PREFINAL LECTURE L2: NORMAL HEMOSTASIS Flashcards
ECs secrete VWF when activated by
vasoactive agents (e.g. thrombin)
Explain hemostasis book based
Hemostasis is a complex physiologic process that keeps circulating blood in a fluid state and then, when an injury occurs, produces a clot to stop the bleeding, confines the clot to the site of injury, and finally dissolves the clot as the wound heals.
(similar answer is acceptable)
When hemostasis system is out of balance, what 2 conditions could be life threatening?
- Hemorrhage (uncontrolled bleeding)
- Thrombosis (pathologic clotting)
The absence of a single plasma procoagulant
may destine the individual to what 3 lifelong consequences?
- Anatomic hemorrhage
- Chronic inflammation
- Transfusion dependence
If this is absent, it would allow coagulation to proceed unchecked, and cause diseases such as thrombosis, stroke, pulmonary embolism, deep vein thrombosis, cardiovascular events.
control protein
Hemostasis involves the interaction of what 3 processes to stop bleeding?
- Vasoconstriction
- Platelet adhesion and aggregation
- Coagulation enzyme activation
The key cellular elements of hemostasis are?
- Cells of the vascular intima
- Extravascular tissue factor (TF) bearing cells
- Platelets
The plasma components/protein that play a role in hemostasis include the
(answer in general term)
- Coagulation and fibrinolytic proteins
- Their inhibitors
It refers to the role of blood vessels and platelets in the initial response to a vascular injury or to the commonplace desquamation of dying or damaged
endothelial cells.
Primary hemostasis
It describes the activation of a series of coagulation proteins in the plasma, mostly serine proteases, to form a fibrin clot.
Secondary hemostasis
End product of primary hemostasis
platelet plug formation
End product of secondary hemostasis
platelet clot
Based on table 35.1, identify if PRIMARY or SECONDARY hemostasis:
Procoagulant substances exposed or
released by damaged or activated
endothelial cells
primary hemostasis
Based on table 35.1, identify if PRIMARY or SECONDARY hemostasis:
The activator, tissue factor, is exposed on cell membranes
secondary hemostasis
Based on table 35.1, identify if PRIMARY or SECONDARY hemostasis:
Delayed, long-term response
secondary hemostasis
Based on table 35.1, identify if PRIMARY or SECONDARY hemostasis:
Rapid, short-lived response
primary hemostasis
Based on table 35.1, identify if PRIMARY or SECONDARY hemostasis:
Involves vascular intima and platelets
primary hemostasis
Based on table 35.1, identify if PRIMARY or SECONDARY hemostasis:
Involves coagulation system and platelets
secondary hemostasis
Based on table 35.1, identify if PRIMARY or SECONDARY hemostasis:
Activated by desquamation and
small injuries to blood vessels
primary hemostasis
Based on table 35.1, identify if PRIMARY or SECONDARY hemostasis:
Activated by large injuries to blood
vessels and surrounding tissues
secondary hemostasis
In primary hemostasis, the blood vessels contract for what purpose?
- Seal the wound
- Reduce the blood flow (vasoconstriction)
Arrange the following events in primary hemostasis:
A) Platelets secrete the contents of their granules
B) Platelets adhere to the site of injury
C) Platelets become activated
D) Platelets aggregate with other platelets to form a platelet
plug
C, B, A, D
Vasoconstriction and platelet plug formation comprise the initial, rapid, short-lived response to vessel damage. However, in order to control major bleeding in the long term, the plug must be reinforced by?
fibrin
Enumerate examples of defects in primary hemostasis.
- Collagen abnormalities
- Thrombocytopenia
- Qualitative platelet disorders
- von Willebrand disease
Inactive form of coagulation factor
zymogens
In secondary hemostasis, coagulation proteins in the plasma, mostly serine proteases, circulate as what before coagulation?
Inactive zymogens (proenzymes)
Zymogens (proenzymes) that become activated during the process of coagulation, form complexes that activate other zymogens in order to ultimately generate what?
thrombin
What is thrombin?
an enzyme that converts fibrinogen to a localized fibrin clot
The final event of hemostasis is?
fibrinolysis
It is the gradual digestion and removal of the fibrin clot as healing occurs.
fibrinolysis
T/F: Coagulation and fibrinolysis are associated with primary hemostasis, while vascular intima and platelets are associated with secondary hemostasis
F
(vascular intima and platelets = primary hemostasis, while
coagulation and fibrinolysis = secondary hemostasis)
T/F: All systems in primary and secondary hemostasis interact
in early- and late-hemostatic events.
T
Platelets secrete
coagulation factors stored in their?
granules
Coagulation complexes form on the platelets’ what?
cell membrane phospholipid
Term used to describe the entire network of blood vessels
vasculature
A blood vessel is structured into what 3 layers?
- Vascular intima
- Vascular media
- Vascular adventitia
Inner layer of blood vessel
vascular intima
Middle layer of blood vessel
vascular media
Outer layer of blood vessel
vascular adventitia
The vascular intima provides the interface between the?
circulating blood and the body tissues
The vascular intima of blood vessels is a monolayer of what metabolically active cells?
endothelial cells (ECs)
Supporting the endothelial cells in the vascular intima is the?
internal elastic lamina
The internal elastic lamina is composed of?
elastin and collagen
The subendothelial connective tissue of the vascular intima varies in veins and arteries. In arteries it is composed of?
- Collagen
- Fibroblasts
- Smooth muscle cells
The subendothelial connective tissue of the vascular intima varies in veins and arteries. In veins it is composed of?
Collagen and fibroblasts
Fibroblasts occupy the connective tissue layer and produce what protein in all blood vessels?
collagen
Smooth muscle cells in arteries and arterioles contract when an injury occurs and primary hemostasis is initiated, but not in the?
walls of veins, venules, or capillaries
The intact vascular endothelium prevents thrombosis through what 3 ways?
- Inhibiting platelet aggregation
- Preventing coagulation activation and propagation
- Enhancing fibrinolysis.
Give the 2 descriptions of the structure of ECs, which provide a smooth inner surface of the blood vessel, promotes even blood flow, and prevents harmful turbulence that otherwise may activate platelets and coagulation enzymes.
rhomboid and contiguous
ECs form a physical barrier separating what?
(1) Procoagulant proteins and platelets in blood from (2) collagen in the vascular intima, and (3) Tissue factor in fibroblasts and smooth muscle cells
these 3 layers are separated by ECs
Provide the anticoagulant property of this endothelial cell substance:
prostacyclin
A platelet inhibitor and a vasodilator
Prostacyclin is synthesized through what pathway
eicosanoid pathway
Based on table 35.2, provide the ANTICOAGULANT property of this INTACT endothelial cell substance:
ECs secrete nitric oxide
A vascular “relaxing” factor
Nitric oxide is synthesized in? Enumerate.
- ECs
- Vascular smooth muscle cells
- Neutrophils
- Macrophages
Aside from smooth muscle relaxation, state other roles of nitric oxide
- Induces subsequent vasodilation
- Inhibits platelet activation
- Promotes angiogenesis and healthy arterioles
Provide the anticoagulant property of this endothelial cell substance:
Tissue factor pathway inhibitor (TFPI)
Controls activation of the tissue factor pathway (aka the extrinsic coagulation pathway)
TFPI limits the activation of what specific complex?
TF:VIIa:Xa complex
What 2 known inhibitors of thrombin formation do ECs synthesize and express on their surfaces?
- Thrombomodulin facilitated by endothelial protein C receptor (EPCR)
- Heparan sulfate
EPCR binds what protein?
protein C
Thrombomodulin catalyzes the ACTIVATION of what pathway?
protein C pathway
The protein C pathway downregulates coagulation by digesting what 2 factors, which thereby inhibits thrombin formation?
activated factors V and VIII
Based on table 35.2, provide the ANTICOAGULANT property of this INTACT endothelial cell substance:
ECs secrete the glycosaminoglycan heparan sulfate
An anticoagulant that regulates thrombin generation
Heparan sulfate enhances the activity of which blood plasma serine protease inhibitor?
antithrombin
Based on table 35.2, provide the ANTICOAGULANT property of this INTACT endothelial cell substance:
ECs secrete TPA
Activates fibrinolysis
TPA stands for
Tissue Plasminogen Activator
T/F: The
pharmaceutical anticoagulant heparin RESEMBLES heparan sulfate of EC in structure and its inhibitory activity when bound to antithrombin.
T
TAFI stands for
Thrombin Activatable Fibrinolysis Inhibitor
If the INTACT endothelium has anticoagulant properties, DAMAGED vascular intima (ECs and subendothelial matrix) has what properties?
procoagulant properties
Arrange the following events:
A) Collagen from subendothelial connective tissues binds and activates platelets.
B) ECs secrete and coat themselves with P-selectin, and also secrete ICAMs and PECAMs
C) ECs secrete von Willebrand factor when activated by vasoactive agents, and they also secrete ADAMTS13
D) EC disruption exposes TF in subendothelial cells and activates the coagulation system through contact with plasma coagulation factor VII, leading to fibrin formation
E) Any harmful local stimulus, whether mechanical or chemical, induces vasoconstriction in arteries and arterioles
E, A, C, B, D
A flexible elastic structural protein
collagen
When collagen binds and activates platelets, it results to an initial platelet adhesion response, which fills in the damaged area until what?
until new ECs grow
Some connective tissue degeneration occurs naturally in aging. This can lead to what tendency in the elderly population?
increased bruising tendency
It is a large multimeric
glycoprotein that acts as the necessary bridge that binds platelets to exposed subendothelial collagen in arterioles and arteries where blood flows rapidly
von-Willebrand factor (VWF)
VWF has been described as a “_______” since it spreads out, create sticky surface, and activated platelets assemble on it
carpet
function of ADAMTS13
cleaves
LARGE VWF MULTIMERS
into
SHORTER CHAINS
An adhesion molecule that promotes platelet and leukocyte binding. ECs secrete and coat themselves with it.
P-selectin
ECs secrete what 2 immunoglobulin-like
adhesion molecules?
ICAMs and PECAMs
ICAM stands for
intercellular adhesion molecules
PECAM stands for
platelet endothelial cell adhesion molecules
EC disruption activates the coagulation system through contact with which factor, leading to fibrin formation?
plasma coagulation
factor VII
In pathologic conditions, TF may be expressed on what cells or molecules?
- Monocytes
- Tissue factor-positive microparticles
TF may be expressed on monocytes during what specific conditions?
inflammation and sepsis
Tissue factor-positive microparticles are derived from?
- Membrane fragments of activated or apoptotic vascular cells
- Surface of some ECs
It surrounds the platelet plug, securing it to the damaged area, such that the blood flow does not dislodge it.
fibrin
Excess arterial occlusion causes what diseases?
- Myocardial infarction
- Stroke
- Peripheral artery disease
Excess venous occlusion causes what diseases?
- Deep vein thrombosis
- Thromboembolic disease
In veins, a bulky red clot is produced which consist of?
- Platelets
- VWF
- Fibrin
- Red blood cells
Based on table 35.3, provide the PROCOAGULANT property of this DAMAGED vascular intima structure:
Smooth muscle cells in
arterioles and arteries
Induce vasoconstriction
Based on table 35.3, provide the PROCOAGULANT property of this DAMAGED vascular intima substance:
Exposed subendothelial collagen
Binds VWF; binds to and activates platelets
Based on table 35.3, provide the PROCOAGULANT property of this DAMAGED vascular intima substance:
Damaged or activated ECs secrete VWF
Important for platelet binding to collagen at site of injury: platelet adhesion as a first line of defense against bleeding
Based on table 35.3, provide the PROCOAGULANT property of this DAMAGED vascular intima substance:
Damaged or activated ECs secrete adhesion molecules:
P-selectin, ICAMs, PECAMs
Promote platelet and leukocyte binding and activation at site of injury
Based on table 35.3, provide the PROCOAGULANT property of this DAMAGED vascular intima structure:
Exposed smooth muscle cells and fibroblasts
Tissue factor exposed on cell membranes
Based on table 35.3, provide the PROCOAGULANT property of this DAMAGED vascular intima structure:
ECs in inflammation
Tissue factor is induced by inflammation
Fibrinolysis is the process of removing the fibrin to restore vessel patency, involving the secretion of?
tissue plasminogen activator (TPA)
During thrombus formation, these 2 binds to polymerized fibrin.
TPA and plasminogen
TPA activates fibrinolysis by
converting plasminogen to plasmin
ECs also regulate fibrinolysis by providing inhibitors to prevent excessive plasmin generation. State the inhibitors.
- Plasminogen Activator Inhibitor-1 (PAI-1)
- Thrombin Activatable Fibrinolysis Inhibitor (TAFI)
A TPA control protein that inhibits plasmin generation and fibrinolysis
Plasminogen Activator Inhibitor-1 (PAI-1)
An inhibitor of plasmin generation, that is activated by thrombin bound to EC membrane thrombomodulin
Thrombin Activatable Fibrinolysis Inhibitor (TAFI)
Elevations in PAI-1 or TAFI can slow what process?
can slow fibrinolysis
Elevations in PAI-1 or TAFI can increase the tendency of what?
can increase the tendency for thrombosis
The diagnosis of blood vessel disorder is often based on
- Clinical symptoms
- Family history
- Laboratory tests that rule out platelet or coagulation disorders
Identify which among the 2 is the large molecule and the small molecule:
- Platelet a-Granules
- Platelet Dense Granules
Platelet a-Granules =
large molecules
Platelet Dense Granules = small molecules
Enumerate the Platelet α-Granules (large molecules)
- β-Thromboglobulin
- Factor V
- Factor XI
- Fibrinogen
- Protein S
- Platelet factor 4
- Platelet-derived growth factor
- VWF
Enumerate the Platelet Dense Granules (Small Molecules)
- Adenosine diphosphate
- Adenosine triphosphate
- Calcium
- Serotonin
Among the Platelet Dense Granules, this molecule activates the neighboring platelets.
Adenosine diphosphate
Among the Platelet Dense Granules, this molecule acts as a vasoconstrictor.
serotonin
Plasma transports at least how many procoagulants?
at least 16 procoagulants
procoagulants are also called?
coagulation factors
Nearly all procoagulants are glycoproteins synthesized in what organ?
liver
Aside from the liver, a few amount of procoagulants are also produced in what cells?
- monocytes
- ECs
- megakaryocytes
Provide the name, function, and half-life (hr):
Factor I
- Name: Fibrinogen
- Function: Thrombin substrate, polymerizes to form fibrin
- Half-Life (hr): 100-150
Provide the name, function, and half-life (hr):
Factor II
- Name: Prothrombin
- Function: Serine protease
- Half-Life (hr): 60
Provide the name, function, and half-life (hr):
Factor III
- Name: Tissue Factor
- Function: Cofactor
- Half-Life (hr): Insoluble
Provide the name, function, and half-life (hr):
Factor IV
- Name: Ionic Calcium
- Function: Mineral
- Half-Life (hr): NA
Provide the name, function, and half-life (hr):
Factor V
- Name: Proaccelerin/
Labile factor - Function: Cofactor
- Half-Life (hr): 24
Provide the name, function, and half-life (hr):
Factor VII
- Name:
Stable factor/
Proconvertin/
Serum prothrombin conversion accelerator - Function: Serine Protease
- Half-Life (hr): 6
Provide the name, function, and half-life (hr):
Factor VIII
- Name: Antihemophilic factor
- Function: Cofactor
- Half-Life (hr): 12
Other name of Factor VIII or Antihemophilic factor
Platelet cofactor 1/
Antihemophilic factor globulin
Provide the name, function, and half-life (hr):
VWF
- Name: von Willebrand factor
- Function: Factor VIII carrier and platelet adhesion
- Half-Life (hr): 24
Provide the name, function, and half-life (hr):
Factor IX
- Name: Christmas factor
- Function: Serine protease
- Half-Life (hr): 24
Other name for factor IX or Christmas factor
Platelet cofactor 2/
Plasma thromboplasmin component
Provide the name, function, and half-life (hr):
Factor X
- Name: Stuart-Prower factor
- Function: Serine protease
- Half-Life (hr): 48–52
Other name of factor X or Stuart-Prower factor
autoprothrombin III
Provide the function and half-life (hr):
Factor XI
- Name:
Plasma thromboplasmin antecedent/
Antihemophilic factor C - Function: Serine protease
- Half-Life (hr): 48–84
Provide the name, function, and half-life (hr):
Factor XII
- Name: Hageman factor
- Function: Serine protease
- Half-Life (hr): 48–70
Other name of factor XII or Hageman factor
Heydman factor/
Heydman stabilizer factor/
Glass factor
Provide the name, function, and half-life (hr):
Prekallikrein
- Name: Fletcher factor, pre-K
- Function: Serine protease
- Half-Life (hr): 35
Provide the name, function, and half-life (hr):
High-molecular-weight kininogen (HMWK)
- Name: Fitzgerald factor
- Function: Cofactor
- Half-Life (hr): 156
Provide the name, function, and half-life (hr):
Factor XIII
- Name: Fibrin-stabilizing factor (FSF)
- Function: Transglutaminase, transamidase
- Half-Life (hr): 150
Provide the name and function
Platelet factor 3
- Name: Phospholipids, phosphatidylserine, PF3
- Function: Assembly molecule
What are the 4 categories of plasma-based components of the coagulation system of blood clotting?
- Procoagulants (zymogens)
- Cofactors
- Anticoagulants (regulatory or control proteins)
- Final fibrinogen substrate
Bind, stabilize, and enhance the activity of their respective enzymes.
Cofactor
The substrate for the enzymatic action of thrombin, and the primary enzyme of the coagulation system
Fibrinogen
Plasma glycoproteins that serve the important function of regulating the coagulation process to avoid unnecessary blood clotting.
Control proteins
In 1958, this committee officially named the plasma procoagulants using Roman numerals in the order of their initial description or discovery.
International Committee for the Standardization of the Nomenclature of the Blood Clotting Factors
When a procoagulant becomes activated, this character appears behind the numeral when written.
a lowercase “a” appears behind the numeral (e.g. activated factor VII is VIIa)
T/F: The factors are customarily identified by their roman numeral rather than their name
F
They’re customarily identified by name rather than Roman numeral
The roman numeral VI, was assigned to a procoagulant that was later determined to be an activated form of what factor?
activated factor V
(VI was withdrawn from the naming system
and was never reassigned)
A cofactor that circulates while linked to a large carrier protein VWF.
Factor VIII (antihemophilic factor)
Prekallikrein and HMWK have never received Roman numerals because
They belong to the kallikrein and kinin systems, respectively, and their primary functions lie within these systems
Phosphatidylserine are required for the coagulation process but were given no Roman numeral; instead they
were collectively called as
platelet factor 3
The coagulation factors work together in what type of pathway, where one factor when activated, activates the next factor in the sequence?
cascade pathway
The purpose of the cascade pathway is to generate what key enzyme? and produce what protein?
- generate key thrombin enzyme
- produce fibrin
A localized thrombus
fibrin
These are proteolytic enzymes of the trypsin family.
Serine proteases
Enumerate the Inactive Zymogen
- Prothombin (II)
- VII
- IX
- X
- XI
- XII
- Prekallikrein
Enumerate the Active Protease
- Thrombin (IIa)
- VIIa
- IXa
- Xa
- XIa
- XIIa
- Kallikrein
The inactive zymogens are enzymes called what?
serine proteases
What factor is not a serine protease but a transglutaminase?
Factor XIII
What reactive amino acid residue is present in the active site of each member of the serine protease family?
reactive seryl amino acid residue
Serine protease acts on its substrate by hydrolyzing the?
peptide bonds
thus digesting the primary backbone of protein
The hydrolysis of peptide bonds and the digestion of the primary backbone of proteins leads to the production of what?
Small polypeptide fragments
Serine proteases are
synthesized as inactive zymogens consisting of how many peptide
chain?
a single peptide chain
Activation of inactive zymogens occur when what action is performed on the zymogen?
When it is cleaved at one or more specific sites
What cleaves the inactive zymogen at one or more specific sites?
the action of another protease during the coagulation process
Enumerate the substrates of thrombin (IIa)
- Fibrinogen
- Factor V
- Factor VIII
- Factor XI
- Factor XIII
Enumerate the cofactor and substrates of VIIa
C: Tissue factor
S: Factor IX and Factor X
Cofactor and Substrate of IXa
C: Factor VIIIa
S: Factor X
Cofactor and Substrate of Xa
C: Va
S: Prothrombin
Substrate of XIa
Factor IX
Cofactor and Substrate of XIIa
C: HMWK
S: Factor XI
Cofactor and Substrate of Kallikrein
C: HMWK
S: Factor XI
The procoagulant cofactors that participate in complex formation are
- Tissue factor
- Soluble plasma factors V, VIII, and HMWK
Tissue factors that participate in complex formation are located on the
- Membranes of fibroblasts
- Smooth muscle cells
The remaining components of the coagulation pathway
are
- Factor XIII
- Phospholipids
- Calcium
- VWF
Labeled as “Other Plasma Procoagulants” in box 35.2
The ultimate substrate of the coagulation pathway.
Fibrinogen
Fibrinogen is primarily hydrolyzed by?
thrombin
T/F: fibrinogen is soluble while fibrin is insoluble
T
The insoluble structural protein of the fibrin clot is further stabilized by what factor?
factor XIIIa
coagulation pathway #1
In the coagulation pathway, the exposed TF activates which factor?
Factor VII
coagulation pathway #2
In the coagulation pathway, the activation of factor VII activates which factors?
factors IX and X
coagulation pathway #3
In the coagulation pathway, this complex activates factor X
Factor IXa:VIIIa complex
coagulation pathway #4
In the coagulation pathway, this complex activates prothrombin (factor II)
Factor Xa:Va complex
coagulation pathway #5
In the coagulation pathway, the resulting thrombin cleaves fibrinogen to form what? and activate what?
to form fibrin
to activate factor XIII
coagulation pathway #6
In the coagulation pathway, the activation of factor XIII stabilizes the?
stabilizes the clot
coagulation pathway #7
In the coagulation pathway, thrombin also activates which factors and cell, in a positive feedback loop?
- Factor V
- Factor VIII
- Factor XI
- Platelet
coagulation pathway #8
In the coagulation pathway, exposure to negatively charged surfaces (e.g., bacterial cell membranes) activates what?
- The contact factors XII
- Prekallikrein (pre-K)
- HMWK
coagulation pathway #9
In the coagulation pathway, the activation of the contact factors XII, pre-K, and HMWK activates which factor?
Factor XI
This ion is required for the coagulation complexes that assemble on platelet or cell membrane phospholipids
Ionized calcium
Through what ions do serine proteases bind to negatively charged phospholipid surfaces?
Positively charged calcium ions
Which specific phospholipid is primarily involved in the binding of serine proteases?
phosphatidylserine
T/F: Coagulation activation is not a localized cell surface process, thus it is not limited to the site of injury.
F
It’s a localized cell surface process,it’s limited to the site of injury
They are dependent on vitamin K during synthesis to produce a functional structure. ENUMERATE
(Procoagulants↓)
- Prothrombin (factor II)
- Factors VII
- Factor IX
- Factor X
(regulatory proteins↓)
- Protein C
- Protein S
- Protein Z
Those that are dependent on vitamin K during synthesis are named the?
prothrombin group
Why is the prothrombin group called as such?
Because of their structural resemblance to prothrombin
All 7 proteins of the Prothrombin Group have how many glutamic acid units?
10 -12 glutamic acid units
The glutamic acid units of the Vitamin K-Dependent Prothrombin Group are located where?
near their amino terminal end
In the Vitamin K-Dependent Prothrombin Group, all are serine proteases
when activated, except these 2
protein S and protein Z
protein S and protein Z are
cofactors
This vitamin is a quinone found in green leafy vegetables
Vitamin K
Vitamin K is produced by what intestinal organisms?
- Bacteroides fragilis
- Escherichia coli
Vitamin K catalyzes an essential posttranslational modification of the prothrombin group
proteins, called?
γ-carboxylation of amino-terminal glutamic acids
When a second carboxyl group is added to the γ carbon, glutamic acid is modified to?
γ-carboxyglutamic
acid
With two ionized carboxyl groups, the γ-carboxyglutamic acids gain a net of what charge?
a net negative charge
With two ionized carboxyl groups, the γ-carboxyglutamic acids gain a net negative charge, which enables them to bind to?
ionic calcium
The bound calcium enables these vitamin K dependent coagulation factors to bind to
negatively charged phospholipids
The purpose of the binding of vitamin K dependent coagulation factors and negatively charged phospholipids is to?
form complexes with other coagulation
factors.
A therapeutic inhibitor of vitamin K
Coumadin (anticoagulant drug)
The vitamin K-dependent procoagulants are released from the liver
without the second carboxyl group added to the γ carbon, during what instances?
- Vitamin K deficiency
- Presence of the anticoagulant drug Coumadin
The vitamin K-dependent procoagulants
without the second carboxyl group added to the γ carbon are called?
des-γ-carboxyl proteins
Other name of des-γ-carboxyl proteins
Proteins Induced by
Vitamin K Antagonists (PIVKA) factors
Why can’t des-γ-carboxyl proteins participate in the coagulation reaction?
Because they cannot bind to calcium and phospholipid
due to lack of second carboxyl group
This is the basis for oral anticoagulant (warfarin,
Coumadin) therapy
Vitamin K antagonism
Vitamin K-dependent procoagulants are essential for the assembly of how many membrane complexes?
3 membrane complexes
The assembly of 3 membrane complexes leads to the generation of what enzyme?
thrombin
Each membrane complex is composed of
- A vitamin K-dependent serine protease
- Its nonenzyme cofactor
- Calcium
The vitamin K-dependent serine protease, its nonenzyme cofactor, and calcium are bound to the negatively charged phospholipid membranes of?
- Activated platelets
- TF-bearing cells
The initial complex called EXTRINSIC TENASE, is composed of?
- Factor VIIa
- TF
- Phopholipid
- Calcium
Extrinsic tenase activates which factors?
factors IX and X
INTRINSIC TENASE is
composed of?
- Factor IXa
- and its cofactor VIIIa
- Phospholipid
- Calcium
Intrinsic tenase activates which factor?
Factor X
T/F: Intrinsic tenase activates factor X but the TF:VIIa complex is much more efficient
F
Intrinsic tenase is much more efficient than TF:VIIa complex
The complex Prothrombinase is composed of?
- Factor Xa
- and its cofactor Va
- Phospholipid
- Calcium
Prothrombinase activates?
Prothrombin
In a multistep hydrolytic process, Prothrombinase converts prothrombin to?
thrombin
The conversion of prothrombin to thrombin in a multistep hydrolytic process releases thrombin and a peptide fragment
called?
prothrombin fragment 1.2
Prothrombin fragment
1.2 in plasma is a marker for
thrombin generation
Each cofactor binds its particular serine protease. When bound to their cofactors, serine proteases gain what advantages?
stability and increased
reactivity
Tissue factor is a transmembrane receptor for which factor?
factor VIIa
T/F: Under normal conditions, TF is not expressed on blood vessel cells.
T
Vessel injury exposes blood to the subendothelial TF-bearing cells and leads
to activation of coagulation through which factor?
Factor VIIa
Does the activation
of Factor VII rate limited by the injury itself?
Yes
TF is expressed in
high levels in cells of what organs?
- Brain
- Lung
- Placenta
- Heart
- Kidney
- Testes
T/F: In inflammatory conditions and sepsis, leukocytes and other cells can also express TF and initiate coagulation.
T
Are Factors V and VIII soluble plasma proteins?
Yes
During platelet activation and secretion, platelets release what factor at the site of injury?
partially activated factor V
The prothrombinase complex accelerates thrombin generation more than how many folds when compared with Xa alone?
300,000-fold
The initial small amount of thrombin generated activates what factor?
first factor V
Thrombomodulin-bound thrombin
activates what protein?
protein C
Protein C inactivates which factor?
Factor Va (Va to Vi)
T/F: Factor V is both activated and then ultimately inactivated by the generation of thrombin
T
A mechanism for activating coagulation in conditions where foreign objects such as mechanical heart valves, bacterial membranes, or high levels of inflammation are present.
intrinsic contact factor complex
HMWK is a cofactor to what 2 plasma procoagulants, in the intrinsic contact factor complex?
factor XIIa and prekallikrein
A transmembrane protein constitutively
expressed by vascular ECs, and a thrombin cofactor in the protein
C pathway.
Thrombomodulin
Together, thrombomodulin and thrombin activate what
protein?
Protein C
A coagulation regulatory protein
Once thrombin is bound to thrombomodulin, it loses what ability?
procoagulant ability to activate factors V and VIII
Activation of protein C, leads to destruction of which factors?
destruction of factors V and VIII
Destruction of factors V and VIII suppresses what?
further generation of thrombin
Destruction of factors V and VIII suppresses further generation of thrombin. What type of feeadback loop is this?
a negative feedback loop
Thrombin bound to thrombomodulin also activates what fibrinolysis inhibitor?
TAFI
Protein S is a cofactor to? 2 answers.
protein C and TFPI
Protein Z is a cofactor to what inhibitor?
Z-dependent protease inhibitor (ZPI)
Based on table 35.10, identify the cofactor’s function and where it binds:
TF
F: Procoagulant
B: Factor VIIa
Based on table 35.10, identify the cofactor’s function and where it binds:
Factor V
F: Procoagulant
B: Factor Xa
Based on table 35.10, identify the cofactor’s function and where it binds:
Factor VIII
F: Procoagulant
B: Factor IXa
Based on table 35.10, identify the cofactor’s function and where it binds:
HMWK
F: Procoagulant
B: Factor XII, prekallikrein
Based on table 35.10, identify the cofactor’s function and where it binds:
Thrombomodulin
F: Control (protein C)
Antifibrinolytic (TAFI)
B: Thrombin
Based on table 35.10, identify the cofactor’s function and where it binds:
Protein S
F: Control
B: Protein C, TFPI
Based on table 35.10, identify the cofactor’s function and where it binds:
Protein Z
F: Control
B: ZPI
Key proteins for hemostasis that are
both critically involved in all protective mechanisms to avoid
blood loss (i.e., platelets, vasculature, and blood coagulation
leading to fibrin formation).
Factor VIII and VWF
Factor VIII is produced by
- Hepatocytes (primarily here)
- Microvascular ECs in lung and other tissues
Is free factor VIII stable in plasma
NO it is unstable
Free factor VIII is unstable in plasma thus it circulates bound to
VWF
During coagulation, what does thrombin do to factor VIII?
cleaves factor VIII from VWF and activates it
Like factor Va, factor VIIIa is also inactivated by what protein?
protein C
Factor VIII and factor IX are the two plasma procoagulants
whose production is governed by genes carried on what chromosome?
The X chromosome
Does Factor VIII deteriorates more slowly than the other coagulation factors in stored blood?
NO (it deteriorates more rapidly)
In thawed component plasma, the factor VIII level drops to approximately how many percent after 5 days?
drops to approximately 50%
VWF is composed of multiple subunits of how many daltons?
240,000 Daltons
The subunits of VWF are produced by which cells, where they combine to form multimers that range from 500,000
to 20,000,000 Daltons
ECs and megakaryocytes
ADAMTS13 stands for
A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13
VWF has receptor sites for both
platelets and collagen
How does the VWF receptor sites for both platelets and collagen allows VWF to act as a bridge?
It binds platelets to exposed subendothelial collagen during platelet adhesion
The primary platelet surface receptor
for VWF
GP Ib/IX/V
This sequence in VWF binds a second platelet receptor during platelet aggregation
Arginine-glycine-aspartic acid (RGD)
sequence
The second platelet receptor
GP IIb/IIIa
Third site on
the VWF molecule binds?
collagen
Fourth site on the VWF molecule binds?
factor VIII
the plasma procoagulant cofactor
VWF is the chaperone for what factor?
Factor VIII
2 common bleeding disorders
- Von Willebrand disease
- Factor VIII deficiency
Levels of VWF vary by ABO blood type. What blood group have lower levels of VWF than any other blood group type?
Type O
T/F: VWF is an acute phase protein, as well as factor VIII
T
VWF and Factor VIII levels increase/decrease(?) in pregnancy, trauma, infection, and stress.
Increase
The “contact factors” are what 3 factors?
- Factor XII
- HMWK (Fitzgerald factor)
- Pre-K (Fletcher factor)
Contact factors are named as such because?
they are activated by CONTACT with negatively charged foreign surfaces
A glycoprotein that circulates
bound to HMWK
pre-K
Factor XIIa transforms pre-K into?
its active form kallikrein
Kallikrein cleaves
HMWK to form?
bradykinin
Factor XII and pre-K are zymogens that are activated to become?
serine proteases
Is HMWK an enzymatic cofactor?
NO
(it is a nonenzymatic cofactor)
Name the complex:
HMWK:pre-K:factor XIIa
contact factor complex
The contact factor complex activates what
factor?
Factor XI
T/F: Deficiencies of factor XII, HMWK, or pre-K causes clinical bleeding disorders.
F
(it does not cause clinical bleeding disorders)
Do deficiencies prolong
laboratory tests and necessitate investigation?
YES
Factor XII is activated in vitro by surfaces with what charge?
negatively charged surfaces
Factor XII is activated in vitro by negatively charged surfaces, such as?
- non siliconized glass
- kaolin
- ellagic acid
Non siliconized glass, kaolin, ellagic acid are used as test reagents
for?
the partial thromboplastin time (PTT, APTT) assay
In vivo, foreign materials such as stents, valve prostheses, and bacterial cell membranes activate contact factors, which can lead to?
thrombosis
Factor XI is activated by what complex and enzyme during coagulation?
- contact factor complex
- thrombin (more significantly)
Deficiencies of factor XI can result in what level of bleeding?
mild and variable bleeding
syndrome with deficiency of factor XI
Rosenthal syndrome
Does the plasma levels of Factor XI correspond
with degree of bleeding?
NO
(it does not necessarily correspond with degree of bleeding)
Main enzyme of the coagulation pathway with multiple key activities.
Thrombin
Despite having multiple functions, the primary function of thrombin is?
cleave fibrinopeptides (FP) A and B from the α and β chains of the fibrinogen molecule
The cleavage of FP A and B from the
α and β chains of the fibrinogen molecule triggers what? 2 answers
- Spontaneous fibrin polymerization
- Beginning of fibrin clot
FPA and FPB are measurable in plasma and serve as a marker of
thrombin activation
Thrombin amplifies the coagulation mechanism by activating which cofactors?
V and VIII and factor XI
Thrombin activating cofactors V and VIII and factor XI, serves to generate what?
generate more thrombin
a positive feedback mechanism
Thrombin also activates factor XIII, which forms COVALENT BONDS between what domains of the fibrin
polymer?
the D DOMAINS of the fibrin polymer
Thrombin activating factor XIII to form covalent bonds between the D domains of the fibrin polymer is to cross-link and stabilize what?
the fibrin clot
Does thrombin initiates aggregation of platelets?
YES
Thrombin bound to thrombomodulin activates the protein C pathway to suppress what process?
coagulation
Thrombin bound to thrombomodulin also activates TAFI to suppress what process?
fibrinolysis
Why is thrombin considered the key protease of the coagulation pathway?
Because of its multiple
autocatalytic functions
(It plays a role in coagulation (fibrin),
platelet activation, regulation of coagulation activation (protein C), and controlling fibrinolysis (TAFI).)
The primary substrate of thrombin
fibrinogen
Fibrinogen is essential for platelet aggregation because it links activated platelets through their receptor called?
GP IIb/IIIa platelet fibrinogen receptor
The normal plasma concentration of fibrinogen ranges from how many mg/dL?
200 to 400 mg/dL
Is fibrinogen the most concentrated of all the plasma procoagulants?
YES
Is fibrinogen an APR?
YES
In the past, 2 coagulation pathways were described, both of which has this factor at the start of a common pathway. What is that factor?
activated factor X
In the past, coagulation experts identified the activation of what factor, as the primary step in coagulation?
factor XII
Why was the activation of factor XII identified as the primary step in coagulation in the past?
because factor XIIa could be found in blood, whereas TF could not
The reaction system that begins with factor XII and culminates
in fibrin polymerization has been called the?
Intrinsic pathway
Enumerate the coagulation factors of the intrinsic pathway, in order of reaction.
- Factor XII
- pre-K
- HMWK
- Factor XI
- Factor IX
- Factor VIII
- Factor X
- Factor V
- Prothrombin (II)
- Fibrinogen
The laboratory test that detects the absence of one or more of the factors involved in the intrinsic pathway is the?
activated partial
thromboplastin time (APTT or PTT)
T/F: The contact system establishes a connection between
inflammation and coagulation activation.
T
The formation of this complex has since proven to be the primary in vivo initiation mechanism for coagulation.
TF:VIIa
TF pathway other name?
extrinsic pathway
TF pathway has been called the extrinsic pathway because?
TF is not present in blood
Extrinsic pathway includes which factors?
- Factors VII
- Factor X
- Factor V
- prothrombin
- Fibrinogen
The test used to measure the integrity of the extrinsic pathway is the?
prothrombin time (PT)
These tests are assays often used in tandem to screen for coagulation factor deficiencies
PT and PTT
This test is used to monitor heparin therapy
APTT
This test is used to monitor warfarin therapy
PT
Why are Factor VIII and Factor IX not considered to be part of the extrinsic pathway?
Because the PT fails to identify their absence or deficiency
This complex in the intrinsic pathway is crucial to the activation of factor X
IXa:VIIIa complex
The 2 pathways (extrinsic and intrinsic) common factors are?
- Factor X
- Factor V
- prothrombin
- fibrinogen
The intrinsic and extrinsic pathways common factors are X, factor V, prothrombin, and fibrinogen. This portion of the coagulation pathway is often called as what pathway?
common pathway
T/F: Intrinsic, extrinsic, and common—are used extensively to interpret IN VITRO laboratory testing of blood plasma and to identify factor deficiencies. They also describe the complex interdependent reactions that occur IN VIVO.
F
(they do not adequately describe the complex interdependent reactions that occur in vivo)
T/F: The extrinsic and intrinsic pathways are not distinct, independent, alternative mechanisms for generating thrombin but are actually INTERDEPENDENT
T
Example:
[1] deficiency of factor VII in the extrinsic pathway can cause significant bleeding, even when the intrinsic pathway is intact
[2] deficiencies of factors VIII and IX may cause severe bleeding, regardless of the presence of a normal extrinsic pathway
Intrinsic pathway doesn’t involve what type of injury?
trauma type injury
Initiation of intrinsic pathway
Damaged blood vessel
In addition to procoagulant and anticoagulant plasma proteins, normal physiologic coagulation requires the presence of what 2 cell types, for the formation of coagulation complexes?
- Cells that
express TF (usually extravascular) - Platelets (intravascular)
Coagulation can be described as occurring in what 2 phases?
initiation and propagation phases
This phase occurs on tissue factor-expressing cells and produces 3% to 5% of the total thrombin generated.
Initiation phase
This phase occurs on platelets, which produces 95% or more of the total thrombin.
propagation phase
In vivo, the principle mechanism for generating thrombin is
begun by the formation of what complex?
extrinsic tenase complex
This phase refers to the extrinsic tenase complex formation and generation of small amounts of
factor Xa, factor IXa, and thrombin
The initiation phase
T/F: The magnitude of the localized response depends largely on
the extent of the injury, such as how large the bleed is, how much tissue is damaged, and how many platelets are available.
T
About how many percent of factor VIIa is present normally in blood in the activated form?
About 1% to 2%
Factor VIIa is inert until bound to?
TF
Factor VIIa is unaffected by?
TFPI and other inhibitors
Factor VIIa binds to TF on the membrane of subendothelial cells, to form what complex?
the extrinsic tenase complex TF:VIIa
TF:VIIa activates low levels of what 2 factors?
factor IX and factor X
A minute amount of thrombin is generated by
- membrane-bound
Xa - Xa:Va prothrombinase complexes
The initial minute amount of thrombin generates feedback to the coagulation
cascade, in order to activate which plasma factors?
- Factors V
- Factor VIII
- Factor XI
The activation of plasma factors V, VIII, and XI serves to amplify what?
Amplify more thrombin generation
Coagulation complexes bound to cell membranes are relatively protected by most inhibitors from being what?
inactivated
If Xa:Va complex dissociates from the cell, it is rapidly inactivated by?
- protease inhibitors TFPI
- Antithrombin
- ZPI
If Xa:Va dissociates from the cell, it is rapidly inactivated by protease inhibitors TFPI, antithrombin, and ZPI until what?
until a threshold of Xa:Va activity is reached
The amount of thrombin generated in initiation phase is small/large(?)
small
T/F: Even though the amount of thrombin generated in initiation phase is small, the platelets, cofactors, and procoagulants become activated.
T
What does the low level of thrombin generated in the initiation phase do:
(1) activates platelets through cleavage of protease activated receptors PAR-1 and PAR-4
(2) activates factor V released from platelet a-granules
(3) activates factor VIII and dissociates it from VWF
(4) activates factor XI, the intrinsic accessory
procoagulant that activates more factor IX
(5) splits fibrinogen peptides A and B from fibrinogen and forms a preliminary fibrin network.
The initial platelet is thus formed
Cleavage of fibrinopeptides from the fibrinogen molecule occurs at which part of the initiation and propagation phase?
- End of the initiation phase
- Beginning of the propagation phase
More than how many percent of thrombin generation occurs during propagation?
more than 95% of thrombin generation
In this phase the reactions occur on the surface of the activated platelet, which now has all the components needed for coagulation.
propagation phase
Platelets are activated at the site of injury by both the?
- Low level thrombin generated in the initiation phase
- Exposed collagen
Platelets partially activated by collagen
and thrombin are referred to as?
COAT platelets
Partially activated COAT platelets have a lower/higher(?) level of procoagulant activity than platelets exposed to collagen alone.
HIGHER level of procoagulant activity
The cofactors Va and VIIIa activated by thrombin in the initiation phase bind to?
platelet membranes
The cofactors Va and VIIIa bind to platelet membranes, and become receptors for what factors?
factors Xa and IXa
IXa generated in the initiation phase binds to what factor on the platelet membrane?
factor VIIIa
IXa generated in the initiation phase
binds to VIIIa on the platelet membrane to form what complex?
intrinsic tenase complex IXa:VIIIa
Does platelet-bound factor XIa generate more factor IXa ?
YES
The intrinsic tenase complex activates factor X at how many folds higher than the extrinsic
tenase complex?
50- to 100-fold higher rate
Factor Xa binds to Va to form what complex?
prothrombinase complex
What does prothrombinase complex do?
activates prothrombin and generates a
burst of thrombin
What procoagulant factor stabilizes the clot?
Factor XIII
Factor XIII is activated by?
thrombin
What pathway is activated when thrombin binds to thrombomodulin?
protein C control pathway
What inhibitor does thrombin activates to inhibit fibrinolysis?
TAFI
They prevent clotting from spreading to other parts of the body. 2 answers.
Protease inhibitors and intact endothelium
4 regulatory functions of inhibitors, or
natural anticoagulants
- Slow the activation of procoagulants
- Suppress thrombin production
- Ensure that coagulation is localized and is not a systemic response
- Prevent excessive clotting or thrombosis
The principal regulators of coagulation
- TFPI
- Antithrombin (AT)
- Activated protein C
(APC).
Acquired or inherited deficiencies of TFPI, antithrombin (AT), and activated protein C (APC), may
be associated with increased incidence of what disease?
venous thromboembolic disease
(because the hemostatic balance is shifted toward increased thrombin generation and coagulation)
A Kunitz-type serine protease inhibitor and is the principal regulator of the TF pathway.
TFPI (Tissue Factor Pathway Inhibitor)
What kunitz binds
to and inhibits factor Xa?
Kunitz-2 domain
What kunitz binds to and inhibits the
VIIa:TF complex?
Kunitz-1
TFPI is primarily synthesized primarily by what cells?
ECs
Aside form ECs, TFPI is also expressed on what cells?
platelets
In the initiation of coagulation, what factors combine to activate factors IX and X?
factor VIIa and TF
TFPI inhibits coagulation in how many steps?
two-step process
First step of TFPI to inhibit coagulation.
binding and inactivating Xa
2nd step of TFPI to inhibit coagulation.
The TFPI:Xa complex binds to TF:VIIa
What type of complex is formed when TFPI:Xa and TF:VIIa binds?
a quaternary complex
What does the quaternary complex of TFPI do?
prevent further activation of X and IX
Can TFPI bind to Factor Xa if Xa is already in the TF:VIIa:Xa complex?
yes
T/F: TFPI provides feedback
inhibition because it is not actively engaged until coagulation is
initiated and factor X is activated.
T
Protein S is the cofactor of which 2 principal regulators?
APC and TFPI
Protein S enhances what inhibitory actrion?
Factor Xa inhibition of TFPI
The TF:VIIa:Xa reaction is short lived because of?
Because of the inhibitory action of TFPI
What will happen once TFPI shuts down the extrinsic tenase complex and Xa?
Additional Xa and IXa production shifts to the intrinsic pathway.
During which phase of coagulation, does factor X activation by IXa:VIII and additional factor IX activation by XIa occur?
propagation phase
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
TFPI
F: With Xa, binds TF:VIIa
H-L: Unknown
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
Thrombomodulin
F: EC surface receptor for thrombin
H-L: Does not circulate, although soluble truncated forms can be measured
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
Protein C
F: Serine protease
H-L: 7–9
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
Protein S
F: Cofactor
H-L: Unkown
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
Antithrombin
F: Serpin (Serine protease inhibitor)
H-L: 68
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
Heparin cofactor II
F: Serpin (Serine protease inhibitor)
H-L: 60
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
Protein Z-dependent protease inhibitor
F: Serpin
H-L: Unknown
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
Protein C inhibitor
F: Serpin
H-L: 23
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
a1-Protease inhibitor (a1-antitrypsin)
F: Serpin
H-L: Unknown
Based on table 35.11, provide the function and half-life(hr) of this coagulation regulatory protein:
a2-Macroglobulin
F: Serpin
H-L: 60
In intact normal vessels, where coagulation would be inappropriate, thrombin avidly binds to what EC membrane protein?
thrombomodulin
Thrombin binding to thrombomodulin triggers an essential coagulation regulatory system called the?
protein C system
The protein C system revises thrombin’s function from a procoagulant enzyme to?
anticoagulant
A transmembrane protein that
binds protein C adjacent to the thrombomodulin-thrombin complex.
EC protein C receptor (ECPR)
EPCR augments the action of the thrombin-thrombomodulin of
at least how many folds, in activating protein C to the serine protease APC?
atleast fivefold
When the activated form of protein C dissociates from EPCR, it binds to its cofactor which is the?
free plasma protein S
The stabilized APC-protein S complex hydrolyzes and inactivates which factors?
factors Va and VIIIa
Protein S is synthesized in what organ?
liver
Protein S circulates in the plasma in how many forms?
2 forms
2 forms of protein S
- Free plasma protein S is free
- Protein S that covalently bound to the complement control protein C4b-binding protein (C4bBP)
About how many percent of protein S is free?
about 40%
About how many percent of protein S is covalently bound to
the complement control protein C4b-binding protein (C4bBP)?
about 60%
T/F: Bound protein S can participate in the protein C anticoagulant pathway
F (it cannot participate)
T/F: Bound protein S and free plasma protein S can both serve as the APC cofactor
F
only free plasma protein S can serve as the APC cofactor
Protein S-C4bBP binding is of particular interest in what conditions?
inflammatory conditions
Why is the binding of protein S to C4b-binding protein (C4bBP) particularly relevant in inflammatory conditions?
because C4bBP is an acute phase reactant
What happens to free protein S levels when plasma C4b-binding protein (C4bBP) levels increase?
free protein S levels become proportionally decreased
because more protein S is bound
More bound protein S and proportionally decreased level of free protein S may increase the risk of?
thrombosis
A vitamin K-dependent plasma glycoprotein that is synthesized in the liver
protein Z
cofactor of ZPI
protein Z
what does ZPI inhibit?
factor Xa
ZPI inhibits factor Xa with the help of what substances
protein Z, Ca, and phospholipids
Which serpins are involved in coagulation and fibrinolysis?
- ZPI
- protein C inhibitor
- α1-protease inhibitor
- α2-macroglobulin
- α2-antiplasmin
- PAI-1
T or F: There is a delicate balance between the activators and inhibitors in fibrinolysis
T
T or F: fibrinolytic process is activated in response to inflammation and coagulation
T
when is the fibrinolytic process activated
several hours after fibrin polymeration and thrombus formation
what happens to fibrinolytic proteins to concentrate and localize fibrinolysis to the site of injury?
it becomes incorporated into the fibrin clot
final stage of hemostatic activation
fibrinolysis
Suppresses fibrinolysis by removing firbin C-terminal lysine binding sites blocking TPA and plasminogen binding
TAFI
difference of TPA and UPA
TPA: secreted by activated endothelium
UPA: kidney cells
secreted by endothelium, inhibits tissue plasminogen activator
plasminogen activator inhibitor-1 (PAI-1)
define plasminogen
inactive form of plasmin
activates plasminogen
tissue plasminogen activator and urokinase plasminogen activator
