Platelets in health and disease

Question 1

What receptor on the megakaryocyte binds thrombopoietin?

Answer 1

the c-mpl receptor

Question 2

platelets play roles in?

Answer 2

Primary homeostasis
Wound healing
Inflammation
Angiogenesis

Question 3

Name some medicines that effect platelet function

Answer 3

Aspirin
Diclofenac
Citalopram
Simvastatin

Question 4

How many platelets per litre of blood?

Answer 4

150-400 x 10^9

Question 5

Where are platelets made?

Answer 5

by megakaryocytes in bone marrow trephine
MKC’s located next to BM sinusoidal endothelial cells
filopodia extend into capillaries
each MKC creates about 4000 platelets

Question 6

What is the most important driving factor in thrombocytopoiesis?

Answer 6

Thrombopoietin, binds to c-mpl receptor

Question 7

Platelet homeostasis

Answer 7

numbers maintained at constant level
require 40,000 new platelets/ micro litre of blood / day
life span = 7-10 days
consumption = senescence OR utilisation in homeostasis

Question 8

Platelet ultrastructure

• electron dense granules
• alpha granules

Answer 8

• Ca2+, Mg2+, ATP, ADP, serotonin
• coagulation factors (fibrinogen, factor 5, VWF)
  platelet derived growth factor, TGF-beta
  heparin neutralising factor, thrombospondin (bind heparin, protect surface coagulation reactions)

Question 9

Primary hemostasis, definitions and steps

Answer 9

the process of forming a platelet plug at the site of vessel injury (BV’s are constantly healing all the time, this is normal)
1. the initial phase of the process is vascular constriction (need to pull platelets onto site and activate them)
platelets become activated, and aggregate at the site of injury, forming a temporary, loose platelet plug
a) Von-Hillenbrand factor binds to exposed collagen –> big protein that forms into multimers (long chains)
b) activated platelets release factors to recruit more platelets and form a surface for coagulation cascade

Question 10

Closer look at coagulation

Answer 10

VW factor adheres to collagen
VW factor attaches to platelet via protein 1B-V-IX
Once platelet activated, get exposure of intergrin alpha(IIb)beta(3)

Question 11

Secretions of healthy endothelium vs secretions of damaged endothelium

Answer 11

Healthy = PGI2 and NO 
Damaged = ADP, TxA2,

Question 12

platelet aggregation cascade

Answer 12

1. Adherence to collagen
2. activation of prostaglandin synthesis
3. thromboxane A2
4. release reaction
5. ADP coagulation activation
   a) thrombin released –>activates clotting cascade
   b) IIb/IIIa fibrinogen receptor expression
   = aggregation

Question 13

How does aspirin affect platelets

Answer 13

inhibits the formation of arachidonic acid, blocks this pathway of platelet activation, but there are still others
take 10 days for the effect of aspirin to completely wear off, as the inhibition is irreversible

Question 14

Thromboxane A2 synthesis in platelets and production of prostacyclin by endothelial cells + aspirin

Answer 14

thromboxane A2 = decrease platelet cAMP = release
Prostacyclin =
- inc platelet cAMP
- inhibits release
- prevents platelet aggregation on normal endothelium
Aspirin
- covalent acetylation of cyclooxyrgenase
- dec thromboxane A2 (enzyme modification permanent)

Question 15

The P2Y(12) receptor

Answer 15

irreversibly blocked by clopidigrel

Question 16

The GPIb-IX-V

Answer 16

binds VW factor

Question 17

Quiescence

Answer 17

NO and PGI2 are released from intact endothelium
Levels of intracellular cyclic nucleotides are elevated
PKA and PKG suppress platelet activation

Question 18

Activation

Answer 18

collagen and thrombin initiate activation following vascular injury
platelets secrete secondary mediators ADP and TxA2

Question 19

Thrombus growth

Answer 19

PLC, PKC, and PI3K support sustained platelet activation 
Intergrin alpha(IIb)beta(3) binds fibrinogen and supports aggregation

Question 20

The breakdown of reasons why platelets can increase of decrease in a patient

Answer 20

DEC production 
- viral infection (EBV, dengue fever) 
- Drugs 
- Bone marrow failure (aplastic anaemia, leukaemia, carcinoma, megaloblastosis) 
INC destruction 
- immune thrombocytopenia (ITP, DIC) 
INC production 
- myeloproliferative neoplasms (polycythemia vera, essential thrombocytopenia, primary myelofibrosis)

Question 21

How do platelets participate in response to vessel injury?

Answer 21

vessel wall

coagulation cascade

Question 22

What is the EDTA effect?

Answer 22

some people get clumping of their blood from the preservative in the blood tube vials

Question 23

thrombocytopenia - what? causes?

Answer 23

= lack of platelets in blood 
causes 
DEC production 
- selective dec megakeryocyte (viral or drugs) 
- general BM failure (aplasia, leukaemia)
INC destruction 
- immune thrombocytopenia 
- other autoimmune e.g. SLE
- Drugs 
- DIC
- viral infection 
OTHER
- hypersplenisim (can cause mild thrombocytopenia cos all the platelets are sitting in there) 
- massive transfusion

Question 24

Immune thrombocytopenia

Answer 24

autoimmune destruciton of sensitised platelets and megakaryocytes
give prednisone then wean them off and see how they go, if still bad take out there spleen, new drug TPO (thrombopoietin-mimetics), binds to thrombopoietin receptor on megakaryocytes in marrow and stimulates to make more platelets (2nd line med)

Question 25

platelet function defect myelodysplasia

Answer 25

class of bone marrow diseases where the way the cells are made is affected therefore platelets don’t work properly

Question 26

hereditary platelet defects vs acquired

Answer 26

acquired far more common 
hereditary examples 
- Glanzmann's thrombasthemia 
- secretory defects 
- minor receptor defects