Skip this Video
Download Presentation

Loading in 2 Seconds...

play fullscreen
1 / 40

HEMOSTASIS - PowerPoint PPT Presentation

  • Uploaded on

HEMOSTASIS. Secondary 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

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about ' HEMOSTASIS' - avonaco-williams

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript


Secondary 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 hemostasis1
  • 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 form
      • Transaminase in active form
  • Coagulation factors are also classified by physical properties
secondary hemostasis2
  • Contact proteins
    • Factors XII, and XI, Prekallikrein (PK), and Kininogen (HMWK)
    • Involved in earliest phases of clotting
    • Partially consumed during coagulation
    • Found in serum
    • Also involved in
    • Fibrinolysis, kinin formation, activation of complement, inflammation
    • Congenital deficiencies
    • Often asymptomatic, except XI deficiency which usually results in a mild bleeding disorder
secondary hemostasis3
  • 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 hemostasis4
  • 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 hemostasis5
  • 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

Extrinsic pathway

Intrinsic pathway

Common 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
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 pathway1
  • 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
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





Once generated, thrombin converts fibrinogen to fibrin and activates F-XIII

  • 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 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
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 hemostasis1
  • 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
  • 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)
  • 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
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
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 balance1
  • 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
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
    • Pl
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 evaluation1
  • 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