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8/3/2019 Platelet Function Platelet Di
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Platelet adhesion, activation
aggregation
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What are the three major ste
involved in the platelet
response to vascular injury
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Platelet adhesion
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Interaction of platelets wit
non-platelet surfaces.
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Platelet activation
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In response to agonists,platelets undergo metaboli
activation resulting in shapchange and secretion.
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Platelet aggregation
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Cross linking of platelet-
platelet surfaces.
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Endothelial cells
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What is plasma Von
Willebrand factor (vWF)
derived from?
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GP Ib/IX complex
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Serves as the binding site o
platelets for vWF to mediat
platelet adhesion.
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collagen & fibronectin
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Multiple proteins in the
subendothelial matrix can bi
vWF, including ____ & ___
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vWF, GP Ib/IX (platelet
receptor), & subendothelia
binding site for vWF
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What are the three things
required for platelet adhesio
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calcium
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Platelet activation requires an
increase in cytoplasmic ____. Thcomes from internal storage sites
(dense tubular system) and theexternal environment through
membrane channels.
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Phospholipase C;
diacylglycerol (DG); inositol
trisphosphate (IP3); protein
kinase C; calcium; calmoduli
dependent protein kinases
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____ converts phosphatidyl-inositol-bisphosp
(PIP2) into ____ and ____. The former activ
____ in contact with the inner leaflet of the
platelet membrane, which phosphorylates
substrate proteins, including a 40-47 kd protei
involved in platelet secretion. The latter releas____ from its storage sites. The increased
cytoplasmic concentration activates ____ and
results in shape change and contraction.
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Phospholipase A2;
thromboxane A2 (TxA2)
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____ releases arachidonic acid from
membrane phospholipids, activating th
prostaglandin pathway. In the platelet
results in synthesis of ____, a potent
agonist which activates the phospholip
C pathway.
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adenylate cyclase;
phosphodiesterase;
Prostacyclin; nitric oxide (N
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cAMP and cGMP serve as regulators of
platelet response; increased levels ofcAMP is regulated by synthesis (____)
and degradation (____). ____ is a pot
stimulator of the former. cGMP issynergistic with cAMP and its level is
increased by ____.
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GP IIb-IIIa; ADP
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Platelet aggregation requires activation
____; in the resting state, it does not bfibrinogen or other adhesive proteins.
Once it has been activated (e.g., by ___
binding to its receptor), it binds fibrinoand other adhesive proteins, including
vWF.
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Fibrinogen
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____ is a dimeric molecule
and its two terminal ends are
mirror images of each other
Consequently, it serves as anexcellent cross-linking agent
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Monomeric
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____ forms of fibrinogen can ser
as fibrin degradation productsbecause they contain a single
binding domain that can competefor binding sites on GP IIb-IIIa an
block platelet aggregation.
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high shear stress; vWF;
fibrinogen
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Aside from ADP activation, ____ canactivate GP IIb-IIIa; with this mechanis
of activation, high molecular weight
multimers of ____, rather than ____ cmediate platelet-platelet interaction.
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Mucocutaneous bleeding, includiecchymoses, petechiae, oral muco
bleeding. Evidence of splenomeg
hepatomegaly andlymphadenopathy should be soug
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Bleeding time, platelet counPT, APTT, vWF:antigen,
vWF:Ristocetin cofactoractivity, & vWF multimers
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List the laboratory procedur
used to determine platelet
function.
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Von Willebrand's disease
(vWD) type 1
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Decrease in quantity of vW
which appears to function
normally.
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vWD type 2
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Mutated form of vWF, often
causing a decrease in highmolecular weight multimers o
vWF; total antigen may benormal. Mutation may affect
binding site for factor VIII.
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vWD type 3
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Absent vWF (autosomal
recessive).
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Recurrent mucocutaneousbleeding (epistaxis, bruisin
menorrhagia) & positive famhistory of bleeding
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What are the clinical featur
of vWD?
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Childhood & early adulthoo
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At what point in life are th
symptoms of vWD most
evident?
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Pregnancy and acute
inflammatory reactions
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When can vWF normalize fo
individuals with vWD?
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Bernard-Soulier syndrome
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Rare, autosomal recessivedisorder due to deficiency o
GP Ib.
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Bernard-Soulier syndrome
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Thrombocytopenia with gian
platelets, abnormal (absent)aggregation with ristocetin a
normal vWF concentration afunction.
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Glanzmann's thrombasthen
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A rare autosomal recessivehereditary disorder
characterized by a deficiencof GP IIb-IIIa.
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Glanzmann's thrombasthen
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A normal platelet count and
morphology, absent primary wavaggregation to ADP (and collagen
and epinephrine), normal
aggregation response to ristocetin
and absent clot retraction.
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Altered platelet membraneantigens (PIA1, Baka and
Leka).
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What is the defect associatewith in Glanzmann's
thrombasthenia?
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Immune thrombocytopeni
purpura (ITP)
P ti t b t ti
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Patients may be asymptomati
or complain of easy bruising opetechiae commonly found on
one the lower extremities whe
the platelet count is less than
20,000.
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Acute (childhood type) ITP
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Type of ITP in which a viral
prodrome is common, there frequent spontaneous
remission, and male:femaleratio close to 1.
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Chronic (adult type) ITP
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Type of ITP in which there is
no antecedent infection, theris infrequent spontaneous
remission, and a male:femalratio of less than 1.
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ITP
Caused by antibodies directed
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Caused by antibodies directed
the platelet membrane; GP Iband IIb-IIIa are frequent targ
of autoantibodies but may no
be the only antigen targeted o
the platelet.
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ITP
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Bone marrow megakaryocytes are often
increased with active platelet sheddingbut in some patients megakaryocytic
hyperplasia may not be present. No
microangiopathic changes (fragmentedRBC's) on peripheral blood film.
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Isolated thrombocytopeniawith an otherwise normal
complete blood count.
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What is the typical
presentation of an ITP?
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Thrombotic thrombocytopen
purpura (TTP)
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Patients typically present wi
an unexplained anemia anthrombocytopenia, and
typically were previously vehealthy.
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women; African Americans
Caucasians
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TTP is more common in ___and may have an increased
risk in ____ compared to
____.
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TTP
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Characterized by thespontaneous development o
microthrombi in multiple
arterioles throughout the bo
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TTP
S h b i
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Severe thrombocytopenia,
fever, neurologic signs,microangiopathic changes o
peripheral blood film, andimpaired renal function.
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Multi-organ microvascula
thrombosis
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What is the hallmark
pathologic lesion in TTP?