BLOOD COAGULATION
week 7-8
Platelets











Platelets are fragments of megakaryocytes with a blue-staining
outer region and a purple granular center
Their granules contain serotonin, Ca2+, enzymes, ADP, and
platelet-derived growth factor (PDGF)
Platelets function in the clotting mechanism by forming a
temporary plug that helps seal breaks in blood vessels
Platelets not involved in clotting are kept inactive by NO and
prostaglandin I2
Size: 1.5-3 M
Life span 7-10 day
Count: 150-400 x 109/L
No nucleus
Surface binding sites for fibrinogen, VWF
Surface platelet antigens, HPA1
Functions:
 Hemostatic plug formation
 Release and synthesis of coagulation factors
Platelet Formation
Endomitotic synchronous nuclear replication
Thrombopoietin major regulator
332 residues, Mr 38KDa
C-MPL receptor for TPO on platelet
7-10 days delay to rise platelet level by TPO
endomytotic synchronous nuclear replication
- enlarge cytoplasmic volume
- Increase of nuclear lobe
~4000 platelets from one megakaryocyte
ultrastructure of platelet
Hemostasis
A series of reactions designed for stoppage of bleeding
Hemostasis

three phases occur in rapid
sequence



immediate vasoconstriction in
response to injury
Platelet plug formation
Coagulation (blood clotting)
Vasoconstriction and Platelet Plug Formation
platelet adhesion and platelet plug formation




platelets do not stick to each other or to the endothelial lining of blood vessels
blood vessel wall (endothelial cells) prevent platelet adhesion & aggregation
platelets contain receptors for fibrinogen and vWF
after vessel injury platelets adhere and aggregate

damage to blood vessel endothelium exposes collagen
 platelets adhere to collagen with VWF and stimulated by thromboxane A2
 platelets stick to exposed collagen fibers and form a platelet plug
 platelets release serotonin and ADP, which attract still more platelets

The platelet plug is limited to the immediate area of injury by PGI2
platelet adhesion and aggregation
Integrin 21
Atherosclerotic Plaque Development
The normal arterial wall
advance stage of atherosclerosis,
consists of smooth
calcified scar tissue forms, if the
muscle and connective
endothelium is damaged and collagen
tissue with an endothelial
exposed, platelet aggregates and
cell lining
thrombus forms, if blood flow is stopped,
heart attack !
Early stages
excess LDL-cholesterol
accumulates between the
endothelium and connective
tissue. There it is oxidized
and phagocytosed.
Macrophages produce
paracrines that attract
smooth muscle cells.
fibrous plaque/
Further cholesterol
accumulation results
in fibrous scar tissue
formation. Migrating
smooth muscle cells
divide, thickening the
arterial wall and
narrowing the lumen.
Coagulation Phase







Two major pathways
 Intrinsic pathway
 Extrinsic pathway
Both converge at a common point
 reactions take place in 3 major phases:
 Prothrombin activator is formed
 Prothrombin is converted into thrombin
 Thrombin catalyzes the joining of fibrinogen into a
fibrin mesh
13 soluble factors are involved in clotting
some of these factors are dependent on Vitamin K
most of these factors are proteases
normally inactive and sequentially activated
hereditary lack of clotting factors lead to diseases such
as hemophilia -A
PHASE ONE: Pathways to Prothrombin Activator
initiated by either the intrinsic or extrinsic pathway
 triggered by tissue-damaging events
 involves a series of procoagulants
 each pathway cascades toward factor X
 activated factor X makes complexes with Ca++, PF3,
and factor V to form prothrombin activator

PHASE TWO:

Pathway to Thrombin
Prothrombin activator catalyzes the transformation
of prothrombin to the active enzyme thrombin
PHASE THREE: Common Pathways to Fibrin Mesh
 Thrombin
catalyzes the polymerization of
fibrinogen into fibrin
 Insoluble fibrin strands form the structural
basis of a clot
 Fibrin causes plasma to become a gel-like trap
 Fibrin in the presence of Ca++ activates factor
XIII that:


Cross-links fibrin
Strengthens and stabilizes the clot
Intrinsic Pathway

All clotting factors are
within the blood vessels

Clotting is slower

Activated partial
thromboplastin test
(aPTT)
Extrinsic Pathway

Initiating factor is outside
the blood vessels - tissue
factor

Clotting is faster - in Sec

Prothrombin test (PT)
Intrinsic
pathway
Extrinsic
pathway
Factors
affected
By Heparin
Vitamin K
dependent Factors
affected by Oral
anticoagulants
Cross linked
Fibrin polymer
Summery Coagulation
Extrinsic
Factor VII
Intrinsic
Factors XII, XI, IX, VIII
Common Path (TT)
Factor X  Factor Xa
Fibrinogen
Thrombin
Fibrin Monomer
Prothrombin  Thrombin
Fibrin Polymer
F-XIIIa
Fibrinogen  Fibrin
Cross Linked
Fibrin
Inhibition of Clotting Factors






Fibrin acts as an anticoagulant by binding thrombin and
preventing its:
 Positive feedback effects of coagulation
 Ability to speed up the production of prothrombin
activator via factor V
 Acceleration of the intrinsic pathway by activating
platelets
Thrombin not absorbed to fibrin is inactivated by
antithrombin III
FDP – Inhibit thrombin
Other Plasma Inhibitors of activated factors
 Heparin, 2 Antiplasmin
 Protein C – Factor VIII and factor V (fibrinolysis)
Blood flow – dilution and clearing
Plasminogen Plasmin (Fibrin, factor V and VIII)
Fibrinolysis
Enhance degradation of clots
 Activation of endogenous protease
 Plasminogen (inactive form) is converted to Plasmin
(active form)
 Plasmin breaks down fibrin clots
 Exogenously administered drugs





Streptokinase - bacterial product - continuous use immune reaction
Urokinase - human tissue derived - no immune response
Tissue plasminogen activator (tPA) - genetically cloned no immune reaction - EXPENSIVE
Inhibitors of fibrinolysis - aminocaproic acid

Lysine analog- inhibits proteases
Fibrin is a fibrillar protein that is polymerised to form a
"mesh" that forms a hemostatic plug or clot and is made
from its zymogen FIBRINOGEN (also called factor I),
a soluble plasma glycoprotein (340 kDa) synthesized in
hepatocytes and megakaryocytes.
Processes in the coagulation cascade activate the
zymogen prothrombin to the serine protease thrombin,
which is responsible for converting fibrinogen into fibrin.
Fibrin is then cross linked by factor XIII to form a clot.
Fibrinogen concentration in blood plasma: 1.5 - 4.0 g/L
In its natural form, fibrinogen bridges between platelets,
by binding to their GpIIb/IIIa membrane proteins
Fibrinogen is a
symmetrical dimer
composed of 6 paired
polypeptide chains (α, β, γ)
linked by disulfide bonds
N-terminal part of these 3
chains contain the Cys that
participate in the crosslinking of the chains.
However, there is no similarity between the C-terminal
part of the α chain and that of the β and γ chains. The
C-terminal part of the β and γ chains forms a domain of
about 270 amino-acid residues.
FIBRINOPEPTIDE a small part on the α and β chains
prevent fibrinogen spontaneous self-polymer formation.
Factor III (Tissue factor, thromboplastin or CD142)
a protein present in subendothelial tissue, platelets, and
leukocytes necessary for the initiation of thrombin formation
from the zymogen prothrombin
The gene is located on chromosome 1p22-p21.
The protein structure of TF consists of three domains:
1. extracellular domain binds factor VIIa.
One of domains of Factor VIIa is carboxylated GLA
domain, binds in the presence of Ca+2 to negatively
charged phospholipids. Binding of VIIa to negatively
charged phospholipids greatly enhances the proteinprotein binding of VIIa to TF.
2. a domain which crosses the hydrophobic membrane.
3. cytoplasmic domain of 21 amino acids length
involved in the signaling function of TF.
Factor V (rarely as proaccelerin or labile factor)
Unlike other coagulation factors, it is not enzymatically active
but functions as a cofactor of the thrombinase complex.
circulates in plasma as a single-chain molecule with a
plasma half-life of about 12 hours (max 36 hours).
Deficiency leads to predisposition for hemorrhage, while
some mutations (most notably factor V Leiden) predispose
for thrombosis
The gene is located on the first chromosome (1q23)
The gene spans 70 kB, consists of 25 exons, and the
resulting protein has a Mr ~330000.
It is genomically related to the family of multicopper
oxidases, and is homologous to coagulation factor VIII.
Intrinsic
pathway
Extrinsic
pathway
Factors
affected
By Heparin
Vitamin K
dependent Factors
affected by Oral
anticoagulants
Cross linked
Fibrin polymer
Factor V is activated by thrombin and is able to bind to
activated platelets.
On activation, factor V is spliced in to heavy (Mr ~ 110K)
and light chains (Mr ~ 73K) which are nonconvalently
bound to each other by Ca++.
The Xa requires Ca++ and Va to convert prothrombin to
thrombin on the cell surface membrane that is the part of
the common pathway in the coagulation cascade.
Factor Va is degraded by activated protein C, one of the
principal physiological inhibitors of coagulation. Protein C
itself is activated by thrombin.
Concentration and action of protein C are important
determinants in the negative feedback loop through
which thrombin limits its own activation.
Factor VII (proconvertin)
It is an enzyme of the serine protease class.
The action of the factor is impeded by tissue factor
pathway inhibitor (TFPI), which is released almost
immediately after initiation of coagulation.
Factor VII is vitamin K dependent
It is produced in the liver
Use of warfarin or similar anticoagulants impairs its
function.
The gene is located on chromosome 13 (13q34).
Hageman factor (factor XII)
It activates factor XI and prekallikrein.
It is an enzyme of the serine protease (or serine
endopeptidase) class
Discovery (1955): from blood sample of the 37-year-old
railroad brakeman John Hageman was found to have
prolonged clotting time in test tubes, even though he had
no hemorrhagic symptoms.
Dr. Oscar Ratnoff found that Mr. Hageman lacked a
previously unidentified clotting factor.
Exposure of human plasma to glass, kaolin, celite, or other negatively
charged surfaces initiates contact activation reactions that trigger the
intrinsic coagulation pathway, the kinin-forming pathway, and the
fibrinolytic pathway.
Proteins that are known to be involved in contact activation of human
plasma include Hageman factor, plasma prekallikrein (Fletcher factor),
coagulation Factor XI (plasma thromboplastin antecedent), and high
Mr kininogen.
Factor IX (Christmas factor)
plasma thromboplastin component (PTC)
a single-chain plasma glycoprotein (Mr 57K) of Ser protease
inactive unless activated by XIa (of the contact pathway) or VIIa
(of the tissue factor pathway).
IXa hydrolyse one Arg-Ile bond in factor X to form factor Xa. It
requires Ca++, membrane phospholipids, and factor VIII as
cofactors.
gene is located on the X chromosome (Xq27.1-q27.2).
Deficiency of factor iX causes Christmas disease (hemophilia B).
Over 100 mutations of factor IX have been described; some
cause no symptoms, but many lead to a significant bleeding
disorder.
Factors Limiting Clot Growth or Formation

Two homeostatic mechanisms prevent clots
from becoming large
 Swift removal of clotting factors
 Inhibition of activated clotting factors
Factors Preventing Undesirable Clotting
 Unnecessary clotting is prevented by the
structural and molecular characteristics of
endothelial cells lining the blood vessels
 Platelet adhesion is prevented by:



The smooth endothelial lining of blood vessels
Heparin and PGI2 secreted by endothelial cells
Vitamin E quinone, a potent anticoagulant
Clot Retraction and Repair
retraction – stabilization of the clot by
squeezing serum from the fibrin strands
 Repair
 Clot



Platelet-derived growth factor (PDGF)
stimulates rebuilding of blood vessel wall
Fibroblasts form a connective tissue patch
Stimulated by vascular endothelial growth
factor (VEGF), endothelial cells multiply and
restore the endothelial lining
Hemostasis Disorders:
Thromboembolytic Conditions


Thrombus – a clot that develops and persists in an
unbroken blood vessel
 Thrombi can block circulation, resulting in tissue
death
 Coronary thrombosis – thrombus in blood vessel of
the heart
Embolus – a thrombus freely floating in the blood stream
 Pulmonary emboli can impair the ability of the body to
obtain oxygen
 Cerebral emboli can cause strokes
A blood clot or thrombus is the final product of the blood
coagulation steps in hemostasis. It is achieved via the
aggregation of platelets that form a platelet plug, and the
activation of the clotting factors.
thrombus is physiologic in injury but pathologic in thrombosis.
a thrombus is a blood clot in an intact blood vessel
thrombus in a large blood vessel will decrease blood flow
through that vessel.
In a small blood vessel, blood flow may be completely cut-off
resulting in the death of tissue supplied by that vessel.
Thrombus dislodge from arteries
and veins and become an
embolus (free-floating). Venous
emboli can block arterioles in the
lung and pulmonary circulation
Greek Thrombos meaning "lump".
Thrombosis

Arterial Thrombosis :


Adherence of platelets to arterial walls - White in
color - Often associated with MI, stroke and
ischemia
Venous Thrombosis :

Develops in areas of stagnated blood flow (deep
vein thrombosis), Red in color- Associated with
Congestive Heart Failure, Cancer, Surgery.
Hemostasis Disorders: Thrombocytopenia
 condition
where the number of circulating
platelets is deficient




Patients show petechiae (small purple blotches
on the skin) due to spontaneous, widespread
hemorrhage
Caused by suppression or destruction of bone
marrow (e.g., malignancy, radiation)
Platelet counts less than 50,000/mm3 is
diagnostic for this condition
Treated with whole blood transfusions
Disseminated Intravascular Coagulation (DIC)
or consumptive coagulopathy
a pathological process where the blood starts to coagulate throughout
the whole body resulting in depletion of platelets and coagulation factors,
paradoxically increases the risk of hemorrhage.
CAUSES of DIC
Sepsis, particularly with gram-negative bacteria.
Obstetric complications (most common), chemicals from the uterus
being released into the blood, or from amniotic fluid embolisms, and
eclampsia or abruptio placentae.
Tissue trauma such as burns, accidents, surgery or shock.
Incompatible blood transfusion reactions or massive blood transfusion
Liver diseases, malignant cancers (Acute promyelocytic leukemia) or
hypersensitivity reactions can produce chemicals leading to DIC.
Viral hemorrhagic fevers bring about their frank effects, paradoxically,
by causing DIC.
Envenomation by some venomous snakes such as the Stephens
Banded Snake, Hoplocephalus stephensi
Hemostasis Disorders: Hemophilias

hereditary bleeding disorders caused by lack of
clotting factors
 Hemophilia A: common type (83%) deficiency of
factor VIII
 Hemophilia B: a deficiency of factor IX
 Hemophilia C: mild type, a deficiency of factor XI
Who can get hemophilia?
1 in 5,000-10,000 male births have hemophilia
~12,000 people have hemophilia in the U.S.
50% of male & female offspring from women who carry the gene get
hemophilia
100% of female offspring from men who have hemophilia develop hemophilia
About 1/3 of cases come from spontaneous gene mutation
What causes hemophilia?
 When clotting does not form
fibrin to stop the bleeding,
excessive bleeding occurs
 Inherited sex-linked recessive
trait with the defective gene
on the X chromosome
 Females are the carrier of
hemophilia
 Since females have two X
chromosomes if one carries
hemophilia the other will
dominate and produce the
clotting factors
 Males on the other hand only
need one bad gene to be a
hemophilic
Symptoms of Hemophilia






Easy bruising or bleeding
Spontaneous bleeding into the joints
Gastrointestinal and urinary tract bleeding
Prolonged bleeding from cuts, tooth extraction or surgery
Can also experience blood in stool and urine
In women, it can cause excessive bleeding during menstruation
joints most
commonly
affected by
Hemophilia. It
most often
occurs at the
knees, hips,
ankles,
shoulders,
and elbows
muscles that
bleed with
Hemophilia are
those in the
the upper arm,
upper leg (front
and back), the
calf and the
front of the
groin
Detection of Hemophilia
When a baby starts to crawl the parents may
notice bruises on stomach, chest, buttock,
and back.
 The baby may also be fussy, not wanting to
walk or crawl
 Other symptoms include long nosebleeds,
excessive bleeding from biting down on the
lips or tongue, excessive bleeding following a
tooth extraction, excessive bleeding following
surgery and blood in the urine.

history of hemophilia







In the Talmud (Jewish writings, 2nd century AD) it is stated that a male
does not have to be circumcised if 2 brothers had already died from
excessive bleeding
Arab physician, Albucasis took notes on many males who died of
excessive bleeding in the 12th century
In 1803 the first case of hemophilia was recorded by Dr. John Conrad
Otto who traced the disease back 3 generations to a family of males who
had what he called, “a hemorrhagic disposition existing in certain families”
The word hemophilia first appeared in a study of University of Zurich by
Hopff in 1828.
From Queen Victoria of England the gene passed to many different monarchies.
Her granddaughter, Alexandra, was married to the Russian Tsar, Nicholas and gave
birth to Alexei, a son born with hemophilia.
That time, the monk named Rasputin performing “miracles” in the court was asked
to cure the disease that inflicted Alexei.
It’s been said that his hypnosis was able to slow down the bleeding of the young
boy, and diminish his pain. In return, the Tsar gave him more power and authority in
his court as a faith-healer.
life span of people with Hemophilia
Year
age at the time of death
Available Treatments
Before 1938
11
none
Before 1968
20
Plasma or Whole
blood transfusions
1968
Less than 40
Cryoprecipitate
1983
64
Freeze dried clotting
factors
1988
40 ( impact of aids)
Freeze dried clotting
factors
1999
Normal life span
Factors produced by
genetic engineering
Modern Treatments




In large injuries, the only way to stop bleeding is to
replace the missing clotting factor.
Clotting factor comes as a dried powder that is mixed
with water. Some are plasma-derived and come right
from donated human plasma.
The mixture is injected as an IV and can now be done at
home as well as in the hospital.
If the hemophilia is severe, routine infusions of blood
might be necessary which are called prophylactics.
Von Willebrand disease (vWD) is the most
common hereditary coagulation abnormality described in
humans (also in Dogs)
It arises from a qualitative or quantitative deficiency of von
Willebrand factor (vWF), a multimeric protein that is required
for platelet adhesion.
vWF is named after Dr. Erik von Willebrand, a Finnish doctor
who in 1924 first described a hereditary bleeding disorder in
families from the Åland islands who had a tendency for
cutaneous and mucosal bleeding, including menorrhagia.
von Willebrand distinguished von Willebrand disease (vWD)
from haemophilia and other forms of bleeding diathesis
without identifying the cause.
In the 1950s, vWD was shown to be caused by a plasma
factor deficiency in the 1970s, the vWF protein was purified
Von Willebrand Factor
a large multimeric glycoprotein present in plasma
can be >20,000 kDa with >80 subunits (250 kDa).
Only the large multimers are functional
vWF monomer contains 2050 amino acid.
produced constitutively in
endothelium (in the Weibel-Palade bodies)
megakaryocytes (α-granules of platelets)
subendothelial connective tissue.
monomer contains specific domains with specific function
the D'/D3 domain binds to Factor VIII
the A1 domain binds to platelet gp1b-receptor,
heparin and possibly collagen
the A3 domain binds to collagen
the C1 domain, binds to platelet integrin αIIbβ3
the "cysteine knot" domain (at C-terminal end), which vWF
shares with PDGF, -β TGFβ) and β- human chorionic
gonadotropin
von Willebrand factor
FUNCTION
primarily binds to Factor VIII important for platelet adhesion (wound sites).
vWF also binds to a number of cells and other molecules:
Factor VIII is bound to vWF whilst inactive in circulation; Factor VIII
degrades rapidly when not bound to vWF. Factor VIII is released from
vWF by the action of thrombin.
vWF binds to collagen, e.g., when it is exposed in endothelial cells due to
damage occurring to the blood vessel.
vWF binds to platelet gpIb when it forms a complex with gpIX and gpV;
this binding occurs under all circumstances, but is most efficient under
high shear stress (i.e., rapid blood flow in narrow blood vessels).
vWF binds to other platelet receptors when they are activated, e.g., by
thrombin (i.e., when coagulation has been stimulated).
Classification of vWD
There are three hereditary types of vWD
Type 1 (60-80% of all vWD cases)
a quantitative defect (heterozygous defective gene)
may not have clearly impaired clotting
most patients usually leads a nearly normal life.
Bleeding may be a problem following surgery, noticeable
easy bruising or menorrhagia (heavy periods).
Decreased levels of vWF are detected (10-45% of
normal, i.e. 10-45 IU).
Classification of vWD
Type 2 (20-30%) with normal levels of vWF is a qualitative defect having
mild bleeding tendency. The multimers are structurally abnormal, or
subgroups of large or small multimers are absent. Four subtypes:
Type 2A is an abnormality of the synthesis/protelysis of the vWF multimers
resulting in small multimer units. Factor VIII binding is normal.
Type 2B is a "gain of function" defect leading to spotaneous binding to
platelets resulting rapid clearance of platelets and large vWF multimers. A
mild thrombocytopaenia may occur. The large vWF multimers are absent in
the circulation and the Factor VIII binding is normal.
Type 2M is caused by decreased or absent binding to GPIb on the
platelets. Factor VIII binding is normal.
Type 2N (Normandy) is a deficiency of the binding of vWF to factor VIII.
vWF antigen level and functional test results remains normal but has a low
factor VIII. This has probably lead to some 2N patients being misdiagnosed
in the past as having hemophilia A.
Classification of vWD
Type 3
the most severe form of vWD
homozygous for the defective gene
may have severe mucosal bleeding
reduced or absent platelet and plasma VWF (<5U/dL)
may have sufficiently low factor VIII
may have occasional hemarthoses (joint bleeding)
Hemostasis Disorders: Bleeding Disorders
Inability to synthesize procoagulants by the
liver results in severe bleeding disorders
 Causes can range from vitamin K deficiency to
hepatitis and cirrhosis
 Inability to absorb fat can lead to vitamin K
deficiencies as it is a fat-soluble substance
and is absorbed along with fat
 Liver disease can also prevent the liver from
producing bile, which is required for fat and
vitamin K absorption

Prevention of Undesirable Clots
 Substances
used to prevent undesirable
clots include:



Aspirin – an antiprostaglandin that inhibits
thromboxane A2
Heparin – an anticoagulant used clinically
for pre- and postoperative cardiac care
Warfarin – used for those prone to atrial
fibrillation
Anticoagulant drugs for thromboembolism
Drug Class
Prototype
Action
Effect
Anticoagulant Heparin
Parenteral
Inactivation of
clotting Factors
Prevent venous
Thrombosis
Anticoagulant Warfarin
Oral
Decrease
synthesis of
Clotting factors
Prevent venous
Thrombosis
Antiplatelet
drugs
Decrease platelet Prevent arterial
Thrombosis
aggregation
Aspirin
Thrombolytic Streptokinase Fibinolysis
Drugs
Breakdown of
thrombi
Heparin and its mechanism of action



Heparin


antithrombin
III
Thrombin



Sulphated carbohydrate
Purified from bovine lungs
Different size
Active in vitro and in vivo
Administration
 Parenteral (only IV or deep s.c.)
 Do not inject IM
Half-life 1 - 5 hrs - monitor aPTT
Adverse effect – hemorrhage
Antidote - protamine sulphate
Heparin
antithrombin
III
Thrombin
antiThrombin
thrombin
III
Descarboxy
Prothrombin
Prothrombin
Vitamin KRED
Oral anticoagulants:
warfarin, dicumarol







Vitamin KOX
NAD
NADH
Warfarin
Isolated from clover leaves
Structurally related to vitamin K
Inhibits production of vit K dependent clotting factors (VII, IX, X)
binds to albumin
Clearance is slow - 36 hrs
Overdose - reversed by vitamin K infusion
Can cross placenta - prohibited during late pregnancies!
Aspirin (Antiplatelet drugs)
Prevents platelet aggregation /adhesion
 Clinical use - prevents arterial thrombus



Myocardial infarction (MI), stroke, heart valve
replacement and shunts
Other antiplatelet drugs are - Dipyridamole,
sulfinpyrazone and Ticlopidine
Mechanism of action
Aspirin inhibits cyclooxygenase (COX)
 COX is a key enzyme involved in the synthesis
of thromboxane 2 (prostaglandins)
 Inhibits platelet aggregation

Prophylactic use of Aspirin
Low dose daily ( 180 mg/day)
 Prevents ischemic attack (ministroke) and MI
 335 mg/day reduced the risk of heart attack in
patients over 50
 More than 1000 mg/day NO EFFECT



High dose inhibits prostacyclin synthesis in cells
surrounding vessels. PS normally prevents platelet
aggregation. Therefore, inhibition of PS leads to
abrogation of the prophylactic benefit of Aspirin
Contraindication - DO NOT give to patients
with glucose 6-PO4 dehydrogenase deficiency
Drug interaction- prototype Warfarin
Category
Drugs that
Promote bleeding
Drugs that
decrease
Warfarin activity
Drugs that
Increase
Warfarin Activity
Mechanism
Representative Drugs
Inhibition of platelets
Aspirin
Inhibition of clotting
Factors
heparin
antimetabolites
Induction of
Barbiturates
metabolizing Enzymes Phenytoin
Promote clotting factor Vitamin K
Synthesis
Colestipol
Reduced absorption
Cholestyramine
Decrease binding to
Albumin
Aspirin, Sulfonamides
Inhibit Degradation
Cimetidine, Disulfiram
Decrease synthesis of
Antibiotics (oral)
Tests of Hemostasis

Screening tests





Bleeding.T - To test Platelet & BV function
Prothrombin.T – Extrinsic
aPTT – Instrinsic
Thrombin.T – Both paths (DIC)
Specific tests



Factor assays
Tests of thrombosis
Platelet function studies:


Adhesion, Aggregation, Release & PG pathway tests.
Bone Marrow study
Prothrombin time (PT)
Tissue Thromboplastin factor III
Mix with phospholipid extract
Add calcium and blood sample
Determine clotting time
Generally 12 - 14 seconds
Used to detect defects in extrinsic
pathway
Activated partial thromboplastin time (APTT)
Blood sample + EDTA or Citrate
No clot (recalcification will result in clot in ~2 - 4 min)
Add calcium
Mix with negatively charged phospholipid
Kaoline (aluminum silicate)
Determine clotting time
Generally clotting occurs in 26 to 33 seconds
Used to detect defects in the intrinsic pathway
Diagnosis of coagulation defects
Prolonged APTT
No change in PT
Defective Intrinsic Pathway
No change in APTT
Prolonged PT
Defective Extrinsic Pathway
Prolonged APTT
Prolonged PT
Defective in Common pathway