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What do platelets have? What do they lack?
platelets contain glycogen granules (dense & alpha), mitchondria, lysosomes (80% of ATP from glycolysis, 20% from OP)
no nucleus, dna, or protein synthesis.
- the granules are a source of ADP, ATP and serotonin (major store of body serotonin)
- alpha-grannules contain clotting factors and PDGF
What is the intrinsic pathway of platelet aggregation?
- Caused by collagen exposure- converged to final common pathway
- triggered by conversion of Factor 12-> Factor 12A
What is the extrinsic pathway of platelet aggregation?
Triggered by trauma , activating factor 7-> factor 7a, which releases tissue factor
How is vitamin K involved in clotting?
- Vitamin K is essential in prothrombin synthesis
- Lack of vitamin K forms abnormal prothrombin (can't bind Ca2+)
Vitamin K antagonists
structural similarities between vitamin K and vitamin K antagonists
- Dicoumarol- find in spoiled sweet clover
- Warfarin- takes 2-3 days to work/high CYP2c9 polymorphism
Drug induced thrombocytopenia
<50,000 PLATELETS / uL; usually 100,000 platelets/ uL
- life-threatening depletion of platelets caused by heparin/drug antibody+factor IV complexing together (not immune memory related, as the antibodies don't last too long)
- -leads to increased thrombosis events (hemorrhage, brusiing nose bleeds, bloody stool)
other drugs that can cause it: quinidine, NSAIDs, penicillin, methotrexate
How do platelets repair broken blood vessels?
- Platelets secrete platelet derived growth factor (PDGF)
- Membrane actin and myosin contract causing platelets attached to fibrin being retracted (retracts the clot) and edges of broken blood vessels being pulled together
- Platelets may be collected and stored for use in surgeries, transplants and cancer therapy to stop bleeding
What does PDGF do?
- Causesproliferation + migration of vascular endothelial cells,smooth muscle cells, and fibroblasts
- helps repairing damaged vascular walls
What is the structure of membrane phospholipids?
- Glycerol backbone (3-carbons) with
- a) fatty acid at position 1 (variable fatty acids)
- b) Arachidonic acid (constant)
- c) polar moiety at position 3 (choline, serine Inositol, ethanolamine)
What are some properties of PGH
Serves as a precursor for thromboxanes, prostaglandins and prostacyclins
Most precursors are large and without activity, but PGH is a small molecule precursor without activity.
How do cox inhibitors (e.g. low-dose aspirin) prevent colon cancer?
Cox inhibitors ill decrease the number of PGG2 that is available to peroxidase.
Since peroxidase also detoxifies carcinogens by oxidation, less PGG2 will mean more carcinogen is detoxified.
What can PGH2 convert to? How does it know which to convert to ?
- TXA2 (platelets-promotes clotting)
- PGI2 (endothelium-prevents clotting)
- PGE 2 (isomerase)-> PGF2A (reductase)
- PGD2 (isomerase)
the converting enzyme is present/not present in the cell.
What does COX-1 do?
- Found in all cells
- PG cytoprotection (especially stomach, kidney) by PGE
- TXA in platelets (clotting function)
inhibitors: aspirin (non-reversible), NSAIDs, antithrombosis drugs (but can cause renal/stomach lesions)
What does COX-2 do?
- Found in inflammatory cells and the brain
- mediates inflammation and pain
- induced by cytokines, mitogens, endotoxins (contributes to rheumatoid arthritis)
- promote colon cancer by preventing apoptosis
- causes premature labour
Inhibitors: nimesulid (selective NSAID), vioxx
- Aspirin-irreversible acteylation of Ser530, prevents arachidonic acid binding (only acetylates Cox-1, inhibits cox-2)
- Mefenamate, Ibuprofen- reversible, competitive with fatty acid binding
- Flurbiprofen- slow binding (salt bridge) competitive inhibition by binding in the hydrophobic channel
- Indomethacin- binds deepest in hydrophobic channel, risk of CHF+hypertension unlike celecoxib
- Celecoxib-black box labelled
- Vioxx- withdrawn
Functions of endothelium in blood pressure regulation
- Extracellular activity
- 1) angiotensin converting enzyme
- 2) ATPase and 5'-nucleotidase degrade ATP and ADP (from platelets)
- 3) Inactivateprostaglandins E and F, and leukotrienes C4 and D4
- Intracellular activity:
- 4) Monoamine oxidase
- 5) Thromboplastin synthesis and secretion (activated state of endothelium) initiate blood clotting
- 6) Synthesis and secretion of plasminogen activators initiates clot fibrinolysis (resting endothelium state)
- Plasma Membrane Activity7) Prostacyclin synthesis and release in resting state (PGI2) prevents platelet aggregation (PGI2 inhibited by some COX-2 inhibitors like rofecoxib)
- 8)endothelium derived relaxing factor/NO
ACE is inhibited by specific dipeptides (sideeffects include agranulocytosis-> lack of neutrophils)
- Angiotensinogen-411 a.a. (liver)
- Renin (protease, synthesized in kidney)
- Angiotensin I- 10 a.a.
- Angiotensin II- 8.a.a
How does smoking affect endothelium function?
- Smoking results in inhaled carbon monoxide
- Carbon monoxide inhibits plasminogen activator, resulting in a procagulant, and anti-fibrinolytic state (leading to thrombophillia)
- 1. Complex Ca2+ with citrate or oxalate
- 2. Heparin* helps remove thrombin (produced by mast cells)
Dugs that generate NO*
- Amyl Nitrite
Amyl nitrite uses
- 1) prescription drug- in glass ampules that are popped and inhaled to relieve angina
- 2) aphrodisiac