COAGULATION, ANTICOAGULATION & IT’S

REVERSAL

Speaker Moderator

Faheem Iqbal Professor G.N. Lone

2nd Year Student Head of Department
B.Sc. Perfusion Technology Cardiovascular & Thoracic Surgery
SKIMS, Soura SKIMS, Soura
OVERVIEW

1. Coagulation
2. Heparin
3. Heparin Resistance
4. Heparin Induced Thrombocytopenia
5. Direct Thrombin Inhibitors
6. Reversal Of Anticoagulation
7. Protamine Reactions
8. Management of Protamine Reactions
COAGULATION
 Coagulation is a process, in which a blood clot is formed by a cascade of
reactions, resulting in the cessation of blood loss from a damaged blood
vessel.
 Coagulation occurs by interaction of a series of proteins, called clotting
factors, that are activated and propagated by a variety of stimuli, including
contact with foriegn surfaces, contact with receptors on the surfaces of the
platelets and by factors produced by the systemic inflammatory response,all
of which are pertinent in the context of Cardiopulmonary bypass.
 Most of the proteins involved in the coagulation cascade are produced by
liver as inactive precursors, known as zymogens, which are modified into
activated clotting factors.
CLOTTING FACTORS

1. I, Fibrinogen
2. II, Prothrombin
3. III, Tissue Factor, Thromboplastin
4. IV, Calcium
5. V, Labile Factor, Proaccelerin
6. VII, Stabile Factor, Proconvertin, Prothrombin Conversion Accelerator
7. VIII, Antihemophiloc Factor A
8. IX, Antihemophiloc Factor B, Christmas Factor, Plasma Thromboplastin Component
9. X, Stuart-Power Factor,Thrombokinase
10. XI, Prothrombin Thromboplastin Antecedent
11. XII, Hageman Factor
12. XII, Fibrin Stabilising Factor
ROUTES OF COAGULATION

 There are two routes of coagulation, namely the extrinsic pathway and the intrinsic pathway,
both of which lead to a final common pathway.
 Extrinsic pathway is activated by the contact with Factor III (Thromboplastin or tissue factor)
from the surface of extravascular cells. In extrinsic pathway, Thromboplastin, in the presence of
calcium, begins a series of reactions, that ultimately activate the Factor X (Stuart-Power Factor),
which in the presence of calcium combines with Factor V (Labile Factor), to form the active
enzyme prothrombinase.
 Intrinsic pathway begins when Factor XII (Hageman Factor) activates by coming in contact with
collagen from damaged blood vessels. Factor XIIa then activates Factor XI (PTA), which in turn
activates Factor IX (Christmas Factor). Then, Factor IXa, along with the platelet phospholipids,
activates Factor X (Thrombokinase), which in the presence of calcium combines with Factor V
(Labile Factor), to form the active enzyme prothrombinase.
 COMMON PATHWAY

 During the common pathway, Prothombinase and

calcium catalyse the conversion of prothrombin into
thrombin, which in turn converts the soluble
Fibrinogen, into loose and insoluble Fibrin threads.
 Thrombin also activates Factor XIII ( Fibrin
Stabilising Factor), which strengthens and stabilises
the Fibrin threads into a sturdy clot.
 In addition to Fibrin threads, a clot also contains red
blood cells, white blood cells and platelets.
HEPARIN

 For any form of extracorporeal circulation, anticoagulation is required, in order to

prevent activation of the coagulation system by contact between blood and non-
biological circuit components.
 Heparin, in it’s unfractionated form, is the standard anticoagulant used in the context
of extracorporeal circulation.
 The reasons for it’s wide use are that:-

1. It has fast onset of action,

2. It’s relatively safe,
3. It’s easy to use,
4. It’s measurable, titrable and reversible, and
5. It’s cost effective.
BASICS OF HEPARIN

 Member of glycosaminoglycan family of carbohydrates.

 Consists of a variably sulfated repeating disaccharide unit.
 Negatively charged at the physiological pH.
 Molecular mass of native Heparin:- 3-40 kDa.
 Molecular mass of commercial Heparin:- 12-15 kDa.
 Chemical Formulla:- C26H42N2037S5.
 Released by basophils and mast cells.
 Derived from bovine lung parenchyma and porcene intestinal mucosa.
 Discovered by Jay McLean in 1916.
 Named by William Howell in 1918.
 Structure explained by Erik Jorpes in 1935.
MECHANISM OF ACTION

 The pentasaccharide sulfation sequence present in Heparin binds to the enzyme inhibitor,
antithrombin (AT)-III and causes a change in its structure, resulting in an increase in it’s activity.
 The activated AT-III then inactivates clotting factors including IIa, IXa, Xa, XIa and XIIa.
 It’s most active against Factor IIa (thrombin) and Factor Xa (Thrombokinase).
 The rate of inactivation of these factors by AT-III can increase upto a thousand fold, due to the
bindind of Heparin.
 In addition, Heparin also increases the activity of Heparin cofactor II, which also inhibits thrombin.
 Its onset is immediate.
 Half life:- 2.5h at doses of 300-400 U/kg.
 Metabolised in liver by heparinase.
 Excreted in urine.
FIGURE 1.3:- MECHANISM OF ACTION OF HEPARIN
FIGURE 1.4:- HEPARIN-AT-III COMPLEX
DOSAGE

 Varies among different centers.

 Most common initial dosage:- 300-400 units/kg.
 Some centers base the initial dose on an ex-vivo Heparin dose-response titration.
 Many centers add 3-4 units per mililitre of prime.
 Supplemental doses are guided by monitoring of anticoagulation, using Activated
clotting time or Heparin concentration monitoring.
 The ACT is a functional essay of Heparin anticoagulation and most centers use a
level between 400-800s, as an acceptable ACT level for conducting CPB.
HEPARIN RESISTANCE

 Failure to raise ACT to expected levels despite sufficient dosage and plasma concentration
of Heparin.
 Mainly results due to AT-III deficiency or dysfunction.
 Also due to the presence of large quantities of heparin-binding protein in the circulation.
 Treatment:-

1. Adminstration of additional Heparin boluses upto 600-800 units/kg.

2. Fresh frozen plasma adminstration.
3. Supplemental AT-III concentrate.
HEPARIN INDUCED THROMBOCYTOPENIA
 Decrease in the number of platelets due to adminstration of Heparin.
 Develops in 5% of patients receiving Heparin.
 Type I HIT:- Mild, transient decrease in platelet count, safe to receive Heparin for cardiac surgery.
 Type II HIT:- Severe, Immune mediated decrease in platelet count, occurs after 5-14 days of Heparin adminstration.
 Cause:- Antibodies against the complex of Platelet Factor 4 and Heparin bind to platelets, activate the platelets and
cause the resultant platelet count to drop precipitously.
 Symptoms:- Thrombocytopenia (mild or severe) and thrombosis (in the setting of endothelial injury).
 Lab tests:- Serotonin Release Essay, Heparin-Induced Platelet Activation Assay, Platelet-Rich Plasma Aggregation
Assay.
 Management:-

1. History of HIT, Antibody negative patients:- Safe to receive Heparin.

2. Acute HIT, Antibody positive patients:- Delay surgery or give DTIs.
3. Combinations of Heparin and antiplatelet agents ( epoprostenol of tirofiban).
DIRECT THROMBIN INHIBITORS
 Directly inhibits the procoagulant and prothrombotic actions of thrombin.
 Don’t require a cofactor.
 Don’t activate platelets.
 Don’t interact with or produce hepatin-dependent antibodies.
 No reversal agent.
 Lepirudin:- Recombinant analogue of hirudin; HL:- 80ms; Monitoring:- ACT or aPTT;
Metabolism:- kidney; Eliminated by hemofiltration.
 Argatroban:- Derived from L-arginine; HL:- 45-55ms; Monitoring:- ACT or aPTT;
Metabolism:- liver; Used in percutaneous coronary intervention.
 Bivalirudin:- Synthetic peptide based on the structure of Heparin; HL:- 25ms; Monitoring:-
ACT, aPTT or ECT; Metabolism:- Kidney; Inferior to Heparin in CPB; Used in cardiac
catheterization laboratories.
PROTAMINE

 Simple alkaline nucleoprotein.

 Polycation due to abundant arginine residues.
 Molecular Mass:- 4300 daltons.
 Only reversal agent for Heparin
 Available as Protamine sulphate and Protamine chloride.
 Produced through rDNA technology.
 Discovered by Fredrich Miesher in 1870 in Salmon sperm.
 It’s Heparin neutralising ability found by Chargaff and Oslon in 1937.
PHARMACOLOGY OF PROTAMINE

 Dosage:- 1.0-1.3 mg per 100 units of Heparin.

 Protamine being a polycation, binds to negatively charged Heparin, forming a
non-covalent comple, which binds to AT-III and HCF-II, resulting in the
neutralisation of heparin’s anticoagulant action.
 Large amounts may inhibit coagulation.
 Rapidly distributed to the extracellular space due to low molecular mass.
 Onset:- 5ms.
 Duration:- 2hrs.
 Half Life:- 7ms.
 Plasma Clearance very fast.
PROTAMINE REACTIONS

1. Pharmacologic Histamine Release:- Due to fast adminstration of

Protamine; can result in bradycardia, vasodilation, sudden hypotension,
pulmonary hypertension, myocardial depression.
2. IgE Mediated True Anaphylaxis:- Occurs in case of previous exposure
to Protamine, reported in insulin diabetic patients only (3%); antibody
screening techniques may help identifying the patients at risk.
3. Non-IgE Mediated Anaphylactoid Reactions:- Derived from activation
of complement and/or bradykinin cascades and direct activation of mast
cells and basophils; similar symptoms to Anaphylaxis, sometimes severe,
leading to cardiovascular collapse.
PREVENTION AND MANAGEMENT OF PROTAMINE REACTIONS
 Management
 Prevention
1. Stop Protamine.
1. Administration of corticosteroids during rewarming,
2. Maintain airway with 100% oxygen.
2. Giving antihistamines before Protamine
3. Stop all inhalational agents.
administration
4. Give crystalloid, colloid or blood for iv volume
3. Slow administering of Protamine (5-15mg/min).
expansion.
4. Administration of protamine through LV or directly
5. Give 500-1000mg calcium.
into the aorta.
6. Give iv bolus of 0.1-1.0mg epinephrine.
7. Use pacemaker.
8. Give atropine and/or adrenaline for bradycardia.
9. Use 50-100mcg phenylephrine for hypotension.
10. If these strategies don’t work, reinitiate CPB.