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PHYSIOLOGY
OF
BLOOD COAGULATION
H E M E O S T A S I S
•The fluidity of the blood is a consequence of
the balance between two processes:
1. blood coagulation (clot formation)
2. blood fibrinolysis (clot dissolution)
•Hemostasis consists of coagulation and
fibrinolysis.
H E M E O S T A S I S
•Coagulation prevents the blood loss from a damaged
blood vessel. It keeps blood within a damage vessel.
•It is the innate response for the body to stop bleeding
and loss of blood.
•Fibrinolysis is a process necessary for clot
dissolution. It prevents blood clots from growing and
becoming problematic.
H E M E O S T A S I S
Three inherent mechanisms contribute to
hemeostasis
Vascular constriction
Formation of platelet plug
Blood coagulation (plasma clotting
factors)
VASCULAR SPASM
Immediately after a blood vessel has been cut or
ruptured, the trauma cause the vessel to contract
and reduce the blood flow.
The contraction results from:
activation of sympathetic nervous system
local humoral factors from the traumatized
tissues and blood platelets (serotonin, epinephrin
tromboxane A2).
Trauma activates sympathetic nervous system what
causes the vessel to contract and reduce the blood flow.
PLATELETS
•Platelets, are also called thrombocytes, are large fragments
from the cytoplasm of bone marrow cells called
megacariocytes.
•Platelets lack a nukeus and cannot reproduct, they have
mitochondrias and enzyme systems capable of producing ATP
and prostaglandins, which are required for their function in
hemostasis.
•The newly formed platelets released from bone marrow spend
up to 2 days in the spleen before they are released into the
blood (1/3 of platelets remains in the spleen, 2/3 is circulating
in the blood).
PLATELETS
•Platelet production in bone marrow is controlled
by a protein called thrombopoetin that causes
proliferation and maturation of megacariocytes.
•The sources of thrombopotin are: the liver, kidney,
smooth muscle and bone marrow.
•Thrombopoetin production is regulated by the
number of platelets in the circulation.
VASCULAR STRUCTURE
Internal membrane
(intima)
Medial membrane
(media)
External
membrane
(adventitia)
endothelium
Basement membrane (collagen)
Elastic membrane (elastin, collagen, fibronectin, GAG)
Vascular
smooth muscle
cells
External elastic membrane(elastin, collagen)
Figure made by prof. Krzysztof Książek
FORMATION OF THE PLATELET
PLUG Platelets adhere to the injured area of the vessel wall,
especially to the injured endothelial cells and to exposed collagen (bridged by von Wiellebrand’s factor( vWF).
Immediately after adhesion they change their characteristic drastically and secret large quantities of ADP, tromboxane A2, which in turn act on nearby platelets to activate them.
Damaged vascular walls elicit activation of increasing number of platelets, that themselves attract more and more
platelets thus forming a platelet plug.
Platelets adhere to the injured area of the vessel wall,
especially to the injured endothelial cells and to exposed
collagen (bridged by von Wiellebrand’s factor( vWF).
Immediately after adhesion platelets change their
shape drastically and secret large quantities of ADP,
tromboxane A2, which in turn act on nearby platelets
to activate them.
PLATELETS
•Platelets contain two specific type of granules – alpha, and
delta.
•Alpha granules release mediators for hemostasis (plasma
cloting factors: I, V, VII, vWF), and growth factors , which
cause vascular endothelial cells, smooth muscle cells and
fibroblast to proliferate and growth.
•Delta granules (or dense granules) contain ADP, Ca 2+,
serotonin and epinephrin → platelet agregation and
vasoconstriction.
Ivy method - 4-8 min
In the Ivy method the blood pressure cuff is
placed on the upper arm and inflated to 40
mm Hg. A disposable lancet is used to make a
shallow incision that 1mm deep on the
underside of the forearm.
BLEEDING TIME
Laboratory evaluation of blood vessels and PTLs
Plasma clotting factors II
Most clotting factors normally are not active.
Their activation requires a cascade of events. One
active clotting factor activates another.
Factors II (prothrombin), VII, IX, X, need vitamin K
as an essential cofactor for their formation in the liver.
Ca2+ ions are required for several steps in the clotting
process.
BLOOD COAGULATION
MECHANISM OF COAGULATION
Two conditions can lead to blood clotting:
1. Blood vessels damage (collagen fibers – initiate
intrinsic pathway).
2. Damage to cells which build the vessel wall
(tissue factor – initiates extrinsic pathway).
Intrinsic and extrinsic pathways initiate the
conversion of prothrombin to trombin.
MECHANISM OF COAGULATION
Trombin is an enzyme that enzymatically causes
polymeryzation of plasma fibrinogen (soluble protein) into
the fibrin threads (insoluble protein) that lead to blood
clotting.
Fibrin threads entrap large numbers of RBCs, WBCs,
platelets and plasma to form a soft gelatinous mass- the
blood clot.
Platelet aggregation is enhanced by thrombin.
BLOOD COAGULATION
Laboratory evaluation of plasma clotting
factors
Within 3-6 minutes after rupture broken
ends of vessel are filled with clot.
Conversion of fibrinogen to fibrin under
the trombin condition is the clotting
process.
COAGULATION TIME Laboratory evaluation of plasma clotting factors
APTT – Activated Partial Tromboplastin Time
(Intrinsic pathway and Common Pathway) – 25-40 s
INR- International Normalized Ratio 0.8-1.2
(Extrinsic Pathway and Common Pathway)
TT –Trombin Time – 15-19 s
(conversion of fibrinogen to fibrin)
COAGULATION TIME
APTT
TT
INR
CLOT DISSOLUTION
The clots must be removed in order to prevent
permanent obstruction.
Plasmin is a proteolytic enzyme that digests fibrin.
It is synthesized from its precursor plasminogen.
Residue of the clot dissolution is removed by the
phagocytic WBCs .
TROMBOPROTECTION I
It is necessery to prevent
excessive clotting and occlusion
of major blood vessels (e.g.,
coronary artery - thrombosis)
and embolisms due to clot
migration.
TROMBOPROTECTION II
1. T R O M B I N I N H I B I T I O N
Antytrombin III – the most important tromboprotective plasma
protein (inactivates also plasma clottinf factors XI, XII)
Heparin (inactivates plasma clottinf factors II, X)
2. C L O T T I N G F A C T O R S I N H I B I T I O N
Protein C and S (vit K dependent) – inhibit factor V, VIII
Vitamin K antagonists (cumarin derivates as warfarin, acenocoumarol)
3. P L A T E L E T I N H I B I T I O N
Prostacyklin (PGI2– inhibits platelets adhesion to normal
endothelium)
Aspirin – inhibit platelets aggregation by blocking TXA2 production by
inhibition of COX-1 and COX-2)
BLOOD
PATOPHYSIOLOGY
BLEEDING DISORDES
BLEEDING DISORDERS
Hemorrhagic diathesis (HD) can be caused by:
Disorders of thrombocytes (thrombocytic HD)
Vascular defects ( vascular HD)
Disorders of the plasma clotting factors (plasma HD)
BLEEDING DISORDERS - SYMPTOMS
Thrombocytic and vascular HD
Ecchymosis and bleeding into the skin (petachiae)
Dermatomes (bruises)
Epistaxis (nosebleeds)
Gastrointestinal, genitourinary and central nervous system
bleeding
Intracranial bleeding (rare, life-threatening)
Plasma HD
Bleeding into joints (large joints in leg), muscles bleeding
(bruises), body cavities bleeding (e.g. pleural cavity,
peritoneal cavity)
petachiae
PLATELET HD I
ACQUIRED THROMBOCYTOPHENIAS (TCP’s)
(Most common HD)
life-threatening symptom: intracranial bleeding (↓20 000/µl PLTs)
Idiopathic thrombocytophenia purpura
(1-3 weeks after viral infection) shortens platelets’ survival due to immune
complex
Diminished platelet formation
aplastic anemia
bone marrow tumors
cobalamine or folate deficiency
Increase platelets destruction
vascular prostheses
artificial valves
Platelets sequestration
enlarged spleen
PLATELET HD II
ACQUIRED THROMBOCYTOPATHIES
(qualitative disorders)
Uremia (diminished platelets adhesion)
Acetylosalicylic acid (ASPIRIN) - used in thrombosis
prophylaxis
Aspirin is a cyclooxygenase inhibitor and causes decreased tromboxane A2
production (vasoconstrictor, aggregation factor)
•Aspirin irreversibly blocks the COX-1 in thrombocytes.
•We should wait for a new platelets for about 1 week, after discontinuation
of therapy
PLASMA HD I
HEREDITARY COAGULOPATHIES
Classical hemophilia A (absence or reduced formation or
defect of factor VIII)
Hemophilia B (IX) = Christmas Disease
Hemophilia C (XI)
Rare homozygous deficiency of factor I (fibrinogen),
II (prothrombin), V, VII, X, XIII
von Willebrand’s disease
HEMOPHILIA A I
The most common of the X-chromosomal recessive form
(one in 10 000 newborn boys)
Women are carriers of the X-chromosom related gene.
Males and homozygotous females (extremely rare) suffer
from hemophilia
bleeding sites are:
- muscles (bruises)
- body cavities (e.g. peritoneal cavity)
- large joints of the leg becoming markedly deformed with
time (hemophilic arthropathy)
HEMOPHILIA A II
The degree of bleeding is related to the amount of factor
activity and the severity of the injury
Spontaneous bleeding is seen with factor activity levels
below 1 % (severe hemophilia)
About 5% activity level for factor VIII is usually enough
for normal living, but not enough when trauma occurs
(mild hemophilia)
von WILLEBRAND’S DISEASE
von Willebrand factor (vWF) is a large multimeric glycoprotein present
in blood plasma and produced in endothelial cells, megakariocytes,
platelets, and subendothelial connective tissue
von Willebrand factor binds to plasma clotting factor VIII, protects it
against inactivation and it is important in platelets agreggation and
adhesion to wound sites
von WILLEBRAND’S DISEASE
Autosomal dominant trait occurring in males and females
In von Willebrand’s disease, both a factor VIII and von Willebrand
factor deficiency exist
The patients suffered from plasma HD ( lack of VIII plasma factor) and
platelets HD (lack of von Willebrand factor = platelets adhesion defect)
Clinical manifestation are typical for platelets HD ;
-deep tissue bleeding (bruises, petachiae)
-Gastrointestinal, genitourinary bleeding (prolonge menstrual bleeding)
- arthropaty (rare)
- peritoneal and intracranial bleeding (rare, life-threatening)
PLASMA HD
AQUIRED COAGULOPATHIES
Liver damage (e.g. liver cirrhosis)
Deficiency or inhibition of vitamin K
• malabsorbtion, malnutrition
• destruction of saprpphytic bacteria by antibiotics of the intestinal flora
• drugs – inhibition by the cumarine derivates (e.g. warfarin,
acenocumarol); is use for oral prophylaxis of thrombosis (anticoagulant
treatment)
Consumption coagulopathy (disseminated intravascular
coagulation DIC)
DISSEMINATED INTRAVASCULAR
COAGULATION (DIC) I
It is a coagulation disorders caused by acute
or chronic activation of thrombin with clot
formation and platelets activation that
secondary results in activation of fibrynolysis
and bleeding (heart failure, acute kidney
failure, circulatory shock)
DISSEMINATED INTRAVASCULAR
COAGULATION (DIC) II
C A U S E S
Cell damage releases large amount of tissue tromboplastin
and initiation of extrinsic clotting pathway (VII plasma
cloting factor)
neoplasm (e.g leukemia)
massive trauma ( e.g. burns, ABO blood mismatches)
Damage of vascular wall and initiation of intrinsic clotting
pathway (XII plasma cloting factor)
- vasculitis
- sepsis (whole-body inflammation caused by inflammation)
- scirculatory shock
← vascular wall damage and exposure of
collagen fibers
← cell damage
and release of
TF
DISSEMINATED INTRAVASCULAR
COAGULATION (DIC) III
P A T O M E C H A N I S M
1. Activation of clotting mechanism
a. tissue tromboplastin (extrinsic clotting pathway)
b. vascular wall damage →endothelial cells’ injury (intrinsic
clotting pathway)
2. Coagulation factors are consumed and depleted
3. Clot occludes the blood vessels and causes tissue ischemia
4. Concomitantly the fibrinolitic system is activated
5. Large number of fibrin and fibrinogen degradation products
impaired fibrin polymerization and platelets activation caused
bleeding → CIRCULATORY SHOCK