Platelets in health and disease Flashcards
What receptor on the megakaryocyte binds thrombopoietin?
the c-mpl receptor
platelets play roles in?
Primary homeostasis
Wound healing
Inflammation
Angiogenesis
Name some medicines that effect platelet function
Aspirin
Diclofenac
Citalopram
Simvastatin
How many platelets per litre of blood?
150-400 x 10^9
Where are platelets made?
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
What is the most important driving factor in thrombocytopoiesis?
Thrombopoietin, binds to c-mpl receptor
Platelet homeostasis
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
Platelet ultrastructure
- electron dense granules
- alpha granules
- 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)
Primary hemostasis, definitions and steps
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
Closer look at coagulation
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)
Secretions of healthy endothelium vs secretions of damaged endothelium
Healthy = PGI2 and NO Damaged = ADP, TxA2,
platelet aggregation cascade
- Adherence to collagen
- activation of prostaglandin synthesis
- thromboxane A2
- release reaction
- ADP coagulation activation
a) thrombin released –>activates clotting cascade
b) IIb/IIIa fibrinogen receptor expression
= aggregation
How does aspirin affect platelets
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
Thromboxane A2 synthesis in platelets and production of prostacyclin by endothelial cells + aspirin
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)
The P2Y(12) receptor
irreversibly blocked by clopidigrel
The GPIb-IX-V
binds VW factor
Quiescence
NO and PGI2 are released from intact endothelium
Levels of intracellular cyclic nucleotides are elevated
PKA and PKG suppress platelet activation
Activation
collagen and thrombin initiate activation following vascular injury
platelets secrete secondary mediators ADP and TxA2
Thrombus growth
PLC, PKC, and PI3K support sustained platelet activation Intergrin alpha(IIb)beta(3) binds fibrinogen and supports aggregation
The breakdown of reasons why platelets can increase of decrease in a patient
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)
How do platelets participate in response to vessel injury?
vessel wall
coagulation cascade
What is the EDTA effect?
some people get clumping of their blood from the preservative in the blood tube vials
thrombocytopenia - what? causes?
= 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
Immune thrombocytopenia
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)
platelet function defect myelodysplasia
class of bone marrow diseases where the way the cells are made is affected therefore platelets don’t work properly
hereditary platelet defects vs acquired
acquired far more common hereditary examples - Glanzmann's thrombasthemia - secretory defects - minor receptor defects
