Management and control

1. Dr Fouad Al-Khalli .
Heamostasis
 The Haemostasis is the arrest (stoppage) of
bleeding, either by the physiological properties of
vasoconstriction and coagulation, or by surgical
means.
 Physiological haemostatic mechanism are most
effective in dealing with injuries in small vessels;
arterioles, capillaries and venules, which are the
most common source of bleeding in everyday
life.
 In contrast, the bleeding from a medium or large
artery is not usually controllable by the body.

2. Dr Fouad Al-Khalli .
Continue of Haemostasis:
 The haemostatic system consists of;
- platelets,
- clotting factors in the plasma and
- vessels walls.
These components of the system interact to seal
leaks in the blood vessels.
 Haemostasis is very important to the
maintenance of homeostasis.
If bleeding is not stopped, excessive blood loss from
a cut or torn vessel can result in a positive-feedback
cycle, consisting of ever-decreasing blood volume
and blood pressure, which disrupts homeostasis and
results in death.

3. Dr Fouad Al-Khalli .
 Formed in the bone marrow from the magakaryocytes.
 It production is under the control of a hormone thrombopoietin
( formed mainly in the liver).
 Life span of platelets (half-life of 4 days) = 7 -10 days.
 Count = 250 000 per mm³(µl) (♂170 – 360 x 10³, ♀180 – 400 x 10³).
 Diameter = 1-2 µm (some may reach 4 µ).
 Have a ring of microtubules around their periphery and an
extensively invaginated membrane with an intricated (complex)
canalicular system in contact with extracellular fluid.
 Platelets Granules:
1. Dense granules: contain nonprotein substances; ADP, serotonin, and
other adenine nucleotides.
2. α-granules: contain proteins other than the hydrolases in the
lysosomes, which are: von Willebrand’s factor, Clotting factors,
Platelet-derived growth factor.
Thrombocytes

4. Dr Fouad Al-Khalli .
Steps of Heamostasis
From: Saladin: Anatomy & Physiology, 3rd ed.,2003.


5. Dr Fouad Al-Khalli .
Haemostatic Mechanisms
The steps of haemostasis that help prevent excessive
blood loss:
1-Vascular spasm,
2- platelet plug formation, and
3- blood coagulation can cause heamostasis.
1. Vascular Spasm: An immediate but temporary
constriction of a blood vessel resulting from contraction
of smooth muscle within the wall of the vessel. This
constriction can close small vessels completely and
stop the flow of blood through them.
• Chemicals also produce vascular spasm. For example,
during platelet plug formation, platelets release
thromboxanes, and endothelial cells release the peptide
endothelin.

6. Dr Fouad Al-Khalli .
Continue of Haemostatic Mechanisms:
2. Platelet plug formation:
• It is an accumulation of platelets that can seal up small tears in
blood vessels.
• Small tears occurs in the smaller vessels and capillaries
many times each day, and platelet plug formation quickly
closes them.
• The formation of platelet plug is a series of steps, many of
which take place simultaneously:
- platelets adhesion.
- platelet release reaction.
- platelet aggregation.
 The activated platelets also display particular
phospholipids, called platelet factor III (PFIII) which is
important in clot-formation.

7. Dr Fouad Al-Khalli .
Platelets Mediated Haemostasis
vWF = von Willebrand’s
factor = F VIII.
PDGF= platelet derived
growth factor
TXA2 = Thromboxane A2
PAF = platelet-activating
factor
(Release)
Continue of :Haemostatic Mechanisms:
From; Color Atlas of Physiology.5th Int.ed.2006.
Secretion
5
4
3
2
1


8. Dr Fouad Al-Khalli .
Platelet Release Reaction:
Collagen exposure or thrombin action stimulate the
release of platelet granule which contents;
 ADP
 Serotonin
 Prostaglandins
 von Willebrand factor (vWF); which also secreted by
endothelial cells.
 Lysosomal enzymes
 Heparin antagonizing factor (platelet factor 4).
 *PAF (Plasma platelet activating factor) activates
phospholypase C and deacyl-glycerol which convert
Arachidonic acid to Thromboxan A2.
* PAF: is secreted by neutrophiles and monocytes.
Continue of Haemostatic Mechanisms:

9. Dr Fouad Al-Khalli .
Collagen + thrombin
Prostaglandins synthesis
Thromboxan A₂
Lowers platelet cAMP
Starts release reaction
Vascular endothelial cells
Release of prostocyclin
Increased level of cAMP
Inhibition
of the release reaction
and aggregation of
platelets.
Platelet Release Reaction
Continue of Haemostatic Mechanisms:
Activation Inhibition

10. Dr Fouad Al-Khalli .
3. Coagulation:
• Coagulation (clotting = a clot formation) of the blood is
the last but most effective defense against bleeding.
• Coagulation is one of the most complex processes
in the body, involving over 30 chemical reactions.
• It is, a transformation of a plasma protein into a solid
gel (a clot = thrombus), which consisting mainly of a
protein polymer known as fibrin.
• Clotting occurs locally around the original platelet
plug and is the dominant haemostatic defense.
• Its function is to support and reinforce the platelet
plug and to solidify blood that remains in the wound
channel.
Continue of Haemostatic Mechanisms:

11. Dr Fouad Al-Khalli .
Factor Name Function Pathway
I = Fibrinogen Converted to fibrin Common
II = Prothrombin Converted to thrombin (enzyme) Common
III = Tissue thromboplastin Cofactor Extrinsic
IV = Calcium ions (Ca⁺⁺ ) Cofactor Intrinsic, extrinsic,
and common
V = Proaccelerin Cofactor Common
VII*= Proconvertin Enzyme Extrinsic
VIII = Antihemophilic factor A Cofactor Intrinsic
IX = Plasma thromboplastin component:
(Christmas factor), AHF-B. Enzyme Intrinsic
X = Stuart - Prower factor Enzyme Common
XI = Plasma thromboplastin antecedent:
Enzyme Intrinsic
XII = Hageman factor Enzyme Intrinsic
XIII = Fibrin stabilizing factor Enzyme Common
*Factor VI is no longer referenced; it is now believed to be the same substance
as activated factor V.
Clotting Factors
Continue of Haemostatic Mechanisms:

12. Dr Fouad Al-Khalli .
XIII
XIIIa
Fibrinogen Fibrin
monomer
Thrombin
Endothelial damage and
exposure of collagen
Tissue injury and exposure
of tissue thromboplastin (III)
XII XIIa
XI XIa
IX IXa
X Xa
VIIa VII
Fibrin
polymer
Prothrombin
Ca²⁺
Ca²⁺, PF3
Va, PF3, Ca²⁺
VIIIa, PF3, Ca²⁺
Intrinsic Pathway Extrinsic Pathway
The Clot Formation (Coagulation)
 Intrinsic pathway
 Extrinsic pathway
 Common pathway
Ca²⁺
Common
pathway

13. Dr Fouad Al-Khalli .
Platelets
Fibrin
network
Trapped red
blood cells
Blood Clot
Blood clot consists of
fibrin fibers that trap red
blood cells, platelets and
fluid.
From: Seeley et al., Anatomy and Physiology, 8th ed., 2008.


14. Dr Fouad Al-Khalli .
Physiological Limitation of Blood coagulation
1. Liberation of certain plasma inhibitors:
Antithrombin III: it is a circulating plasma protein ( a
protease inhibitor ) which bind to serine protease in the
coagulation system. This binding is activated by Heparin, so the
antithrombin III binds to, and inhibits factors II, VII, IX, Xa, and XI.
2. Fibrinolytic System:
Endothelial Thrombomodulin is thrombin-binding protein forming
a complex which acts as anticoagulant:
Thrombomodulin + thrombin
Protein C Active protein C*
Inactivate VIIIa Inactivate Va
Plasminogen Plasmin
(Plasmin has a very strong fibrinolytic effect.)
3. Removal and dilution of the activated factors by blood.
* TPA= tissue
plasminogen
activator

15. Dr Fouad Al-Khalli .
Inhibition of Blood Clotting System
From Color Atlas of Pathophysiology- Thieme.
TFPI
TFPI = tissue factor pathway inhibitor
Extrinsic
Pathway
Intrinsic
Pathway
Antithrombin
III
Heparin
Thrombin
Protein
C

16. Dr Fouad Al-Khalli .
TFPI
Antithrombin
III Heparin
Inhibition of Blood Clotting System
*
* Thrombin also play a
role in inactivation of
factor Va and VIIIa.
See next plat.
Modifid from Color Atlas of Physiology: 5th ed., 2003.
TFPI = tissue factor pathway inhibitor.

17. Dr Fouad Al-Khalli .
 Thrombin first bind to a thrombin
receptor, (thrombomodulin), on
endothelial cells.
 Then activates protein C, which
inactivates clotting factors VIIIa and
Va
 This binding also eliminates
thrombin’s procoagulant effects.
Inactivation of factors VIIIa and Va
From: Vander et al.: Human Physiology: 9th ed., 2004.
Procoagulant:
1. Cleaves fibrinogen to fibrin
2. Activates clotting factors XI, VIII, V, and XIII
3. Stimulates platelet activation
Anticoagulant:
Thrombin indirectly inactivates factors VIIIa and Va via protein C.
Actions of Thrombin

18. Dr Fouad Al-Khalli .
Plasminogen
Plasma kallikrein
Urokinase
Streptokinase*
Staphylokinase*
Tissue plasminogen
activator
Plasmin
Fibrin mesh-work
Soluble
fibrinopeptides
α₂-Antiplasmin
Tranexamic acid*
Basic Fibrinolytic System
And Plasminogen activators
From Color Atlas of Pathophysiology. Int. ed. 2006.
* = drugs

19. Dr Fouad Al-Khalli .
Anticlotting Role of Endothelial Cells
Action Result
1. Normally provide an intact barrier
between the blood and subendothelial
connective tissue factor.
Platelet aggregation and the formation of
tissue factor–VIIa complexes are not
triggered.
2. Synthesize and release PGI₂ and nitric
oxide.
These inhibit platelet activation and
aggregation.
3. Secrete tissue factor pathway
inhibitor (TFPI).
Inhibits the ability of tissue factor–factor VIIa
complexes to generate factor Xa.
4. Bind thrombin (via thrombomodulin),
which then activates protein C.
Active protein C inactivates clotting factors
VIIIa and Va.
5. Display heparin molecules on the
surfaces of their plasma membranes.
Heparin binds antithrombin III, and this
molecule then inactivates thrombin and
several other clotting factors.
6. Secrete tissue plasminogen
activator.
Tissue plasminogen activator catalyzes the
formation of plasmin, which dissolves clots.

20. Dr Fouad Al-Khalli .
Liver
Synthesizes
Bile salts
Clotting
factors
Bile salts in
bile
In GIT
Absorption of vit . K
Vit. K in the blood Clotting factors
In the blood
Role of Liver in Clotting
From: Vander et al.: Human Physiology: 9th ed., 2004.
Factor
II, VII, IX,
and X.

21. Dr Fouad Al-Khalli .
Anticoagulants
In Vitro:
1. Calcium precipitators:
- Na citrate (non toxic).
- Ammonium oxalate (toxic).
- EDTA (ethylene diamine tetraacetic acid)
2. Prevention of platelet aggregation:-
Smooth wall surface by coating the wall by
silicone oil, or paraffin oil (silicone or paraffin
coated test tubes).
3. Addition of anticoagulant: as heparin.

22. Dr Fouad Al-Khalli .
In Vivo:
1. Heparin: The mucoprotein naturally produced by mast
cells and granulocytes, acts as cofactor for the action
of antithrombin III, and so facilitates its anticoagulant
effects. The clotting factors that are inhibited are the
active forms of factors II, IX, X, XI, and XII. Heparin
also inhibits platelets function.
2. The coumarin drugs (Warfarin and Decomarol):
Interferes with the action of vit. K, and prevents it from
taking part in the synthesis of prothrombin (II), VII, IX,
and X in the liver. has the same action.
3. Aspirin: Inhibits the aggregation of the platelets by
inhibiting the platelet thromboxan A2 formation.
4. Streptokinase and Urokinase; which are activators of
plasminogen to plasmin.
Continue of: Anticoagulants

23. Dr Fouad Al-Khalli .
Intravascular
thrombosis
The causes Abnormalities of Haemostasis
From: Color Atlas of Pathophysiology : 2000. Theime
1
2
3
4
1.Defect in clotting mechanism.
2.Disorders of platelets.
3.Defect of blood vessels.
4.Intravascular thrombus forming.

24. Dr Fouad Al-Khalli .
Continue of Abnormalities of Haemostasis
1. Defect in clotting mechanism:
a) Acquired:
Lack of Vit. K leads to decreased factor II, VII, IX and
X, as in obstructive jaundice.
b) Hereditary: (Haemophilias):
Congenital disease, transmitted by female but only
male suffers from it (as an X chromosome linked
recessive trait by clinically unaffected female carriers
to males):
- Haemophilia A : absence of factor VIII – 85%
- Haemophilia B : absence of factor IX - 14 15%
- Haemophilia C : absence of factor XI - rare ??.
The most common bleeding sites are the muscles and the large joints of the leg, the latter
becoming markedly deformed with time (hemophilic arthropathy).

25. Dr Fouad Al-Khalli .
2. Disorders of Platelets:
a) Decrease of platelet number:
Thrombocytopenia ; as in purpura which
leads to easy bruisbility (blue and black
spots on the skin).
b) Defective platelets: normal count but
defective: as in: Thrombocytopathia =
thrombostaenia purpura.
3. Defect of the Blood Vessels:
Vascular purpuras as in typhus and typhoid.
Continue of Abnormalities of Haemostasis

26. Dr Fouad Al-Khalli .
Continue of Abnormalities of Haemostasis
4. Intravascular Thrombosis:
a) Abnormalities of Blood Vessels:
- Atherosclerosis, Trauma, Loss of venous tone (e.g.,
varicosities).
b) Abnormalities in Blood Flow:
- stasis; as in pregnancy and neoplasia.
- hyperviscosity; as in polycythaemia vera .
- turbulences; as in coarctation of the aorta.
c) Abnormalities of the Blood:
- Increased platelets count; as in thrombocythemia.
- Hypercoagulable states; as in increased activation
of clotting factors ( operation; ↑ activity of clotting F.
and ↓ activity of fibrinolysis).

27. Dr Fouad Al-Khalli .
Haemostatic Tests
1.Quick Test:
- Plasma is transiently made incoagulable with
substances that form complex with Ca² (citrate,
oxalate, or EDTA = ethylenediaminetetraacetic acid).
- An excessive amount of Ca² and tissue
thrombokinase are then added and a resulting
clotting time is compared with serial dilutions
of normal plasma.

28. Dr Fouad Al-Khalli .
2. Partial Thromboplastin Time (PTT):
- Kephalin, kaolin (substances for contraction
activation) and Ca² are added to the citrated
plasma and time until clotting is measured
( NV = 25 -38sec.).
3. Plasma Thrombin Time:
- Thrombin is added to the citrated plasma
and the clotting time is measured (NV= 18 –
22 sec).
4. Bleeding Time: normal = < 5 min.
5. Platelets Count: NV 250 000 per µl
Continue of Haemostatic Tests

29. Dr Fouad Al-Khalli .
Interpretation of Clotting Test Results
From Color Atlas of Pathophysiology. Int. ed. 2006.
PTT= Partial thromboplastin time.
HMK= Heigh molecular weight kininogen.