R&C Chapter 4 - Hemodynamic Disease Flashcards
What are the main steps of hemostasis?
- Arteriolar vasoconstriction
- Primary hemostasis - platelet plug
- Secondary hemostasis - fibrin deposition
- Clot stabilization & resorption
What is the main factor involved in arteriolar vasoconstriction?
Endothelin
How do platelets initially bind to disrupted endothelium (receptor and ligand)?
von Willebrand Factor (vWF) on subendothelial collagen glycoprotein Ib (GpIb) on platelet
What is the main type of collagen in the ECM?
Type 1
What is the main type of collagen in the cell basement membrane?
Type 4
Which organs have continuous capillaries?
Muscle Brain Thymus Bone Lung Fat
Which organs have fenestrated capillaries
Intestinal villi Kidney glomeruli Endocrine glands Choroid plexus Ciliary process of eye
Which organs have discontinuous capillaries?
Spleen
Liver
Bone marrow
What triggers binding of fibrinogen to GpIIb-IIIa?
ADP
What is Glanzmann thrombasthenia a deficiency of?
GpIIb-IIIa
What is Bernard-Soulier syndrome a deficiency of?
GpIb
What are contained within platelet alpha granules?
P-selectin Fibrinogen Factor 5 & 8 vWF Thrombospondin Fibronectin Platelet factor 4 PDGF TGF-B
What are contained within platelet dense granules?
Ionized calcium ADP & ATP GDP & GTP Vasoactive amines: serotonin, histamine Epinephrine
On exposure to ECM, platelets undergo:
- Adhesion
- Shape change
- Activation
- Secretion
- Aggregation
What two actions constitute “platelet activation”?
Granule secretion + shape change
What triggers platelet activation?
Thrombin
ADP
How does thrombin trigger platelet activation?
Platelet’s protease activator receptor (PAR) cleaved by thrombin
What molecule is translocated to the platelet surface during shape change, and what is its function?
Phosphatidylserine
Provide binding site for calcium (foundation for coagulation factor complex assembly)
What is the role of calcium in coagulation reactions?
Holds components together by binding to y-carboxylated glutamic residues
What are fibrin degradation products (FDPs) formed from?
Dissolution of insoluble/cross-linked fibrin
Which molecule localizes neutrophils to fibrinogen?
alpha-m-B2 integrin
Thrombomodulin is downregulated by which molecules?
IL-1
TNF
TGF-B
Endotoxin
Chediak-Higashi Syndrome has what coagulative abnormality?
Defective platelet storage of ADP
What are the functions of kallikrein?
Chemotactic Activates factor 9 Cleaves C3 --> C3a + C3b Cleaves HMWK --> bradykinin Cleaves plasminogen to plasmin
Vitamin K is a cofactor in which reaction?
Conversion of glutamic acid to y-carboxyglutamic acid
What are the Vitamin K dependent coagulation factors?
Factors 2, 7, 9, 10
Protein C & S
What are substances that inhibit conversion of glutamic acid to y-carboxyglutamic acid?
Dicumarol (Moldy sweet clover/Melilotus alba)
Warfarin
Sulfaquinoxaline
What inherited coagulation disorder do Devon Rex cats have?
Deficient binding of y-glutamyl carboxylase to Vitamin K
PTT measures what clotting pathway?
Intrinsic
PT measures what clotting pathway?
Extrinsic
What factors are evaluated with PTT?
1, 2, 5, 8, 9, 10, 11, 12, 13
What factors are evaluated with PT?
1, 2, 5, 7, 10, 13
What is the PTT protocol?
Add negative particles (glass beads), phospholipids and calcium to plasma, then measure time to form fibrin clot
What is the PT protocol?
Add tissue factor, phospholipids and calcium to plasma, then measure time to form fibrin clot.
What cell produces/releases tissue factor?
Activated/injured endothelial cells
Subendothelial fibroblasts and smooth muscle cells
What molecules activate endothelial cells to produce tissue factor?
Endotoxins IL-1 TNF TGF-B Thrombin
Inflammation leads to hypercoagulability via:
Increased: TF, platelet reactivity, fibrinogen, phosphatidylserine, PAI-1
Decreased: thrombomodulin
Vascular B2 receptors stimulated by epinephrine result in:
Vasodilation
Vascular alpha receptors stimulated by norepinephrine result in:
Vasoconstriction
Brain vasculature lacks which type of receptor?
Alpha receptors (vasoconstriction)
Which molecules result in retraction of cross-linked fibrin clot?
Calcium, ATP
Which factor is responsible for cross-linking of fibrin clots?
Factor 13a
Which two extrinsic pathway factors combine to activate factor 10?
Tissue factor
Factor 7a
Which intrinsic pathway factors combine to activate factor 12?
HMWK
Pre-kallikrein
Factor 12
What does activated factor 12 activate?
Factor 11 Factor 7 Kinins Kallikrein Plasminogen
Which extrinsic pathway factors combine to activate factor 10?
Factor 8a
Factor 9a
What activates factor 7?
Factor 2a Factor 9a Factor 10a Factor 12a Kallikrein
Which factors does thrombin activate?
Factors 1, 5, 7, 8, 11, 13
Which factors does factor 10 activate?
Factors 2, 13
Which factors does the TF-factor 7 complex activate?
Factor 9, 10
Factor 9 is activated by which factors?
Factor TF-7a
Factor 11a
Kallikrein
What activates factor 8?
Thrombin
What activates factor 5?
Thrombin
What activates factor 13?
Thrombin, Factor 10a
What activates fibrinogen?
Thrombin
Thrombin is which factor number?
2a
Fibrin is which factor number?
1a
Tissue factor is which factor number?
3
Which organ produces prothrombin?
Liver
Where are y-carboxylated glutamic acid residues acquired?
Liver
What are the functions of thrombin?
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
What conditions trigger thrombin to become an anti-coagulant?
Encounters normal endothelium and binds thrombomodulin
Excess production
What are the anticoagulant activities of thrombin?
Stimulate endothelial cells to produce tPA, NO, PGI2
Activates protein C
Destroys factor 5 & 8 (instead of activates)
What is the function of plasmin?
Breaks down fibrin and interferes with fibrin polymerization
What activates plasminogen?
Factor 11, 12
Kallikrein
Tissue plasminogen activator (tPA)
What cell synethesizes tissue plasminogen activator (tPA)?
Endothelial cells
What stimulates tissue plasminogen activator (tPA) activity?
Binding with fibrin
What inhibits plasminogen/plasmin?
Plasminogen activator inhibitor (PAI) Anti-plasmins: - alpha-2 antiplasmin - antithrombin III - alpha-2 macroglobulin - alpha-2 antitrypsin - C1 inactivators?
What do antiplasmins inhibit?
Plasmin
Activated protein C
What are the functions of PAIs?
Inhibit tissue plasminogen activator (tPA) and urokinase
Inactivates activated protein C, plasmin and thrombin
What are the anticoagulant factors produced by endothelial cells?
PGI2 NO Thrombomodulin Protein C receptor Protein S Heparin-like molecules Tissue plaminogen activator (tPA) Adenosine diphosphatase Annexin V Tissue Factor Pathway Inhibitor (TFPI)