The document summarizes key aspects of hemostasis including: 1. Platelet aggregation forms a primary plug at sites of vascular injury through interactions with von Willebrand factor, collagen, and fibrinogen bridges between platelets. Inherited deficiencies of von Willebrand factor or glycoprotein IIb/IIIa result in bleeding disorders. 2. The coagulation cascade is a series of enzymatic reactions that results in thrombin generation and fibrin deposition to form a clot. Thrombin both converts fibrinogen to fibrin and activates platelets. 3. Counterregulatory mechanisms like the endothelial barrier and fibrinolytic system activate proteins like tissue plasminogen activator and plasmin to limit clotting

1. HEMOSTASIS
Dr G VENKATA RAMANA
MBBS DNB FAMILY MEDICINE

2. ENDOTHELIUM
• The balance between the anticoagulant and procoagulant activities of
endothelium often determines whether clot formation, propagation, or
dissolution occurs
• Normal endothelial cells express a multitude of factors that inhibit the
procoagulant activities of platelets and coagulation factors and that augment
fibrinolysis
• These factors act in concert to prevent thrombosis and to limit clotting to sites
of vascular damage
• However, if injured or exposed to proinflammatory factors, endothelial cells
lose many of their antithrombotic properties
• Antithrombotic properties of endothelium
• Platelet inhibitory effects
• Serve as a barrier that shields platelets from subendothelial vWF and collagen
• Synthesize prostacyclin (PGI2), nitric oxide(NO), and adenosine diphosphatase
that inhibit platelet activation and aggregation
• Bind and alter the activity of thrombin, one of the most potent activators of
platelets

3. • Anticoagulant effects
• Thrombomodulin and endothelial protein C receptor bind thrombin and protein C
respectively
• Thrombin cleaves and activates protein C, a vitamin K–dependent protease that requires a
cofactor, protein S
• Activated protein C/protein S complex is a potent inhibitor of factors Va and VIIIa
• Heparin-like molecules
• Bind and activate antithrombin III, which inhibits thrombin and factors IXa, Xa, XIa, and XIIa.
• Tissue factor pathway inhibitor
Binds and inhibits tissue factor /factor VIIa complexes.
• Fibrinolytic effects
• Synthesize tissue plasminogen activator t-PA, a key component of the fibrinolytic pathway.

4. PLATELETS
• Alpha granules contains Dense granules contains
1. Adhesion molecule P-selectin
2. Proteins involved in coagulation
fibrinogen, factor V, and vWF
3. Protein factors involved in
wound healing such as
Fibronectin, platelet factor 4 ,
platelet-derived growth factor and
transforming growth factor-β.
1. Adenosine diphosphate (ADP)
and Adenosine triphosphate
2. Serotonin
3. Epinephrine
4. Ionized Calcium
• Forms primary plug that initially seals vascular defects
• Provide a surface that binds and concentrates activated
coagulation factors.
• Disc-shaped anucleate cell fragments
• Their function depends on several glycoprotein receptors, a
contractile cytoskeleton,and two types of cytoplasmic granules

7. HEMOSTASIS
• Process by which
blood clots form at
sites of vascular injury
• Events in Hemostasis
• Arteriolar
vasoconstriction
• Primary hemostasis:
the formation of the
platelet plug
• Secondary
hemostasis: deposition
of fibrin
• Clot stabilization and
resorption

8. A.VASOCONSTRICTION
• Reduces blood flow to the injured area
• By reflex neurogenic mechanisms and
• Endothelin,a potent endothelium-derived vasoconstrictor

9. B.PRIMARY HEMOSTASIS
• Platelet adhesion
• Mediated largely via interactions with vWF
• vWF acts as a bridge between the platelet surface receptor
glycoprotein Ib (GpIb) and exposed collagen
• Genetic deficiencies of von willebrand factor (von Willebrand
disease),or GpIb (Bernard-Soulier syndrome) result in bleeding
disorders
• Shape change
• From smooth discs to spiky “sea urchins” with greatly
increased surface area.
• Alterations in glycoprotein IIb/IIIa that increase its affinity for
fibrinogen
• Translocation of negatively charged phospholipids
(phosphatidylserine) to the platelet surface
• Phospholipids bind calcium and serve as nucleation sites for
the assembly of coagulation factor complexes

10. • Secretion (release reaction) of granule contents
• Secretion of granule contents with changes in shape- platelet
activation
• Platelet activation is triggered by thrombin and ADP.
• Platelet activation and ADP release begets additional rounds
of platelet activation-recruitment
• Activated platelets also produce the prostaglandin
thromboxane A2 ,a potent inducer of platelet aggregation.
• Aspirin inhibits platelet aggregation and produces a mild
bleeding defect by inhibiting cyclooxygenase, a platelet
enzyme that is required for TxA2 synthesis.
• Platelet aggregation
• The conformational change in glycoprotein IIb/IIIa allows
binding of fibrinogen, a large bivalent plasma polypeptide that
forms bridges between adjacent platelets, leading to their
aggregation
• Inherited deficiency of GpIIb-IIIa results in a bleeding disorder
called Glanzmann thrombasthenia

12. Platelet aggregation
• The conformational change in glycoprotein
IIb/IIIa that occurs with platelet activation
allows binding of fibrinogen, a large
bivalent plasma polypeptide that forms
bridges between adjacent platelets,
leading to their aggregation.
• inherited deficiency of GpIIb-IIIa results in
a bleeding disorder called Glanzmann
thrombasthenia).

13. • C.SECONDARY HEMOSTASIS
• Vascular injury exposes tissue factor at the site of injury.
• Tissue factor binds and activates factor VII , setting in
motion a cascade of reactions that culiminates in thrombin
generation.
• Thrombin cleaves circulating fibrinogen into insoluble
fibrin, creating a fibrin meshwork,and also is a potent
activator of platelets, leading to additional platelet
aggregation at the site of injury
• D.THROMBUS AND ANTITHROMBOTIC EVENTS
• Clot stabilization and resorption
• Polymerized fibrin and platelet aggregates undergo
contraction to form a solid, permanent plug that prevents
further hemorrhage.
• At this stage, counterregulatory mechanisms (eg.t-PA) are
set into motion that limit clotting to the site of injury and
eventually lead to clot resorption and tissue repair

15. Coagulation Cascade
• The coagulation cascade is series of amplifying enzymatic
reactions that leads to the deposition of an insoluble fibrin
clot.
• Each reaction step involves an enzyme (an activated
coagulation factor), a substrate (an inactive proenzyme form
of a coagulation factor), and a cofactor (a reaction
accelerator).
• These components are assembled on a negatively charged
phospholipid surface, which is provided by activated platelets.
• Assembly of reaction complexes also depends on calcium,
which binds to γ-carboxylated glutamic acid residues that are
present in factors II, VII, IX, and X.
• The enzymatic reactions that produce γ-carboxylated glutamic
acid use vitamin K as a cofactor and are antagonized by
drugs such as Coumadin, a widely used anti-coagulant.

16. Coagulation Cascade

17. Coagluation cascade

19. ROLE OF THROMBIN
• Conversion of fibrinogen into cross linked fibrin
• Thrombin directly converts soluble fibrinogen into fibrin monomers
that polymerize into an insoluble fibril, and also amplifies the
coagulation process, not only by activating factor XI, but also by
activating two critical cofactors: factors V and VIII.
• It also stabilizes the secondary hemostatic plug by activating factor
XIII, which covalently crosslinks fibrin
• Platelet activation through its ability to activate PARs
• Pro-inflammatory effects
• PARs also are expressed on inflammatory cells, endothelium, and
other cell types, and activation of these receptors by thrombin is
believed to mediate proinflammatory effects that contribute to tissue
repair and angiogenesis
• Anticoagulant effects
• on encountering normal endothelium, thrombin changes from a
procoagulant to an anticoagulant; this reversal in function prevents
clots from extending beyond the site of the vascular injury

20. Role of thrombin in hemostasis and cellular activation.

21. FACTORS THAT LIMIT COAGULATION
• Simple dilution blood flowing past the site of
injury washes out activated coagulation
factors, which are rapidly removed by the
liver.
• A second is the requirement for negatively
charged phospholipids,are mainly provided
by platelets that have been activated by
contact with subendothelial matrix at sites of
vascular injury.
• Counterregulatory mechanisms involve
factors that are expressed by intact
endothelium adjacent to the site of injury

22. FIBRINOLYTIC CASCADE
• limits the size of the clot and contributes to its later
dissolution
• Plasmin breaks down fibrin and interferes with its
polymerization
• generated by enzymatic catabolism of the inactive
circulating precursor plasminogen, either by a factor
XII–dependent pathway or by plasminogen activators.
• The most important plasminogen activator is t-PA; it is
synthesized by endothelium and is most active when
bound to fibrin
• Once activated, plasmin is in turn tightly controlled by
counterregulatory factors such as α2-plasmin inhibitor,
a plasma protein that binds and rapidly inhibits free
plasmin.

23. FIBRINOLYTIC SYSTEM