LOW MOLECULAR WEIGHT HEPARIN : BASIC & APPLIED ASPECT. Seminar Guide Dr. Rajkondawar. Introduction : New Generation heparin Prepared from enzymatic and chemical depolymerisation of unfractionated heparin (UFH) Mean molecular weight of 4000 - 6000 IU.
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BASIC & APPLIED ASPECT
The Coagulation Cascade
Heparin / LMWH(AT-III dependent)
Courtesy of VTI
INTERACTION OF HEPARIN CO-FACTORS WITH THROMBIN
Heparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II
- - - -
ANTITHROMBIN AND FREE THROMBIN
AT alone does not inactivate free-thrombin
INACTIVATION OF THROMBIN BYHEPARIN-AT COMPLEXES
Heparin binds to antithrombin and increases the rate of thrombin inactivation
EFFECT OF ANTITHROMBIN ON FIBRIN-BOUND THROMBIN
The rate at which AT inactivates
fibrin-bound thrombin is reduced 50-fold
Inhibition of thrombin requires simultaneous binding of heparin to AT-III through the unique pentasaccharide sequence and binding to thrombin through a minimum of 13 additional saccharide units. Inhibition of factor Xa (Xa) requires binding heparin to AT-III through the unique pentasaccharide without the additional requirements for binding to Xa. 5 indicates unique high-affinity pentasaccharide.
MECHANISMS RESPONSIBLE FOR THE PHARMACOKINETIC ADVANTAGES OF LOW OLECULAR WEIGHT HEPARINS OVER UNFRACTIONATED HEPARIN
At least as effective as low-dose unfractionated heparin but can be given once daily and cause fewer hematomas at injection sites.
Low risk (Minor surgery, duration < 30 minutes.)
Dalteparin, 2500 U 1–2 hr before surgery and once daily after surgery Enoxaparin, 2000 U 1–2 hr before surgery and once daily after surgery Nadroparin, 3100 U 2 hr before surgery and once daily after surgery Tinzaparin, 3500 U 2 hr before surgery and once daily after surgery
High risk (Major abdominoperineal surgery gynaec, duration > 30 minutes.)
Dalteparin, 5000 U 10–12 hr before surgery and once daily after surgery Enoxaparin, 4000 U 10–12 hr before surgery and once daily after surgery Ardeparin, 50 U/kg twice daily starting 12–24 hr after surgery
Incidence of DVT in hip fracture is 43% and mortality is 12% when thromboprophylaxis is not given.
Patency of femoropopliteal bypass graft:
Relationship Between Molecular Weight and Anticoagulant Activity of Heparin Fractions
As the no. of oligosaccharides increases and mol. wt. increases - antithrombin activity increases
Therefore heparin with highest mol. wt. has highest antithrombin activity
Minimum of 18 saccharides chain length is required to form a complex with antithrombin
1. Usually not indicated
2. Required under two conditions
a) Obese patient
b) Patient with renal failure
c) Patient on hemodialysis
3. Cromogenic anti Xa assay
4. Exact cut off value has not been determined but value > 0.8 U/Ml is associated with increased bleeding tendency
4. Target range of peak antifactor Xa is
(i) 0.85 IU/ml for Tinzaparin.
(ii) 1.3 IU/ml for Nadroparin.
(iii) 1.05 IU/ml for dalteparin.
5. Best time to perform anti Xa assay is 4 hrs after SC. injection.
6. For twice daily administration, range is 0.6 to 1.0 U/ml
7. Frequent monitoring of anti Xa in patient with renal failure
Incidence of death, MI, angina14 d 16.6% 19.8% p=.01930 d 19.8% 23.3% p=.016
Minor bleeding30 d 13.8% 8.8% p<.001
Major bleeding30 d 6.5% 7.0% NS
Death alone14 d 2.2% 2.3% NS30 d 2.9% 3.6% NS
1.0 mg/kg q 12 h
Non-Q Wave MI
UFH5,000 U bolus + infaPTT 55-85 sec
min 48h, max 8 Days
Need for coronary angioplasty (initial) 15% 20% p=.04 coronary angioplasty (30d) 18% 22% p=.08 diagnostic cath (30d) 57% 63% p=.04 Initial hospitalizationmean drug cost in U.S.* $155 $80 mean total cost of care $11,857 $12,620mean duration of treatment 2.3 daysmutidose vial enoxaparin - 1 mg/kg at $0.38/mg
q 12 h
TIMI 11B - Study Design
< 65 kg > 65 kg
40 mg 60 mg
q 12 h
30 mg IV bolus +
1.0 mg/kg q 12 h
Non-Q Wave MI
70 U/kg IV bolus +
min 72h, max 8 Days
Primary endpoint Death / MI / Urgent Revscularization
Odds ratio Risk Reduction p-val
Day 8 0.71 21% 0.02
Day 14 0.79 21% 0.0005
Day 43 0.80 20% 0.0006
European Society of Cardiology - August 1998
DOSAGE DURATIONFor the prevention of 1 mg/kg q12h SC minimum 2 days; usual duration ischemic complications with oral aspirin therapy of therapy: 2 to 8 daysof unstable angina and (100 to 325 mg once daily) non-Q-wave myocardialinfarction (MI) whenconcurrently administeredwith aspirin
Clinical trials are underway.
Animal studies have shown that LMWH inhibits metastases and angiogenesis necessary for tumor growth.