Anticoagulation in neurosurgery heparin warfarin_ppt

1. HEPARINS AND WARFARINS
Macquarie Neurosurgery
Samson Sujit Kumar Gaddam
15.11.2012
EBS presentation 1

2. HEPARIN
Heparin 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
THRO
Heparin
ATIII MBIN
( II )
Pentasaccharide
EBS presentation 2

3. 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 drip
low dose: 5000U s/c, bd
Monitor activated Partial thromboplastin time (aPTT)
Initial measured every 6 hours then daily
Goal 2-2.5X DVT
EBS presentation 3

4. 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 injury
Recent craniotomy
Patients with coagulopathy
Hemorrhagic infarction
Bleeding ulcer
Uncontrolled hypertension
Severe hepatic or renal disease
<4-6 hrs before an invasive procedure
EBS presentation 4

5. Side effects
Bleeding 1-5% of patients
Heparin 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 gangrene
Osteoporosis
EBS presentation 5

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. 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 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. 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 hematoma
Dalteparin 2500 U s/c qd
Antidote; Protamine (1mg=100U)
Ardeparin 50 U/Kg, S/C, BID, 3.3 hr half-life
Danaparoid Heparinoid, 5500Da
Mixture of non-heparin glycosaminoglycans
Inhibits Xa
Half-life is 24 hrs
750 U S/C, BID
No antidote
Others Tinzaparin, Bemiparin (RCT for DVT safe),, Certoparin (Safe)
EBS presentation 8

9. Synthetic Heparins
Fondaparinux 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. IF PATIENT IS ON HEPARINS AND NEEDS SURGERY
Elective Emergency
Stop infusion 4-6 hr Cannot wait for 4- 6 hrs
S/C heparin: last dose >12hrs Reverse with protamine
LMWH: 24-48hrs after last dose LMWH: Reverse with protamine
longer in renal failure
Factor Xa level assay
EBS presentation 10

11. Warfarin
Derivative of 4-hydroxycoumarin
-
Warfarin
Epoxide reductase
Vitamin K +↓
-------------------------------------→ Activated Vit.K
Activated Vitamin K
Factors II,VII,IX,X
+ ϒ carboxylation
Carboxylated Factors
Protein 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. Onset of action depends on half-life of the factors (in hrs): VII 6hr
IX 24
X 36
II 50
C 8
S 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)
EBS presentation 12

13. 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, TIA
3-4 recurrent systemic embolism, mechanical heart valves
Contraindications:Pregnancy
EBS presentation 13

14. Interactions
Decreased effect binding to Cholestyramine in GI
hypoproteinemia (nephrotic syndrome)
hepatic enzyme induction (barbiturates, CBZ)
Increased Vit K
Increased 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. 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. 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
EBS presentation 16

17. IF PATIENT IS ON WARFARIN AND NEEDS SURGERY
Elective Emergency
Stop warfarin 3 days prior FFP 2 units (15ml/Kg), 6 units if prolonged PT
Begin 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. 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 days
3 days post surgery
Low dose:
Minidose heparin- no increased bleeds
Enoxaparin -11% in bleed (Dickinson et al)
EBS presentation 18

19. References
1.Goodman & Gilman’s Manual of Pharmacology and Therapeutics
2. Khaldi et al., Venous Thromboembolism: deep vein thrombosis and pulmonary
Embolism in a neurosurgical population. J Neurosurg 2011;114:40-6.
3. Hacker et ., Subcutaneous heparin doesnot increase post operative complications
In Neurosurgical patients. J Critical Care 2012;27:250-4.
4. MacDoanld RL et al., Safety of peri-operative subcutaenous heaprin for prophylaxis of
Venous thromboembolism in patients undegoing craniotomy. Neurosurgery 1999;45:245-51.
5. Constantini S et al., Safety of perioperative minidose heparin in pateints undergoing brain
Tumor surgery: A prospective randomized double blind study. J Neurosurg 2001;94:918-21
6. DickinsonLD et al., Enoxaparin increases the incidence of post operative intracranial
Hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in
Patients with brain tumors. Neurosurgery 1998;43:1074-81
EBS presentation 19