Upload
flowerprincess0
View
218
Download
0
Embed Size (px)
Citation preview
8/3/2019 8 Blood ClottingAstud(32 1)
1/51
Blood coagulation
1 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
2/51
Hemostasis
2 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
3/51
Blood clotting
The ability of the body to control (stop) the flow ofblood (bleeding) following vascular injury
Is a complex process by which blood forms clots
3 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
4/51
Hemostasis:
Hemostasis is defined as a property of circulation
whereby blood is maintained within a vessel and the
ability of the system to prevent excessive blood loss
when injured.
Hemostasis is composed of 3 major stages that occur
in a set order following the loss of vascular integrity.
4 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
5/51
Hemostasis (cont.):
DAMAGE TO BLOOD VESSEL leads to:
1. Vasoconstriction.
2. The formation of platelet plug.
3. The production of a web of fibrin proteins that
penetrates and surrounds the platelet plug.
5 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
6/51
Steps in Hemostasis
1. Vascular Constriction:
Immediate constriction of blood vessel
Vessel walls pressed togetherbecome sticky/adherent
to each other
Minimize blood loss
6 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
7/51
Steps in Hemostasis(Cont.):
2. Platelet Plug formation:
PLATELETS attach to exposed collagen with the presence ofvon Willebrand factor (vWF) and Glycoprotein IbIX
Aggregation of platelets causes release of chemical
mediators (ADP, Thromboxane A2)
ADP attracts more platelets
Thromboxane A2(powerful vasoconstrictor)
* promotes aggregation & more ADP
Leads to formation of platelet plug!
7 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
8/51
Platelet
In adults, platelets originate in the red bone marrow by
fragmentation of the cytoplasm of mature
megakaryocytes(Gr. Megas, big, + karyon, nucleus, + kytos),
which, in turn, arise by differentiation of megakaryoblasts.
Megakaryoblasts. Megakaryocytes Platelets.
Platelets are repelled from each in absence of blood vessel
damage.
8 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
9/51
Role of platelets in blood clotting:
Platelets (Thrombocytes) have several functions in blood
clotting:
Form platelet plug at the site of injury Sites of activation of some clotting factors (II, X) Provide the surface on which certain clotting
factors bind (Va, Xa, II, Ca2+)
Sources of some clotting factors (XIII, PL)9 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
10/51
Role of platelets in blood clotting (cont....):
If platelets are not lysed, blood does not clot
Individuals with thrombocytopenia (low platelets), bleeding
for a long time
Platelets deficiency can be due to many agents
(drugs, some infections, ionizing radiation)
10 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
11/51
Simplified diagram to illustrate platelet production from Megalocytes.
11 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
12/51
Hemostasis: Vasoconstriction & Plug Formation
12 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
13/51
Platelets adhesion
13 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
14/51
Steps in Hemostasis (cont)
3- Blood Coagulation (clot formation):
Final Step in Hemostasis:
Transformation of blood from liquid to solid
Clot reinforces the plug
Multiple cascade steps in clot formation
Fibrinogen FibrinThrombin
14 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
15/51
Clotting Cascade
A cascade is a mechanism in which enzymes activate other
enzymes sequentially usually leading to an amplification of
an initial signal.
Participation of 14 different clotting factors (except for
calcium and thromboplastin, clotting factors are proteins)
These factors circulate as inactive zymogens
15 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
16/51
Clotting Cascade (cont)
Factors are designated by a Roman numeral (I, II, III, IV,
V, VI, VII, VIII, X, IX, XI, XII, XIII).
Active forms are usually designated by the letter a afterthe Roman numeral and may also have a different name for
example: Ia/ Fibrin).
Cofactors are needed for many reactions in the cascade
example: Calcium, platelet factor 3 (PF3).
16 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
17/51
Coagulation Factors (Cont.)
The intrinsic and extrinsic coagulation pathways are a series
of reactions involve coagulation factors known as
1. Enzyme precursors (zymogens)
2. Non-enzymatic (cofactors)
3. Calcium (Ca ++)
4. Phospholipids (PL).
All coagulation factors normally are present in the plasma, with
PL being provided by platelets.
17 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
18/51
Zymogens: Factors II, VII, IX, X, XI, XII, and prekallikrein
NO biologic activity until converted by enzymes to activeenzymes called serine proteases
Cofactors Factors V, VIII, tissue factor, and HMWK
18 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
19/51
Clotting Cascade (cont)
The last step of the cascade leads to insoluble fibrin as the
end product.
The reactions leading to fibrin formation can be divided into
the extrinsic, intrinsic and common pathways.
Both pathways are initially independent, then they converge
on common pathway leading to the formation of a fibrin
clot !
19 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
20/51
Clotting Cascade
Inactive
Active
CLOT !
Ca2+
PL
Ca2+
20 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
21/51
Clotting Cascade
A cascadeis a mechanism in which enzymes activate other
enzymes sequentially usually leading to an amplification of
an initial signal.
Each of these pathways leads to the conversion offactor X
(inactive) to factor Xa(active)
21 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
22/51
Hemostasis: Coagulation & Clot Stabilization
Prothrombin Ca++
Fibrinogen
Fibrin
Polymerization
22 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
23/51
Intrinsic Pathway:
The formation of clot in response to abnormal vessel wall in
absence of tissue injury is the result ofintrinsic pathway
Begins with the activation offactor XII
(Hageman factor)
23 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
24/51
Extrinsic Pathway
Fibrin clot formation in response to tissue injury is the
result ofextrinsic pathway
Requires tissue factors external to blood: Factor III
(Tissue Thromboplastin)
Each of these pathways leads to the conversion offactor
X(inactive) to factor Xa(active)
24 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
25/51
Intrinsic Clotting Pathway
Under normal physiological conditions, it is less
significant to hemostasis than extrinsic pathway
Under abnormal physiology (hyperlipidemic states;
bacterial infiltration) activation of thrombosis via intrinsic
clotting cascade
25 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
26/51
Intrinsic Clotting Pathway (cont)
The intrinsic pathway requires:
1. The factors VIII, IX, X, XI, and XII2. The proteins: Prokallikrein (PK),
High MW Kininogen (HK)
3. Calcium ions
4. PLs from platelets
26 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
27/51
Intrinsic Clotting Pathway (cont)
Initiation of the intrinsic pathway occurs when Prokallikrein
(PK), high MW Kininogen (HK), factorXI, and factor XII are
exposed to a negatively charged surface Contact phase.
Contact phaseoccurred as result of interaction with:
o PLs,
o Circulating lipoprotein particles (VLDL, Chylomicrons)
o On the surface of bacteria
27 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
28/51
Clotting Cascade
Inactive
Active
CLOT !
Ca2+
PL
Ca2+
28 Blood Coagulation
Th i i h i i d h i f i j bF t III i f t i th f t VII hi h t l dF t X i th it t hi h th i t i i d t i iTh fi l th f bl d l tti i l
8/3/2019 8 Blood ClottingAstud(32 1)
29/51
Inactive
Active
CLOT !
The extrinsic pathway is triggered at the site of injury bytrauma(serious injury or shock to the body), which activates factor VIIand releases a lipoprotein, called tissuefactor (Factor III), fromblood vessels
Factor IIIis a cofactor in the factor VIIa which catalyzedactivation offactor X (inactive) to factor Xa (active)
Factor Xa is the site at which the intrinsic and extrinsiccoagulation cascade converge
The final common pathway of blood clotting involvesactivation of prothrombin into thrombin
29 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
30/51
Coagulation cascade
30 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
31/51
thrombin
Prothrombin is soluble single chain glycoprotein (72kDa) synthesizedin liver
Thrombin is produced by the enzymatic cleavage of two sites on
prothrombin by activated Factor X (Xa) and generate active 2 chain
thrombin molecule which is then released from platelet surface The A and B chains of thrombin are held together by a dissulfide
bond
A B
S S
+21
Fragment 2 -1 Active thrombin
(34 kDa)
A B21
S S
Xa Xa
Fragment 2 -1 Prethrombin
Prothrombin(72kDa) Converts fibrinogen to fibrin31 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
32/51
Thrombin in Hemostasis
Factor Xa
32 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
33/51
33
Factor Va is subsequentlyinactivated by further action
of thrombin to limit activation of prothrombin to
thrombin
The activation of prothrombin occurs on the surface
of activated platelets and requires assembly of
prothrombinase complex consisting of platelet
anionic PLs, Ca2+
, factor Xa and prothrombin
This complex is termed factor Vawhich isactivated by
traces of thrombin
Factor Xa produced by either intrinsic or extrinsic
pathway activates prothrombin (factor II) tothrombin
(factor IIa) which converts fibrinogen to fibrin
Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
34/51
Fibrinogen (Factor I):
Fibrinogen is soluble plasma glycoprotein that consists
of 3 non identical pairs of polypeptides chains (A,
B, )2 covalently linked by disulfide bonds.
It has a molecular weight of 340kDa .
Represent the first coagulation factor.
34 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
35/51
The A and B portions of the
A and B chains, termed
Fibrinopeptide A (FPA) and
Fibrinopeptide B (FPB)
Release of FBs by thrombin
generate fibrin monomer (weak)
Thrombin
Aggregate spontaneously forming
insoluble fibrin polymer (fibrin clot)
(hard, insoluble)
Conversion of
Fibrinogen to Fibrin
35 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
36/51
Controlof thrombin level:
There are 2 principal mechanisms by which thrombin activity isregulated:
1. The predominant form of thrombin in circulation is the
inactive prothrombin, whose activation requires the pathways
of proenzyme activation (coagulation cascade) At each step
in the cascade, feed back mechanism regulate the balance
between active and inactive enzymes
2. Activation of thrombin is also regulated by 4 specific thrombin
inhibitors (natural inhibitors of blood clotting):
36 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
37/51
Natural inhibitors of blood clotting
1- Antithrombin III
Is the most important one: contributes 75% of antithrombinactivity in plasma
It is a plasma protein that inactivates thrombin by forming anirreversible complex with it
It resembles 1-antitrypsin except that it inhibits thrombinmuch more strongly than it inhibits elastase
Also, it blocks other serine proteases in the clotting cascadenamely, factors XIIa, XIa, IXa, and Xa
37 Blood Coagulation
N l i hibi f bl d l i ( )
8/3/2019 8 Blood ClottingAstud(32 1)
38/51
Natural inhibitors of blood clotting (cont)
2.Heparin
The inhibitory action of antithrombin III is enhanced by
heparin
It is a negatively charged polysaccharide found in mast cells
near the walls of blood vessels and on the surfaces of
endothelial cells
Heparin acts as an anticoagulant by increasing the rate of
formation of irreversible complexes between antithrombin
III and the serine protease clotting factors
38 Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
39/51
Natural inhibitors of blood clotting (cont)
3. Alpha 2-macroglobulins:
Contributes most of the remaining (25%) of antithrombin
activity in plasma
4. Alpha 1-antitrypsin:
Acts as a minor inhibitor under physiological conditions, which
normally inhibits elastase
Alpha 1-Antitrypsin activity normally increases markedly afterinjury to counteract excess elastase arising from stimulated
neutrophils
39Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
40/51
Dissolution of fibrin clot : fibrinolysis(The removal of fibrin from the blood)
Clot is slowly dissolved by the fibrin splitting called
Plasmin
Plasmin gets trapped in clot and slowly dissolves it by
breaking down the fibrin meshwork at various places,
leading to the production of circulating fragments that arecleaved by other proteases or by the kidney and liver.
40Blood Coagulation
Di l i f fib i l fib i l i
8/3/2019 8 Blood ClottingAstud(32 1)
41/51
Dissolution of fibrin clot : fibrinolysis
(cont)
Plasminogen is the inactive pre-cursor that is activated by
activators in plasma:
1. Tissue plasminogen activator (t-PA)
2. Urokinase (to lesser extend)
Is produced as a precursor prourokinase by epithelial
cells
Its main action is probably in the degradation of
extracellular matrix
41Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
42/51
Dissolution of fibrin clot : fibrinolysis (cont)
Inactive t-PA is released from vascular endothelial cells following
injury
It binds to fibrin and is consequently activated
Active t-PA converts plasminogen into plasmin
42
Dissolves the clot
Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
43/51
Coagulation factor disorders
Inherited bleedingdisorders
Hemophilia A and B
Von Willebrand disease
Other factor deficiencies
Acquired bleedingdisorders
Liver diseaseVitamin K deficiency
43Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
44/51
Coagulation factor disorders (cont)
1- Hemophilia A and BAre the best-known coagulation factor disorders
Hemophilia A Hemophilia B
Coagulation factor deficiency Factor VIII Factor IX
Inheritance X-linked X-linked
recessive recessive
Incidence 1/10,000 males 1/50,000 males
44Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
45/51
2- von Willebrand Disease It is the most common hereditary bleeding disorder and is
characterized as being inherited autosomal recessive or
dominant
In this disease there is a defect in von Willebrand factor
(vWF) which:
1. acts as a carrier for factor VIII
2. mediates the binding of glycoprotein Ib (GPIb) to
collagen
Coagulation factor disorders (cont)
45Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
46/51
2- von Willebrand Disease
Coagulation factor disorders (cont)
This binding helps the activation of platelets and formation
of primary hemostasis
vWD is characterized by excessive bleeding in infants
because platelets fail to form hemostatic plug
46Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
47/51
3- Deficiency of Vitamin K
Source of vitamin K Green vegetablesSynthesized by intestinal flora
Required for synthesis Factors II, VII, IX ,Xcontribute to bleeding disorders
Causes of deficiency Malnutrition
Biliary obstructionMalabsorption
Antibiotic therapy
47Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
48/51
Function of Vitamin K
Vitamin K is essential for the functioning of several proteins
involved in blood clotting (II, VII, IX and X)
These proteins contain a unique modified glutamate residue,
called carboxyglutamate (Gla).
These proteins are synthesized as inactive precursors that are
activated by the vitamin K-dependent carboxylase which
converts glutamate in these proteins to carboxyglutamate
forming mature clotting factors.
1. Formation of carboxyglutamate
48Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
49/51
Function of Vitamin K (cont)1.Formation of carboxyglutamate (cont)
-
49Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
50/51
Function of Vitamin K (cont)
Dicumarol,
Warfarin
- (Gla residue)
(mature)
1.Formation of carboxyglutamate (cont)
50Blood Coagulation
8/3/2019 8 Blood ClottingAstud(32 1)
51/51
Function of Vitamin K (cont)
The Gla residue of prothrombin is a natural high affinity binder
(chelator) of positively calcium ions, hence the designation of
calcium as a co-factor (factor IV) in the schematic.
The prothrombin-calcium complex is then able to bind to PLs
essential for blood clotting on the surface of platelets.
2. Interaction of prothombin with platelets
Blood Coagulation