HEMOSTASIS Secondary hemostasis. SECONDARY HEMOSTASIS Also called the fibrin forming coagulation...
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Transcript of HEMOSTASIS Secondary hemostasis. SECONDARY HEMOSTASIS Also called the fibrin forming coagulation...
HEMOSTASISSecondary hemostasis
SECONDARY HEMOSTASIS
Also called the fibrin forming coagulation system
The purpose is to reinforce the platlet plug System mediated by many coagulation
factors present in an inactive form in blood.Factors are assigned Roman numerals, I through
XIII Assigned in order of discovery, not place in reaction
sequence Each one has one or more common names or synonyms Roman numeral followed by letter “a” indicates the
activated form of the factor All are produced in the liver. The von Willebrand factor is
also produced in endothelial cells and megakaryocytes.
SECONDARY HEMOSTASIS
Are divided into three categories based on hemostatic function Substrate –fibrinogen (Factor I), which is the
main substrate used to make fibrin Co-factors – accelerate enzymatic reactions
(factors V and VIII, HK, S, and C) Enzymes
Serine proteases in active formTransaminase in active form
Coagulation factors are also classified by physical properties
SECONDARY HEMOSTASIS
Contact proteins Factors XII, and XI, Prekallikrein (PK), and
Kininogen (HMWK) Involved in earliest phases of clotting Partially consumed during coagulation Found in serumAlso involved in Fibrinolysis, kinin formation, activation of
complement, inflammationCongenital deficiencies Often asymptomatic, except XI deficiency
which usually results in a mild bleeding disorder
SECONDARY HEMOSTASIS
Prothrombin Group Vitamin-K Dependant Clotting Factors Factors-II, -VII, -IX, -X, Prt C and S (and Z) All contain γ-carboxyglutamic acid
Critical for Ca++ binding properties Need Ca++ to bind to phospholipid surface
All but Factor-II found in serum Drugs that act as antagonists to Vitamin K
(Warfarin and Coumadin) inhibit the Vitamin K dependent carboxylation of glutamic acid
SECONDARY HEMOSTASIS
Fibrinogen Group Thrombin-Sensitive Clotting Factors
Factors I (fibrinogen), -V, -VIII, and -XIII All are acted upon by thrombin in the process of blood
coagulation None found in serum
The cascade theory of blood coagulation Involves a series of biochemical reactions Transforms circulating substances into an
insoluble gel through conversion of fibrinogen to fibrin
Requires Plasma proteins Phospholipids calcium
CASCADE THEORY OF COAGULATION Each coagulation factor is converted to an active
form by the preceeding factor in the cascade Calcium participates in some of the reactions as
a co-factor The blood coagulation cascade occurs on cell
surface membranes. Clotting factors bind to the phospholipid
membrane surface and rearrange until a complex including enzyme, substrate, and cofactor is formed.
Subendothelial tissue exposed with vascular injury and platlet surface provide the critical membranes
The membrane localizes the reaction to the site of injury
SECONDARY HEMOSTASIS
Three different complexes assemble on the phospholipid membrane
The pathways for the formation of these complexes are Intrinsic Extrinsic Common -Both intrinsic and extrinsic pathways
converge to share factors in the common pathway Both intrinsic and extrinsic pathways require
initiation Intrinsic - all factors involved in clot formation are in the
vascular compartment Extrinsic- is initiated when a tissue factor not found in
blood enters the vascular system
COMPLEXES ON MEMBRANE
Common pathway
Intrinsic pathwayExtrinsic pathway
Fibrin formation
EXTRINSIC PATHWAY
The extrinsic pathway is initiated when there is an injury to a blood vessel wall
In the presence of the tissue factor released from the injured nonvascular tissue (factor III or thromboplastin) and calcium (factor IV), factor VII is activated to factor VIIa
Factor VIIa activates factor X to Xa Factor VIIa can also activate factor IX
in the intrinsic pathway to IXa
EXTRINSIC PATHWAY
INTRINSIC PATHWAY
Is initiated following exposure to negatively charged foreign substances such as collagen, subendothelium, or phospholipids.
Factor XII is activated to XIIa. XIIa then interacts with the contact factors,
prekallikrein and kininogen, to activate Factor XI to XIa
XIa then activates Factor IX to IXa in the presence of Ca++
IXa participates along with co-factor VIII:C, Ca++, and PF3 (a source of phospholipids), to activate Factor X which leads to the generation of thrombin
IXa -factor VIIIa-phospholipid-Ca++ is called the tenase complex
INTRINSIC PATHWAY
The complex of IXa, VIIIa, X, PF3,and Ca++ assembles on the surface of activated platlets (supply the phospholipid).
The surface provides the protective environment for the enzymatic reactions to occur
In plasma, VIII circulates as a complex in association with C which has the procoagulant activity and von Willebrand factor (vWF) which functions as a carrier protein.
VIII requires enhancement by the generated enzyme thrombin to amplify its activity
INTRINSIC PATHWAY
COMMON PATHWAY
Intrinsic and extrinsic pathways Converge on the common pathway Both pathways activate Factor-X to Xa
Xa in the presence of Factor V, Ca++ and phospholipid converts prothrombin (Factor II) to its active form thrombin (IIa)
Thrombin then feeds back to activate factors VIII and V, converts fibrinogen to soluble fibrin, and helps to stabilize the fibrin monomer by converting factor XIII to XIIIa.
XIIIa cross-links the fibrin monomers to form a stable fibrin polymer
F-Xa, F-Va, PL, Ca++ (Prothrombinase Complex)
Prothrombin Thrombin
Fragment 1.2
Thrombin F-XIIIa
Fibrinogen Fibrin Cross-linked Fibrin
FP-AFP-B
F-XIII
Once generated, thrombin converts fibrinogen to fibrin and activates F-XIII
COMMON PATHWAY
FIBRINOGEN
3 stages of conversion of fibrinogen to fibrin Proteolysis
Thrombin cleavage of fibrinogen results in fibrin monomers
Polymerization Spontaneous self-assembly into fibrin polymers
Stabilization Introduction of covalent bonds into fibrin polymers by
XIIIa
THROMBIN ACTION
COAGULATION PATHWAY
COAGULATION CASCADE
THROMBIN Thrombin plays a central role in the
bioregulation of hemostasis in both normal and pathologic conditions.
Thrombin mediated mechanisms in hemostasis include Acts as a potent platlet aggregating and secretion
agent. Amplification of the coagulation mechanism by
activating co-factors V, VIII, and factor XI. Thrombin activation of V and VIII act as a positive
feedback to amplify the generation of more thrombin Cleavage of XIII to XIIIa for fibrin stabilization Complexing with endothelial cell thrombomodulin
to activate protein C Activated protein C inactivates co-factors Va and VIIIa,
slowing down thrombin formation Stimulation of tissue repair
INHIBITION OF COAGULATION
Antithrombin is a potent physiologic inhibitor of thrombin, factors Xa, IXa, XIa, and XIIa, activated protein C, and kallikrein
In the presence of heparin, the inactivation of thrombin and Xa by AT is significantly increased
INHIBITOR PATHWAY OF COAGULATION
PRIMARY AND SECONDARY HEMOSTASIS
Sequence after vessel injury Vasoconstriction
Controlled by vessel smooth muscle; enhanced by chemicals secreted by platelets
Platelet adhesion Adhesion to exposed subendothelial connective tissue
Platelet aggregation Interaction and adhesion of platelets to one another to form
initial plug at injury site
PRIMARY AND SECONDARY HEMOSTASIS
Sequence cont’d Fibrin-platelet plug
Coagulation factors interact on platelet surface to produce fibrin; fibrin-platelet plug then forms at site of vessel injury
Fibrin stabilization Fibrin clot must be stabilized by F-XIIIa
CELL BASED MODEL OF HEMOSTASIS
Specific cellular receptors for coagulation proteins promote hemostasis which occurs in three overlapping phases Initiation – involves tissue-factor bearing cell and
production of small amounts of thrombin Amplification – involves platlet activation and
sets the stage for large scale throbin production Propagation – the activated platlet surface
protects factor XI and results in an explosive burst of thrombin formation
CELL BASED MODEL OF HEMOSTASIS
FIBRINOLYSIS
Activation of coagulation also activates fibrin lysis Fibrinolysis results in a gradual enzymatic cleavage of
fibrin to soluble fragments Limits the extent of the hemostatic process Reestablishes normal blood flow
Important component Localized activation of plasminogen (PLG) to plasmin Plasmin enzyme system (the fibrinolytic system)
FIBRINOLYSIS
Plasmin Responsible for degradation of fibrin (or
fibrinogen) Distinct protein fragments produced
Fibrin degradation products (FDPs) Sites of plasmin cleavage
Similar in fibrin and fibrinogen Plasmin also destroys factors V, VIII and other
coagulation factors
PLASMIN ACTION
KININ AND COMPLEMENT SYSTEMS
The kinin system is also activated by both coagulation and fibrinolytic systems The kinin system is important in inflammation,
vascular permeability, and chemotaxis The complement system is activated by
plasmin
INTERRELATIONSHIP OF COAGULATION, FIBRINOLYTIC, KININ, AND COMPLEMENT SYSTEMS
HEMOSTATIC BALANCE
The regulation of hemostatic and fibrinolytic processes is dynamic Balance between
Pro- and anti-hemostatic mediators Pro- and anti-fibrinolytic mediators
Balance can be upset if any components are Inadequate Excessive
Development of thrombi Excessive local or systemic activation of
coagulation Sustained bleeding
Excessive local or systemic fibrinolytic activity
HEMOSTATIC BALANCE
When hemostasis is delayed Either platelet disorder or a coagulation defect
Bleeding episode may be prolonged Imbalance created between
An abnormally slow hemostatic rate A normal rate of fibrinolysis
An inadequate fibrinolytic response May retard lysis of a thrombus and even contribute to
its extension
BALANCE OF CLOTTING AND FIBRINOLYSIS
LABORATORY EVALUATION OF HEMOSTASIS
Bleeding disorders present differently depending upon the causative problem
Platlet disorders present as petechiae and bleeding into mucous membranes because of failure to form the platlet plug
Patients with coagulation defects may develop deep spreading hematomas and bleeding into the joints with evident hematuria because of failure to reinforce the platlet plug.
P P
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LABORATORY EVALUATION
Three different categories of disorders may be found Vascular and platlet disorders Coagulatioin factor deficiencies or specific inhibitors Fibrinolytic disorders
Tests to differentiate between these include Platlet count Peripheral blood smear evaluation Ivy bleeding time (N=2.5-9.5 min) or platlet
function analyzer (PFA) Prothrombin time (PT) – test contains
thromboplastin and calcium chloride and measures measures the extrinsic and common pathways (Normal=11-13 sec)
LABORATORY EVALUATION Activated partial thromboplastin time (APTT) -
contact activators and a platlet substitute and calcium chloride are added to measure the intrinsic and common pathways (Normal usually 23-35 sec, may vary depending upon analyzer used, reagents used, and patient population)
Thrombin time (TT) – add thrombin and measure the time required for thrombin to convert fibrinogen to fibrin (common pathway) (N=15-22 sec)
Mixing studies with PT and APTT abnormal results -patient plasma is mixed with normal plasma to distinguish between factor deficiencies and coagulation inhibitors If assay is corrected – due to factor deficiency If partially corrected or uncorrected – due to inhibitor
Coagulation factor assays Assays for fibrin degradation products – evidence of
fibrinolysis