This presentation tries to give answer to the common questions surgical residents face in dealing treating the patients with DVT

1. Anticoagulation in Deep Vein Thrombosis
(According to American College of Chest Physician guidelines)
Jibran Mohsin
Resident, Surgical Unit I
SIMS/Services Hospital, Lahore

2. Rationale
• Anticoagulant therapy remains the mainstay of
medical therapy for DVT because it(s)
– Is noninvasive,
– Treats most patients (approximately 90%) with no
immediate demonstrable physical sequelae of DVT,
– Has low risk of complications, and
– outcome data demonstrate an improvement in
morbidity and mortality.

3. Ideal Anticoagulant Drug
• Prevent pathologic thrombosis
– Limiting reperfusion injury
– i.e. preservation of extrinsic pathway (Tissue Factor-
VIIa initial phase)
• Allow physiologic thrombosis
– Limiting bleeding(normal response to vascular injury)
– i.e. attenuation of secondary intrinsic pathway
propagation phase
TILL NOW…………NO SUCH DRUG EXIST…..All anticoagulant drugs have increased bleeding risk
as their principle toxicity

4. AnticoagulantDrugs
Thrombin Inhibitors
Direct
Parenteral
Hirudin (Lepirudin)
Bivalirudin
Argatroban
Oral
Ximelagatran
Dabigatran
Indirect Heparin
Unfractionated
heparin (UFH)
LMWH (enoxaparin,
Dalteparin, Tinzaparin)
DanaparoidVitamin K antagonist
Coumarin
anticoagulants
Warfarin
Factor Xa inhibitor
Indirect
Fondaparinux
(subcutaneous)
Direct
Apixaban (oral)
RIVAROXIBAN (oral)

5. OPTIONS
Initial short-term anticoagulation Long-term anticoagulation
Conventional Heparin
Unfractionated heparin-UFH (IV)
Fixed-dose UFH (SC)
LMWH (SC)
Warfarin (oral)
New Factor Xa inhibitor
• Fondaparinux (SC)
Factor Xa inhibitors
• Rivaroxaban (oral)
• Apixaban (oral)
Direct thrombin inhibitors
• Dabigatran (oral)

6. Indirect Thrombin Inhibitors
Antithrombin(AT): endogenous anticoagulant;
inactivates IIa(thrombin), IXa, Xa, XIa and
XIIa

7. Heparin
• Heterogeneous mixture of sulfated mucopolysaccharides
• Cofactor for AT-protease interaction without being consumed
• Mechanism of Action
– Also inhibits activation of factor VIII
Inactivates inhibits conversion
Low Dose factor Xa prothrombin to thrombin
High Dose factors IX, X, XI, and XII and thrombin fibrinogen to fibrin

8. Etymology
• In 1916, McLean, a second-year medical student
at Johns Hopkins University,
– working under the guidance of Howell
– investigate procoagulant preparations,
– isolated a fat-soluble phosphatide anticoagulant in
canine liver tissue
• hence its name (hepar or "ήπαρ" is Greek for
"liver")
– similar to word HEPATIC

9. Heparin
• Onset: IV (immediate); SC (20-30 min)
• Metabolized in the liver (partial) and
reticuloendothelial system (partial)
• Half-life: 60-90 min average (longer at higher
doses)
• Excretion: Urine

10. Parameter Unfractionated Heparin (UFH) Low Molecular Weight Heparin
(LMWH)
Molecular Weight 5000 – 30,000 <9,000
Bioavailability Low high
Clotting factors effected IIa (Thrombin), IXa, Xa Xa (less effect on thrombin)
Efficacy Equal
Dosing Loading followed by continuous
infusion
OD or BD
Monitoring aPTT None
Risk of recurrent DVT 4 %
Risk of PE 2 %
Risk of major bleeding 3%

11. Units of Dosage
• Poor correlation between concentration of a
given heparin preparation and its effect on
coagulation due to
– Family of molecules of different molecular weight
UFH* sodium USP units per milligram
Enoxaparin* milligrams
Dalteparin, Tinzaparin and Danaparoid Anti factor Xa units
*Heparin and Enoxaparin extracted from porcine intestinal mucosa or bovine lung

12. Monitoring of Heparin Effect
Unfractionated Heparin(UFH) aPTT*(2-3 times baseline)
Levels of UFH Protamine Titration
(therapeutic levels 0.2-0.4 unit/mL)
Anti-Xa units
(therapeutic levels 0.3-0.7 unit/mL)
LMWH No monitoring required except in renal failure**,
pregnancy, obesity(>150 kg)
Anti Xa units- 4 hours after dose
(therapeutic level 0.5-1 unit/mL ------ BD dosing)
(therapeutic level 1.5 units/mL-----OD dosing)
*Use of PTT for heparin monitoring is problematic
• No standardization scheme for PTT as for PT i.e. INR (range 1.6 -6 times control PTT)
• Prolonged baseline PTT due to factor deficiency or inhibitors or lupus coagulant
** IV heparin treatment of choice in end stage renal disease

13. Dosage
UFH Therapeutic IV Loading Dose Infusion dose
80 units/kg 18 units/kg/hr
5000 units 1300 units/hr
S/C Loading Dose Maintenance Dose
250 units/kg 250 units/kg q12hr
17,500 units 250 units/kg q12hr
Prophylactic(S/C) 5000 units SC q8-12hr, OR
7500 units SC q12hr
Prophylactic Therapeutic
Enoxaparin
(s/c)
30 mg twice daily OR
40 mg once daily
1 mg/kg twice daily
1.5 mg/kg once daily
Dalteparin
(s/c)
5000 units once daily 200 units/kg once daily
*Start Heparin/LMWH within the first 24 hours of diagnosis, reducing the incidence
of recurrent VTE during the first 3 months from 25% to 5%

14. Toxicity
• Bleeding (major side effect)
– More in elderly female and renal failure
• Anaphylaxis/Allergy to heparin of animal origin
• Reversible alopecia
• Osteoporosis and spontaneous fracture (long-term, high-dose use)
• Clear postprandial lipemia
– Activation of lipoprotein lipase
• Mineralocorticoid deficiency
• Increased ALT/AST
• Local effects: Pain, local irritation, erythema, injection site ulcer.

15. New thrombus/thrombocytopenia while patient on
heparin therapy………..suspect HIT
• Heparin Induced Thrombocytopenia(with or without thrombosis)
– immune-mediated reaction resulting from irreversible aggregation of
platelets
– Systemic hypercoagulable state
– 1-4 % (10-30 % medscape) cases treated with UFH for min 7 days
– Surgical patients>pediatrics>pregnancy(rare)
– Bovine UFH >Procine UFH > LMWH
– Venous(more common) and arterial thrombosis
• Increased risk in presence of indwelling catheter/prosthetic cardiac valve
– Monitoring
• frequent platelet count
– TREATMENT
• Stop heparin(if platelets <100, 000) and use direct thrombin inhibitor or
fondaparinux

16. Contraindications
– Severe thrombocytopenia
– Uncontrolled, active bleeding (except DIC)
– Conditions in which coagulation tests cannot be
performed at appropriate intervals

17. Cautions
Any risk factor for hemorrhage
– subacute bacterial
endocarditis,
– blood dyscrasias/impaired
hemmostasis
– Menorrhagia/Threatened
abortion
– dissecting aneurysm,
– Major(spinal/brain/eye)
surgery,
– spinal anesthesia/Lumbar
puncture,
– GI ulcerative lesions,
– Impaired renal/ liver disease,
– Severe HTN,
– Intracranial hemorrhage
– Visceral Carcinoma
– Active Tuberculosis

18. Protamine Sulfate
• IV Preparation
– Reconstitute with 5 mL sterile water
– Resulting solution equals 10 mg/mL
• IV Administration
– Inject without further dilution over 1-3 min;
– maximum of 50 mg in any 10 min period
– Rapid IV infusion causes hypotension
• Storage
– Refrigerate
– Avoid freezing

19. Protamine Sulfate
• not to exceed 50 mg/10 minutes (Excess protamine Anticoagulant effect)
• Monitor aPTT 5-15 min after dose then in 2-8 hr
• In accidental overdoses of heparin, consider t1/2 heparin 60-90 min
• In setting without bleeding complications, consider observation, rather than
reversal of anticoagulation with protamine (avoids ADR's)
• Complex of protamine and heparin may degrade over time requiring further doses
Time Elapsed Since Heparin Dose Dose of protamine (mg)
<30 minutes (< 0.5 half life) 1-1.5 mg/100 units of heparin
30-120 minutes (0.5-1 half life) 0.5-0.75 mg/100 units of heparin
>120 minutes (> 1 half life) 0.25-0.375 mg/100 units of heparin

20. Protamine Sulfate
• Incomplete neutralization of LMWH
• No effect on fondaparinux/danapariod -
plasmapheresis
overdose given within 8 hr >8 hr of overdose or
bleeding continues after 4 hr after first dose
Enoxaparin 1 mg per mg enoxaparin 0.5 mg per mg enoxaparin
if PTT prolonged 4hr after protamine overdose
Dalteparin or
Tinzaparin
1 mg per 100 units 0.5 mg per 100 units

21. Factor Xa inhibitors
• Indirect
– Fondaparinux
• Direct
– Rivaroxiban

22. Fondaparinux
• Synthetic pentasaccharide molecule
• Binds At with high specific activity
– Efficient inactivation of factor Xa
• Longer half life of 15 hours
– Once daily s/c dosing
• Use in case of HIT

23. Rivaroxaban
• Highly selective direct Factor Xa inhibitor with
oral bioavailability and rapid onset of action
• Effects last approximately 8–12 hours,
– but factor Xa activity does not return to normal within 24 hours
– so once-daily dosing is possible
• Predictable pharmacokinetics across a wide spectrum of
patients (age, gender, weight, race)
– With flat dose response across an eightfold dose range (5–40 mg)
ONE TABLET…..ONE DOSE……………ONCE A DAY

24. Rivaroxiban
• Allows predictable anticoagulation with no
need for
– dose adjustments and
– routine coagulation monitoring(except in liver and
renal disease)

25. Rivaroxaban
• 10 mg:
– Prevention of venous thromboembolism(VTE) in adult
patients undergoing elective hip or knee replacement
surgery. (2008)
• 15 mg / 20 mg:
– Prevention of stroke and systemic embolism in adult
patients with non-valvular atrial fibrillation (2011)
– Treatment of DVT and PE, and (2012)
– prevention of recurrent DVT and PE in adults. (2012)

26. Apixaban
• Highly selective, orally bioavailable, and reversible
direct inhibitor of free and clot-bound factor Xa
• Indication
– prevention of stroke and systemic embolism in patients
with nonvalvular atrial fibrillation(Dec 2012)
– prophylaxis of DVT and PE in adults who have undergone
hip- or knee-replacement surgery (March 2014)
– Treatment DVT and PE (August 2014)

27. Direct Thrombin Inhibitors(DTIs)
Parenteral
• Bivalent DTIs
– Catalytic /active site
– Substrate recognition site
• Hirudin/Lepirudin
• Bivalirudin
• Monovalent DTIs
– Active site only
• Argatroban
Oral
• Example
– Dabigatran

28. Dabigatran
• Indication:
– reduce the risk of stroke in patients with nonvalvular atrial
fibrillation(2010)
– Treatment of DVT and PE in patients who have been treated
with a parenteral anticoagulant for 5-10 days(April 2014)
– reduce the risk of DVT and PE recurrence in patients who have
been previously treated
– Prevention of VTE in hip/knee replacement surgery
• Equivalent efficacy/safety to LMWH
• No routine monitoring

29. Coumarin (French term for the tonka bean, coumarou)
Anticoagulants
Etymology
Early 1920s Discovery of an anticoagulant substance from in
spoiled sweet clover silage  causing hemorrhagic disease in
cattle(north US and Canada)
In 1930s Chemists at University of Wisconsin identified
toxic agent as bishydroxycouramin
Synthetic derivative(dicumarol, wafarin) used as
rodenticides(RAT poison)
In 1954 warfarin(brand name= Coumadin) introduced as
antithrombotic agent in humans

30. Etymology
Wiscosin
Alumni
Research
Foundation
A
R from coumarin
I
N

31. Pharmacokinetics
• 99 % bound to plasma albumin
– Small volume of distribution
– Long half life (36 hours)
– Lack of urine excretion
• Clinically used warfarin
– equimolar mixture of levo S-warfarin(4 times
more potent) and dextro R-warfarin

32. Pharmacokinetics
• Absorption
– Onset: 36-48 hr
– Peak plasma time: 1.5-3 days
– Duration: 2-5 days
• Half-life: 20-60 hr (patient specific)

33. Mechanism of Action
Blockade of gamma-carboxylation of several glutamate residues in prothrombin (II) and
factors VII, IX and X as well as endogenous anticoagulant Protein C and S

34. Administration
• Initial dose
– Standard doses of 5-10 mg
– rather than large loading doses formerly used
• Initiate warfarin on day 1 or 2 of LMWH or unfractionated heparin
therapy
– Overlap warfarin and parenteral anticoagulant for at least 5 days
– until desired INR (>2.0) maintained for 24 hours
– THEN discontinue heparin
• Check INR after 2 days and adjust dose according to results
• Typical maintenance dose ranges between 5-7 mg/day

35. Rationale for heparin overlap with warfarin for initial 5 days
• Prevents Warfarin-induced skin necrosis

36. Rationale for heparin overlap with warfarin for initial 5 days
• After 8 hours of initiation of warfarin
– Anticoagulant Protein C is depleted vs
– Already formed procoagulant factors are still present
• Because warfarin inhibits synthesis of future factors, with NO effect on already
formed factors (unlike heparin, which inhibits already formed factors thus having
immediate effect)
– Resulting in imblanace between procoagulants and anticoagulants
• HYPERCOAGULABLE STATE  thrombisis in skin blood vessels skin necrosis
• TRANSIENT ACQUIRED PROTEIN C DEFICICENCY
Factors inhibited by Warfarin Half life
Procoagulant Factors Factor II 2-5 days (app 60 hours)
Factor VII 6 hours
Factor IX 24 hours
Factor X 40 hours (app 2 days)
Anticoagulant Facots Protein C 8 hours
Protein S

37. Warfarin induced skin necrosis
• Typical patient appears to be an obese, middle aged
woman
• Usually occurs between the 3rd and 10th days of
therapy
• Associated with the use of large loading doses at the
start of treatment
– Increased initial dose(max 0.75 mg/kg) hasten onset of
anticoagulant effect
– Beyond this dosage, speed of onset is independent of dose
size

38. Warfarin induced skin necrosis
• Pain and redness lesions develop a sharp
border and become petechial hard
and purpuric
– Then resolve or progress to form large, irregular,
bloody bullae necrosis slow-
healing eschar formation.
• Favored sites
– breasts, thighs, extremities, intestine, buttocks and
penis, all areas with subcutaneous fat

39. INR range and treatment duration
• Maintain an INR of 2.0-3.0
Condition Time of Duration
Surgery-provoked DVT or PE 3 months
Transient (reversible) risk factor-induced DVT or PE 3 months
First unprovoked proximal DVT or PE with low or
moderate bleeding risk
Extended treatment
consideration with periodic (ie,
annual) risk-benefit analysis
First unprovoked proximal DVT or PE with high
bleeding risk
3 months
First unprovoked distal DVT regardless of bleeding risk 3 months
Second unprovoked DVT or PE with low or moderate
bleeding risk
Extended treatment
Second unprovoked DVT or PE with high bleeding risk 3 months

40. INR range and treatment duration
Condition Time of Duration
DVT/PE and active cancer Extended treatment, with periodic risk-
benefit analysis
(ACCP recommends LMWH over vitamin K
antagonist therapy)
Prevention of VTE for total knee
arthroplasty, total hip arthroplasty, and
hip fracture surgery
Minimum treatment duration of 10-14
days, with a recommendation to extend
outpatient therapy to 35 days
(ACCP recommends LMWH over vitamin K
antagonist therapy)
(INR) must be monitored closely (daily or alternate days) until the target is achieved,
then weekly for several weeks. When the patient is stable, monitor monthly

41. Toxicity
• Hemorrhage
• Warfarin necrosis
• Osteoporosis
• Calcification of valves and arteries
• Purple toe Syndrome (usually within 3 to 8 weeks of commencement)
– small deposits of cholesterol breaking loose and causing embolisms in blood
vessels in the skin of the feet,
– causing a bluish purple color and may be painful.
– typically thought to affect the big toe, but it affects other parts of the feet as
well, including the bottom of the foot (plantar surface)

42. Warfarin Resistance
• Defined as progression or recurrence of a
thrombotic event while in therapeutic range
– Genetic
• Mutation in target enzyme gene
– Acquired
• Most common in advanced GI malignancies
(Trousseau’s syndrome)
• LMWH superior to warfarin in such cases

43. Reversal of Warfarin Action
• Omit 1-2 doses, or hold warfarin;
– monitor INR
– adjust warfarin dose accordingly
• INR is in therapeutic range,
– simple discontinuation of the drug for five days is usually
enough to reverse the effect and cause INR to drop below
1.5.
• INR 4.5-10, no bleeding:
– 2012 ACCP guidelines suggest against routine use;
– 2008 ACCP guidelines suggest considering vitamin K1
(phytonadione) 1-2.5 mg PO once

44. Reversal of Warfarin Action
• INR >10, no bleeding:
– 2012 ACCP guidelines recommend vitamin K1 PO (dose not specified);
– 2008 ACCP guidelines suggest 2.5-5 mg PO once; INR reduction
observed within 24-48 hr, monitor INR and give additional vitamin K if
needed
• Minor bleeding, any elevated INR:
– Consider 2.5-5 mg PO once; may repeat if needed after 24 hr
• Major bleeding, any elevated INR:
– 2012 ACCP guidelines recommend prothrombin complex concentrate,
+ vitamin K1 5-10 mg IV (dilute in 50 mL IV fluid and infuse over 20
min)
– FFP, recombinant factor VIIa(rFVIIa)

45. Vitamin K1
• IV rate not to exceed 1 mg/min
– Dilute in preservative-free NS, D5W, or D5NS
• Use of high vitamin K doses (10-15 mg) may cause
warfarin resistance for ≥1 week
PO IV
Onset 6-10 hours 1-2 hour
Peak effect 24-48 hours 12-14 hour
Route When can be repeated?
PO 12-48 hours
IV 6-8 hours

46. Pregnancy and Lactation
Pregnancy Lactation
Heparin category: C Not excreted in breast milk;
compatible
Warfarin* category: D
for women with mechanical heart valves
who are at high risk for thromboembolism;
category X (i.e. contraindicated)
for other pregnant populations
Not excreted in breast milk;
compatible
*Exposure during pregnancy causes
• major congenital malformations (abnormal bone formation),
• fatal fetal hemorrhage, and
• increased risk of spontaneous abortion and fetal mortality

47. Inpatient Versus Outpatient Treatment
• Acute DVT may be treated in an outpatient setting with
LMWH(UFH 2nd line due to risk HIT)
• Admitted patients may be treated with
– Heparin products
• Unfractionated heparin (UFH)
• Low-molecular-weight heparin (LMWH; eg, enoxaparin)
– Factor Xa inhibitors
• Fondaparinux
• Rivaroxaban

48. Exclusion criteria for outpatient management
MEDICAL FACTORS SOCIAL FACTORS
Suspected or proven concomitant PE Unavailable or unable to arrange
close follow-up care
Significant cardiovascular or pulmonary comorbidity Unable to follow instructions
Iliofemoral DVT Homeless
Contraindications to anticoagulation No contact telephone
Familial or inherited disorder of coagulation:
• antithrombin III (ATIII) deficiency,
• prothrombin 20210A,
• protein C or protein S deficiency, or
• factor V Leiden
Geographic (too far from hospital)
Familial bleeding disorder Patient/family resistant to
outpatient therapy
Pregnancy
Morbid obesity (>150 kg)
Renal failure (creatinine >2 mg/dL)

49. Limitations of anticoagulation
• Although it inhibits propagation, it does not remove
the thrombus
• Variable risk of clinically significant bleeding is
observed
• In 2-4% of patients, DVT progresses to symptomatic PE
despite anticoagulation
• In the setting of a PE, 8% of patients have recurrences
despite anticoagulation,

50. Limitations of anticoagulation
• Although anticoagulation markedly reduces
the risk of PE and extension of the DVT,
– it does not reduce the incidence of
postthrombotic syndrome (PTS),
– which requires expedited removal of the existing
thrombus without damaging the underlying
venous valves.

51. Anticoagulation for Calf Vein DVT
• At certain centers, patients with isolated calf vein
DVT are treated with full anticoagulant therapy.
RECOMMENDATIONS
Symptomatic short-term anticoagulation for 3 months
Asymptomatic with isolated calf vein DVT do not require anticoagulation
surveillance ultrasound studies over 10-14 days
to detect proximal extension is recommended
instead.

52. Anticoagulation for Calf Vein DVT
• Suspected or diagnosed isolated calf vein DVT
may be discharged safely on a NSAID
or aspirin
– with close follow-up care and repeat diagnostic
studies (ie, ultrasonography) in 7 days to evaluate
for proximal extension.

53. THANK YOU