HEPARINS AND WARFARINSMacquarie NeurosurgerySamson Sujit Kumar Gaddam15.11.2012                            EBS presentatio...
HEPARINHeparin is a glycosaminoglycan. Granules of mast cells (fragments of12000Da, about 40monosaccharide units))Activate...
Onset of action    IV (immediate), S/C: 1-2 hoursHalf life          Depends on dose (IV): 100U/Kg (1hr), 400U/Kg (2.5hr), ...
USESRapid onset of actionTreatment               DVT, PE, CardiacLow dose:               Prophylaxis of DVT (Khaldi et al....
Side effectsBleeding       1-5% of patientsHeparin induced thrombocytopenia (HIT)               IgG antibodies to complex ...
Antidote:   Protamine sulphate            1mg = 100U heparin.            Monitor aPTT            IV 50mg in any 10min     ...
LOW MOLECULAR WEIGHT HEPARINSMW:           3000-8000 daltonsPreparation   gel chromatography/partial depolymerisationMecha...
Enoxaparin   30mg bd for 7-14 days             peak in 3-5 hrs             Half life: 4.5hr             Antidote: Protamin...
Synthetic HeparinsFondaparinux         Synthetic pentasaccharide                     Inhibits Xa                     sub c...
IF PATIENT IS ON HEPARINS AND NEEDS SURGERY  Elective                           EmergencyStop infusion 4-6 hr             ...
WarfarinDerivative of 4-hydroxycoumarin                                               -                                   ...
Onset of action depends on half-life of the factors (in hrs): VII   6hr                                                   ...
Usage       Prevent progression or recurrence of DVT/PEDosage      Oral 5mg od for 2-4 days, then 2-5mg odMonitor     Prot...
InteractionsDecreased effect   binding to Cholestyramine in GI                   hypoproteinemia (nephrotic syndrome)     ...
Antidote:   1.Vitamin K1 (aqueous solution), 10-15mg IM            Takes 6-12hrs to act (depends on liver function)       ...
Side effectsHemorrhage <5% per year in patients (INR 2-3)Birth defects CNSPurple toe syndrome (cholesterol emboli, 3-8 wks...
IF PATIENT IS ON WARFARIN AND NEEDS SURGERY        Elective                                     EmergencyStop warfarin 3 d...
WHAT TO DO?Patients with incidental aneurysm         Depends on indicationPatients on anticoagulation who develop   SAH Re...
References1.Goodman & Gilman’s Manual of Pharmacology and Therapeutics2. Khaldi et al., Venous Thromboembolism: deep vein ...
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Anticoagulation in neurosurgery heparin warfarin_ppt

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Anticoagulation in neurosurgery heparin warfarin_ppt

Anticoagulation in neurosurgery heparin warfarin_ppt

  1. 1. HEPARINS AND WARFARINSMacquarie NeurosurgerySamson Sujit Kumar Gaddam15.11.2012 EBS presentation 1
  2. 2. HEPARINHeparin is a glycosaminoglycan. Granules of mast cells (fragments of12000Da, about 40monosaccharide units))Activates Antithrombin III that inhibits thrombin (II), Xa, IXaAntithrombin (suicide substrate) : synthesized in liver and circulates in theplasma. Heparin increases its activity by 1000 fold.Also activates platelets (high doses). Inhibits only soluble thrombin THRO Heparin ATIII MBIN ( II ) Pentasaccharide EBS presentation 2
  3. 3. Onset of action IV (immediate), S/C: 1-2 hoursHalf life Depends on dose (IV): 100U/Kg (1hr), 400U/Kg (2.5hr), 800U/Kg (5hr) Prolonged in PE, hepatic cirrhosis, end stage renal diseaseElimination RES and small amounts in urineCommercial prep. Porcine mucosa and bovine lungDosage s/c, IV, 5000U bolus, then 800-1000U/hr IV drip low dose: 5000U s/c, bdMonitor activated Partial thromboplastin time (aPTT) Initial measured every 6 hours then dailyGoal 2-2.5X DVT EBS presentation 3
  4. 4. USESRapid onset of actionTreatment DVT, PE, CardiacLow dose: Prophylaxis of DVT (Khaldi et al., 43% reduction in LL DVT among 555 pts) (Hacker et al., 522 patients: no post op hemorrhage) (Macdonald RL et al., s/c heparin started at induction: safe)Safe in pregnancyCONTRAINDICATIONSRecent head injuryRecent craniotomyPatients with coagulopathyHemorrhagic infarctionBleeding ulcerUncontrolled hypertensionSevere hepatic or renal disease<4-6 hrs before an invasive procedure EBS presentation 4
  5. 5. Side effectsBleeding 1-5% of patientsHeparin induced thrombocytopenia (HIT) IgG antibodies to complex of heparin and PF4 on platelets These complexes activate platelets >50% decrease or 150,000/Ul 0.5% of medical patients, higher in surgical patients 5-10 days after starting Rx (earlier if Rx with Heparin within 3-4/12) Thrombotic complications in 50% of these patients Venous and arterial thrombosis, adrenal hemorrhage, skin lesions Diagnosis: Heparin dependent platelet activation assay or antibody assay Treatment: Stop heparin Start on Lepirudin **Warfarin can precipitate gangreneOsteoporosis EBS presentation 5
  6. 6. Antidote: Protamine sulphate 1mg = 100U heparin. Monitor aPTT IV 50mg in any 10min Protamine can cause anaphylaxis, hypotension, ventricular dysfunction EBS presentation 6
  7. 7. LOW MOLECULAR WEIGHT HEPARINSMW: 3000-8000 daltonsPreparation gel chromatography/partial depolymerisationMechanism Short length can inhibit Xa onlyAction: High ratio of anti-factor Xa to anti-IIa activity. Greater bioavailability Predictable plasma levels No need to monitor biologic activity (APTT) Longer half life Low incidence of thrombocytopenia Lower risk of osteoporosis/hemorrhage *Need to monitor anti-factor Xa assay in ESRD patients EBS presentation 7
  8. 8. Enoxaparin 30mg bd for 7-14 days peak in 3-5 hrs Half life: 4.5hr Antidote: Protamine Protamine: 1mg =1mg of enoxaparin (<8hrs) 0.5mg=1mg of enoxaprain (if within 8-12 hrs) Increase incidence of spinal epidural hematomaDalteparin 2500 U s/c qd Antidote; Protamine (1mg=100U)Ardeparin 50 U/Kg, S/C, BID, 3.3 hr half-lifeDanaparoid Heparinoid, 5500Da Mixture of non-heparin glycosaminoglycans Inhibits Xa Half-life is 24 hrs 750 U S/C, BID No antidoteOthers Tinzaparin, Bemiparin (RCT for DVT safe),, Certoparin (Safe) EBS presentation 8
  9. 9. Synthetic HeparinsFondaparinux Synthetic pentasaccharide Inhibits Xa sub cut, once a day, peak activity in 2-3 hrs Half life: 17-21 hrs Lesser toxicity (No HIT) Contraindicated in severe renal failure EBS presentation 9
  10. 10. IF PATIENT IS ON HEPARINS AND NEEDS SURGERY Elective EmergencyStop infusion 4-6 hr Cannot wait for 4- 6 hrsS/C heparin: last dose >12hrs Reverse with protamineLMWH: 24-48hrs after last dose LMWH: Reverse with protamine longer in renal failure Factor Xa level assay EBS presentation 10
  11. 11. WarfarinDerivative of 4-hydroxycoumarin - Warfarin Epoxide reductase Vitamin K +↓ -------------------------------------→ Activated Vit.K Activated Vitamin KFactors II,VII,IX,X + ϒ carboxylation Carboxylated FactorsProtein C, S II, VII, IX, X ϒ glutamyl carboxylase (complexes can bind Ca) **No effect on carboxylated molecules in the circulation EBS presentation 11
  12. 12. Onset of action depends on half-life of the factors (in hrs): VII 6hr IX 24 X 36 II 50 C 8 S 30Appears in blood within an hours and peaks in 2-8 hours99% protein bound (albumin)Elimination Metabolized and eliminated in urine and stoolHalf-life 25-60 hours (mean of 40 hours) EBS presentation 12
  13. 13. Usage Prevent progression or recurrence of DVT/PEDosage Oral 5mg od for 2-4 days, then 2-5mg odMonitor Prothrombin time (PT)Goal International Normalized Ration (INR) 2-3 DVT, TIA 3-4 recurrent systemic embolism, mechanical heart valvesContraindications:Pregnancy EBS presentation 13
  14. 14. InteractionsDecreased effect binding to Cholestyramine in GI hypoproteinemia (nephrotic syndrome) hepatic enzyme induction (barbiturates, CBZ) Increased Vit KIncreased effect Hepatic enzyme inhibition (clopidogrel, cotrim, fluxetine amiodarone, antifungals, metronidazole, tolcapone, zafirlukast) Displacement from protein (loop diuretics, valproate) Reduced Vit K (antibiotics) Low concentration of coagulation factors (hepatic)Variant alleles Cause decreased clearance of drug CYP2C9*2 AND 3 10-20% Caucasians, <5% of Asians EBS presentation 14
  15. 15. Antidote: 1.Vitamin K1 (aqueous solution), 10-15mg IM Takes 6-12hrs to act (depends on liver function) Usually require 25-35mg IV route: complication: 1mg/min Requires hours to act 2. Prothrombin Complex Concentrate (II,IX,X) 3. FFP (15ml/Kg), 2-3 units EBS presentation 15
  16. 16. Side effectsHemorrhage <5% per year in patients (INR 2-3)Birth defects CNSPurple toe syndrome (cholesterol emboli, 3-8 wks)Coumadin necrosisNewer Phenprocoumon (longer half life: 5days) Acenocoumarol (shorter half-life: 10-24 hours) Not in US EBS presentation 16
  17. 17. IF PATIENT IS ON WARFARIN AND NEEDS SURGERY Elective EmergencyStop warfarin 3 days prior FFP 2 units (15ml/Kg), 6 units if prolonged PTBegin LMWH ( mechanical valves) Vit K (IV)Check PT on admission (<13.5, INR <1.4) Prothrombin complex concentrate (II, IX,X)If PT not normal needs reversal (acts 4-5 times more quickly than FFP)Vit K (IM) EBS presentation 17
  18. 18. WHAT TO DO?Patients with incidental aneurysm Depends on indicationPatients on anticoagulation who develop SAH ReversalBrain tumor Can use anticoagulation (Altschuler et al)After craniotomy Full dose: Not for 3-5 days 3 days post surgery Low dose: Minidose heparin- no increased bleeds Enoxaparin -11% in bleed (Dickinson et al) EBS presentation 18
  19. 19. References1.Goodman & Gilman’s Manual of Pharmacology and Therapeutics2. Khaldi et al., Venous Thromboembolism: deep vein thrombosis and pulmonaryEmbolism in a neurosurgical population. J Neurosurg 2011;114:40-6.3. Hacker et ., Subcutaneous heparin doesnot increase post operative complicationsIn Neurosurgical patients. J Critical Care 2012;27:250-4.4. MacDoanld RL et al., Safety of peri-operative subcutaenous heaprin for prophylaxis ofVenous thromboembolism in patients undegoing craniotomy. Neurosurgery 1999;45:245-51.5. Constantini S et al., Safety of perioperative minidose heparin in pateints undergoing brainTumor surgery: A prospective randomized double blind study. J Neurosurg 2001;94:918-216. DickinsonLD et al., Enoxaparin increases the incidence of post operative intracranialHemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis inPatients with brain tumors. Neurosurgery 1998;43:1074-81 EBS presentation 19

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