117, 119, 120: Hemostasis- Overview, Platelet Function, Coagulation, Fibrinolysis Flashcards
(131 cards)
1
Q
Deficiency in which component of hemostasis leads to Hemophilia B?
Does this affect primary or secondary hemostaiss?
A
Factor IX
This affects secondary hemostasis
2
Q
What is the function of prostaglandin I2 in endothelial cells?
A
Increases platelet cAMP to keep platelets in a quiescent, non-adherent state
3
Q
How does Von Wilebrand Factor trigger platelet activation?
List the steps
A
VWF engages platelets by binding Gp Ib-V-IX (aka Gp Ib, the receptor on platelets for VWF)
- Platelets restructure their actin cytoskeleton
- Rounding, extended pseudopodia
- Changing shape = platelet activation
- Platelets transmit intracellular signals
- Increased Ca2+ flux through platelets
- Integrin Gp IIb/IIIa (aka alpha-IIb-beta-3) activation
- Firm platelet adhesion and spreading
4
Q
What is the function of RAP 1 and Talin in platelet function?
A
RAP1 and Talin are activated by signals inside of the platelet that are initiated by signals at the surface
They function to make Gp IIb/IIIa a better receptor for fibrinogen at the platelet surface
(inside-out signaling)
5
Q
What is the difference between atherosclerosis and arteriosclerosis?
A
Arteriosclerosis is the stiffening or hardening of arterial walls
Atherosclerosis is a common form of arteriosclerosis, in which the artery narrows due to plaque buildup (deposits of cholesterol, lipids, and lipid-containing macrophages)
6
Q
Which deficiencies would inhibit platelet adhesion to the endothelium?
A
Deficiencies in…
- Von Willebrand Factor
- Gp Ib
7
Q
Which clotting factor catalyzes the crosslinking of fibrin?
A
FXIIIa
Thrombin activates FXIII to FXIIIa
8
Q
Which clotting factors are active in the intrinsic pathway?
A
Activated by silicates or phospholipids
- FXI is activated by…
- FXII (in the absense of tissue factor)
-
Priming thrombin (aka FIIa generated by TF/extrinsic pathway)
- Also activate FVIII, FV
- FXIa activates FIX
- FVIIIa + FIXa activate FX
- Tenase complex
Common pathway (where intrinsic and extrinsic converge)
- FXa + FVa cleave prothrombin to thrombin (FIIa)
- Prothrombinase complex
- Thrombin cleaves fibrinogen to fibrin
9
Q
What factors are normally expressed by blood vessels to prevent thrombosis?
A
- Non-adhesive surfaces
- Laminar flow
- Intact entodhelium shields underlying coagulation factors
- Platelet inhibiting factors
- Nitric Oxide
- Prostacyclin
- Adenosine Diphosphatase
- Anti-coagulant factors
- Thrombomodulin
- Endothelial Protein C receptor
- Heparin-Like molecules
- Tissure Factor pathway inhibitor
10
Q
What substances do endothelial cells produce in response to activated platelets?
A
- Monocyte chemoattractant protein 1 (MCP-1)
- Intracellular adhesion molecule (ICAM)
- ROS
11
Q
Where are arterial thrombi likely to occur?
A
Branch points with low-shear, turbulent flow and/or endothelial injury
12
Q
What is the tenase complex?
A
FVIIIa + FIXa
Activates FX -> FXa
13
Q
What 3 factors are released form endothelial weibel-palade bodies in primary hemostasis?
A
Endothelin -> vasoconstriction
VWF -> Platelet adherence and aggregation
P-Selectin -> Binds leukocytes and platelets to initiate rolling and activation
14
Q
What do dense granules in platelets contain?
A
- ADP
- ATP
- Serotonin
- Pyrophosphate
- Ca2+
15
Q
What is disseminated intravascular coagulation?
How does it occur?
A
Disseminated intravascular coagulation (DIC) is a paradoxical state that involves both excessive clotting and excessive bleeding
Uncontrolled coagulation
- > Coagulation factors/platelets get used up
- > Bleeding everywhere
16
Q
What activates FX?
A
Initiation: Tissue factor + FVIIa
Amplification: Tenase complex (FVIIIa + FIXa)
17
Q
What is the function of Nitric Oxide in endothelial cells?
A
Increases platelet cGMP to keep platelets in a quiescent, non-adherent state
18
Q
What is tissue factor?
A
A transmembrane glycoprotein that is de-encrypted from the membrane bilayer
19
Q
Prolonged PT and prolonged aPTT indicate which abnormality?
A
- Deficiencies in…
- FV
- FX
- FII (prothrombin)
- Fibrinogen
- Or deficiciencies in one of (FVIII, FIX, FXI) AND FVII
- Anticoagulant therapy
20
Q
During arterial thrombus formation, what activates leukocytes?
A
Thrombin and factor Xa, via protease-activated receptors (PARs)
21
Q
Which anti-coagulant components are induced by the coagulation cascade?
Why?
A
Activation of the coagulation cascade also triggerst the activation of factors to limit clot formation
- Produced normally by the endothelium:
- Thrombomodulin
- Endothelial protein C receptor
- Heparin-like molecules
- Tissue Factor pathway inhibitor
- Protein C
- Protein S
- Antithrombin III
22
Q
What are the 2 major classes of inhibitors of fibrinolysis?
List examples in each category
A
Inhibitors of fibrionolyis promote clot survival
- Inhibitors of plasminogen activation bind or degrade lysine binding sites on fibrin
- Plasminogen activator inibitor 1 (PAI-1)
- Lipoprotein A
- Thrombin activatable fibrinolysis inhibitor (TAFI)
- Activated Protein C inhibitor (APC inhibitor)
- Inhibitors of plasmin
- Antiplasmin
- Alpha-2 macroglobulin
- Pharmacologic lysine mimetics
- Eta-aminocaproid acid
- Tranexamic acid
- TADI
- Serine protease inhibitors
23
Q
Why does Adenosine Disphsphatase inhibit hemostasis?
Is it an anti-platelet or anti-coagulant?
A
ADP induces the conformational change in Gp IIb/IIIa that allows it to bind to fibrinogen
Adenosine diphosphatase is an anti-platelet agent produced normally by endothelial cells that breaks down ADP, preventing it from contributing to platelet activation
24
Q
List the major components involved in hemostasis
A
- Blood Vessels
- Platelets
- Glycoprotein receptors
- Alpha granules
- Dense granules
- Coagulation proteins
- Red and White blood cells
25
What is the role of the thrombin generated during **initiation?**
* Activate platelets
* Cleave FVIII from its attachment to VWF
* Activate FXI and FV
26
Deficiency in which component of hemostasis leads to Bernard Soulier Syndrome?
Does this affect primary or secondary hemostaiss?
Gp Ib
Affects primary hemostasis
27
Which phopholipid binding proteins work to inhibit coagulation?
How do they work?
* Annexin V
* Beta 2-glycoprotein-1
They bind to phophatidyl serine and prevent the attachment of coagulation complexes
28
In general, what do platelets do to promote atherosclerotic lesions?
Platelets adhere to the site of injury and secrete inflammatory mediators
29
Platelets produce superoxide ions.
What do they do?
Superoxide ions produced by platelets participate in...
* Nitric Oxide scavenging
* Lipid peroxidation
* Generation of other ROS
These function to activate platelets and macrophages in an **atherosclerotic legion**
30
Which glycoprotein receptors on platelets mediate primary hemostasis when activated?
What do they bind to?
**Gp 1b** binds to Von Willebrand Factor in the subendothelium
**Gp IIb/IIIa** binds to circulating fibrinogen. This begins the process of platelet aggregation
31
Describe the response to injury hypothesis
Atherosclerosis develops due to a chronic inflammatory/healing **response to endothelial injury**
* **Injury + dysfunction**
* -\> Accumulation fo LDL, oxidized LDL
* -\> Monocyte adhesion
* -\> Migration into intima
* -\> Macrophages become foam cells
* -\> Smooth muscle proliferation
* -\> ECM production
* -\> T-cell recruitment
* -\> Accumulation of lipids in the plaque
32
Which leukocyte receptor binds to platelet P-selectin?
What is the effect?
PSGL-1 (P-selectin glycoprotein ligand-1)
Binding of P-selectin to its receptor initiates leukocyte rolling
33
Which coagulation protiens are vitamin K dependent?
X, IX, VII, II
34
The component labeled #2 binds to Von Willebrand Factor
## Footnote
**What is it?**
Gp Ib
35
What is the function of the secretion phase of platelet activation?
Secretion activates the coagulation cascade, which activates **thrombin**
Activated thrombin...
* Increases **platelet activation**
* Activates fibrinogen to **fibrin**
36
List the 4 stages of hemostasis
1. Vasoconstriction
2. Primary hemostasis
3. Secondary hemostasis
4. Clot resolution
37
When fibrin polymers crosslink, which parts bind together?
The **glutamic acid of one D-domain** binds to the **lysine of an adjacent D-domain** to form a glutamyl lysine bridge.
This is catayzed by **FXIIIa.** Ca2+ is required!
38
Describe the steps of secondary hemostasis
1. The weak **platelet plug formed in primary hemostasis is stabilized** by progression of the coagulation cascade.
The coagulation cascade is triggered by exposed **tissue factor** that is present in subendothelial smooth muscle and fibroblast cells
Coagulation factors assemble on the negatively charged phospholipid surface on activated platelets **when linked by Ca2+**
2. Factors XII, XI, X, IX, VIII, VII, V, II (thrombin), Fibrinogen are involved
3. The end goal: **throbin (II) cleaves fibrinogen to fibren**
This causes cross-linking of fibrin and stabilization of the clot
39
Which coagulation protein cleaves fibrinogen to fibrin?
II (aka thrombin)
40
Deficiency in which component of hemostasis leads to Glanzmann Thromboasthenia?
Does this affect primary or secondary hemostaiss?
Gp IIb/IIIa
Affects primary hemostasis
41
What is the role of CD 39 ecto-ADPase in platelet function?
What inhibits it?
Normally, CD 39 ecto-ADPase has a role in maintaining platelet quiescence
It is inhibited by ROS produced by activated platelets, which promotes thrombosis
42
In venous thrombosis, how is tissue factor activated? What does it do?
Tissue factor is activated in response to platelet-leukocyte interactions
* Proinflammatory cytokines are secreted
* Platelet P-selectin binds to leukocyte PSGL-1
When tissue factor is activated, it **activates the clotting cascade via the extrinsic pathway**
43
Which test measures the function of the intrinsic clotting pathway?
Activated partial thromboplastin time (aPTT)
44
What is Antithrombin III?
What do they do?
Antithrombin III is an anti-coagulant protien that is activated by the coagulation cascade, to limit the clot. It is stimulated by heparin
**It inhibits:**
* **Thrombin**
* **IXa**
* **Xa**
* **XIa**
* **XIIa**
45
What is the function of antithrombin in coagulation?
How does it work?
Antithrombin inhibits...
* Thrombin
* Antithrombin acts as a bait that traps thrombin
* FIXa
* FXa
* FXIa
* FXIIa
Its action is potentiated by vessel wall proteoglycans and heparin
46
What is hemostasis?
The process by which blood clots from at the site of vascular injury to prevent or limit bleeding
47
What do alpha granules in platelets contain?
Pre-formed
* Beta-thromboglobulin
* Platelet derived growth factor (PDGF)
* Fibrinogen
* Coagulation Factor V
* Von Willebrand Factor
* High molecular weight kininogen
* RANTES
* CXCL 12
* CXCL 7
* CD40L
* P-Selectin
* Factors involved in wound healing
* Fibronectin
* Platelet factor 4 (CXCL4)
* Platelet-derived growth factor
* TGF-Beta
Synthesized
* Thromboxane A2
* Tissue Factor mRNA
* IL-1beta mRNA
* Superoxide ion
48
What activates plasminogen to plasmin?
Tissue plasminogen activator (t-PA) and urokinase (u-PA)
49
What is aPTT used for?
How is it initiated?
aPTT is initiated by adding silicate to activate FXII
It is used to evaluate deficiencies in the **intrinsic coagulation pathway**
* Hemophilia
* Deficiencies in FXI, FIX, or FVIII
* Von Willebrand Disease
* Monitor heparin and argatroban therapy
50
What activates FVIII?
Priming/trace thrombin (FIIa)
FVIII is activated when it is **cleaved from its attachment to VWF**
51
Which substances are produced by healthy endothelial cells to keep platelets in quiescence?
* Nitric Oxide
* Increases platelet cGMP
* Prostaglandin I2
* Increases platelet cAMP
* CD39 ecto-ADPase
* Removes ADP and ATP
52
What is the role of t-PA and u-PA in clot homeostasis?
t-PA and u-PA activate plasminogen to plasmin
Plasmin lyses fibrin clots by liberating cross-linked D-dimers
53
What is the prothrombinase complex?
What does it do?
Prothrombin + FXa + FVa
Activates prothrombin -\> thrombin
54
In the initiation phase of coagulation, what activates FV?
FXa
55
Describe the amplification phase of coagulation
* Priming/trace thrombin (FIIa) from initiation
* Cleaves FVIII from VWF to make **FVIIa**
* Activates FXI
* Activates FV
* FXIa ativates FIX
* F Va + platelets activates the **tenase complex**
* Tenase complex = FIXa + FVIIIa
* The tenase complex activates FX
* FXa + FVa activates prothrombin to **thrombin**
* ****Prothrombinase complex
* **Lots of thrombin is generated**
* Thrombin cleaves fibrinogen to **fibrin**
56
Normal PT and prolonged aPTT indicate what abormality?
Hemophilia, Von Willebrand Disease, or heparin use
(Deficienceis in FVIII, FIX, FXI)
57
Deficiency in factor IX would lead to which disease?
Hemophilia B
58
What secretes tissue factor pathway inhibitor (TFPI)?
Intact endothelial cells
59
What are the general differences between alpha granules and dense granules?
Both alpha and dense granules are contianed in platelets
* Alpha granules contain **proteins**
* Dense granules contain **small molecules**
60
What substances are secreted during the secretion phase of platelet activation?
Autocring, soluble secondary mediators that **activate and trap nearby platelets**
* ADP
* ATP
* Serotonin
* Thromboxane A2
61
Which way do arterial thrombi grow?
What about venous thrombi?
Arterial thrombi extend **retrograde to flow**
Venous thrombi extend in the **direction of flow**
62
When fibrin monomers polymerize to form a fibrin polymer, which parts bind together?
Non-covalnt bonds form between the **terminal D-domains of one molecule and the central E-domain of a 2nd molecule**
63
What is the role of P-selectin in primary hemostasi?
P-selectin is a lectin that binds leukocytes and platelets
Binding of P-selectin (platelets) to PSGL-1 (leukocytes) initiates rolling, and then release of tissue factor
64
Which factors are contained in the dense granules of platelets?
* ADP
* ATP
* Ionized Ca2+
* Serotonin
* Epinephrine
* Thromboxane A2
* Cyclooxygenase mediates the production of thromboxane A2
* Thromboxane A2 induces platelet aggregation
65
What is the role of leukocytes in the formation of atherothrombi?
Leukocyte-platelet interactions promote atherogenesis
* Leukocytes interact with **platelet P-selectins**, causing the expression of **platelet-derived cytokines**
* Leukocytes are activated by **thrombin and factor Xa**
66
Where does amplifacation of the coagulation cascade occur?
On the surface of platelets
Ca2+ is required to bind clotting factors to the the externalized phosphatidyl serine on the membrane
(Both are negatively charged)
67
What stimulates endothelial cells to produce MCP-1, ICAM, and ROS?
Activated platelets in an atherothrombosis
68
The component labeled #4 binds to Gp IIb/IIIa on multiple platelets, thus helping them aggregate.
## Footnote
**What is it?**
Fibrinogen
69
What is the role of endothelin in primary hemostasis?
Vasoconstriction
70
Which test measures the function of the extrinsic clotting pathway?
Prothrombin time (PT)
71
What are the 3 events that could initiate clotting?
Clotting is initiated when **blood is exposed to...**
* **A transmembrane protein**
* **Tissue factor**
* **A foreign surface**
72
Deficiency in which component of hemostasis leads to Hemophilia A?
Does this affect primary or secondary hemostaiss?
Factor VIII
Affects secondary hemostasis
73
What do intact endothelial cells secrete to inhibit coagulation?
* ADAMTS13
* Nitric Oxide
* Prostacyclin
* TFPI
* Thrombomodulin
74
Prolonged PT and normal aPTT indicate what abormality?
FVII deficiency
| (early liver disease)
75
Which leukocytes are the first responders in venous throbosis?
Monocytes and neutrophils
76
What is the function of CD39 ecto-ADPase in endothelial cells?
Removes ADP and ATP to keep platelets in a quiescent, non-adherent state
77
What is the function of thromboxane A2?
Throboxane A2 is produced in **activated platelets** by platelet cyclooxygenase via the thromboxane synthase complex
It functions to **activate new platelets** and **increase platelet activation**
78
Deficiency in Protein C and/or Protein S would lead to what phenotype?
Cannot stop clotting/cannot limit clot formation
79
What is the role of Protein C in coagulation?
Protein C is activated when **thrombin binds to thrombomodulin**
Activated protein C + free protein S (its cofactor) **cleave FVa and FVIIa to inactivate them**
This is an example of feedback inhibition to limit coagulation
80
What is the role of phospholipid scramblase in platelet activation?
When **p****hospholipid scramblase**is activated in response to high intracellular Ca2+, it**induces externalization of phosphatidyl serine**
This creates a negatively charged environment on the platelet surface, that when combined with **Ca2+,** is **ideal for coagulation factor assembly**
81
Deficiencies of which components of hemostasis would lead to problems with **primary hemostasis?**
VWF
Gp IIb/IIIa
Gp Ib
82
What activates FIX?
FXIa
83
How can venous thrombosis be protective?
It can seal off sites of infection and cell damage
84
What is the PT test used for?
How it it initiated?
It is initiated by **adding tissue factor**
It is used to evaluate deficiencies in the **extrinsic coagulation pathway**
* Liver disesase
* Low FVII
* Monitor warfarin therapy
85
The component labeled #3 resides in the subendothelium. When it is exposed upon injury, it binds to Gp Ib
## Footnote
**What is it?**
Von Willebrand Factor (VWF)
86
Which clotting factors are active in the extrinsic pathway?
* Tissue factor
* FVII
Common pathway (where intrinsic and extrinsic converge)
* FXa + FVa cleave prothrombin to thrombin (FIIa)
* Prothrombinase complex
* Thrombin cleaves fibrinogen to fibrin
87
Describe the alternate pathway of coagulation
An **alternative way to activate the intrinsic pathway**, if tissue factor is absent (and cannot generate trace amounts of thrombin through the extrinsic pathway)
* FXII is activated by polyphosphate when it binds to...
* Neutrophil extracellular traps (NETS) or
* Negatively charged surfaces
* FXIIa activates FXI, which re-joins the intrinsic pathway
* FXIa actiavates FIX
* FIXa + FVIIIa activate FX
* FXa + FVa cleave prothrombin -\> Thrombin
* Thrombin cleaves fibrinogen -\> Fibrin
Note: FXIIa also activates prekallikrein, which is active in immune function
* Promotes autoactivation
88
What is the role of polyphosphate in coagulation?
Polyphosphate is a negatively charged molecule that is released from injured tissues and platelets
It accelerates the activation of FXII
89
Which glycoprotein receptor on platelets binds to collagen to promote platelet adhesion?
GP Ia-IIa
90
What is the role of FXII in coagulation?
In the absence of tissue factor, **FXII will activate the alternate pathway**
* FXII is activated by polyphosphate when it binds to
* Neutrophil extracellular traps (NETS) **or**
* Negatively charged surfaces
* FXIIa activates prekallikrein
* Promotes autoactivation
* FXIIa activates FXI, **which re-joins the intrinsic pathway**
* FXIa actiavates FIX
* FIXa + FVIIIa activate FX
* FXa + FVa cleave prothrombin -\> Thrombin
* Thrombin cleaves fibrinogen -\> Fibrin
91
What is Factor V Leiden?
What phenotype does it lead to?
Factor V Leiden is a genetic muation that leads to **resistance to activated protein C**
People with this mutation have trouble limiting clot formation, resulting in **excessive clotting**
92
What is the effect of FXII deficiency?
* **No bleeding problems**
* Normally, the tissue factor pathway initiates the generation of trace amounts of thrombin, which activate the intrinsic pathway
* FXII only plays a major role in the absence of tissue factor
* May affect the **immune response**
* Due to lack fo prekallikrein
* May affect some clotting tests
* aPTT
93
Which glycoprotein receptor on platelets binds to cologen and promotes platelet activation?
GP VI
94
Deficiency of Gp IIb/IIIa would lead to which disorder?
What step of hemostasis would be inhibited?
Glanzmann Thromboasthenia
Deficiency of Gp IIb/IIIa means that platelets canot bind fibrinogen, and therefore cannot aggregate
95
Why is the **amplification** step necessary for clotting?
The trace amounts of thrombin (FIIa) made during initiation are inhibited by **Tissue Factor Pathway Inhibitor (TFPI)**
Initiation generates enough thromin to...
* Activate platelets
* Cleave VIII from its attachemnt to VWF
* Activate FXI and FV, **which work to amplify the coagulation pathway**
96
In which layer of arteries do atherosclerotic plaques form?
Intimia/inner media of large and medium-sized arteries
97
Describe the steps of primary hemostasis
1. **Platelet Adhesion:** Gp 1b binds to exposed VWF
2. **Platelet Activation:** They change shape induced by ADP
**Gp IIb/IIIa** undergoes a conformational change that increases its affinity for fibrinogen (mediated by ADP)
**Negatively charged phospholipids** are sent to the platelet surface. In combination with **Ca2+,** they provide a site for assembly of the coagulation factor complexes
3. Platelets **secrete granule contents** when they are activated
Activate the coagulation cascade
Throboxane A2 is produced
4. **Platelet aggregation** via binding Gp IIb/IIIa of multiple platelets to fibrinogen. Initial aggregation is reversible
RBCs, WBCs become trapped in platelet aggregate
98
Describe the steps of venous thrombus formation
* Endothelial activation and leukocyte recruitment
* Monocytes and neutrophils respond first
* Leukocyte rolling
* Involves selectins
* Platelet : Leukocyte interactions via...
* Proinflammatory cytokines
* P-selectin (platelet) : PSGL-1 (leukocyte)
* PSGL-1 = P-selectin glycoprotein ligand-1
* Tissue factor is exposed and activated in response to ^
* **Activation of the clotting cascade** (via extrinsic pathway)
* **Development of venous thrombosis**
99
Deficiency in factor VIII would lead to which disease?
Hemophilia A
100
What protein factors (bioactive lipids) are synthesized by activated platelets?
What do they do?
* IL-1 beta
* Increases endothelial cell adhesion
* Increases cytokine production
* Matrix metalloproteinases
* Promote ECM degradation and remodeling
* ROS
* Increaes consuption of NO
* Inhibits CD39 ecto-ADPase (normally participates in quiescence)
* Can contribute to activation of new platelets
101
What is the role of TFPI?
TFPI binds FXa to inhibit the common pathway
TFPI inhibits the TF:FVIIa complex to inhibit the tissue factor (extrinsic) pathway
102
Do platelets play a bigger role in arterial throbosis or venous thrombosis?
Arterial
(More RBC and fibrin in venous thrombosis)
103
Deficiency (\<30%) of which clotting factors would prolong both PT and aPTT?
FV, FX, FII (prothrombin)
104
What are the three major complications of atherosclerotic lesions?
* Stenosis
* Weakening of the aterial wall
* -\> Aneurysm/rupture
* Plaque rupture
* Thrombosis or embolization
105
List the 4 phases of platelet activation
1. **Adhesion** - Binding to the subendothelial matrix
2. **Activation** - Change from quiescent -\> promote hemostasis
3. **Secretion** - Release of granule contents
4. **Aggregation** - Binding to other platelets through active Gp IIb/IIIa
106
In the initiation phase of fibrin formation, what activates FX?
Tissue factor + FVIIa
107
What is the role of phosphatidyl serine in platelet activation?
When **posphatidyl serine** is externalized by activated phospholipid scramblase (in respone to high intracellular Ca2+), its **negative charge** **makes the surface of the platelet ideal for coagulation factor assembly.**
108
The component labeled #1 binds to fibrinogen
**What is it?**
Gp IIb/IIIa
109
What activates FXII?
FXII is usually inert
It is activated when it is exposed to **surface polyphosphates and white blood cells**
110
What is the role fo annexin V and Beta 2-glycoprotein-1 in coagulation?
These phospholipid binding proteins **inhibit coagulation**
They bind to phophatidyl serine and prevent the attachment of coagulation complexes
111
What factors live in the subendothelium that promote coagulaton when exposed?
Von Willebrand Factor
Collagen
Tissue Factor
112
Describe the tissue factor pathway
* Tissue fator + FVIIa activate FX
* FXa activates FV
* FXa + FVa cleave prothrombin to thrombin
* Prothrombinase complex
* **Trace amounts of thrombin (FIIa) are generated**
* Cleaves FVIII from its attachement to VWF
* Activates FXI and FV
* **These work to generate more thrombin during amplification**
113
What is the cutoff for normal PT?
Normal is \<13s
114
What are platelets?
Disk-shaped cell fragments that shed into the blood from **megakaryocytes** (myeloid lineage stem cells in the bone marrow)
Platelets do not contain nuclei
They can change shape easily
115
In an environment of atheroma formation, would you expect to find an inflammatory state or anti-inflammatory state?
Inflammatory
Activated platelets put factors into their environment that promote inflammation and atheroma formation
116
Why do hemophiliacs bleed even though the extrinsic pathway is uninhibited?
The trace amounts of thrombin generated by the tissue factor (extrinsic) pathway are not enough to overcome TFPI and initiate coagulation
You need the ampilifcation step of the intrinsic pathway (which involves FVIII, FIX, FXI) in order to generate sufficient thrombin for coagulation
117
Deficiencey of Gp Ib would lead to which disease?
Which step of hemostasis would be inhibited?
Bernar Soulier Syndrome
Platelets would be unable to bind to VWF in the endothelium. This would prevent platelets from **adhering** to the endothelium and **activating**
118
What is the role of Ca2+ in coagulation?
Ca2+ is the limiting factor of coagulation
It links the externalized, **negatively charged phosphatidyl serine** on the membrane of the platelets to the **negatively charged clotting factors**
119
How does plasmin affect fibrin clots?
Plasmin is an enxyme that lyses fibrin clots by liberating cross-linked D-dimers
120
What inside of platelets activates the aggregation/procoagulation response on the platelet surface?
High cytosolic Ca2+ in platelets
* Activates phospholipid scramblase
* Causes externalization of phosphatidyl serine externalization
* Surface of platelet becomes negatively charged
* **With Ca2+, the surface of the platelet is able to host coagulation factor assembly**
* **Thrombin and fibrin can be generated**
* **Lipid rafts with tissue factor are shed as microparticles**
****
121
What are Protein C and Protein S?
What do they do?
Protein C and Protein S are anti-coagulant protiens that are activated by the coagulation cascade, to limit the clot
## Footnote
**They inhibit factors Va, VIIIa**
122
What is prekallikrein? What does it do?
* **Prekallikrein** is the precursor of the serine protease **kallikrein. Prekallirein** is cleaved by FXIIa to Kallikrein, which...
* Activates FXII (**Autoactivation**)
* Converts HMWK to **bradykinin**
* Converts plasminogen to **plasmin**
* Activates **complement** formation
* Converts prorenin to **renin**
123
What is the cutoff for normal aPTT?
Normal is \<34s
124
What activates FV?
Initiation: FXa
Amplification: Priming amount of thrombin (FIIa)
125
What is the role of cathepsins in primary hemostasis?
Cathepsins are secreted by leukocytes after they have migrated into tissues
They **activate platelets** to form **leukocyte-platelet aggregates**
**This promotes the formation of the temporary hemostatic plug**
126
Describe the steps of arterial thrombosis
* **Platelets interact with VWF and collagen**
* Rolling and adhesion begins
* Gp Ib : VWF
* alpha2-beta1 (Gp Ia-IIa) : Collagen
* **Platelets are activated**
* Ca2+ flux leads to shape changes and Gp IIb/IIIa activation
* **Platelets form firm adhesions** via receptor : ligand interactions
* alpha-IIb-beta-3 (Gp IIb/IIIa) : Fibrinogen, VWF
* alpha-5-beta-1 : Fibronectin
* **Leukocytes are recruited** by platelet chemokines
* Leukocytes interact with platelet P-selectin
* Cytokines expressed by platelets
* **Platelet-leukocyte interactions promote atherogenesis**
* **Leukocytes are activated** by thrombin and factor Xa via protease-activaeted receptors
127
What are the first endothelial factor that interacts with platelets after injury?
* Von Wilebrand Factor
* Collagen
* Basement Membrane Proteins
Function to interact with platelets and induce rolling
128
How does thrombin activate fibrinogen to fibrin?
What makes it so strong?
* Thrombin cleaves **fibrinopeptides A and B** from fibrinogen
* This **exposes the knobs, so they can bind to pockets**
* ****-\> Aggregation of fibrin monomers
* -\> Formation of fibrin polymer by linking terminal D-domains to central E comains
* Thrombin activates FXIII
* FXIIIa catalyzes crosslinking = **strength**
* Glutamic acid of one D-domain binds to the lysine of an adjacent D-domain to form a **glutamyl lysine bridge**
129
What activates FXI?
Priming/trace thrombin (FIIa)
130
What role do microparticles play in hemostasis?
Microparticles carry tissue factor, which is critical for initiating the coagulation pathway via the extrinsic pathway.
They arise from leukocytes, macrophages, and platelets
| (The extrinsic pathway produces trace thrombin (FIIa) that activates the intrisic pathway)
131
What is a D-dimer?
How is it produced?
A D-dimer is a cross-linked fragment of fibrin
It is produced when a clot is lysed by plasmin
