This document discusses anticoagulants and the blood coagulation process. It covers the intrinsic and extrinsic coagulation pathways, platelet membrane proteins involved in coagulation, and factors in the coagulation cascade. It also summarizes different types of anticoagulants including heparin, low molecular weight heparins, oral anticoagulants like warfarin, and newer direct thrombin and factor Xa inhibitors. Laboratory tests for monitoring anticoagulant therapy are also discussed.
3. BLOOD
COAGULATION
Also known as clotting
Process by which blood changes from a liquid to
a gel, forming a blood clot.
It potentially results in hemostasis, the cessation
of blood loss from a damaged vessel, followed by
repair.
The mechanism of coagulation involves
activation, adhesion and aggregation of platelets,
as well as deposition and maturation of fibrin.
4. GPIa/IIa and GPIb are platelet membrane proteins that bind to collagen and von Willebrand factor
(vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4
are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP
(adenosine diphosphate); when stimulated by agonists, these receptors activate the fibrinogen-binding
protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion.
Thromboxane A2 (TXA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2
(PGI2; Prostacyclin) synthesized by endothelial cells, inhibits platelet activation.
7. TISSUE FACTOR
TF is a non-enzymatic
lipoprotein cofactor that
greatly increases the
proteolytic efficiency of
VIIa.
It is present on the surface
of cells that do not normally
contact plasma (e.g.,
macrophages and smooth
muscle cells) and initiates
coagulation outside a
broken blood vessel.
12. COAGULATION IN-VITRO TEST
ethylenediamine-
tetraacetic acid (EDTA) or citrate
activated
partial thromboplastin time (aPTT) or clotting time
prothrombin time (PT). Also known as international
normalized ratio (INR).
*blood
test
that
measures
how
long
it
takes
blood
to
clot.
13. intrinsic
coagulation pathway
extrinsic coagulation pathway
Pathway affected PT aPTT
Intrinsic Pathway Normal (12-14s) Prolonged
Extrinsic Pathway Prolonged Normal (26-32s)
Common Pathway Prolonged Prolonged
Use Monitoring of Warfarin
Evaluation of Vitamin K
deficiency or severese
malnutrition
Assessment of liver function
Assessment of clotting factor
functions in Haemiphilia and Von-
Willebrand disease
16. CLASSIFICATION OF ANTI-COAGULANTS
I. Used in vivo II. Used in vitro
A.
Parenteral anticoagulants
B.
Oral anticoagulants
(i) Indirect thrombin
inhibitors:
Heparin,
Low molecular weight
heparins,
Fondaparinux,
Danaparoid
(ii) Direct thrombin
inhibitors:
Lepirudin,
Bivalirudin,
Argatroban
i) Coumarin
derivatives:
Bishydroxycoumarin
(dicumarol),
Warfarin sod,
Acenocoumarol
(Nicoumalone),
Ethyl biscoum acetate
(ii) Indandione
derivative:
Phenindione.
(iii)Direct factor Xa
inhibitors:
Rivaroxaban
(iv)Oral direct thrombin
inhibitor:
Dabigatranetexilate
B. Calcium complexing
agents:
Sodium citrate: 1.65 g
for 350 ml of blood; used
to keep blood in the fluid
state for transfusion;
ANTICOAGULANT
ACID CITRATE
DEXTROSE SOLUTION
2.2 g/100 ml (75 ml is
used for 1 unit of blood).
Sodium oxalate: 10 mg
for 1 ml blood
Sodium edetate: 2 mg
for 1 ml blood
A. Heparin: 150 U
to prevent clotting
of 100 ml blood.
Used in
blood taken
for
investigation
17. HEPARIN (Unfractionated Heparin; UFH)
D-glucosamine-L-iduronic acid
D-glucosamine-D-glucuronic acid
*HEPARIN SOD., BEPARINE, NUPARIN 1000 and 5000 U/ml in 5 ml vials for injection.
18. PHARMACOLOGICAL ACTION
Heparin Activates plasma AT III Heparin-AT III complex
Binds to clotting factors of intrinsic and common pathways (Xa, Iia, Ixa, Xia, XIIa and XIIIa
inactivates them
20. PHARMACOKINETICS
*Heparin released from mast cells is degraded by tissue macrophages—it is not a physiologically circulating
anticoagulant.
## After i.v. injection of doses < 100 U/kg, the t½ averages 1 hr. Beyond this, dose-dependent inactivation is seen
and t½ is prolonged to 1–4 hrs. The t½ is longer in cirrhotics and kidney failure patients, and shorter in patients
with pulmonary embolism.
26. UFH vs LMWH
UFH LMWH
High molecular weight (15 000)
Low bioavailability (< 30%)
Binds to proteins
Short half-life
Low anti-Xa:anti-IIa ratio
Significant drug interaction
Risk of heparin-induced thrombocytopenia
Requires monitoring of blood levels and dose
adjustment
Risk of osteoporosis more
Low molecular weight (4500–6000)
High bioavailability (> 90%)
No protein binding
Long half-life
High anti-Xa:anti-IIa ratio
No drug interaction
Lower risk of heparin-induced thrombocytopenia
Fixed dose (weight adjusted)
Risk of osteoporosis much less
Turpie et al., CMAJ • APR. 2, 2002; 166 (7)
36. MECHANISM OF ACTION
This carboxylation is
essential for the ability of the clotting factors to bind Ca2+ and to get bound to phospholipid surfaces, necessary
for the coagulation sequence to proceed.
37. Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006);
DRUGS AFFECTING COAGULATION, BLEEDING AND THROMBOSIS, KDT, 7th Edition page no 615
49. HEPARIN VS ORAL ANTICOAGULANTS
Parameters Heparin Warfarin
Chemistry
Source
Route of admin.
Onset of action
Duration of action
Activity
Mechanism
Antagonist
Variability in response
Lab. control
Drug interactions
Use
Mucopolysaccharide
Hog lung
Parenteral (i.v., s.c.)
Immediate
4–6 hrs
In vitro and in vivo
Blocks action of factor X and thrombin
Protamine sulphate
Little
aPTT/clotting time (desirable)
Few and not significant
To initiate therapy
Coumarin derivative pig intestine
Synthetic
Oral
Delayed (1–3 days)
3–6 days
In vivo only
Inhibits synthesis of clotting factors
Vit K
Marked
Prothrombin time/INR
(essential)
Many and significant
For maintenance
