgery or hip # or stroke or spinal cord injury or multiple trauma

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THROMBOPROPHYLAXIS FOR GENERAL SURGERY Risk categoriesRecommended prophylaxis 1.Low risk :Minor sx + < 40 & no other risk factor Early mobilization 2. Moderate risk:Major sx+ >40yr no other risk factor LDUH 1 Or LMWH 1 : First dose 2 hr before surgery 3.High risk: major sx.+ >40yr other risk factor LDUH 2 Or LMWH 2 : First dose 2hr before surgery 4.Very high risk :major sx.+ >40yr other risk factor LDUH 2 Or LMWH 2 as above plus mechanical aid

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Prophylaxis regimens LDUH 1 - Unfractionated heparin 5000 u s.c every 12 hr LDUH 2 - Unfractionated heparin 5000 u s.c every 8 hr LMWH 1 :Enoxaparin 40 mg s.c O.D or Dalteparin 2500 u s.c O.D LMWH 2 :Enoxaparin 30 mg s.c every 12 hr or Dalteparin 5000 u s.c O.D Mechanical aid: Graded compression stockings or intermittent pneumatic compression

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Thrombprophylaxis for hip & knee Sx. Procedures : Elective hip & knee arthroplasty, hip # surgery Drug regimen: Use any one of following 1.LMWH:Enoxaparin 30 mg s.c every12hr.Give 1 st dose 12-24hr before Sx. Or 6hr after Sx. 2.Fondaparinaux : 2.5mg s.c O.D.First dose 6- 8hr after Sx. 3.Adjusted dose warfarin to achieve INR of 2-3. Give first dose the evening before Sx.

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Thrombprophylaxis for hip & knee Sx. Duration of thromboprophylaxis A.For elective hip & knee surgery, prophylaxis should continue for 10 days after surgery B. For hip # surgery, prophylaxis should continue for 28 to 35 days after surgery

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Thromboprophylaxis for other conditions

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Clinical situationRecommended prophylaxis 1.Major trauma1. LMWH 2 Or IPC 2.Spinal cord injury2. LMWH 2 + IPC 3.Intracranial sx.3. IPC 4.Gyanecologic sx. a.Benign disease b.Malignancy 4a. LDUH 1 4b. LDUH 2 Or LMWH 2 5.Urologic sx. a.Closed procedure b.Open procedure 5a. Early mobilization only 5b.LDUH 1 Or IPC 6.High risk medical condition 6.LDUH 1 Or LMWH 1

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Prophylaxis regimens LDUH 1 - Unfractionated heparin 5000 u s.c every 12 hr LDUH 2 - Unfractionated heparin 5000 u s.c every 8 hr LMWH 1 :Enoxaparin 40 mg s.c O.D or Dalteparin 2500 u s.c O.D LMWH 2 :Enoxaparin 30 mg s.c every 12 hr or Dalteparin 5000 u s.c O.D Leg compression methods: Graded compression stockings(GCS) or intermittent pneumatic compression(IPC)

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Methods of thromboprophylaxis Mechanical - External leg compression 1.Graded compression stockings 2.Intermittent pneumatic compression Pharmacologic 1.Low dose unfractionated heparin 2.Low molecular weight heparin 3.Adjusted dose warfarin 4.Fondaparinaux

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Graded compression stockings Thromboembolic deterrent (TED stockings) Create 18 mm Hg external pressure at ankles & 8 mm Hg in thigh Resulting 10 mm Hg pressure gradient driving force for venous outflow from legs Shown to reduce VTE when used alone for abdominal & neurosurgery However considered least effective method not used alone for moderate & high risk of VTE.

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Intermittent pneumatic compression Inflatable bladders that are wrapped around lower leg Inflated create 35 mmHg external compression at ankles & 20 mmHg at thighs Create pumping action by inflating & deflating at regular interval- augments venous outflow Used after intracranial Sx & trauma victims who are at risk of bleeding

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Low dose unfractionated heparin Rationale for low dose heparin Heparin indirect acting drug Must bind to cofactor anti-thrombinIII(AT) to produce effect Heparin-AT complex inactivates factors IIa(thrombin), IXa, Xa, Xia & XIIa Inactivation of IIa is sensitive R n occur at heparin doses far below those needed for inactivation of other coagulation factors Small doses of heparin can inhibit thrombus formation without producing full anticoagulation

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Low dose unfractionated heparin Dosing regimen: 5000 u b.d or t.d.s daily More frequent dosing (t.d.s) recommended for higher risk condition Surgical prophylaxis: 1 st dose 2hr before Sx. Postoperative prophylaxis continued for 7-10 days or untill pt. fully ambulating Effective thromboprophylaxis for high risk medical cond. & most non-orthopedic surgical prophylaxis

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Low molecular weight heparin More potent & more uniform anticoagulant activity than UFH. Advantage : Less frequent dosing,lower risk of bleeding & HIT No need for routine anticoagulant monitoring with full anticoagulant dosing Disadvantage : 10 times more costly (per day) than UFH More effective than UFH for orthopedic procedures involving knee & hip, major trauma including spinal cord injury

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Low molecular weight heparin Dose : Enoxaparin O.D. 40 mg for moderate risk cond. & B.D. 30 mg for high risk cond. Dalteparin O.D. dose 2500 U for moderate risk cond. & 5000 U for high risk cond. Timing : Non orthopedic Sx. 2 hr before Sx Orthopedic Sx. 6 hr after Sx Excreted primarily by kidney. Pt. in renal failure:Enoxaparin dose reduced to 40 mg o.d for high risk cond. No dose adjustment for Dalteparin

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Adjusted dose warfarin Vitamin K antagonist prevents carboxylation activation of coagulation factors II, VII, IX, and X Advantage : Preop dose not increase bleeding tendency during Sx d/t delayed onset Can be continued after discharge if prolonged prophylaxis Disadv.: Multiple drug interactions Monitoring lab test Difficulty adjusting doses d/t delayed onset

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Adjusted dose warfarin Dosing regimen Initial dose : 10mg P.O. evening before Sx F/b 2.5 mg daily starting the evening after Sx. Dose adjusted keep INR 2-3

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Fondaparinux Synthetic anticoagulant, an anti-Xa pentasaccharide Predictable anticoagulant effect No lab. monitoring required. Prophylactic dose 2.5 mg O.D s.c. inj. given 6- 8 hr after Sx. Contraindication : Severe renal impairment creatinine clearance < 30ml/hr. Wt. < 50 kg marked increase in bleeding

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Natural course of thromboembolism DVT in lower extremity may arise in calf vein or in proximal veins Thrombous may extend proximally to iliac veins & IVC Incidence of thrombosis in upper extremity increasing d/t widespread use of central venous catheter DVT may occur in deep pelvic vein or renal vein Can be thrombous formation in right side of heart d/t atrial fibrillation

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Most clinically important & fatal pulmonary embolism occurs from proximal than distal DVT in leg PE occur in 50% of pt. with proximal DVT, while asymptomatic thrombosis of leg vein is observed in 70% pt with PE On early ambulation, thrombus in deep veins may resolve completely

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Post-thrombotic syndrome may develop in 25% of patients, 2yrs after initial diagnosis and proper t/t of DVT Inadequate t/t of DVT result in 20-30% risk of recurrent VTE & collaterals develop parallel to thrombosed segment of vein

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Diagnostic approach to thromboembolism The Clinical evaluation Clinical presentation of acute pulmonary embolism is nonspecific No clinical or lab findings that will confirm or exclude diagnosis of pulmonary embolism

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Clinical & lab findings in pt. with suspected pulmonary thromboembolism FindingsPositive predictive value Negative predictive value Dyspnea 37% 75% Tachycardia 47% 86% Tachypnea 48% 75% Pleuritic chest pain 39% 71% Hemoptysis 32% 67% Hypoxemia 34% 70% Elevated d- dimer 27% 92%

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Plasma d- dimer levels Quantitative plasma D-dimer ELISA rises - DVT or PE because of plasmin's breakdown of fibrin. Elevation of D-dimer indicates endogenous although often clinically ineffective thrombolysis. Sensitivity >80% for DVT & >95% for PE. D-dimer is less sensitive for DVT than PE because DVT thrombus size is smaller. D-dimer is a useful "rule out" test.

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Plasma d- dimer levels It is normal (

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Ultrasonography of the Deep Leg Veins Criteria for Establishing the Diagnosis of Acute DVT Lack of vein compressibility (the principal criterion) Vein does not "wink" when gently compressed in cross-section Failure to appose the walls of vein d/t passive distension Direct Visualization of Thrombus Homogenous Low echogenicity Abnormal Doppler Flow Dynamics Normal response: calf compression augments Doppler flow signal and confirms vein patency proximal and distal to Doppler Abnormal response: flow blunted rather than augmented with calf compression

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Spiral CT scan Computed tomography (CT) of the chest with intravenous contrast is the principal imaging test for diagnosis of PE Pt. must be able to breath hold for 30sec Best suited for detecting clots in main pulmonary artery When imaging is continued below the chest to the knee, pelvic and proximal leg DVT can also be diagnosed by CT scanning. Sensitivty 93% & specificity 97%

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Radionuclide lung scan 2nd-line diagnostic test for PE. Used for patients who cannot tolerate i.v. contrast Small particulate aggregates of albumin labeled with a gamma-emitting radionuclide are injected i.v & are trapped in the pulmonary capillary bed. Perfusion scan defect indicates absent or decreased blood flow, possibly d/t PE. High probability scan : two or more segmental perfusion defects in presence of N ventilation. Diagnosis of PE is very unlikely in pt. with N and near- N scans but is about 90% certain in patients with high- probability scans.

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Pulmonary angiography Most accurate method for detecting pulmonary emboli. Invasive catheter-based diagnostic testing reserved for patients with technically unsatisfactory chest CTs. Definitive diagnosis of PE - intraluminal filling defect in more than one projection. Secondary signs of PE include abrupt occlusion ("cut-off") of vessels, segmental oligemia or avascularity, prolonged arterial phase with slow filling, or tortuous, tapering peripheral vessels

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ALGORITHM FOR DIAGNOSTIC IMAGING SUSPECT DVT OR PE ASSESS CLINICAL LIKELIHOOD DVTPE NOT LOWLOW NOT HIGH HIGH D-DIMER IMAGING TEST NEEDED HIGHNORMAL NO DVT D - DIMER NORMALHIGH IMAGING TEST NEEDED NO PE

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CLINICAL DECISION RULES LOW CLINICAL LIKELIHOOD OF DVT IF THE POINT SCORE IS ZERO OR LESS CLINICAL VARIABLESCORE 1.ACTIVE CANCER 2.PARALYSIS, PARESIS OR RECENT CAST 3.BEDRIDDEN FOR >3 DAYS ;MAJOR SURGERY 3 CM 7.PITTING EDEMA 8.COLLATERL SUPERFICIAL NON VARICOSE VEINS 9.ALTERNATIVE DIAGNOSIS AT LEAST AS LIKELY AS DVT 1 1 - 2

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CLINICAL DECISION RULES HIGH CLINICAL LIKELIHOOD OF PE IF POINT SCORE EXCEEDS 4 CLINICAL VARIABLE SCORE 1.SIGN AND SYMPTOMS OF DVT 2.ALTERNATIVE DIAGNOSIS LESS LIKELY THAN PE 3.HEART RATE >100 / min 4.IMMOBILISATION >3 DAYS ;SURGERY WITHIN 4 WEEKS 5.PRIOR PE OR DVT 6.HEMOPTYSIS 7.CANCER 3.0 1.5 1.5 1.0

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ALGORITHM FOR DVT DIAGNOSIS DVT IMAGING TEST VENOUS ULTRASOUND DIAGNOSTIC STOP NONDIAGNOSTIC MRCTPHLEBOGRAPHY

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Color duplex scan of DVT

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ALGORITHM FOR PE DIAGNOSIS PE IMAGING TEST CHEST CT DIAGNOSTIC STOP NONDIAGNOSTIC/ UNAVAILABLE LUNG SCAN DIAGNOSTIC STOP NONDIAGNOSTIC VENOUS ULTRASOUND POSITIVE TREAT FOR PE NEGATIVE TRANSESOPHAGEAL ECHO MR/PULM ANGIOGRAPHY

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Antithrombotic therapy Anticoagulation Initial t/t of thromboembolism that is not life threatening is anticoagulation with heparin Standard t/t of both DVT & acute PE is UFH continuous i.v infusion using wt. based dosing

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Antithrombotic therapy UFH Target aPTT 23 times the upper limit of laboratory normal. Usually equivalent to aPTT of 6080 s. Nomograms based upon patient's wt. may assist in adjusting dose of heparin Give an initial bolus of 80 units/kg, f/b an initial infusion @18 units/kg/hr. Check aPTT 6 hr after infusion & adjust heparin dose

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Antithrombotic therapy LMWH Therapeutic dose : Enoxaparin 1mg/kg s.c inj. every 12hr Warfarin anticoagulation Pt. with reversible cause of VTE (major Sx.) Warfarin can be started on on first day of heparin therapy When INR 2-3 heparin can be discontinued Oral anticoagulation continued at least 3 months

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Thrombolytic therapy Reserved for life threatening cases of PE with hemodynamic instability Alteplase: 0.6mg/kg over 15min Reteplase : 10U i.v. bolus & repeat in 30 min Contraindications : intracranial disease, recent Sx., trauma. Overall major bleeding rate ~ 10%, including 1 3% risk of intracranial hemorrhage.

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Inferior vena caval filters Mesh like filter device can be placed in IVC To trap thrombi that break loose from leg vein &prevent them from trvelling to lungs Indications (1) active bleeding that precludes anticoagulation (2) recurrent venous thrombosis despite intensive anticoagulation. Inserted percutaneously through IJV or femoral vein & are placed below renal vein if possible

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Neuraxial blockade in patients who have or will receive anticoagulant prophylaxis (1) Neuraxial anesthesia/analgesia should generally be avoided in patients with known bleeding disorder (2) Avoided in pt.whose preoperative hemostasis is impaired by antithrombotic drugs

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NSAIDs & aspirin do not appear to increase risk of perispinal hematoma. Thienopyridine platelet inhibitors clopidogrel & ticlopidine discontiue for 5 to 14 days Insertion of spinal needle or epidural catheter should be delayed at least 8 to 12 h after s.c. dose of heparin or a twice daily prophylactic dose of LMWH At least 18 h after O.D. LMWH injection

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(3) Anticoagulant prophylaxis delayed if hemorrhagic aspirate (ie, a bloody tap) encountered during initial spinal needle placement. (4) Removal of an epidural catheter should be done when the anticoagulant effect is at a minimum (usually just before the next scheduled s.c inj.). (5) Anticoagulant prophylaxis should be delayed for at least 2 h after spinal needle or epidural catheter removal.

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(6) If warfarin is used - continuous epidural analgesia not be used for longer than 1 or 2 days because of unpredictable anticoagulant effect If prophylaxis with a VKA is used at the same time as epidural analgesia, INR should be 1.5 at time of catheter removal.

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( 7)Postoperative prophylaxis with fondaparinux - safe in pt. who have received a spinal anesthetic No safety data about its use along with postoperative continuous epidural analgesia. Long half-life of fondaparinux & renal mode of excretion raise concerns about potential for accumulation,in elderly d/t associated impairment of renal function.

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With concurrent use of epidural analgesia & anticoagulant prophylaxis, all patients should be monitored for s/s of cord compression. Progression of lower extremity numbness or weakness, bowel or bladder dysfunction, & new onset of back pain. If spinal hematoma is suspected, diagnostic imaging and definitive surgical therapy performed rapidly to reduce the risk of permanent paresis.

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