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Anticoagulation and dvt
Anticoagulant therapy is crucial for the treatment of deep vein thrombosis (DVT), primarily due to its noninvasive nature and low risk of complications. Various anticoagulant drugs such as heparin, fondaparinux, rivaroxaban, and others have been discussed, detailing their mechanisms, pharmacokinetics, and specific indications for use. Additionally, considerations of safety, risks, and monitoring for adverse effects and complications like heparin-induced thrombocytopenia are addressed.
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Anticoagulation and dvt
- 1. Anticoagulation in DeepVein Thrombosis (According to American College of Chest Physician guidelines) Jibran Mohsin Resident, Surgical Unit I SIMS/Services Hospital, Lahore
- 2. Rationale • Anticoagulant therapyremains 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 IndirectHeparin 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 anticoagulationLong-term anticoagulation Conventional Heparin Unfractionated 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)
- 6. Indirect Thrombin Inhibitors Antithrombin(AT):endogenous anticoagulant; inactivates IIa(thrombin), IXa, Xa, XIa and XIIa
- 7. Heparin • Heterogeneous mixtureof 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. Heparin • Storage – Storeheparin 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
- 11. 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%
- 12. 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
- 13. Monitoring of HeparinEffect 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
- 14. Dosage UFH Therapeutic IVLoading 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%
- 15. Toxicity • Bleeding (majorside 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.
- 16. New thrombus/thrombocytopenia whilepatient 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
- 17. Contraindications – Severe thrombocytopenia –Uncontrolled, active bleeding (except DIC) – Conditions in which coagulation tests cannot be performed at appropriate intervals
- 18. Cautions • Any riskfactor 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
- 19. Protamine Sulfate • IVPreparation – 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
- 20. Protamine Sulfate • notto 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
- 21. Protamine Sulfate • Incompleteneutralization 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
- 22. Factor Xa inhibitors •Indirect – Fondaparinux • Direct – Rivaroxiban
- 23. Fondaparinux • Synthetic pentasaccharidemolecule • 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
- 24. Rivaroxaban • Highly selectivedirect 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
- 25. Rivaroxiban • Allows predictableanticoagulation 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).
- 26. 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)
- 27. 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)
- 28. 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
- 29. Hirudin • Specific irreversiblethrombin 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
- 30. Bivalirudin • Administered IV –Rapid onset and offset of action • Short half life – 20 % renal clearance – Rest metabolic • Also inhibit platelet activation • Indication: PCI
- 31. Argatroban • Indication: – HITwith 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
- 32. Dabigatran • Indication: – reducethe 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
- 33. Coumarin (French termfor 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
- 34.
- 35. Pharmacokinetics • Administrated assodium 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
- 36. Pharmacokinetics • Absorption – Onset:36-48 hr – Duration: 2-5 days – Peak plasma time: 1.5-3 days • Half-life: 20-60 hr (patient specific)
- 37. Mechanism of Action Blockadeof gamma-carboxylation of several glutamate residues in prothrombin (II) and factors VII, IX and X as well as endogenous anticoagulant Protein C and S
- 38. 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
- 39. Rationale for heparinoverlap with warfarin for initial 5 days • Prevents Warfarin-induced skin necrosis
- 40. Rationale for heparinoverlap 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
- 41. Warfarin induced skinnecrosis • 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
- 42. Warfarin induced skinnecrosis • 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
- 43. INR range andtreatment 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
- 44. INR range andtreatment 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
- 45. INR range andtreatment duration Condition Time of Duration 1st episode venous thrombosis and documented 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
- 46. Toxicity • Hemorrhage • Warfarinnecrosis • 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)
- 47. Warfarin Resistance • Definedas 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
- 48. Reversal of WarfarinAction • 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
- 49. Reversal of WarfarinAction • 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)
- 50. Vitamin K1 • IVrate 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
- 51. Pregnancy and Lactation PregnancyLactation 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
- 52. Inpatient Versus OutpatientTreatment • 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
- 53. Exclusion criteria foroutpatient 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)
- 54. 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,
- 55. 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.
- 56. Anticoagulation for CalfVein 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.
- 57. Anticoagulation for CalfVein 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.
- 58.