History

• discovered accidentally in 1916

• extract from liver (& heart) that retards coagulation

PHARMACOLOGY

Structure

• polysaccharide

• 3000 — 40000 daltons [1 dalton wt of hydrogen]

• strongest macromolecular acid in body

because of its acidity must be bound to Na⁺ or Ca⁺⁺ when administered

Biology

• resides in mast cells

• unknown physiological function (plays no role in antithrombosis in blood)

• Heparan (related) found on endothelial cells — attracts antithrombinIII (ATIII) thereby inhibiting anticoagulation at bloodendothelial interface

Tissue sourcecommercial preparation

• isolated from porcine & bovine liver, lung & intestinal mucosa

• ?slight advantage of lung heparin for CPB

Pharmacokinetics

• peak effect 2 minutes after IV injection;

• on CPB, peak effect 10 20 minutes after (?initial) admin (due to hypothermia, hemodilution)

Distribution

• as is macromolecular & highly polarized expect most to remain in plasma

• % plasma bound: 95

• some uptake into ECF, alveolar macrophages, splenic/hepatic endothelial cells. vascular smooth muscle may account for heparin rebound

Elimination & Excretion

• Half life is dose dependent

^{• 1}/₂ life 126 24 minute [400 U/Kg]

^{• 1}/₂ life 93 6minute [200 U/Kg]

• hypothermia and renal impairment delays heparin elimination

• hepatic impairment has little effect

• heparin is metabolised by the reticuloendothelial system & renally eliminated

Pharmocodynamics

Fibrin formation inhibition

• induces anticoagulation by primarily potentiating the activity of ATIII

• to a lesser degree induces anticoagulation by binding to cofactor II [II inactivates thrombin independent of ATIII]

• attaches to ATIII, thereby altering ATIII, thereby rendering it more attractive to thrombin

• increases the thrombin inhibitory potency of ATIII by >1000X

• Thrombin enzymatically converts fibrinogen to fibrin + activates cofactors V & VIII

• ATIII inhibits thrombin + IXa, XIa & XIIa

Variability of patient response

• the response to a fixed heparin dose varies substantially from patient to patient in terms of both clotting times & plasma heparin concentrations

SIDE EFFECTS

• Bleeding: most common side effect, post operative bleeding 2° inadequate heparin neutralisation or heparin rebound

_• SVR BP (1020%)

• Effects on platelets: heparin binds avidly to platelets numerous ramifications

HEPARIN DOSING & MONITORING

sensitivity	test	pathway tested	substrate
high	Thrombin time	Common	plasma
high	Activated partial thromboplastin time	Intrinsic + common	plasma
moderate	Activated clotting time	Intrinsic + common	blood
low	Prothrombin time	Extrinsic + common	? plasma

• TT & APTT are unclottable at heparin concentrations used in CPB not used

• diatomaceous earth (celite) is used as the activant in ACT

ACT

• use of ACT served as a turning point in heparin management during CPB

• as heparin exerts its anticoagulative effect at multiple sites along the coagulation cascade . . . will affect all coagulation tests

• baseline range (unheparinised): approx 90 seconds

• prewarming testtube increases reproducibility (ACT with temp)

• use of various concentrations of kaolin in tube produces different sensitivities

• hemodilution may increase or have no effect on ACT

• aprotinin increases ACT (effect may be specific to celiteactivated ACT)

• 1.0 1.2 mg protamine is used to reverse 100U heparin

Optimal ACT

a) [BULL recommendations]

• clots do not form in the oxygenator at ACT>300 sec

• <180 sec are life threatening

• 180 — 300 sec are cause for concern

• minimum safety of 300 sec [lower for membrane oxygenators?]

• maintaining at > 600 sec is unwise

b) [Gravlee recommendations]

• 1. admin 300U/kg heparin IV

• 2. after 35 min assess arterial ACT

• 3. give additional heparin if req to achieve ACT:

i) >300 sec prior to CPB

ii) >300 sec during normothermic CPB

iii) >400 sec during hypothermia (< 30°C)

• 4. monitor ACT every 30 min or more freq if patient is resistant to hepain induced ACT prolongation

Heparin resistance

• “need for higher than normal heparin doses to induce sufficient anticoagulation for the safe conduct of CPB”

• normally see a marked interpatient variability in the anticoagulation response to a fixed heparin dose (U per Kg)

• in most cases simply require increased dosages of heparin to overcome resistance

causes of heparin resistance include:

• heparin therapy, thrombocytosis (>700,000), septicaemia, ATIII deficiency

ATIII Deficiency

• can be inherited or acquired

• Heparin therapy decreases ATIII to min 60% normal

• DIC & surgery increase the consumption of ATIII

• CPB & autologous blood removal decreases ATIII levels by dilution

• liver cirrhosis reduces ATIII by reduced production

• usually requires increased heparin dosages or rarely FFP

Heparininduced thrombocytopenia (HIT)

• seen in approx 28% patients on heparin

• average onset time of 9 days

• due to binding of IgG antibodies with platelet bound heparin activates platelets adhesion, aggregation & platelet clots

• danger of thrombotic complications

• may use low molecular wt heparin which has a lower affinity for platelets