Hemostasis Flashcards
What are the 4 steps of Hemostasis?
•Composed of four steps:
- vascular spasm
- formation of a platelet plug
- formation of a blood clot
- repair of damage
What is a platelet?
Derived from megakaryocyte (fragment)
150,000 - 300,000/ um^3 normal range
What organs produce THROMBOPOIETIN (TPO)?
Produced by liver, kidney
What is the receptor on Platelets that binds TPO?
The MPL receptor.
What happens when TPO binds to MPL?
•binds to the mpl (CD-110) receptor
•found on platelets,
megakaryocytes & other
hematopoietic cells.
• JAK2/STAT5
• phosphorylation and
subsequent transcription and
translation of various genes.
If high number of platelets then it is taken up by platelets and destroyed. not much free to act on megakaryocytes.
If low number of platelets then it is free. Increases differentiation of stem cells & maturation rate.
How can you get polycythemia vera?
A mutation in the TPO receptor on
platelets has recently been
implicated in causing polycythemia
vera – the platelets are unable
internalize & destroy the TPO, so its
action becomes continuous.
What does a normal platelet contain?
•actin & myosin
- cell contraction
- empty vesicles*
•mitochondria (ATP & ADP*)
•remnants of the ER
(Ca++ storage)
- Cyclooxgenase (COX1)
- thromboxane A2*
- fibrin stabilizing factor (clot stability)*
- Platelet-derived growth factor(repair)*
- Serotonin (5-HT)
Where do platelets comes from?
• Platelets are cell fragments derived from megakaryocytes.
• Production of platelets is controlled by thrombopoietin.
•Under normal conditions, TPO is continually secreted by
the liver and kidney, but destroyed by the platelets.
•If platelet levels drop, there is less destruction of TPO, so
TPO can act.
•TPO acts on ALL cell lineages.
What is a vascular spasm?
•Myogenic response to injury – Vascular smooth muscle
contracts on own.
•Serotonin (5HT) and Thromboxane A2 from platelets
contributes.
•Minor contribution from a neural reflex.
•Reduces blood loss by slowing/stopping blood flow out.
How is a platelet plug formed?
With damage to vessel wall
•collagen exposed
•platelets will bind to collagen (2 step
process)
Part I:
Von Willebrand Factor
• Plasma protein
• bind between collagen and platelet (receptor).
Part 2:
•binding of platelet receptor
(integrin) to collagen
HEMOSTASIS:
Step 2 - Formation of a platelet plug
Activation of platelet
• platelet swells
• extends podocytes.
- platelets swell.
- contraction
- granules leave platelet.
- platelets stick to vessel wall and
to each other
(thromboxane A2 & ADP)
•Platelet plug stops
bleeding from small
breaks - nose, skin.
How does blood coagulation occur?
3 essential steps:
•Formation of prothrombin activator
•Activation of thrombin
•Creation of fibrin from fibrinogen
•Clot retraction
Clot Retraction
•get rid of excess fluid within clot
•solidify clot
•platelets required
•bind fibrin polymer together
•actin and myosin in platelet -
contraction
•also requires calcium
What does Platelet-derived Growth Factor do?
Secreted by platelets:
•Platelet-derived Growth Factor
• stimulate fibroblast to grow into
area.
• Fibroblasts differentiate into smooth
muscle, etc… to close the hole.
How are clots removed?
Plasminogen
•made by liver
•floating in plasma
•not active form
Activation of Plasminogen
•Tissue plasminogen activator
•released by damaged tissue
•activation is inhibited by tPA inhibitor
(blood)
• Relies on delayed activation of a fibrinolytic enzyme
(plasmin) that is found in the blood in an inactive form
(plasminogen).
• Plasminogen is prevented from becoming active by a
plasmin inhibitor, while activation requires tissue
plasminogen activator (tPA) released from the damaged
tissue.
• The binding of thrombin to thrombomodulin activates
Protein C, which inactivates the plasmin inhibitor.
• Once the inhibitor is inactivated, tPA can convert
plasminogen to plasmin.
• Plasmin breaks down fibrin to remove the clot.
What systems limit clotting?
• Because the enzymes of the clotting cascade are always
present in the blood, we have to work to prevent clotting that
is not required.
• Factors that limit clotting include:
• Smooth endothelial lining of the vessels.
• Continuous flow of blood (preferably not turbulent).
• Platelet repelling action of the glycocalyx.
• A variety of endogenous anti-coagulants, including fibrin,
heparin, prostacyclin, and anti-thrombin III.
•Protein C, when activated, inactivates factors V and VIII.
What is Thrombocytopenia?
< 25,000: spontaneous bleeding.
• Platelet plug failure (not closing “normal”
breaks)
• Causes:
•stem cell damage
•leukemia
•TPO or mpl gene mutation.
