Normal Hemostasis I and II Flashcards
Normal hemostasis
is a process by which blood in the vascular system remains liquid and free from clots, yet permits the rapid formation of solid clots to plug defects (holes) in ruptured or injured blood vessels.
abnormal hemostasis
is the process by which blood forms a clot within
intact blood vessels (vessels which have not ruptured).
Abnormal hemostasis is a pathologic process that represents the activation of the clotting system when there are no ruptured vessels.
hemostasis (normal or abnormal) depends on what 3 things
a. Blood vessel wall: endothelium and subendothelial components.
b. Platelets and platelet release products
c. Coagulation and fibrinolytic systems
endothelin
Endothelin is a potent vasoconstricting agent released from the endothelial cells in distress.
what happens immediately after a blood vessel is injured?
Vasoconstriction
occurs immediately and briefly through reflex neurogenic mechanisms.
may mediate humoral factors released from endothelium such as endothelin.
serves to reduce blood loss.
what are the 2 components of primary hemostasis
Platelet adherence
Activation
where is serotonin released from and what does it do
released from platelets and causes vasoconstriction
what do platelets adhere to during primary hemostasis
subendothelial collagen that is exposed by the injury
what happends during platelet activation
The platelets change in shape and release chemicals such as adenosine diphosphate, thromboxane A2 and serotonin which recruit additional platelets to the site of injury and promote aggregates to form, resulting in a hemostatic plug.
what are the steps in primary hemostasis?
- Platelets adhere to the damaged vessels (GP Ib binding to vWF)
- Platelets undergo shape change, from discoid formation (extending pseudopods)
- Light granules (alpha) release PF4, PDGF and other proteins. Dense granules (beta) release ADP, Ca+2, histamine, serotonin and epinephrine
- Recruitment. Activated platelets recruit other platelets
- Hemostatic plug formation. Several platelets aggregate and form a plug
light granules
(aka alpha) Contain fibrinogen, fibronectin, coagulation factors V and VIII, platelet factor 4** (heparin-binding chemokine) and growth factors, PDGF (platelet derived growth factor) and TGFβ (transforming growth factor beta).
dark granules
(aka beta) Contain ADP, ATP, ionized calcium, histamine, serotonin and epinephrine.
Secondary hemostasis:
Simultaneously, tissue factor is released at the site of
injury from the endothelial cells which combine with platelet factors to initiate the plasma coagulation cascade, ultimately forming thrombin. The coagulation proteins form complexes on the platelet surface utilizing the phospholipids of the platelet membrane.
secondary hemostasis process
- Tissue Factor: Procoagulant released from various cells. Promotes coagulation.
- Phospholipid complex expression: Surface phospholipids are expressed. Promotes the coagulation process.
- Thrombin generation: By the activation of coagulation cascade, thrombin is generated.
- Fibrin polymerization: The formed fibrin is polymerized by Factor XIIIa.
thrombin’s action
converts fibrinogen to fibrin
differences between primary and secondary hemostasis
primary is only platelet involvement no fibrin until secondary
coagulation does not occur until secondary
what is responsible for formation of platelet-thrombin plug (permanent plug)
Thrombin stimulates recruitment and activation of additional platelets. Thrombin enzymatically converts fibrinogen to fibrin.
what are components of the thrombus
platelets and fibrin with Erythrocytes and leukocytes
composition of the clot depends on what factors?
the vascular sites and the patients own pathophysiologic state
thrombus vs embolis
thrombus is a stationary clot while an embolus is a clot that is moving through the blood stream
t-PA
dissolves clots
thrombomodulin
blocks the coagulation cascade (prevents clot formation)
role of the endothelium in hemostasis
Endothelial cells modulate elements of the hemostasis-coagulation sequence.There are two possible pathways depending on the circumstances.
A. Antithrombotic effect (normal state).
B. Prothrombotic effect (response to injured endothelium).
Antithrombotic Effect of the endothelium consists of what 3 components
Antiplatelet effect
Anticoagulant effect
Fibrinolytic effect
Antiplatelet effect of the endothelium
Intact endothelium prevents platelets and coagulation proteins from coming into contact with subendothelial collagen.
Normal endothelial cells secrete prostacyclin and nitric oxide that prevent platelet aggregation.
what does prostacyclin do and where is it secreted from
secreted by the endotheilal cells. prevents platelet aggregation and vasodilates
what does nitric oxide do and where is it secreted from
secreted by the endothelial cells. prevents platelet aggregation and vasodilates
how is protein C activated
Thrombomodulin combining with thrombin to create a complex. Protein S acts as a co-factor for protein C activation
what is protein S function
secreted from the endothelium, protein S is a cofactor required for protein C activation by thrombin-thrombomodulin
antithrombin
an important anticoagulant protein. it combines with heparin-like molecules, for an anticoagulant effect
what has an indirect anticoagulant effect
The endothelial cell membrane contains receptors which play an indirect role in anticoagulation.
Anticoagulant effect
The endothelial cell membrane contains receptors which play an indirect role in anticoagulation.
Heparin-like molecules, combine with a naturally occurring anticoagulant protein, antithrombin
Thrombomodulin, combines with thrombin creating a complex that activates protein C.
The endothelium also secretes protein S which is a cofactor for protein C activation.
Fibrinolytic effect
Endothelial cells also secrete plasminogen activators (t-PA) which promote fibrinolysis.
Plasminogen is converted to plasmin and dissolves the clot.
what secretes plasminogen activators (t-PA) and what do they do
t-PA lyses the clot and activates plasminogen to plasmin to dissolve the clot
protein C’s function
degrades Factor Va and Factor VIIIa
Prothrombotic Effect of endothelial cells
Normal endothelial cells inhibit platelet adherence and prevent blood clotting.
Injury causes a loss of these anticoagulant mechanisms. = more likely to have a thrombosis
Endothelial cells function in prothrombotic effect
secrete von Willebrand factor, tissue factor, cytokines
Platelet adhesion to endothelial cells occurs.
von Willebrand factor
a protein, which forms a molecular bridge between platelets and sub endothelial collagen.
tissue factor activates
the extrinsic sequence of the coagulation cascade.
promotes the generation of thrombin and formation of a clot.
Once the clot is formed it traps other cells such as erythrocyctes and leukocytes.
what do Cytokines released by injured endothelial do
stimulate cells to synthesize more tissue factor
platelet definition
Platelets are discoid, anuclear cells which play a major role in hemostasis.
platelet structure
a. The plasma membrane contains many glycoprotein receptors which play a role in the attachment of platelets to subendothelial proteins (via von Willebrand factor)
inter-adherence between platelets (via fibrinogen) and secretion of substances from intra-cytoplasmic platelet granules.
b. Platelet cytoplasma contains two types of granules which contain substances which play a role in hemostasis. (light and dark granules)
Platelet receptors
i. Glycoprotein IIb/IIIa
ii. Glycoprotein Ib
iii. Thrombin
iv. Serotonin
v. ADP
how do platelets attach to the subendothelium
molecular bridge
how does the platelet attach to collagen
glycoprotein receptor (GP Ib) attaches to the von Willebrand factor which in turn attaches to collagen
what is the purpose of adhesion
Adhesion is a critical reaction because it prevents the blood flow from dislodging the adherent platelets and unplugging the defect in the vessel wall.
glanzmann thrombasthenia is a deficiency of what?
Glycoprotein IIb/IIIa
bernard-soulier syndrome is a deficiency of what?
Glycoprotein Ib
what initiates platelet activation
by molecules binding with platelet membrane GP IIb/IIIa receptors
what do platelets release when activated
granular content including such substances as coagulation factors, ADP, calcium and thromboxane A2.
what activates the phospholipid complex
The phospholipid complex is activated when negatively charged phospholipids become exposed on the platelet surface.
what is the purpose of the phospholipid complex
This complex serves as a site on which coagulation factors combine with ionized calcium to activate the intrinsic pathway.
what does the release of ADP and thromboxane A2 from activated platelet granules do
initiates a reaction which serves to recruit, activate and aggregate platelets.
what does Serotonin and thromboxane A2 do and where are they released from?
released by platelet granules, vasoconstrict the vessel, decreasing the size of injury, reducing blood flow and the likelihood of the plug detaching from the vessel wall.
thrombin’s function
converts fibrinogen (soluble) to fibrin
IIa aka
thrombin
what stabilizes a fibrin clot
transamidase enzyme (XIIIa) and TAFIa.
what factor activates prothrombin (factor II) to thrombin (IIa)
factor Xa
what factors are involved in the intrinsic pathway
VIII, IX, XI, XII
what factors are involved in the extrinsic pathway
VII, and tissue factor
what factors are common to both pathways
X, V, II, XIII
what test do you use for the intrinsic pathway
APTT
what test do you use for the extrinsic pathway
PT aka INR
which factor of the clotting cascade is not a serine protease
Factor XIIIa (aka fibrin stablizing factor) which is a transaminase
thrombin can amplify the coagulation cascade by activating which other factors
factors VIII and V
The fibrinogen group consists of
Factors I, V, VIII and XIII
The prothrombin group consists of and contain
Factors II, VII, IX and X
All of these proteins contain γ-glutamic acid which is needed for the binding of calcium.
all are produced in the liver (can become deficient in liver disease)
warfarin inhibits which factors
Factors II, VII, IX and X (The prothrombin group)
The Contact group consists of
Factors XI, XII, Fletcher factor (Prekallikrein), Fitzgerald factor (HMW Kininogen). (cause clotting in a glass tube due to contact but are not activated by plastic)
important Inhibitors of the Coagulation System
- Antithrombin III (AT)
Heparin cofactor II (HC II) - Tissue factor pathway inhibitor (TFPI)
Antithrombin
is a plasma inhibitor which also mediates the anticoagulant actions of heparin.
Heparin cofactor II
a weak inhibitor of thrombin.
Tissue factor pathway inhibitor
potent inhibitor of tissue factor.
what is the Fibrinolytic System
The fibrinolytic system is a network of enzymes that are responsible for the dissolution of a formed clot.
When activated these enzymes can also facilitate the digestion of fibrinogen
what are the inhibitors of the fibrolytic system
- **Plasminogen activator inhibitor (PAI)
- α2-antiplasmin
- α2-macroglobulin - Thrombin activable fibrinolytic inhibitor (TAFI)
test used to detect a DVT
d-dimer test
fibrinolysis process
endogenous t-PA activates plasminogen that is within the clot to plasmin. Plasmin digests the fibrin and fibrinogen
what influences the thrombogenic process
Such conditions as blood flow, endothelial cell composition, size of the blood vessel and the degree of oxygenation influences this process.
three major factors contribute to thrombosis
- Injury to endothelium resulting in the release of tissue factor
- Alterations in blood composition
- Stasis
components to virchows triangle
abnormal blood flow
endothelial damage
hyper coagulable state
what is a Hypercoagulable State and what factors contribute to it
Imbalance of the blood coagulation mechanisms leading to thrombotic transitions.
Age, smoking, oral contraception and diet also play important roles in contributing to a hypercoagulable state. Thrombotic stroke, myocardial infarction and peripheral arterial thrombosis result from this syndrome.
primary (genetic) hypercoagulable states
Molecular thrombophilias
Inhibitor deficiency
which coagulation factor is activated by contact with surfaces and is capable of triggering the intrinsic pathway of coagulation?
XII
