R&C Chapter 4 - Hemodynamic Disease Flashcards

1
Q

What are the main steps of hemostasis?

A
  1. Arteriolar vasoconstriction
  2. Primary hemostasis - platelet plug
  3. Secondary hemostasis - fibrin deposition
  4. Clot stabilization & resorption
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2
Q

What is the main factor involved in arteriolar vasoconstriction?

A

Endothelin

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3
Q

How do platelets initially bind to disrupted endothelium (receptor and ligand)?

A
von Willebrand Factor (vWF) on subendothelial collagen
glycoprotein Ib (GpIb) on platelet
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4
Q

What is the main type of collagen in the ECM?

A

Type 1

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5
Q

What is the main type of collagen in the cell basement membrane?

A

Type 4

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6
Q

Which organs have continuous capillaries?

A
Muscle
Brain
Thymus
Bone
Lung
Fat
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7
Q

Which organs have fenestrated capillaries

A
Intestinal villi
Kidney glomeruli
Endocrine glands
Choroid plexus
Ciliary process of eye
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8
Q

Which organs have discontinuous capillaries?

A

Spleen
Liver
Bone marrow

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9
Q

What triggers binding of fibrinogen to GpIIb-IIIa?

A

ADP

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10
Q

What is Glanzmann thrombasthenia a deficiency of?

A

GpIIb-IIIa

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11
Q

What is Bernard-Soulier syndrome a deficiency of?

A

GpIb

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12
Q

What are contained within platelet alpha granules?

A
P-selectin
Fibrinogen
Factor 5 & 8
vWF
Thrombospondin
Fibronectin
Platelet factor 4
PDGF
TGF-B
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13
Q

What are contained within platelet dense granules?

A
Ionized calcium
ADP & ATP
GDP & GTP
Vasoactive amines: serotonin, histamine
Epinephrine
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14
Q

On exposure to ECM, platelets undergo:

A
  1. Adhesion
  2. Shape change
  3. Activation
  4. Secretion
  5. Aggregation
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15
Q

What two actions constitute “platelet activation”?

A

Granule secretion + shape change

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16
Q

What triggers platelet activation?

A

Thrombin

ADP

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17
Q

How does thrombin trigger platelet activation?

A

Platelet’s protease activator receptor (PAR) cleaved by thrombin

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18
Q

What molecule is translocated to the platelet surface during shape change, and what is its function?

A

Phosphatidylserine

Provide binding site for calcium (foundation for coagulation factor complex assembly)

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19
Q

What is the role of calcium in coagulation reactions?

A

Holds components together by binding to y-carboxylated glutamic residues

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20
Q

What are fibrin degradation products (FDPs) formed from?

A

Dissolution of insoluble/cross-linked fibrin

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21
Q

Which molecule localizes neutrophils to fibrinogen?

A

alpha-m-B2 integrin

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22
Q

Thrombomodulin is downregulated by which molecules?

A

IL-1
TNF
TGF-B
Endotoxin

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23
Q

Chediak-Higashi Syndrome has what coagulative abnormality?

A

Defective platelet storage of ADP

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24
Q

What are the functions of kallikrein?

A
Chemotactic
Activates factor 9
Cleaves C3 --> C3a + C3b
Cleaves HMWK --> bradykinin
Cleaves plasminogen to plasmin
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25
Q

Vitamin K is a cofactor in which reaction?

A

Conversion of glutamic acid to y-carboxyglutamic acid

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26
Q

What are the Vitamin K dependent coagulation factors?

A

Factors 2, 7, 9, 10

Protein C & S

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27
Q

What are substances that inhibit conversion of glutamic acid to y-carboxyglutamic acid?

A

Dicumarol (Moldy sweet clover/Melilotus alba)
Warfarin
Sulfaquinoxaline

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28
Q

What inherited coagulation disorder do Devon Rex cats have?

A

Deficient binding of y-glutamyl carboxylase to Vitamin K

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29
Q

PTT measures what clotting pathway?

A

Intrinsic

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30
Q

PT measures what clotting pathway?

A

Extrinsic

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31
Q

What factors are evaluated with PTT?

A

1, 2, 5, 8, 9, 10, 11, 12, 13

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32
Q

What factors are evaluated with PT?

A

1, 2, 5, 7, 10, 13

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33
Q

What is the PTT protocol?

A

Add negative particles (glass beads), phospholipids and calcium to plasma, then measure time to form fibrin clot

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34
Q

What is the PT protocol?

A

Add tissue factor, phospholipids and calcium to plasma, then measure time to form fibrin clot.

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35
Q

What cell produces/releases tissue factor?

A

Activated/injured endothelial cells

Subendothelial fibroblasts and smooth muscle cells

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36
Q

What molecules activate endothelial cells to produce tissue factor?

A
Endotoxins
IL-1
TNF
TGF-B
Thrombin
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37
Q

Inflammation leads to hypercoagulability via:

A

Increased: TF, platelet reactivity, fibrinogen, phosphatidylserine, PAI-1

Decreased: thrombomodulin

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38
Q

Vascular B2 receptors stimulated by epinephrine result in:

A

Vasodilation

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39
Q

Vascular alpha receptors stimulated by norepinephrine result in:

A

Vasoconstriction

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40
Q

Brain vasculature lacks which type of receptor?

A

Alpha receptors (vasoconstriction)

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41
Q

Which molecules result in retraction of cross-linked fibrin clot?

A

Calcium, ATP

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42
Q

Which factor is responsible for cross-linking of fibrin clots?

A

Factor 13a

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43
Q

Which two extrinsic pathway factors combine to activate factor 10?

A

Tissue factor

Factor 7a

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44
Q

Which intrinsic pathway factors combine to activate factor 12?

A

HMWK
Pre-kallikrein
Factor 12

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45
Q

What does activated factor 12 activate?

A
Factor 11
Factor 7
Kinins
Kallikrein
Plasminogen
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46
Q

Which extrinsic pathway factors combine to activate factor 10?

A

Factor 8a

Factor 9a

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47
Q

What activates factor 7?

A
Factor 2a
Factor 9a
Factor 10a
Factor 12a
Kallikrein
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48
Q

Which factors does thrombin activate?

A

Factors 1, 5, 7, 8, 11, 13

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49
Q

Which factors does factor 10 activate?

A

Factors 2, 13

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50
Q

Which factors does the TF-factor 7 complex activate?

A

Factor 9, 10

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51
Q

Factor 9 is activated by which factors?

A

Factor TF-7a
Factor 11a
Kallikrein

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52
Q

What activates factor 8?

A

Thrombin

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53
Q

What activates factor 5?

A

Thrombin

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54
Q

What activates factor 13?

A

Thrombin, Factor 10a

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55
Q

What activates fibrinogen?

A

Thrombin

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56
Q

Thrombin is which factor number?

A

2a

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57
Q

Fibrin is which factor number?

A

1a

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58
Q

Tissue factor is which factor number?

A

3

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59
Q

Which organ produces prothrombin?

A

Liver

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60
Q

Where are y-carboxylated glutamic acid residues acquired?

A

Liver

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61
Q

What are the functions of thrombin?

A

Conversion of fibrinogen to fibrin
Platelet activation (activates PAR)
Pro-inflammation (activates PAR on leukocytes)
Vascular repair (stimulates endothelial cells and macrophages to produce PDGF)
Pro- and anti-coagulation

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62
Q

What conditions trigger thrombin to become an anti-coagulant?

A

Encounters normal endothelium and binds thrombomodulin

Excess production

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63
Q

What are the anticoagulant activities of thrombin?

A

Stimulate endothelial cells to produce tPA, NO, PGI2
Activates protein C
Destroys factor 5 & 8 (instead of activates)

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64
Q

What is the function of plasmin?

A

Breaks down fibrin and interferes with fibrin polymerization

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65
Q

What activates plasminogen?

A

Factor 11, 12
Kallikrein
Tissue plasminogen activator (tPA)

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66
Q

What cell synethesizes tissue plasminogen activator (tPA)?

A

Endothelial cells

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67
Q

What stimulates tissue plasminogen activator (tPA) activity?

A

Binding with fibrin

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68
Q

What inhibits plasminogen/plasmin?

A
Plasminogen activator inhibitor (PAI)
Anti-plasmins:
- alpha-2 antiplasmin
- antithrombin III
- alpha-2 macroglobulin
- alpha-2 antitrypsin
- C1 inactivators?
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69
Q

What do antiplasmins inhibit?

A

Plasmin

Activated protein C

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70
Q

What are the functions of PAIs?

A

Inhibit tissue plasminogen activator (tPA) and urokinase

Inactivates activated protein C, plasmin and thrombin

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71
Q

What are the anticoagulant factors produced by endothelial cells?

A
PGI2
NO
Thrombomodulin
Protein C receptor
Protein S
Heparin-like molecules
Tissue plaminogen activator (tPA)
Adenosine diphosphatase
Annexin V
Tissue Factor Pathway Inhibitor (TFPI)
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72
Q

What are the pro-coagulant factors produced by endothelial cells?

A

Tissue factor
von Willebrand’s Factor
Plasminogen Activator Inhibitor-1
Antiplasmin: Anti-thrombin III

73
Q

What vascular repair factors are produced by endothelial cells?

A

PDGF
TGF-B
FGF

74
Q

What are the functions and source of prostacycline (PGI2)?

A

Vasodilation
Inhibits platelet activation and adhesion
Endothelial cells

75
Q

What are the functions and source of nitric oxide?

A

Vasodilation
Inhibits platelet aggregation
Suppresses thrombin pathway (acts w/ protein C and ATIII)
Endothelial cells

76
Q

What are the functions and source of thrombomodulin?

A

Binds and inactivates thrombin –> protein C activation

Endothelial cells

77
Q

What are the functions, source and cofactors of Protein C receptor?

A

Enhances protein C activity –> inhibition of factors 5a & 8a
Endothelial cells (Protein C = Liver)
Protein S, vitamin K

78
Q

What are the functions and source of Protein S?

A

Cofactor for protein C and TFPI
Inhibits factor 5, 8, 10 activation
Endothelial cells & platelets

79
Q

What are the functions and source of heparin-like molecules?

A

Bind & concentrate ATIII on endothelial surface
Accelerates ATIII activity
Enhances release of TFPI from endothelial cells
Endothelial cells

80
Q

What are the functions and source of tissue plasminogen activator (tPA)?

A

Stimulates conversion of plasminogen to plasmin

Endothelial cells

81
Q

What are the functions and source of adenosine diphosphatase?

A

Degrades ADP to inhibits its procoagulatory effects

Endothelial cells

82
Q

What are the functions and source of annexin V?

A

Inhibits formation of thrombin and factor 10a
Binds negatively charged phospholipids and Ca2 (displaces other coagulation factors)
Endothelial cells

83
Q

What are the functions, source and cofactor of tissue factor pathway inhibitor (TFPI)?

A

Inhibits TF-7a complex
Inhibits factor 10
Endothelial cells & platelets
Protein S

84
Q

What are the functions of tissue factor?

A

Complex with 7a to start extrinsic pathway

85
Q

What are the functions and source of von Willebrand’s Factor?

A

Allow platelet GpIB binding

Endothelial cells

86
Q

What are the functions and source of plasminogen activator inhibitor-1 (PAI-1)?

A

Inhibitors plasminogen activators tPA and uPA
Inhibits activated protein C, thrombin, plasmin
Endothelial cells & platelets

87
Q

What are the functions and source of antiplasmin antithrombin III (ATIII)?

A
Degrades all activated coagulation factors (EXCEPT 7) 
Inhibits plasmin and kallikrein activity
Inhibits kinin formation
Inhibits complement activation
Binds heparin on endothelial surfaces
Endothelial cells
88
Q

What are the functions and source of endothelin?

A

Vasoconstriction

Endothelial cells

89
Q

What cytokines do endothelial cells produce?

A

IL-1, 6, 8

90
Q

What leukocyte adhesion molecules do endothelial cells produce?

A
MAdCAM-1
ICAM-1
VCAM-1
PECAM-1
P-selectin
E-selectin
91
Q

What are the anti-coagulant factors produced by platelets?

A

Adenosine triphosphate (ATP)
Protease Nexin II
Tissue Factor Pathway Inhibitor (TFPI)
Protein S

92
Q

What are the pro-coagulant factors produced by platelets?

A
Thromboxane A2
Phospholipids (ex. phosphatidyl serine)
Adenosine diphosphate (ADP)
Calcium
Platelet Factor 4
Thrombospondin
Fibrinogen
Factors 5, 11, 13
von Willebrand Factor
Antiplasmins: a2 antiplasmin and a2 macroglobulin
Plasminogen Activator Inhibitor-1 (PAI-1)
Serotonin
93
Q

Which vascular repair factors are produced by platelets?

A
PDGF
TGF-B
B-thromboglonulin
VEGF
EGF
94
Q

What is the hemostastic-related function and cellular source of ATP?

A

Inhibits platelet aggregation

Platelets - dense granules

95
Q

What is the function and cellular source of protease nexin II?

A

Inhibits factor 11a

Platelets

96
Q

What is the function and cellular source of TFPI?

A

Inhibits TF/7a complex of intrinsic pathway

97
Q

What is the function and cellular source of thromboxane A2?

A

Induces vasoconstriction
Enhances platelet aggregation
Platelets

98
Q

What is the function and cellular source of phosphatidylserine?

A

Provides site for coagulation reactions

Platelets

99
Q

What is the function and cellular source of ADP?

A

Mediates platelet aggregation and activation

Platelets - dense granules

100
Q

What is the hemostatic-related function and cellular source of calcium?

A

Cofactor in coagulation reactions (2, 7, 9, 10, 11)

Platelets - dense granules

101
Q

What is the function and cellular source of Platelet Factor 4?

A

Promotes platelet aggregation
Inhibits heparin reaction
Platelets - alpha granules

102
Q

What is the function and cellular source of thrombospondin?

A

Platelets - alpha granules

103
Q

What is the function and cellular source of fibrinogen?

A

Fibrin precursor
Concentrated by binding to platelet receptor GpIIb-IIIa
Platelets - alpha granules

104
Q

What is the function and cellular source of factor 5?

A

Enhances factor 10 conversion of prothrombin to thrombin

Platelets - alpha granules

105
Q

What is the function and cellular source of factor 11?

A

Converts 9 to 9a

Platelets

106
Q

What is the function and cellular source of factor 13?

A

Cross-links fibrin clots

Platelets

107
Q

What is the function and cellular source of von Willebrand factor?

A

Promotes platelet adhesion to subendothelial collagen via platelet receptor GpIb
Platelets - alpha granules

108
Q

What is the function and cellular source of antiplasmins?

A

Inhibit plasmin

Platelets

109
Q

What is the function and cellular source of serotonin?

A

Vasoconstriction

Platelets - dense granules

110
Q

What is the function and cellular source of B-thromboglobulin?

A

Promotes fibroblast chemotaxis

Platelets

111
Q

What are the disorders of primary hemostasis?

A
Thrombocytopenia
Platelet dysfunction (ex. receptors)
von Willebrand Factor deficiency
112
Q

What is hemophilia A?

A

Factor 8 deficiency

113
Q

What is hemophilia B?

A

Factor 9 deficiency

114
Q

How are hemophilia A & B inherited?

A

X-linked

115
Q

What molecules does activated endothelium downregulate and what is the net effect?

A
Procoagulative state
Thrombomodulin
Protein C receptor
TFPI
PAI
116
Q

What viruses result in endothelial injury?

A
Canine adenovirus-1
Equine morbillibirus (Hendra)
Equine herpesvirus
Equine arterivirus/arteritisvirus
Ovine orbivirus (blue tongue)
Bovine pestivirus (BVD)
Porcine pestivirus (CSF)
117
Q

What bacteria result in endothelial injury?

A

Salmonella typhimurium
Mannheimia hemolytica
Erysipelothrix rhusiopathiae
Haemophilus somni

118
Q

What fungi result in endothelial injury?

A

Aspergillus
Mucor
Absidia
Rhizopus

119
Q

What parasites result in endothelial injury?

A
Strongylus vulgaris larvae
Dirofilaria immitis
Spirocerca 
Aelurostrongylus
Angiostrongyles
120
Q

What are immune-mediated causes of vasculitis?

A

Purpura hemorrhagica

Feline infectious peritonitis

121
Q

What are toxic causes of endothelial injury?

A

Endotoxins

Claviceps

122
Q

What are nutritional causes of endothelial injury?

A

Vitamin E/seleneium deficiency (microangiopathy)

123
Q

What conditions cause hypercoagulability via enhanced platelet activity?

A
Diabetes mellitus
Nephrotic syndrome
Malignant neoplasia
Heartworm disease
Uremia
124
Q

What conditions cause hypercoagulability via increased clotting factor activation?

A

Nephrotic syndrome
DIC
Neoplasia

125
Q

What conditions cause hypercoagulability via antithrombin III deficiency?

A

DIC
Hepatic disease
Glomerular amyloidosis

126
Q

What conditions cause hypercoagulability via metabolic abnormalities?

A

Hyperadrenocorticism
Hypothyroidism
Amyloidosis

127
Q

In the hyperdynamic stage of sepsis, stimulation of lactate production and subsequent lactic acidosis is the result of______.

A

Epinephrine stimulated aerobic glycolysis

128
Q

What metabolic abnormality decreases neutrophil function?

A

Insulin resistance/hyperglycemia

129
Q

Insulin resistance is related to impaired surface expression of what molecule?

A

GLUT-4 (glucose transporter)

130
Q

What ATP breakdown product results in hydroxyl radicals?

A

Hypoxanthine

131
Q

LPS binds which receptors?

A

CD4, TLR4

132
Q

LPS activation of endothelial cells leads to _____.

A

Inhibition of anticoagulant products (ex. TFPI, thrombomodulin)

133
Q

LPS activation of monocytes and macrophages leads to _____.

A

Production of TNF, IL-1, IL-6, IL-8 and chemokines

134
Q

LPS directly activates:

A

Factor 12

Complement –> C3a + C3b

135
Q

What feature of the osteoblastic hematopoietic stem cell niche favors stem cell quiescence and self-renewal?

A

Hypoxia

136
Q

What drugs can cause platelet dysfunction?

A

COX inhibitors
B-lactam antibiotics
Calcium channel blockers

137
Q

In the tissue factor pathway, tissue factor on the vessel wall requires ____ to generate fibrin.

A

Protein disulfide isomerase

138
Q

Antithrombin III degrades all activated coagulations except ____.

A

7a

139
Q

What is the integrin version name of GpIIbIIIa?

A

aIIbB3

140
Q

Platelet Factor 4 and Thrombospondin share whicht two functions?

A

Promote platelet aggregation

Inhibit heparin action

141
Q

Which of the anti-plasmins are first to bind and neutralize plasmin?

A

Alpha-2 antiplasmin

142
Q

Which anti-plasmins are the major inhibitors of activated protein C?

A

Alpha-2-antitrypsin

Alpha2-antiplasmin

143
Q

What is the most common canine inherited coagulopathy?

A

vWF

144
Q

What is the most common bovine inherited coagulopathy?

A

Factor 11

145
Q

Which inherited coagulopathies are associated with no to mild bleeding?

A
1 (Except goats)
2
7
9 (except large dogs)
12
Pre-kallikrein
146
Q

Which inherited coagulopathies are associated with severe bleeding?

A

8
10
11
Vitamin K deficiency

147
Q

Which growth factor is often inappropriately high in patients with ITP?

A

TPO (thrombopoietin)

148
Q

How are aged platelets normally cleared?

A

Desialylated –> recognized and cleared by hepatic Ashwell-Morell receptors –> trigger liver to produce more TPO

149
Q

Which receptor does TPO bind to on megakaryocytes?

A

MpI (myeloproliferative leukemia protein)

150
Q

Megakaryocyte presentation of what endogenous molecule can lead to a CD8+ T cell immune response and thrombocytopenia?

A

CD61 (platelet GpIIIa)

151
Q

How does platelet clearance differ in mice with ITP?

A

Opsonized with anti-platelet antibodies –> cleared by hepatic and splenic reticuloendothelial cells (no Ashwell-Moreel receptor feedback)

152
Q

What is the CD name for platelet GpIIb?

A

CD41

153
Q

Which CD is expressed exclusively on platelets and megakaryocytes?

A

CD41

154
Q

Which mutation is commonly associated with polycythemia vera (PV)?

A

JAK2

155
Q

Which (mutually exclusive) mutations are commonly associated with essential thrombocytopenia (ET)?

A

JAK2
CALR
MPL

156
Q

What does CALR encode for?

A

Calcium binding protein chaperone for ER

157
Q

Hereditary thrombotic thrombocytopenic purpura is associated with what mutation?

A

ADAMTS13

158
Q

What is the normal function of ADAMTS13?

A

Metalloproteinase (zinc and calcium dependent) that cleaves newly synthesized, non-globular vWF to appropriate size for function

159
Q

What is decreased ADAMTS13 activity associated with?

A

Increased size of vFW multimers

Increased risk of microvascular thrombosis

160
Q

What are the principal sources of ADAMTS13?

A

Endothelial cells and hepatic stellate cells

161
Q

How is ADAMTS13 released and how does it circulate?

A

Active form

Closed conformation with CUB domain backfolded

162
Q

What conditions allow interaction of vWF with ADAMTS13?

A

Shear stress –> unfolds vWF multimers (globular form) –> exposes platelet binding sites (A1) and ADAMTS13 cleavage sites (A2)

163
Q

What molecules regulates megakaryocyte endomitosis?

A

Stathmin
Phosphorylation/inactivation: mitotic spindle formation
Hypophosphorylation/activation: polploidization due to lack of spindle formation

Levels decrease in late stage MK

164
Q

What correlates with the number of platelets ultimately produced from megakaryocytes?

A

DNA content (ploidy)

165
Q

What platelet glycoproteins link to what molecules under low shear stress?

A

GpIIb-IIIa to fibrinogen

166
Q

What platelet glycoproteins link to what molecules under high shear stress?

A

GpIb-IX-V and collagen link to vFW bridge

167
Q

What are the platelet shape change agonists?

A
ADP
Collagen
Epinephrine
Thrombin
Thromboxane
Platelet activating factor
168
Q

What are the three main inducers of platelet aggregation?

A

ADP
TXA2
Thrombin (binds to GpIIbIIIa receptor with ADP and TXA2, and converts fibrinogen to fibrin)

169
Q

Which platelet glycoproteins bind exposed collagen?

A

GpVI

GpIa/IIa

170
Q

What is the decrease in and severity of vWF type I?

A

Partial decrease in all multimers

Mild

171
Q

What is the decrease in and severity of vWF type II?

A

Decrease in HMW multimers (excessive cleavage by ADAMTS13)

Severe

172
Q

What is the decrease in and severity of vWF type III?

A

Decrease in activity

Severe

173
Q

Which coagulation factors get consumed during clotting?

A

Factor 5
Factor 8
Fibrinogen

174
Q

All clotting factors are made in the ____, except Factor ___ which is made by____.

A

Liver
8
Endothelial cells, platelets

175
Q

Which lab clotting test is first to be prolonged with Vitamin K deficiency?

A

PT (extrinsic and common)

176
Q

Which lab clotting test requires platelets to work?

A

ACT (activated clotting time)

177
Q

What does thrombin time measure?

A

Conversion of fibrinogen to fibrin

178
Q

Which clotting factors do non-mammals lack?

A

12, prekallikrein and HMWK

11 (low to absent)

179
Q

What can trigger activation of latent TGF-B?

A
Integrin binding
Proteases and MMPs (2 and 9)
Acidic pH
ROS
Thrombospondin-1