Coagulation Course: Lecture 4
ANTICOAGULATION PRACTICES Dr. Akram Al-Hilali 2009
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Anticoagulation Agents
Heparin
Unfractionated Heparin Low molecular weight Heparin (e.g. Clexane, Innohep)
Oral Anticoagulants- warfarin (coumadin) New drugs
Pentasaccharides Hirudin
Antiplatelet and fibrinolytic drugs are not strictly anticoagulant agents 08/06/14
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HEPARIN STRUCTURE
Non-branched chain of polysaccharide, made up of multiple repeats of two basic, highly sulphated sugars: glucosamine and glycan Naturally occurring heparin is made up of a mixture of molecules varying in the number of repeats of these molecules. Numbers range from very short (5) to very long. This is the Unfractionated Heparin. Molecular weight ranges from 3 to 50 K-Daltons. Shortest active molecule contains 5 repeats. LMWH is also a mixture but molecules are all short. 08/06/14
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HEPARIN Structure
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HEPARIN UNIT AND CHAIN
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PENTASACCHARIDES
5 SUGARS ONLY
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NOTES ON I.V. HEPARIN
Bolus dose, followed by drip. Initial drip dose is 1000u per hour for adults. Bolus effect continues for roughly 8 hours. Do not check PTT within those hours for the purpose of adjusting the drip dose. When PTT is checked drip dose is adjusted to make PTT of patient 1½- 2½ that of normal control (or mean of its range). Ratio depends on clinical condition. Do not raise or drop doses abruptly. If ratio is above 4 hold for 2-6 hours and restart at lower dose Rechecking is best done 2 hours after new dose is started. 08/06/14
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SOME DIFFERENCES BETWEEN UH AND LMWH
Smaller doses of the LMW and Pentasaccharides are needed than UH. UH mostly inhibits thrombin (antithrombin co-factor) while LMWH and PS affect Xa. UH needs monitoring by TT or PTT. LMWH and PS do not need except occasional check. Shorter half life on UH. If given in s.c. doses then it should be at least twice daily. HIT and HITT are a little commoner with UH
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HOW TO CORRECT HEPARIN EFFECT? Hold
heparin If going for invasive procedure or there is bleeding from overdose protamine sulphate can be given. 1 mg protamine sulphate neutralizes roughly 100 units of heparin. Give i.v. in 50 ml. glucose saline with very slow drip in the first few minutes, as it may cause anaphylaxis. 08/06/14
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HIRUDIN Natural hirudin is secreted by the leeches used for therapeutic blood letting at the site of blood suction. Now it is being produced by recombinant technology It is a foreign protein and cannot be used effectively over a long period because of inhibitor development. It is a potent antithrombin. Available in the market. Used in HIT
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WARFARIN Vitamin K Function Vitamin K plays a key role in the proper synthesis of the liver coagulation factors. It is essential for the addition of glutamate residue to the proteins. This residue is needed for the interaction with Ca++, without which the coagulation factors will be inactive.
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VITAMIN K FUNCTION NAD(P)H
NAD(P) Glu+CO2+O2
K
GluA+H2O
K
KH2
1
Dithiol (SH2) 2
3
Dithiol(S2)
K
Dithiol (S2)
Dithiol(SH2) Step1-Carboxylation of Glutamate Steps 2 & 3- Reconversion of epoxide into hydroquinone in 2 steps K KH2 has two alternative pathways. Coumarin derivatives : inhibit the dithiol reduction of vit K 08/06/14
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VITAMIN K-DEPENDANT COAGULATION FACTORS Factor
II (Prothrombin) Factor IX Factor VII Factor X
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Protein
C Protein S
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VITAMIN K ANTAGONISTS Prevent the dithiol reduction of vitamin K Vitamin K absorbed from food will be functional but not re-usable. The less vitamin K in food, the more effective is the antagonist, and vise versa. Actual effect will be production of inactive coagulation factors. Delay in appearance of effect is due to time taken to use up the previously formed functional factors.
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COAGULATION FACTOR IN PLASMA AFTER STARTING WARFARIN
% Factor concentrate
Ac tiv e
ve i t ac In
Warfarin started
0
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fa ct o r
tor c fa
24 hrs
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VITAMIN K ANTAGONISTS When
vitamin K is given for correction of overdose its effect is also delayed, due to gradual synthesis of active factors to replace the inactive factors in the plasma. Counteraction of vitamin K therapy effect, by resumption of antagonists, also takes a long time to show. Plasma therapy supplies active coagulation factors instantaneously. 08/06/14
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VITAMIN K ANTAGONISTS Functional
factors of shorter half life will disappear from the blood first. Factor of shortest half life is VII. Factor VII is only active in the extrinsic coagulation pathway (PT). Therefore, PT is more sensitive than PTT to the effect of vitamin K antagonists. 08/06/14
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PHARMACOKINETICS Protein binding of warfarin and drugs Competition by drugs in metabolic pathways of the liver (Enzyme inducer or inhibitor) Hepatocellular function effect. Availability of vitamin K from food. Absorption of vitamin K from intestine. Role of colonic flora as vitamin K source.
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PROTHROMBIN TIME Plasma sample and sampling problems Reagents Calcium chloride Thromboplastin Sources Sensitivities Reporting of results PT in seconds - Prothrombin activity Prothrombin Ratio - INR
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INR = (PT patient/PT Control)
ISI
PT IN SECONDS
REAGENTS FROM DIFFERENT SOURCES
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PERCENTAGE OF COAGULATION FACTORS
0%
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NOTES ON WARFARIN THERAPY
Remember drug interactions of warfarin. Check for non-prescription, as well as prescribed drugs. Remember food stuff with excess vitamin K, that can reduce warfarin effect. Remember that warfarin effect does not show before 48 hours and stopping warfarin does not lead to reduction of INR before 24-48 hours. Do not depend on INR result of 24-48 hours after loading dose to rush to adjustment of dose. One of the best practices for follow up is to have a big clinic with PT done in the clinic. 08/06/14
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HOW TO CORRECT INR?
Hold warfarin only, if time allows, there is no bleeding or INR is up to 6 only. Otherwise, the antidote is Fresh Frozen Plasma. Dose is 10-20 ml/kg. It has to be repeated after 12 hours if original INR is >8, or if there is bleeding. Give FFP fast, in order for it to be effective (1 unit over 10-15 minutes). If given for surgery do not give it except 2 hours or less prior to surgery time 08/06/14
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MAIN DIFFERENCES BETWEEN HEPARIN AND WARFARIN Heparin is a direct inhibitor of coagulation factors (Xa and Prothrombin). If you add it to a blood sample it will inhibit coagulation at once. Warfarin is not an inhibitor to coagulation factors in the blood. It affects synthesis of active coagulation factors. So it takes time to work.
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