Anticoagulation in Deep Vein Thrombosis(According to American College of Chest Physician guidelines)

Jibran Mohsin

Resident, Surgical Unit I

SIMS/Services Hospital, Lahore

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.

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

An

tico

agu

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rugs

Thrombin Inhibitors

Direct

Parenteral

Hirudin (Lepirudin)

Bivalirudin

Argatroban

Oral

Ximelagatran

Dabigatran

Indirect Heparin

Unfractionated heparin (UFH)

LMWH (enoxaparin, Dalteparin, Tinzaparin)

DanaparoidVitamin K antagonistCoumarin

anticoagulantsWarfarin

Factor Xa inhibitor

IndirectFondaparinux

(subcutaneous)

Direct

Apixaban (oral)

RIVAROXIBAN (oral)

OPTIONS

Initial short-term anticoagulation Long-term anticoagulation

Conventional HeparinUnfractionated heparin-UFH (IV)

Fixed-dose UFH (SC)

LMWH (SC)

Warfarin (oral)

New(NO Monitoring required)

Factor Xa inhibitor• Fondaparinux (SC)

Factor Xa inhibitors • Rivaroxaban (oral)• Apixaban (oral)

Direct thrombin inhibitors• Dabigatran (oral)

Indirect Thrombin InhibitorsAntithrombin(AT): endogenous anticoagulant;

inactivates IIa(thrombin), IXa, Xa, XIa and

XIIa

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

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

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

Heparin

• Storage– Store heparin solutions at room temperature; do not freeze– Do not use if discolored/precipitates– Autoclavable

• IV Preparation– Recommended infusion concentration– 25,000 units in 500 mL D5W – 50 units/mL premixed infusion solution

• IV Administration– IV injection may be given undiluted or diluted in 50-100 mL NS or D5W– Infusion: Dilute in NS, D5W, or other compatible fluid– Continuous IV therapy is preferred

• intermittent IV therapy produces a higher incidence of bleeding abnormalities

– Invert IV bag at least 6 times to ensure mixing and prevent pooling of medication– Use constant-rate IV infusion pump

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%

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 120 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

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

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, OR7500 units SC q12hr

Prophylactic Therapeutic

Enoxaparin(s/c)

30 mg twice daily OR40 mg once daily

1 mg/kg twice daily1.5 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%

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.

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

Contraindications

– Severe thrombocytopenia

– Uncontrolled, active bleeding (except DIC)

– Conditions in which coagulation tests cannot be performed at appropriate intervals

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

• Allergy/Hypersensitivity/HIT

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

• For IV use only

• Administer slow IVP (50 mg over 10 min)– Rapid IV infusion causes hypotension

• Storage– Refrigerate– Avoid freezing

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

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

Factor Xa inhibitors

• Indirect

– Fondaparinux

• Direct

– Rivaroxiban

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

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

Rivaroxiban

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

• data suggested that there are no grounds for avoiding rivaroxaban use in high-risk groups (eg, fragile patients, cancer patients, and patients with a large clot).

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)

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)

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

• Merits over parenteral– Fixed dosing

– Predictable anticoagulant response

– Routine coagulation monitoring not necessary

– Don’t interact with Cyt P450

– Rapid onset/offset• Immediate anticoagulation

• No overlap with other druds

Hirudin

• Specific irreversible thrombin inhibitor from medicinal leeches(Hirudo medicinalis) saliva

• Recombinant form Lepirudin

• Little effect on platelets/BT

• Route: parenterally

• Monitoring: aPTT

• Indication: HIT

• Great caution in renal insufficiency (as NO anitdote)

• Adverse Effect: – enhanced anticoagulant effect due to Ab against thrombin-lepirudin comlex(40 % cases

–long term use)– Life threatening anaphylactic reactions on re exposure

Bivalirudin

• Administered IV– Rapid onset and offset of action

• Short half life– 20 % renal clearance– Rest metabolic

• Also inhibit platelet activation

• Indication: PCI

Argatroban

• Indication:– HIT with or without thrombosis– Coronary angioplasty in HIT

• Short half life– Give infusion

• Monitored by aPTT

• Liver (not renal) clearance

• Cause increased INR (difficulty in transition to warfarin)

DTI of choice

Renal disease Argatroban

Liver Disease Lepirudin

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

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

Etymology

Wiscosin

Alumni

Research

Foundation

A

R from coumarin

I

N

Pharmacokinetics

• Administrated as sodium salt

• 100 % bioavailability

• 99 % bound to plasma albumin– Small volume of distribution– Long half life (36 hours)– Lack of urine excretion

• Clinically used warfarin is equimolar mixture of levo S-warfarin(4 times more potent) and dextro R-warfarin

Pharmacokinetics

• Absorption

– Onset: 36-48 hr

– Duration: 2-5 days

– Peak plasma time: 1.5-3 days

• Half-life: 20-60 hr (patient specific)

Mechanism of ActionBlockade 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

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

Rationale for heparin overlap with warfarin for initial 5 days

• Prevents Warfarin-induced skin necrosis

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

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

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 bullaenecrosis slow-healing eschar formation.

• Favored sites– breasts, thighs, extremities, intestine, buttocks and

penis, all areas with subcutaneous fat

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

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

INR range and treatment duration

Condition Time of Duration

1st episode venous thrombosis anddocumented antiphospholipid antibodies or 2 or more thrombophilic conditions(combined factor V Leiden and prothrombin 20210A gene

mutations),

at least 12 months-life long

Any one of the following: deficiencies of antithrombin, protein C, or protein S; factor V Leiden; prothrombin 20210A; hyperhomocysteinemia; or high factor VIII levels (>90th percentile)

Life threatening PE

6-12 months till life long

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)

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

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

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)

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

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

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

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)

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,

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.

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.

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.

– Patients with suspected DVT but with negative initial noninvasive study results need to be reassessed by their primary care provider within 7 days.

– Patients with ongoing risk factors need to be reevaluated at 1 week to detect proximal extension because of the limited accuracy of noninvasive tests for calf vein DVT.

THANK YOU