Hemostasis Flashcards
1
Q
What is Hemostasis?
A
- The arrest of bleeding
- Hemo = blood
- Stasis = Halt, slow
- A normal physiological response to localized vascular injury
- It is a complex process
- A balanced interaction between:
- Blood vessels
- Platelets
- Coagulation factors
- Tibrinolytic and thrombolytic factors
2
Q
What is the goal of hemostasis?
A
Rapid return to norml blood flow and fluidity following vascular injury
3
Q
What is the norml functino of blood vessels?
A
- Provide unimpeded movement of blood to areas of need
- Neur-chemical regulation of flow
- Endothelium is a critical blood vessel component influencing vascular homeostasis
- Multifunctional and complex:
- Forms the vascular lining
- Secretes mediators
- Multifunctional and complex:
4
Q
What role does normal endothelium play in homeostasis?
A
- Normal endothelium generally induces vascular relaxation and anti-clotting properties
- Nitric oxide
- Prostacyclin
- Alpha-2-macroglobulin
- Thrombomodulin
- Protein S
5
Q
What are the Anti-clotting characteritics and what do they do?
A
-
Prostacyclin
- Enhanves vascular relaxation nd inhibis platelet adhesion and activation
-
Nitric oxide
- Maintains vascular relaxation and inhibits platelet activation
- Participates with Protein C and antithrombin to suppress thrombin production
-
Thrombomodulin
- Binds thrombin to intitiate Protein C activation
-
Protein S
- Cofactor in Protein C pathoway and independently inhibits activation of Factors VIII and X
6
Q
What role does Damaged endothelium play in hemostasis
A
- Damaged endothelium has predominately pro-clotting properties
- Release of Tissue Factor from activted endothelium and subendothelial tissues
- Exposure of underlying collagen and other subendothelil conponents provide sites for platelet adhesion
7
Q
What are the Pro–clotting characteristics and their function?
A
-
Tissue Factor:
- Released following endothelial injury, possibly by activated endothelium
-
Von willebrand Factor:
- Forms bridges for platelet adhesion and aggresion
-
Plasminogen Activator Inhibitor-1:
- Inhibits fibrinolysis
8
Q
What is the normal function of platelets
A
- Platelets
- membrane-bound cytoplasmic fragments derived from megakaryocytes in the bone marrow
- Trhombopoietin is the main regulator of production
- Colony stimulating factors: IL-3, IL-6, IL-11 also participate
- membrane-bound cytoplasmic fragments derived from megakaryocytes in the bone marrow
9
Q
What is the platelets role in Primary Hemostasis?
A
- Plaetlets are the principle mediators of primary hemostasis
- Platelets bind to damaged endothelium or subendothelium to form a primary hemostatic platelet plug to Prevent blood loss
10
Q
What is Primary Hemostasis?
A
- The primary vascular and platelet response to vascular injury
- Vascular contraction
- Endothelial activation
- Pro- and anti-clotting activity
- Platelet plug formation
- Most effective for minor vascular injury
11
Q
What vascular changes occur during Primary Hemostais?
A
- Contraction of mucsle layers of the blood vessle cause transient vasoconstriction
- Neurogenic stimuli
- Endotherlial and platelt products
- Endothelial activation
- Pro-coagulation to limit bleeding
- Anti-coagulation to limit clotting
12
Q
What happens with platelets during primary hemostasis?
A
- Sequential activities in primary hemostasis
- Adhesion
- Aggregation
- Secretion
- Contraction
13
Q
What happens during Adhesion of Platelets in Primary Hemostasis?
A
- Platelets adhere to subendothelial substances at sites of vascular injury
- Coating of subendothelial collagen by von willebrand factor acceleratesadhesion by a receptor-mediated process
- Platelet GPIb binds to vWF on damaged surface
14
Q
What happens to platelets during Aggregation in Primary Hemostasis
A
- Platelets stick to each other to build up an adequate platelet mass for primary hemostasis
- Conformational change induces expression of GPIIb-IIIa
- Fibrinogen foms bridges between platelets
15
Q
What happens to platelets during secretion in primary hemostasis?
A
- Conformational change indued by adhesion/aggregtion results in granule release:
- Platelet granules contain numerous preformed substances
- Adhesions stimulates production of platelet membrane-associated substances involved in clotting
- Thromboxane
- Platelet Factor 3 (anionic membrane phospholipids including phosphatidylserine)
16
Q
What is the content of a Platelet a-granule ?
A
- Factor V
- Fibrinogen
- Thormbospondin
- Fibronectin
- Transforming growth factor-beta (TGF-beta)
- Epidermal growth factor
- Albuminn
- B-Thromboglobulin
- Platelet Factor 4
- Platelet-derived growth factor (PDGF)
- Endothelial cell growth factor (ECGF)
17
Q
What is the content of a Platelet Dense granule?
A
- ATP
- GTP
- Calcium
- Serotonin
- ADP
- GDP
- Magnesium
- 5’ hydroxytryptamine
18
Q
What happens to platelets during contraction in Primary Hemostasis?
A
- Contraction minimizes the size of teh primary hemostatic plug
- Platelet actin and myosin and interplatelet fibrinogen bridges are teh major mediators
- This occurs during the resolution stages of primary hemostasis
- Lysis of fibrin formed by secondary hemostasis (fibrinolysis) will occur concurrently
- Contraction and fibrinolysis minimize the size of the platelet/fibrin plug and initiates vascular repair
19
Q
What is Coagulation?
A
- A highly regulated cascde of reactions that form a variety of products involved in hemostasis
- Participants include:
- Enxymatic coagulation factors
- Non-enzymtic co-factors
- Described by severl different models:
- Classical Coagulation pathways
- Integrated model of coagulation
20
Q
What are the Enzymatic Coagulation Factors?
A
- Proenzymes
- Plasma proteins that circulate in inactive forms
- Produced mainly in hepatocytes
- Upon activation, they gin teh suffix “a”
- Exception: Prekallikrein → Kallikrein
- Include Factors II, VII, IX, X, XI, XII, XIII, Prekallikrein
- Plasma proteins that circulate in inactive forms
21
Q
What are teh Non-enzymatic Coagulation Factors?
A
- Cofactors
- Non-enzymatic participants that are necessary for enxymatic coagulation reations
- Cofacotrs include Factors I, III, V, VIII, High Molecular Weight Kininogen, Ca+2, and phospholipids
- Ionized free calcium is required
22
Q
What are the Classical Coagulation pathways?
A
- Extrinsic pathway
- Intrinsic pathway
- Common pathway
23
Q
What is the Coagulation Intrinsic Pathway?
A
- Activation of Factor XII (Hageman Factor) is the key stp
- Factor XIIa initiates the cascade leading to activation of Factor X
- Factor XII initiates some important non-coagulant pathways
- Contact factors (Factor XII, HMWK, and PK) initiate te pathway by binding negatively charged surfaces, like collagen
- HMWK circulates in association with PK and Factor XI
- Binding of HMWK brings reactants into close association on the activating surface
- XIIa facilitates binding of HMWK to the activating surface
- HMWK circulates in association with PK and Factor XI
- Probbly initiated secondary to extrinsic and common pathway activation
- Propagates and amplifies thrombin formation initiated by the extrinsic pathway
- Likely plays secondary role in vivo
- individuals with deficiencies of Factor XII, HMWK, and PK don’t have bleeding tendencies
24
Q
What is the Coagulation Extrinsic Pathway?
A
- Activated by the release of Tissue Factor (TF, Factor III) by damaged endothelial surfaces
- “Tissue Factor Pathway”
- Factor III reacts with Factor VII to cause the activation of Factor X
25
What is the Coagulation Common Pathway?
* This pathway is initiated by activated Factor X
* Factor Xa can be generated by both intrinsic and extrinsic pathways
* Major step in the pathway is the conversion of protrhombin (Factr II) to thrombin (Factor IIa)
* Prothrobin (Factor II) is converted by the prothombinase complex
* Complex consists of Factors Xa and Va, and cacium on a phospholipid surface
* Fibrin monomers cleaved by trhombin from fibrinogen self-polymerize
* Factor XIII helps to cross-link and stabilize the fibrin polymers
26
What is the Integrated Model of Coagulation?
* Many points of interaction between each of the classical pathways
* A web-like integrated model may more appropriately demonstrate the integration and amplifcation that occur *in vivo*
* Key Points:
* TF-VIIa activates X (common) and IX (intrinsic)
* Thrombin-initiated activation of Factors V, VIII, and XI amplifies intrinsic and common pathways
* Activation of extrinsic Factor VII by Factors XIIa and IXa and kallikrein
27
How is Hemostasis regulated?
* Hemostasis is a fine balance between pro- and anti- clotting mechanisms
* Major function of regulatory pathways is to confine hemostasis to only those locations it is needed
* Factors that regulate hemostasis include:
* Depletion of activted coagulation factors
* Clearance of activaed coagulation factors
* most are complexed by inhibitors and then cleared from teh circulation by hepatocytes orteh mononuclear/phagocyte system
* Inactivation of activated coagulation factors or products
28
What are the Coagulation inactivators/inhibitors?
* Antithrombin (Antithrombin III)
* Protein S: Protein C: Thrombomodulin
* Tissue Factor Pathway Inhibitor
29
What is Antithrombin?
* The MAJOR circulating anti-coagulant
* Antithrombin degrades all activated cogulation factors except fr Factor VIIa
* It accounts for about 80% of the thrombin-activity of plasma
30
What is Protein C?
* A Vitamin K-dependent anti-coagulant and pro-fibrinolytic agent
* Protein C is actvated by thrombin
* Activated Protein C complexes with Protein S on phospholipid surfaces and inactivates factors Va and VIIa
31
What is Fibrinolysis?
* Dissolution of clots is important to maintain flow and fluidity of blood through the damaged area
* It is ctivated simultaneously with coagulation
* Plasmin is the major mediator of fibrinolysis
* Must be well balanced and timed:
* Too fast/excessive - clot may degrade before vascular repair occurs
* Too slow/minimal - clot persistened may lead to permanent vessel alteration and reduce blood flow
32
What are Fibrin Degradation Products?
* Produce an anti-thrombotic, pro-hemorrhagic state
* Major fragments include X, D, Y, and E
* They impair platelet function
* They compete with fibrinogen for binding sites on thrombin and platelets
* They interfere with fibrin polymerization
* They increase during coagulation, DIC, inflammation, hemorrhage, or drecreased clearance dur to lier or kidney disease
33
What are the Fibrinolytic inactivators/inhibitors?
* Plaminogen activator inhibitor - 1
* Antiplamins
* C1 inhibitor
34
What does plaminogen activator inhibitor -1 do
* inhibits tissue plaminogen activator and urokinaseto prevent conversion of plaminogen to plasmin
35
What do antiplamins do?
* Function cooperatively to prevent excessive plamin activity
* a - 2 - antiplamin is the first to bind and neutralize plamsin
* rapid inhibition of circulating plamin so fibrinolysis remains localized
* a - 2- macrolobulin binds excess plasmin after a-2-antiplasmin becoes saturated
* a-1-antitrypsin binds plasmin after a-2-macroglobulin becomes saturated
36
What is C1 inhibitor
* Modulated the complement, coagulatin, kinin, and fibrinolytic pathways
* Inhibits:
* Activation of C1
* Cleavage of C2 and C4
* Coagulation factors XIIa and XIa
* Activation of plaminogen
* Activation of kallikrein
37
What is the endpoint of hemostasis?
* When the damaged vessel is repared and the platelet/fibrin clot contracts and is lysed
