EBS presentation 1

HEPARINS AND WARFARINS

Macquarie Neurosurgery

Samson Sujit Kumar Gaddam15.11.2012

EBS presentation 2

HEPARINHeparin is a glycosaminoglycan. Granules of mast cells (fragments of 12000Da, about 40monosaccharide units))

Activates Antithrombin III that inhibits thrombin (II), Xa, IXa

Antithrombin (suicide substrate) : synthesized in liver and circulates in the plasma. Heparin increases its activity by 1000 fold.

Also activates platelets (high doses). Inhibits only soluble thrombin

THROMBIN ( II )

ATIII

Pentasaccharide

Heparin

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Onset of action IV (immediate), S/C: 1-2 hours

Half life Depends on dose (IV): 100U/Kg (1hr), 400U/Kg (2.5hr), 800U/Kg (5hr)Prolonged in PE, hepatic cirrhosis, end stage renal disease

Elimination RES and small amounts in urine

Commercial prep. Porcine mucosa and bovine lung

Dosage s/c, IV, 5000U bolus, then 800-1000U/hr IV driplow dose: 5000U s/c, bd

Monitor activated Partial thromboplastin time (aPTT)Initial measured every 6 hours then daily

Goal 2-2.5X DVT

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USES

Rapid onset of action

Treatment DVT, PE, Cardiac

Low 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 pregnancy

CONTRAINDICATIONS

Recent head injuryRecent craniotomyPatients with coagulopathyHemorrhagic infarctionBleeding ulcerUncontrolled hypertensionSevere hepatic or renal disease<4-6 hrs before an invasive procedure

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Side effects

Bleeding 1-5% of patients

Heparin induced thrombocytopenia (HIT)

IgG antibodies to complex of heparin and PF4 on plateletsThese complexes activate platelets>50% decrease or 150,000/Ul0.5% of medical patients, higher in surgical patients5-10 days after starting Rx (earlier if Rx with Heparin within 3-4/12) Thrombotic complications in 50% of these patientsVenous and arterial thrombosis, adrenal hemorrhage, skin lesionsDiagnosis: Heparin dependent platelet activation assay or antibodyassayTreatment: Stop heparin

Start on Lepirudin

**Warfarin can precipitate gangrene

Osteoporosis

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Antidote: Protamine sulphate 1mg = 100U heparin.Monitor aPTTIV 50mg in any 10minProtamine can cause anaphylaxis, hypotension, ventricular dysfunction

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LOW MOLECULAR WEIGHT HEPARINS

MW: 3000-8000 daltons

Preparation gel chromatography/partial depolymerisation

Mechanism Short length can inhibit Xa only

Action: High ratio of anti-factor Xa to anti-IIa activity. Greater bioavailabilityPredictable plasma levelsNo need to monitor biologic activity (APTT)Longer half lifeLow incidence of thrombocytopeniaLower risk of osteoporosis/hemorrhage

*Need to monitor anti-factor Xa assay in ESRD patients

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Enoxaparin 30mg bd for 7-14 dayspeak in 3-5 hrsHalf life: 4.5hr Antidote: ProtamineProtamine: 1mg =1mg of enoxaparin (<8hrs)0.5mg=1mg of enoxaprain (if within 8-12 hrs) Increase incidence of spinal epidural hematoma

Dalteparin 2500 U s/c qdAntidote; Protamine (1mg=100U)

Ardeparin 50 U/Kg, S/C, BID, 3.3 hr half-life

Danaparoid Heparinoid, 5500DaMixture of non-heparin glycosaminoglycansInhibits XaHalf-life is 24 hrs750 U S/C, BIDNo antidote

Others Tinzaparin, Bemiparin (RCT for DVT safe),, Certoparin (Safe)

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Synthetic Heparins

Fondaparinux Synthetic pentasaccharideInhibits Xasub cut, once a day, peak activity in 2-3 hrsHalf life: 17-21 hrsLesser toxicity (No HIT)Contraindicated in severe renal failure

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IF PATIENT IS ON HEPARINS AND NEEDS SURGERY

Elective Emergency

Stop infusion 4-6 hrS/C heparin: last dose >12hrsLMWH: 24-48hrs after last dose

longer in renal failureFactor Xa level assay

Cannot wait for 4- 6 hrsReverse with protamineLMWH: Reverse with protamine

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Warfarin

Vitamin K -------------------------------------→ Activated Vit.K

Activated Vitamin K

Epoxide reductase ↓

Warfarin

-+

Factors II,VII,IX,XProtein C, S

Carboxylated FactorsII, VII, IX, X(complexes can bind Ca)

ϒ carboxylation+

Derivative of 4-hydroxycoumarin

ϒ glutamyl carboxylase

**No effect on carboxylated molecules in the circulation

EBS presentation 12

Onset of action depends on half-life of the factors (in hrs): VII 6hrIX 24X 36II 50C 8S 30

Appears in blood within an hours and peaks in 2-8 hours

99% protein bound (albumin)

Elimination Metabolized and eliminated in urine and stool

Half-life 25-60 hours (mean of 40 hours)

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Usage Prevent progression or recurrence of DVT/PE

Dosage Oral 5mg od for 2-4 days, then 2-5mg od

Monitor Prothrombin time (PT)

Goal International Normalized Ration (INR)2-3 DVT, TIA3-4 recurrent systemic embolism, mechanical heart valves

Contraindications:Pregnancy

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Interactions

Decreased effect binding to Cholestyramine in GIhypoproteinemia (nephrotic syndrome)hepatic enzyme induction (barbiturates, CBZ)Increased Vit K

Increased effect Hepatic enzyme inhibition (clopidogrel, cotrim, fluxetineamiodarone, 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 drugCYP2C9*2 AND 3 10-20% Caucasians, <5% of Asians

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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

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Side effects

Hemorrhage <5% per year in patients (INR 2-3)

Birth defects CNS

Purple toe syndrome (cholesterol emboli, 3-8 wks)

Coumadin necrosis

Newer Phenprocoumon (longer half life: 5days)Acenocoumarol (shorter half-life: 10-24 hours)Not in US

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IF PATIENT IS ON WARFARIN AND NEEDS SURGERY

Elective Emergency

Stop warfarin 3 days priorBegin LMWH ( mechanical valves)Check PT on admission (<13.5, INR <1.4)If PT not normal needs reversalVit K (IM)

FFP 2 units (15ml/Kg), 6 units if prolonged PTVit K (IV)Prothrombin complex concentrate (II, IX,X)(acts 4-5 times more quickly than FFP)

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WHAT TO DO?

Patients with incidental aneurysm Depends on indication

Patients on anticoagulation who develop SAH Reversal

Brain tumor Can use anticoagulation (Altschuler et al)

After craniotomy Full dose:Not for 3-5 days3 days post surgeryLow dose:Minidose heparin- no increased bleedsEnoxaparin -11% in bleed (Dickinson et al)

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References

1.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 in Patients with brain tumors. Neurosurgery 1998;43:1074-81