Karius Hemostasis Flashcards
Hemostasis
the steps taken by the body to limit blood loss, but hemostasis is NOT confined only to the blood clot
Hemostasis four steps
- vascular spasm
- formation of platelet plug
- formation of a blood clot
- repair of damage
TPO
thrombopoietin (TPO)
protein hormone with an amine terminal similar to erythropoietin (EPO) but unique carboxyl terminal
TPO stimulates megakaryocytes to produce platelets
made by liver and kidney
in liver, the parachymal sinusoidal cells
in the kidney, the proximal convoluted tubules
stimulus for its release is uncertain
EPO
erythropoietin TPO
produced in liver, stimulates red blood cell production in the bone marrow in response to hypoxia
produced by liver and kidney
Platelet production control
they bind thrombopoietin to their mpl receo
mpl receptors
found in platelets, megakaryocytes, and other hematopoietic cells
utuilized Jak/Stat and phosphorylation, subsequent transcription and translation of various genes
a high number of platelets indicates
lots of TPO bound to the mpl receptors. they internalize signal and destroy it.
not much free to act on megakaryocytes
not much free TPO in the body or to act on megakaryocytes
low number of platelets indicates
small amount of TPO bound to platelets; TPO is not being destroyed
there’s LOTS of TPO free in the blood
TPO increases
increases differentiation of stem cells and maturation rate/
effects on all cell lines
megakaryoblast –> ______ —> ____
megakaryocyte, platelet (thrombocytes)
TPO acts on
all cell lines in the body
polycythemia vera
mutation in TPO receptor
, platelets unable to internalize and destrou TPO so its actions become continuous
platelet internal mechanisms (7 things)
actin and myosin for cell contraction and emptying vesicles
mitochondria for ATP and ADP
remnant of the ER (for calcium storage)
COX1 (prostaglandin production
Cox1 produces thromboxane A2
Fibrin Stabilizing Factor (clot stability)
Platelet derived growth factor (repair)
Serotonin
Platelet membrane becomes ____ when activated. It also contains important ________ and receptors for ______
sticky, phosholipids, collagen
If platelet levels drop, what happens to TPO
their quantity increases, so they can act
If platelet levels increase, what happen to TPO
their quantity decrease, and their destruction marks them off from acting
What cell lines does TPO act on?
all cell line
Erythropoiesis vs Thrombopoiesis
What is their respective sources?
Ery - kidneys and liver
Thrombo - liver
what triggers EPO and TPO release?
EPO: low oxygen
TPO: constitutive (constant)
Control of EPO and TPO hormones, respectively
EPO: Hypoxia Inducible Factor (HIF) accumulation in renal cells
TPO: internalization/destruction of TPO
Receptors for EPO and HPO release
EPoR and MPL
Cells that express receptors for EPO vs HPO
EPoR expressed by pluripotent stem cell, RBC precursors
MP: pluripotent stem cells, platelets, all hematopoietic cell lines
Erythropoietin’s effect
causes daughter cells in Erythroid cell line to undergo mitosis
Thrombopoietin’s effect
increases division and maturation of all blood cell lineages
Hemostasis: step 1
MYOGENIC spasm induces vascular occlusion.
occurs spontaneously in response to injury, no neurons or reflexes involved
Platelet factors include
serotonin and thromboxane A2 contribute to spasm
“contributing factors” to the vascular spasm (step 1 of hemostasis)
neural reflex from nociceptors (mechanical response)
not sufficient or necessary for spasm to occur, minor contribution
Hemostasis Step 2: overview of steps
formation of the platelet plug followed by binding of platelets to exposed collagen (two step process)
Hemostatic plug formation step 2: platelet activity
a. binds to exposed collagen at site of injury using VWF
1. uses Von Willebrand Factor 2. plasma protein 3. bind between collagen and platelet receptor
b. platelet integrin receptor binding to collagen
during the second phase of a hemostatic plug formation, what do platelets do upon activation?
- swell and extend podocytes
- contraction
- granules leave platelet
- platelets stick to vessel wall and each other
What do thromboxane A2 and ADP do
they are released during self aggregation of platelets
Hemostasis Step 3: role and steps
blood coagulation
- formation of prothrombin activator
- thrombin activation
- conversion of fibrinogen to fibrin
leading to CLOT RETRACTION
Hemostasis step 3: Clot Retraction
This step gets rid of excess fluid in the clot to solidify it.
Platelets are required (to bind fibrin together, as well as their actin/myosin platelet contractions)
also requires calcium
Hemostasis step 4
Repair of damage
Repair of damage
Platelet secretion of Platelet derived fibroblast growth factor
stimulates fibroblasts to grow into area
fibroblasts grow into smooth muscle etc to close the hole
Getting rid of the clot
achieved by plasminogen
floating freely in blood
tPA: tissue plasminogen activator, released by damaged tissues.
tPAi: inhibits tPA, in the blood
Thrombomodulin is located on the
endothelial cell, and bind thrombin
Thrombomodulin activates thrombin on the endothelial cell: what does it activate
Protein C, which inactivates tPAi, allowing tPA to activate Plasminogen from zymogen form: Plasminogen —> Plasmin
plasmin lysis fibrin
Prevention of Clotting: the role of smooth surfaces
prevents platelets from rupturing
Prevention of clotting: the role of membrane proteins
endothelial cell glycocalyx repels platelets
thrombomodulin activates thrombin
Chemicals which limit clotting (4)
- Fibrin: binds thrombin and prevents it working
- Prostacyclin (PG12) made by injured cells, limits platelet aggregation
- Antithrombin III: binds and prevents thrombin from working
- Heparin: made from mast cells, increases efficacy of antithrombin
Protein C
Inhibits tPAi AND inactivates the VIIIa–Va complex responsible for activating prothrombin
what is the outcome of TPO being internalized by platelets?
they are destroyed, so they cant stimulate other hematopoietic cell lines
mpl biochemical pathway
JAK/STAT
JAK2 activated —> STATs 1, 3, 5 activated (Stat 1/3 dimerize, stat 5 homodimerizes
TPO actions on megakaryocytes, platelets, and other hormone interactions
causes SIZE and NUMBER of megakaryocytes to increase
causes platelet specific markers to develop
stimulates endomitosis and polyploidy of megakaryocytes
works with erythropoietin to stimulate RBC production
works with IL-3, or Steel Factor to upregulate RBC and WBC factors to differentiate
Platelets: actin and myosin?
just like in skeletal muscle, they have cross bridges that undergo cycling causing contraction of the cell
they help SQUEEZE extra fluid out of clot
help empty vesicles
Cyclooxygenase (COX 1)
enzyme that catalyzes production of thromboxane A2. prostaglandins
Fibrin Stabilizing Factor
XIII, causes covalent bonds to form between fibrin monomers
platelet derived growth factor
aids in repair of damaged tissue
what does Thromboxane do exactly?
binds to GPCR on smooth muscle and triggering calcium release
causes an increase in IP3
causes release of calcium from intracellular stores of the smooth muscle cell
how is the platelet held in place during clot formation?
two points of contact: von willebrand factor between collagen and platelet, and integrins on the platelets interacting with the collagen
