Deep Vein Thrombosis_2003

DEEP VEIN THROMBOSIS PRESENTED BY:

SIM SUI THENG HOSPITAL MIRI

OUTLINE 2

Introduction Epidemiology Risk Factors Clinical Assessment Prophylaxis Treatment Pharmacology Conclusion References

INTRODUCTION 3

Thrombus – a solid mass formed along the endothelium

from blood constituents Venous thrombosis – process of clot (thrombus) formation within the veins Deep Vein Thrombosis (DVT)

Endogenous fibrinolysis

Accumulation of fibrin & platelets at direction of blood flow

Residual thrombus will organize, vein incompletely recanalize

Venous thrombi develop within deep vein

DVT Narrowing of lumen + valvular incompetency

INTRODUCTION 4

3 main factors predispose to thrombus formation

Endothelial Injury

Virchow’s Triad

-Mechanical -Chemical -Inherited lack of natural anticoagulants -Pregnancy -OCP etc

Hypercoagul ability

Venous Stasis -Prolonged immobility -Obesity -CHF -Varicose vein -Shock

INTRODUCTION 5

DVT can occur spontaneously or in patients admitted to

hospital either for surgical or medical problem Most common site: vessels of the legs No local symptoms may be produced; warmth, aching & swelling of the calf/thigh may develop together with erythema (‘palpable cord’) If untreated, 50% of proximal DVT will embolize to the lungs resulting in pulmonary embolism (PE)  fatal!

EPIDEMIOLOGY 6

Venous thromboembolism affects 1 – 2 per 1000

people in general population each year Reported incidence of DVT in hospitalized patients varies from 0.45-30% Types of patients vs incidence of DVT in hospitals Types of patients

Incidence of DVT (%)

General surgical*

2.2-15.3 2-5

Gynaecological*

2.4 6

Orthopaedic*

4.0-62.5 7-8

Medical (CHF, COAD) #

16

ICU

25-32 10-12

Post-stroke

11-53

9

13-15

*Post-operative patients #Absence of prophylaxis

RISK FACTORS 7

Table 1: Risk Factors for Thromboembolism from Thromboembolic Risk Factors (THRIFT) Consensus Group, 1992 1

CLINICAL ASSESSMENT 8

Table 2: Clinical Model for Predicting Pretest Probability of Lower Limb DVT16

MANAGEMENT 9

Generally there are two approaches: 

Prophylaxis Mechanical method (graduated elastic compression stocking & intermittent pneumatic compression devices)  Pharmacological approaches (UFH, LMWH, oral anticoagulants & new agents) 



Treatment  Mechanical

method (stents & filters)  Pharmacological approaches (supportive therapy + anticoagulation)

PROPHYLAXIS 10

Recommended for hospital patients at moderate-high risk of VTE Two types of prophylaxis:  

Primary prophylaxis – Prevent occurrence via drugs/devices Secondary prevention – Early detection & treatment via screening post-operative patients using a reliable test

Primary prophylaxis is preferred because safer, easier to

administer and more cost-effective Should be started before surgery & continue until patient is fully mobile Duration of prophylaxis:   

Low-moderate risk: At least 5 days or until hospital discharge High risk: Until illness & immobility have resolved or until hospital discharge Continue prophylaxis for weeks for pts with continuing risk factors

PROPHYLAXIS 11

Mechanical Method 

  

Graduated elastic compression stocking & intermittent pneumatic compression devices Reduce incidence of DVT Enhance protection afforded by low dose heparin Advantages: 



Maybe an option for ppl C/I to anticoagulant drugs (risk of bleeding)

Disadvantages:  Cannot

effectively wear these stockings due to unusual limb size &

shape  Not much clinical trials support effectiveness to reduce fatal PE

PROPHYLAXIS 12

Pharmacological approach  Low dose unfractionated heparin  s/c

5000U q12h post-surgery  In ortho surgery, s/c 3500U q8h, starting 2 days pre-surgery & adjusting the APTT ratio in upper normal range 

Low molecular weight heparin (LMWH)  Given

s/c as once daily dosing  Generally more effective therapy compared to UFH 

Oral anticoagulant  Used

when heparin is C/I  Warfarin is used & maintain INR at 2.0-2.5 or 2.0-3.0 (ortho) 

The pentasaccharide fondaparinux sodium  Dose:

2.5mg od, target to ortho surgery, starting 6H postoperation, 2.5mg od for 5-9 days

PROPHYLAXIS 13

Table 3: Risk Stratification & Prevention Strategies in Medical & Surgical Patients17-18

PROPHYLAXIS 14

Table 4: Prevention strategy for deep vein thrombosis vs medical condition 1 Medical condition Prevention Strategy Intracranial neurosurgery

IPC, may add LMWH 48h post-operatively

Knee replacement

Either LMWH, fondaparinux or adjusted dose oral anticoagulants (target INR 2.0-3.0), continue for 710 days

Hip replacement

Either LMWH, fondaparinux or adjusted dose oral anticoagulants (target INR 2.0-3.0), continue for at least 10 days

Hip fracture

Warfarin (target INR 2.0-3.0), fondaparinux or fixed dose LMWH started pre-operatively, may combine graduated compression stockings

Multiple trauma

LMWH, may add IPC

*IPC- Intermittent Pneumatic Compression

PROPHYLAXIS 15

Medical condition

Prevention Strategy

Acute Stroke with paralysis of LMWH, may add graduated compression stockings lower limb with or without IPC Pregnancy (for high risk women only)

S/C low dose UFH or LMWH

Extended travel (>6 hours & additional risk factors)

Single dose LMWH or graduated compression stockings

TREATMENT 16

Objectives:    

Relieve symptoms Reduce the risk of PE to the systemic circulation Prevent post-thrombotic syndrome Prevent recurrence

TREATMENT 17

Anticoagulation 1) Low dose unfractionated heparin Check baseline APTT, PT, RF, LFT, FBC, thrombophilia screen (if necessary) Check APTT at 6, 12, 24 hours (must achieved target 1.5-2.5 within 24 hours)

Overlapped warfarin with heparin, start 5mg on 1st 2 days, then adjust daily dose according INR

Discontinue heparin* once target INR achieved w/i 2 consecutive days

Check platelet count from D3 until end of 2nd week *Usual duration of heparin regimen: 5-7 days

TREATMENT 18

To standardize management of IV UFH, a weight-

based normogram is used Table 5: Management of IV UFH using weight-based normogram 1 APTT ratio Dose Initial dose

80IU/kg bolus, then 18IU/kg/hr

APTT < 35s (<1.2x control)

80IU/kg bolus, then increase infusion rate by 4IU/kg/hr

APTT 35-45s (1.2-1.5x control)

40IU/kg bolus, then increase infusion rate by 2IU/kg/hr

APTT 46-70s (1.5-2.3x control) No change APTT 71-90s (2.3-3x control)

Decrease infusion rate by 2IU/kg/hr

APTT > 90s (>3x control)

Hold infusion for 1 hour, then decrease infusion rate by 3IU/kg/hr

TREATMENT 19

Anticoagulation (con’t) 2)Low Molecular Weight Heparin (LMWH) Table 6: LMWHs & Its Recommended Dosage in Treatment of DVT 1,19 LMWH recommended Dose Enoxaparin (Clexane®)

1.5 mg/kg od OR 1 mg/kg bd

Dalteparin (Fragmin®)

200 IU/kg od OR 120IU/kg bd

Nadroparin (Fraxiparine®)

0.1 ml/kg bd

Nadroparin (Fraxiparine® Forte)

0.1 ml/kg od

Tinzaparin (Innohep®)

175 IU/kg od

*Warfarin will be started on D1 of LMWH and overlapped for 5 days *Monitoring of LMWH with anti-Xa level is generally not necessary except in renal failure, extreme obesity & late pregnancy *Target therapeutic range: 0.6-1.0 units/ml

TREATMENT 20

Anticoagulation 3) Heparinoids 19 o o

Used in patients with history of heparin-induced thrombocytopenia Danaparoid sodium: IV 2500 units followed by 400 units/hr for 2 hours, then 300 units/hr for 2 hours, then 200 units/hr for 5 days

3) Hirudins 19 o o

Used in patients with history of heparin-induced thrombocytopenia Lepirudin: IV 400mcg/kg followed by 150mcg/kg/hr (adjusted according to APTT) for 2-10 days

3) Fondaparinux sodium 19 o o

Targeted to orthopedic surgery patients S/C 5 mg od (<50kg), 7.5 mg od (50-100kg), 10 mg od (>100kg) for at least 5 days

TREATMENT 21

Time

Table 7: Duration of Therapy 1 Therapy

3 to 6 months

1st event with reversible or timelimited risk factors (Eg. surgery, trauma, immobility, estrogen use)

6 months

Idiopathic VTE, 1st event

12 months to life time - 1st event with cancer until resolved

Persistent risk factors (Eg. antithrombin deficiency, recurrent event)

- Following discharge, patients should be followed up within a week with a repeat INR - If INR remains within therapeutic range, the same dose is maintained & next followup will be 2 weeks later - If INR still within therapeutic range, then monthly follow-up with INR is advised - Frequent visits are required if therapeutic INR is not achieved

TREATMENT 22

Supportive treatment  Adequate

analgesia (Non-aspirin analgesics)  Legs are elevated above heart  Graduated elastic compression stockings applied as soon as patient can tolerate  Encourage mobilisation

PHARMACOLOGY 23

Unfractionated Heparin 

  

 

MOA: Potentiates the action of antithrombin III and thereby inactivates thrombin (as well as activated coagulation factors IX, X, XI, XII and plasmin) and prevents the conversion of fibrinogen to fibrin 13 Onset: Immediate (IV); ~20-30mins (S/C); not IM (hematoma) Does not cross placenta & not excreted in breast milk Renal & hepatic clearance, affected by obesity, renal function, hepatic function, malignancy, presence of PE & infections Anticoagulant response is nonlinear Main side effects: Bleeding, thrombocytopenia, osteoporosis (long term therapy), hyperkalemia

PHARMACOLOGY 24

Unfractionated Heparin (Con’t) 



Drug Interactions: Cephalosporins ( bleeding risk), drugs that affect platelet function (aspirin, NSAIDS, dipyridamole, ticlopidine, clopidogrel etc), IV nitroglycerine ( anticoagulation effect), penicillins, warfarin, tetracycline, quinine, digoxin Monitoring parameters:  Platelet

counts  FBC & signs of bleeding  APTT (measured 6 hours after IV administration)

PHARMACOLOGY 25

Low Molecular Weight Heparin (Enoxaparin)  MOA: Similar to UFH except it strongly inhibits factor Xa more than UFH  Onset: Peak effect (2-4 hours)  Anti-Xa activity to a fixed dose of LMWH is highly correlated with patient’s body weight  can be given S/C od or bd w/o need for lab monitoring of APTT  Can be used in pregnancy (risk B) & breastfeeding  Not need dose adjustment (except in pregnancy, morbid obesity, renal failure)  Side effects: bleeding (13%), injection site hematoma (9%), fever (8%)

PHARMACOLOGY 26

Low Molecular Weight Heparin (Con’t) 



Drug interactions: drugs which affect platelet function (Aspirin, NSAIDS, dipyridamole, ticlopidine, clopidogrel etc), thrombolytic agents, warfarin Monitoring parameters: Platelet counts  Occult blood  Anti-Xa activity 

PHARMACOLOGY 27

Table 8: Comparison of Unfractionated Heparin & Low Molecular Weight Heparin Heparin

Unfractionated Heparin Low Molecular Weight Heparin

MOA

Anti-XIIa, XIa, IXa, VIIa, antithrombin

Mostly anti-Xa

Route of administration

S/C & IV

S/C

Bioavailability

S/C – 10-30% at low doses, > 90% 90% at higher doses IV – 100% (theoretically)

Effective half life

S/C – 1.5 hours IV – 30 mins

4 hours

Between & within individual Extensive variation

Minimal

Monitoring

APTT

Not required (Anti-Xa)

Elimination

Liver and kidney

Kidney

Cost

$

$$$

PHARMACOLOGY 28

Warfarin  MOA: Inhibits Vitamin K epoxide reductase in the liver, an enzyme required for the activation of factors II, VII, IX, X  Onset: 36-72 hours, full therapeutic effect: 5-7 days  Oral absorption is rapid & complete (F~100%)  Hepatic metabolism via CYP2C9, minor include CYP2C19, 1A2, 3A4  Crosses placenta & cause embryopathy (nasal hypoplasia, stippled epiphyses) in 1st trimester, CNS abnormalities & fetal hemorrhage  C/I in pregnancy!  Can be used in breastfeeding (does not enter breast milk)  Side effects: bleeding, angina, purple toes syndrome, skin necrosis

PHARMACOLOGY 29

Warfarin (Con’t) 

Factors influencing INR:  Dietary

Vitamin K intake  Alcohol consumption  Underlying diseases: diarrhea, prolonged fever, CHF, liver disease, hepatic congestion, hyper- and hypothyroidism  Concurrent drug administered 

Monitoring parameters:  PT  INR  Signs

& symptoms of bleeding (gum bleeding, dark stool, hematuria, skin petechiae etc)

PHARMACOLOGY 30

Warfarin (Con’t) Table 9: Clinically Significant Warfarin Drug Interactions Antibiotics Oral contraceptives Omeprazole/Ranitidine Antiepileptics Antifungals Statins Antiplatelets/anticoagulants Thyroid drugs NSAIDS

CONCLUSION 31

DVT is a potentially fatal disease because it can progress to PE if not

being managed carefully Prophylaxis should be initiated according to risk factors either pharmacologically or mechanically After confirm on a diagnosis of DVT, decide on treatment regimen (UFH/LMWH +/- warfarin), duration & monitor patient closely Upon discharge, on going anticoagulation is essential to prevent recurrence COMPLIANCE, COMPLIANCE, COMPLIANCE…

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