Platelet adhesion Exposed subendothelium

+ plasma protein (VWF)

+ platelet Glycoprotein (GP1b/9/5)
Platelet activation - Activated by TF
- ADP, TXA2 and thrombin by platlets trigger
GPCR in other platlet
Collagen + GP1a/IIa
Then change shape and release granules
Platelet Aggregation Platelet Glycoprotein alpha2b beta 3a
+ fibrinogen
+ vWD
Forming crosslinks and thrombus stabilization
Strongest Platelet agonist and responsible for Thrombin
fibrinogen to fibrin to stabilize platelet plug
Activated platelet releases what DENSE is SAD
1. Adenosine diphosphate
2. Serotonin
Thromboxane A2

Glanzmann thrombasthenia Disorder of GP2b3a

Profound defect in aggregation
Bernard Soulier Syndrome Loss of GP1b/9/5

Giant platelet, thrombocytopenia, defect in adhesion Bernard Soulier Syndrome

Mutation responsible for Glanzmann ITGA2B
Thrombasthenia ITGB3
Loss of function
Consanguineous Iraqi Jew bleeding immediately GT
after birth, prolonged bleeding time, platelet
aggregometry have decreased ADP, Epi, Thrombin,
Collagen and TXA2. Normal ristocetin.
Types of GT Type 1 < 5% GT (75% of patients)
Type 2 5-20% GT
Variant type >20%
Disorder of GP1b/9/V complex BSS
Recessive
Epistaxis, menometrorrhagia, gingival hemorrhage, BSS
GI Bleed, thrombocytopenia
PBSL large platelet 1/3
Platelet aggregometry: failure in ristocetin not
corrected with addition of normal plasma
PFA normal or prolonged in ADP, Epinephrine,
Collagen
Aggregation to thrombin is normal in high doses, low
in low doses
Gain of function of GP1BA Platelet type von Willebrand disease
- Enhanced binding of VWF to GP1ba
Thrombocytopenia with enhanced VWF Response; PT-VWF or Type 2B VWD
large platelets
Difference in treatment of t2b vwd and pt-vwf Exogenous vwf – type 2b
Platelet transfusions for pt-vwf
Oculocutaneous albinism, bleeding diathesis, Hermansky Pudlak Syndrome
pulmonary fibrosis, granulomatous colitis, - Defect in lysosome related organelles
immunodeficiency with severe bleeding
Oculocutaneous albinism, immunodeficiency, mild Chediak Higashi Syndrome
bleeding tendency - From LYST variant  BEACH domain
Alpha granule disorder with thrombocytopenia <50k Gray Platelet Syndrome
and large platlets, platelet with paucity of granules, - NBEAL2 linked to vesicle transport
bleeding disorder and splenomegaly and
myelofibrosis
Disorders of perforin or vesicular trafficking Familial Hemophagocytic Lymphohistiocytosis
Lack of phosphatidylserine exposure after activation SCOTT Syndrome
leading mild bleeding disorder with procoagulant
activity
Normal bleeding time
PT abnormal
Normal aggregometry
Bleeding disorder Quebec Platelet Disorder (PLAU)
Autosomal dominant
Reduced platelet
Decreased alpha granules
Decreased epinephrine

Most distinct clinical feature of platelet function Easy bruising and bleeding
disorder
Most platelet disorders have minor to moderate GT and BSS
bleeding except
Bleeding disorder plus eczema WAS, Jacobson Syndrome, DiGeorge
Heart Disorders plus bleeding Jacobson or TAR
Sensorineural deafness plus bleeding with renal MYH9 related disease
impairment, with dohle bodies DIAPHI variants
Bleeding disorder related to leukemia RUNX, ETV6, GATA1
Decreased platelet size with bleeding disorder WAS
Platelet aggregometry with decreased first wave of Lacks fibrinogen
aggregation - GT
- Or inability to activate a2bb3 LAD-3
Decreased risocetin aggregation but corrects with VWD
normal plasma - Doesn’t correct BSS
Decreased platelet aggregometry with collagen GPVI
Decreased in Arachidonic Acid Aspirin
Treatment of Serious Bleeding in Platelet Dysfunction Platelet Transfusion prior surgery or invasive
procedures
- Leukocyte depleted due to decrease
alloimmunization
Desmopressin improves platelet function due to Increased formation of procoagulant platelets
Factor 7a recombinant infusion pathophy in platelet Increases thrombin generation through TF
disorders dependent mechanism
- For GT related
Tranexamic acid and aminocaproic acid for ginigival Tranexamic acid 10ml in 5% solution QID
bleeding, epistaxis menorrhagia, dental extractions
how?
True or false TRUE
Acquired platelet disorders are usually mild
Mechanism of Action of Aspirin in platelet Inactivates COX by acetylation at 529
COX1 platlets and many tissues
COX2 – endothelial cells
COX1  TXA2  platelet aggregation and
vasoconstriction
Block COX1 decrease TXA2
Low ADP, Epi, Collagen
No response to arachidonic
PG is completely inhibited by what dose of aspirin 100mg once daily
30mg for 7-10 days
TRUE or FALSE True
Aspirin prolongs bleeding time - May be prolonged 1-4 days after aspirin has
been discontinued
How long till platelet aggregation tests are abnormal 1 week
with aspirin intake?
NSAID mechanism of action Reversibly inhibits COX enzymes
Doesn’t prolong bleeding time
NSAID contraindication Hemophilia
HIV infection with zidovudine
NSAD and Aspirin co-administration would lead to - Block COX-1 acetylation of aspirin  impair
antithrombotic effect
- Give aspirin 2 hrs before ingestion
Thienopyridine MOA Ticlopidine, Clopidogrel and Prasugel
- Depend on CYP 450 to form active
metabolites irreversibly inhibit P2Y12 ADP
receptor
When is the maximal effect of thienopyridines? 4-6 days
How long does thienopyridines persist? 4-10days
Major thrombin receptor in humans? PAR-1
-PAR4 is unnecessary for platlet activation

Anti-PAR1 Vorapaxar
- High incidence of ICH
Atorpaxar
Anti-A2bB3a Abciximab, eptifibatide and tirofiban
- Impair platelet aggregation
B-lactam platelet dysfunction MOA Dose dependent prolongation of bleeding time in
normal volunteers, reduce platelet aggregation and
secretion
- Max 1-3 days of administration
Heparin MOA for platelet dysfunction Inhibits generation and action of platelet agonist
 thrombin
Function of fibrinolytic therapy Endogenously from fibrin meshes
(tpa, urokinase and streptokinase) activates plasminogen to plasmin
plasmin enzyme breaks cross links between fibrin
molecules
- High levels of fibrin degradation products 
impair aggregation
- Plasmin degrades GP1b
- Inhibit arachidonic acid
- Lysis of fibrinogen
cGMP agonists like nitroprusside effect on platelet Increases bleeding time at 6-8mkm
CCB action in platlet Epinephrine induced aggregation at high doses
Acquired VWD 1M -1.5M platelets in MPN can be Infusion of DDAVP or Factor 8/vWF concentrates
corrected by
Most common platelet abnormality in MPN Decrease in aggregation and granule secretion
Reduce platelet responsiveness to epinephrine
TRUE or FALSE TRUE
JAK2 mutation in ET increases thrombotic risk
Redness and burning of extremities is called Erythromelalgia
-associated with ET and PRV
-arteriolar platelet thrombi
Risk for thrombosis in MPN Increase leukocyte count
Number reticulated platletes
Phlebotomy target in PRV <45%
Platelet count level target in thrombocytosis <400k
High risk ET Above 60
Previous thrombosis
- Hydroxyurea
Prophylaxis ET plus thrombosis Aspirin
High risk pregnant ET/PRV patients Platelet >1.5
Major bleeding
Major thrombotic episodes
Previous pregnancy complications
- LWMH during pregnancy
- IFNalpha if previous major bleed or >1.5M
Low risk pregnant ET/PRV Maintaint Hct <45%
LMWH 4000U/day for 6 weeks after delivery
Aspirin 100mg/day during pregnancy
Pathophy if platelet defect in dysproteinemia Monoclonal protein  interact with platelet surface
Bleeding in ITP patient or SLE patient platelet >30k, Platelet dysfunction
what would you suspect
Pathophy of thrombocytopenia post bypass Hemodilution and adhesion to artificial surfaces in
circuit
absence of inflammation, retiform purpuric lesions Small vessel occlusion
Retiform with inflammatory purpuric lesions vasculitis