Clinical anesthesiology

Assignment submitted to: ma’am Maidah

Submitted by: Isra Javed
Date: 30-05-202
Roll no: OS-01
Topic: Coagulation cascade.

COAGULATION CASCADE

Definition:

Coagulation, also known as clotting, is the process by which blood changes from a
liquid to a gel, forming a blood clot. It potentially results in hemostasis, the
cessation of blood loss from a damaged vessel, followed by repair.
 Hemostasis
Hemostasis is the natural process in which blood flow slows and a clot forms to
prevent blood loss during an injury, with hemo- meaning blood, and stasis meaning
stopping. During hemostasis, blood changes from a fluid liquid to a gelatinous
state.

Steps of Hemostasis
Hemostasis includes three steps that occur in a rapid sequence:
(1) Vascular spasm, or vasoconstriction, a brief and intense contraction of blood
vessels
(2) Formation of a platelet plug and
(3) Blood clotting or coagulation, which reinforces the platelet plug with fibrin
mesh that acts as a glue to hold the clot together. Once blood flow has ceased,
tissue repair can begin.

Coagulation begins almost instantly after an injury to the blood vessel has
damaged the endothelium lining the blood vessel. Exposure of blood to the
subendothelial space initiates two processes:
 changes in platelets, and
 The exposure of subendothelial tissue factor to plasma factor VII, which
ultimately leads to cross-linked fibrin formation. Platelets immediately
form a plug at the site of injury; this is called primary
hemostasis. Secondary hemostasis occurs simultaneously: additional
coagulation (clotting) factors beyond factor VII respond in a cascade to
form fibrin strands, which strengthen the platelet plug.
Function:
The function of the coagulation pathway is to keep hemostasis, which is the
blockage of a bleeding or hemorrhage. Primary hemostasis is an aggregation of
platelets forming a plug at the damaged site of exposed endothelial cells.
Secondary hemostasis includes the two main coagulation pathways, intrinsic and
extrinsic, that meet up at a point to form the common pathway. The common
pathway ultimately activates fibrinogen into fibrin. These fibrin subunits have an
affinity for each other and combine into fibrin strands that bind the platelets
together, stabilizing the platelet plug.
 Blood coagulation

Blood coagulation is a process that changes circulating substances within the

blood into an insoluble gel. The gel plugs leaks in blood vessels and stops the loss
of blood. The process requires coagulation factors, calcium and phospholipids.
 The coagulation factors (proteins) are manufactured by the liver.
 Ionized calcium (Ca++) is available in the blood and from intracellular
sources.
 Phospholipids are prominent components of cellular and platelet
membranes. They provide a surface upon which the chemical reactions of
coagulation can take place

Mechanism
The mechanism by which coagulation allows for hemostasis is an intricate process
that is done through a series of clotting factors. The intrinsic pathway consists of
factors I, II, IX, X, XI, and XII. The extrinsic pathway consists of factors I, II,
VII, and X. Factor VII is called stable factor. The common pathway consists of
factors I, II, V, VIII, and X. The factors circulate through the bloodstream as
zymogens and are activated into serine proteases. These serine proteases act as a
catalyst to cleave the next zymogen into more serine proteases and ultimately
activate fibrinogen.
The following are serine proteases: factors II, VII, IX, X, XI and XII. These are
not serine proteases: factors V, VIII, XIII.
 The intrinsic pathway is activated through exposed endothelial collagen
 The extrinsic pathway is activated through tissue factor released by
endothelial cells after external damage.
Intrinsic Pathway
o This pathway is the longer pathway of secondary hemostasis.
o It begins with the activation of Factor XII (a zymogen,
inactivated serine protease) which becomes Factor XIIA
(activated serine protease) after exposure to endothelial collagen.
o Factor XIIA acts as a catalyst to activate factor XI to Factor
XIA.
o Factor XIA then goes on to activate factor IX to factor IXA.
o Factor IXA goes on to serve as a catalyst for turning factor X
into factor Xa. This is known as a cascade.
o For example, the concentration of factor IX is more than that of
factor XI. When factor II is activated by either intrinsic or extrinsic
pathway, it can reinforce the intrinsic pathway by giving positive
feedback to factors V, VII, VIII, XI, XIII. This makes factor XII
less critical; patients can actually clot well without factor XII. The
intrinsic pathway is clinically measured as the partial
thromboplastin time (PTT).

Extrinsic Pathway
o The extrinsic pathway is the shorter pathway of secondary
hemostasis.
o Once the damage to the vessel is done, the endothelial cells
release tissue factor which goes on to activate factor VII to factor
VIIa.
o Factor VIIa goes on to activate factor X into factor Xa.
o This is the point where both extrinsic and intrinsic pathways
become one.
o The extrinsic pathway is clinically measured as the prothrombin
time (PT).
Common Pathway
o This pathway begins at factor X which is activated to factor Xa.
o The process of activating factor Xa is a complicated reaction
o Tenase is the complex that cleaves factor X into factor Xa
o Tenase has two forms: extrinsic, consisting of factor VII, factor III (tissue
factor) and Ca2+, or intrinsic, made up of cofactor factor VIII, factor IXA,
a phospholipid, and Ca2+.
o Once activated to factor Xa, it goes on to activate factor II (prothrombin)
into factor IIa (thrombin).
o Also, factor Xa requires factor V as a cofactor to cleave prothrombin into
thrombin.
o Factor IIa (thrombin) goes on to activate fibrinogen into fibrin.
o Fibrin subunits come together to form fibrin strands, and factor XIII acts on
fibrin strands to form a fibrin mesh. This mesh helps to stabilize the
platelet plug.
Negative Feedback
To prevent over-coagulation, which causes widespread thrombosis, there
are certain processes to keep the coagulation cascade in check.
o As thrombin acts as a procoagulant, it also acts as a negative
feedback by activating plasminogen to plasmin and stimulating the
production of antithrombin (AT).
o Plasmin acts directly on the fibrin mesh and breaks it down. AT
decreases the production of thrombin from prothrombin and
decreases the amount of activated factor X.
Protein C and S also act to prevent coagulation, mainly by inactivating
factors V and VIII.
 coagulation factors
The coagulation factors are numbered in the order of their discovery. There
are 13 numerals but only 12 factors. Factor VI was subsequently found
to be part of another factor. The following are coagulation factors and
their common names:

 Factor I - fibrinogen
 Factor II - prothrombin
 Factor III - tissue thromboplastin (tissue factor)
 Factor IV - ionized calcium ( Ca++ )
 Factor V - labile factor or proaccelerin
 Factor VI - unassigned
 Factor VII - stable factor or proconvertin
 Factor VIII - antihemophilic factor
 Factor IX - plasma thromboplastin component, Christmas factor
 Factor X - Stuart-Prower factor
 Factor XI - plasma thromboplastin antecedent
 Factor XII - Hageman factor
 Factor XIII - fibrin-stabilizing factor

The liver must be able to use Vitamin K to produce Factors II, VII, IX,
and X. Dietary vitamin K is widely available from plant and animal
sources. It is also produced by normal intestinal flora. A deficiency is
rare but may occur:

 in newborns because they must first develop normal flora to

produce Vitamin K, or
 When the flora is disturbed by broad-spectrum antibiotics.
Organs Involved
One of the organs intimately involved in the coagulation process is the
liver. The liver is responsible for the formation of factors I, II, V, VII,
VIII, IX, X, XI, XIII, and protein C and S.  Factor VII is created by
the vascular endothelium.

Pathophysiology
 Hemophilia A and B are inherited in an x-linked recessive pattern.
 In hemophilia A there is a deficiency in factor VIII.
 In hemophilia B there is a deficiency in factor IX.
 Hemophilia C is an autosomal recessive mutation, where there is a
deficiency in factor XI.
 Factor V Leiden is a genetic mutation more prevalent in people
European descent.
 Deficiencies in protein C and S also can lead to hypercoagulable
states due to an inability to appropriately inhibit factors V and VIII
respectively.

CURRENT CONCEPT OF COAGULATION

Newer model describes coagulation with following steps:
 Initiation
It occurs by expression of TF in damaged vessel which binds factor VIIa to
activate factor IX and factor X. This activation of factor IX by TF-VIIa complex
serves as the bridge between classical extrinsic and intrinsic pathways.

 Amplification
Thrombin that is generated in the initiation phase further activates factor V and
factor VIII, which serves as a cofactor in prothrombinase complex and accelerates
the activation of Factor II by F Xa and of F Xa by F IXa, respectively.
  Propagation
The accumulated enzyme complexes (tenase complex and prothrombinase
complex) on platelet surface support robust amounts of thrombin generation and
platelet activation. This ensures continuous generation of thrombin and
subsequently fibrin to form a sufficiently large clot.

 Stabilization
Thrombin generation leads to activation of factor XIII (fibrin stabilizing factor)
which covalently links fibrin polymers and provides strength and stability to fibrin
incorporated in platelet plug.
 Regulators
Coagulation with arrows for negative and positive feedback.
Five mechanisms keep platelet activation and the coagulation cascade in
check.

Protein C
 Protein C is a major physiological anticoagulant.
 It is a vitamin K-dependent serine protease enzyme that is activated by
thrombin into activated protein C (APC).
 Protein C is activated in a sequence that starts with Protein C and thrombin
binding to a cell surface protein thrombomodulin. Thrombomodulin binds
these proteins in such a way that it activates Protein C.
 The activated form, along with protein S and a phospholipid as cofactors,
degrades FVa and FVIIIa.

Antithrombin
 Antithrombin is a serine protease inhibitor (serpin) that degrades the serine
proteases: thrombin, FIXa, FXa, FXIa, and FXIIa.
 It is constantly active, but its adhesion to these factors is increased by the
presence of heparin sulfate (a glycosaminoglycan) or the administration
of heparins (different heparinoids increase affinity to FXa, thrombin, or
both).

Tissue factor pathway inhibitor (TFPI)

 Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF).
It also inhibits excessive TF-mediated activation of FVII and FX.

Plasmin
  Plasmin is generated by proteolytic cleavage of plasminogen, a plasma
protein synthesized in the liver.
 Plasmin proteolytically cleaves fibrin into fibrin degradation products that
inhibit excessive fibrin formation.

Prostacyclin
 Prostacyclin (PGI2) is released by endothelium and activates platelet
Gs protein-linked receptors.
 This, in turn, activates adenylyl cyclase, which synthesizes cAMP. cAMP
inhibits platelet activation by decreasing cytosolic levels of calcium and, by
doing so, inhibits the release of granules that would lead to activation of
additional platelets and the coagulation cascade.

Anticoagulants
Many anticoagulants prevent unnecessary coagulation, and those that genetically
lack the ability to produce these molecules will be more susceptible to coagulation.
These mechanisms include:
 Protein C: a vitamin K-dependent serine protease enzyme that degrades
Factor V and factor VIII.
1. Antithrombin: a serine protease inhibitor that degrades thrombin, Factor
IXa, Factor Xa, Factor XIa, and Factor XIIa.
2. Tissue factor pathway inhibitor (TFPI): limits the action of tissue factor
(TF) and the factors it produces.
3. Plasmin: generated by proteolytic cleavage of plasminogen, a potent
fibrinolytic that degrades fibrin and destroys clots.
4. Prostacyclin (PGI2): released by the endothelium and inhibits platelet
activation.
5. Thrombomodulin: released by the endothelium and converts thrombin into
an inactive form
Coagulation begins almost instantly after an injury to the blood vessel has
damaged the endothelium lining the blood vessel. Exposure of blood to the
subendothelial space initiates two processes: changes in platelets, and the
exposure of subendothelial tissue factor to plasma factor VII, which ultimately
leads to cross-linked fibrin formation
 Coagulation tests
o Prothrombin time
o Activate partial thromboplastin time
o Thrombin time
o Fibrinogen level
o Tests for platelet disorders
o Platelet count
o Platelet aggregation test
o Skin bleeding time