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MLSCI 230 > Platelets > Flashcards

Platelets Flashcards

1
Q

hemostasis

A

physiologic process by which the body stops bleeding while maintaining blood in the fluid state within the blood vessels
3 properties:
- keeps blood circulating in fluid state
- produces controlled, localized clot when injured
- dissolves clot once wound has healed

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2
Q

formation of the platelet plug

A

primary hemostasis

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3
Q

stabilization of the platelet plug through the activation of coagulation factors to form fibrin

A

secondary hemostasis

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4
Q

hemostasis players

A

interactions between

  • blood vessels
  • platelets
  • coagulation proteins
  • coagulation inhibitors
  • fibrinolytic system
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5
Q

thrombopoitein analogs

A
  • romiplostim

- eltrombopag

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6
Q

platelet production

A

cytokine influencers

  • thrombopoietin
  • IL-3 (early)
  • IL-6, IL-11 (later)

molecular influencers

  • GATA1 (early differentiation)
  • RUNX1 (drives switch from mitosis to endomitosis (meg maturation)
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7
Q

sometimes the earliest PLT progenitor detectable by morphology

A

megakaryoblast

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8
Q

acute megakaryoblastic leukemia

A
  • intermediate size
  • granular basophilic cytoplasm with pseudopods
  • most common form of AML seen in Down Syndrome before age 3
    > associated with mutated GATA1
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9
Q

maturation from the megakaryoblast to mature megakaryocyte involves two main steps:

A
  • endomitosis
  • cytoplasmic maturation

this is followed by shedding of PLTs in a process called thrombocytopoiesis

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10
Q

how is the abundant cytoplasm state of mature megakaryocytes reached?

A

through repeated rounds of endomitosis

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11
Q

what is endomitosis?

A
  • mitosis without telophase and cytokinesis

- increased DNA content and cytoplasm without cell separation into daughter cells

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12
Q

cytoplasmic maturation of megakaryocytes

A
  • increased DNA content allows increased synthesis of cytoplasmic contents
    > granules
    > demarcation membrane system (DMS): membrane repository support increase in membrane SA needed with PLT formation
    > microtubules and other organelles
  • PLTs form from the mature meg cytoplasm
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13
Q

thrombocytopoesis

A
  • megs locate near BM sinusoids and shed PLTs into the bloodstream
  • megs form cytoplasmic extensions - proplatelet processes
  • processes pierce through or between sinusoid epithelial cells into venous blood
  • organelles move along tubules to the end of the processes
  • processes extend and branch
    > until cytoplasm is a mass of protoplatelets
    > protoplatelets released from meg body
  • protoplatelets fragment further into PLTs
  • naked megakaryocte nucleus undergoes apoptosis
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14
Q

PLT morphology

A
  • ~3um diameter
  • 8-10 fL in volume
  • no nucleus in mammals
  • visible granular on peripheral blood film
  • biconvex in circulation (in resting state) round on blood film
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15
Q

reticulated PLTs

A
  • young PLTs containing high amounts of RNA
  • larger than mature platelets
  • released compensation for thrombocytopenia (if marrow is working)
    > differentiate between thrombocytopenia due to PLT destruction vs. bone marrow failure
    > signify marrow regeneration after chemotherapy or transplant
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16
Q

PLT ultrastructure

A
  1. peripheral zone
    - receptor/transmitter region
  2. sol-gel zone
    - cytoskeleton
  3. organelle zone
    - metabolic machinery
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17
Q

peripheral zone

A
  • glycocalyx
    > PLT membrane surface
    > thick and adhesive - ready for PLT function
    > absorbs plasma proteins, transport to storage organelles via endocytosis
  • plasma membrane = invades the PLT interior, forming the Surface Connected Canalicular System
    > functions as a pathway: extracellular Ca2+ uptake, secretion of intracellular material such as granule contents in platelet activation
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18
Q

peripheral zone plasma membrane contains:

A
  • phospholipid bilayer
    > inner phospholipids flip to the outer layer with activation
    > phospholipids act as a surface for coagulation factors
  • glycoprotein receptors
    > involved in PLT adhesion and aggregation
    > including VWF (GPIIb/IX/V), fibrinogen (GPIIb/IIIa)
    > collagen (GPVI)
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19
Q

Sol-Gel Zone

A 
- circumferential microtubules:
 > located just within PLT membrane
 > encase the PLT; maintain discoid shape 
- microfilaments
> located within PLT cytoplasm
> composed of actin and myosin
> becomes contractile with activation 
  shape change
  granule content release
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20
Q

organelle zone

A 
dense tubular system (DTS)
- derived from endoplasmic reticulum
- sequestration of calcium
 > controls PLT contraction & activation via Ca++ release
- site of eicosanoid synthesis
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21
Q

eicosanoid synthesis

A
  • AKA prostaglandin, cyclooxygenase or thromboxane pathway
    > prostaglandins and thromboxanes = eicosanoid subtypes
    > cyclooxygenase = enzyme involved in eicosanoid synthesis
  • PLT activation pathway
  • starts in membrane and finishes in the dense tubular system
  • aspirin inhibits cyclooxygenase function
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22
Q

alpha granules

A 
- 50 to 80 granules/plt
contents = 
- coagulation proteins = fibrinogen, factor V, VIII
- vWF
- PLT factor 4
- PLT derived growth factor
- proteins!
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23
Q

dense granules

A 
- 2--7 granules/plt
contents =
- ADP
- ATP
- Calcium
- Mg
- serotonin
- small molecules!
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24
Q

primary hemostasis

A

platelet plug formation

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25
Q

secondary hemostasis

A

procoagulant function

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26
Q

PLT function

A
  • initial adhesion to site of injury
  • PLT activation with: shape change, secretion of granule contents, aggregation of platelets to form platelet plug
  • providing procoagulant surface and scaffold for fibrin clot formation
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27
Q

platelet receptor to its agonist

A

GP-VI = collagen
PAR1 & PAR4 = thrombin
P2Y1 & P2Y12 = ADP
thromboxane receptor = thromboxane A2 (TXA2)

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28
Q

shape change of PLTs

A
  • microtubules rearrange w activation

- from discoid shape at rest to spherical with projections

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28
Q

shape change of PLTs

A
  • microtubules rearrange w activation

- from discoid shape at rest to spherical with projections

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29
Q

initial formation of platelet plug via adhesion, activaton, aggregation

A

primary hemotasis

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30
Q

defect in primary hemostasis results in

A 
mucosal bleeding
 > nose bleeds 
 > menorrhagia
early post-op bleeding
petechiae
ex: VWD, PLT disorders
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31
Q

activation of a series of plasma proteins to form a fibrin clot

A

Secondary hemostasis; “Coagulation Cascade”

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32
Q

defects in secondary hemostasis

A
  • joint bleeds
  • delaye bleeding post-op
  • deep hematomas
  • example: hemaphilia A ( Congenital Factor VIII deficiency)
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33
Q

at around what count does bleeding normally occur

A

at 20 x 10^9 or even less

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34
Q

when are manual PLT counts used

A

for samples with many giant platelets

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35
Q

types of automated PLT counts

A
  • electrical impedence counting
  • fluorescent plt count
  • flow cytometry
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36
Q

disadvantages of electrical impedance counting

A
  • overlap between cells of extreme size may result in erroneous counts
  • falsely high PLT counts
    > extremely mcrocytic RBCs
    > RBC fragments
  • falsely low PLt counts
    > giant PLTs
    > PLT clumping
    > PLT satellitism
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37
Q

flow cytometry for PLT counting

A
  • immunological PLT counting
  • PLT antigens labeled (CD41 (GPIIb), CD61 (GPIIIa))
  • antigensm ust be present in normal amounts
  • expensive (not routine)
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38
Q

quantitative platelet abnormalities

A
  • thrombocytosis = primary, secondary (reactive)

- thrombocytopenia

39
Q

primary thrombocytosis

A

clonal disordes; MPNs

  • essential thrombocythemia
  • polycythemia vera
  • primary myelofibrosis
  • chronic myeloid leukemia
40
Q

secondary (reactive) thrombocytosis

A

influence of proinflammatory cytokines (IL-6) and TPO

  • infection/inflammation
  • post-opeerative state
  • iron deficiency/blood loss
  • post-splenectomy
41
Q

thrombocytopenia can arise due to

A
  • decreased production
  • splenic sequestraation
  • dilutional thrombocytopenia
  • increased destruction
42
Q

decreased PLT production (congenital)

A
  • macrothromboytopenias (eg. May-Hegglin anomaly)

- megakaryocyte hypoplasia (Fanconi anemia, thrombocytopenia with absent radii)

43
Q

decreased PLT production (acquired)

A
  • toixns: alcohol, drugs
  • viral infection
  • ineffective thrombopoiesis (B12/folate def; myelodysplastic syndrome)
44
Q

May-Hegglin anomaly

A
  • large PLTs + Dohle neutrophil inclusions
  • thrombocytopenia in 30-50%
  • MYH9 mutation
    > nonmuscle myosin heavy chain => cytoskeletal protein
    > autosomal dominant
  • other MYH9 disorders may also be associated with sensorineural hearing loss and/or renal disease
45
Q

thrombocytopenia with absent radius

A
  • severe thrbocytopenia at birth + congenital absence/hypoplasia of radial bones
  • PLTs 10-30 x 10^9/L as infant but increase to normal levels by 1 y/o
  • impaired DNA repair
  • autosomal recessive, rare
46
Q

splenic sequestration

A
  • ” distributional thrombocytopenia”

- normally 1/3 PLTs in spleen; increasing spleen size = increased proportion of PLTs pooling in spleen

47
Q

severe portal hypertension

A

up to 9% of PLTs may be sequestered in the spleen

- total PLT mass normal and clinical bleeding is uncommon

48
Q

massive hemorrhage w RBC and fluid support but without PLT transfusion

A

dilutional thrombocytopenia

49
Q

increased destruction of PLTs

A

IMMUNE
- ITP (immune thrombocytopenia purpura) = autoimmune
- FNAIT (fetal/neonatal alloimmune thrombocytopenia)
- drugs
= viral infections

NON-IMMUNE

  • microangiopathic hemolytic anemia
  • cardiopulmonary bypass
50
Q

assessing PLT function

A 
bleeding time
PFA-100
PLT aggrgation studies
thromboelasstography
morphologic assessment & EM
flow cytometry
51
Q

bleeding time disadvanatges

A

poorly reproducible
not a good predictor of surgical bleeding
time consming
invasive

52
Q

advantages of bleeding time

A

studies natural hemostasis
no expensive equipment
no anticoagulation artifacts

53
Q

bleeding time may be prolonged in …

A
  • thrombocytopenia or PLT function disorders (but not specific for PLT abnormalities)
  • decreased or defective fibrinogen
  • vWD
  • vascular abnormalities (Ehlers-Danlos syndrome)
54
Q

agglutination

A

PLT adhesion but not activation

> induced by Ristocetin

55
Q

aggregation

A

adhesion and activation

56
Q

primary wave

A

reversible aggregation by exogenous agonist only

57
Q

secondary wave

A

irreversible aggregation resulting from release of endogenous ADP

58
Q

Ristocetin

A

induces agglutination of PLTs by plasma VWF binding to PLT GPIb-IX

59
Q

list of agonists

A
  • ADP
  • arachidonic acid
  • epinephrine
  • collagen
  • thrombin receptor activating peptide
60
Q

provides global assessment of the dynamics of clot development, stabilization, and dissolution

A

thromboelastography

> uses whole blood?

61
Q

anti-CD42b

A

GPIb

62
Q

what is the impact of Aspirin on the Eicosanoid pathway?

A

(ASA)
inhibition of cyclooygenase andd reduced thromboxanse A2 synthesis ; blocks platelet aggregation
- aggregation with arachidonic acid impaired, but normal with a direct agonist of the thromboane A2 receptor (U46619)

63
Q

acquired platelet function disorders

A
  • drugs (ASA, NSAIDs, etc.)
  • liver disease
  • uremia (chronic kidney disease)
  • cardiopulmonary bypass
  • hematologic neoplasms (MDS, MPNs, Multiple Myeloma - dysproteinemia)
64
Q

congenital platelet function disorders

A
  • Benard-Soulier syndrome (disorder of adhesion)
  • Storage Pool Disease (diorders of granules)
  • Glanzman’s Thrombasthemia (disorder of aggregation)
65
Q

Bernard-Soulier syndrome

A
  • defects in GPIb
    > autosomal recessive
    > VWF binding
  • thrombocytopenia with giant PLTs
  • aggregation studies:
    > normal aggregation to ADP, epi, collagen, AA
    > reduced aggregation to thrombin and agglutination to ristocetin
66
Q

T or F. PLt count for storage pol diseases are typically normal

A

T! non-specific abnormalities on aggregation studies

67
Q

Storage Pool Diseases

A
  • alpha granule def = Gray PLT syndrome; rare; PLTs grey due to def of alpa grans
  • dene granule def = more common; reduce # of dense granules visible by whole mount PLT EM
68
Q

Glanzmann’s Thrombasthenia

A
  • autosomall recessive def of GPIIb/IIIa
  • abnormal response to all activating agonists (ADP, collagen, AA, thrombin, epi)
  • normal agglutination to Ristocetin
69
Q

heparin-induced thrombocytopenia

A
  • HIT; conundrum!
  • drug rxn to heparin anticogulation
  • thrombocytopenia
  • but potential severe clots with rapid limps loss or death
  • history key for diagnosis as is detection of anti-PF4/heparin Ab
  • therapy is prompt anticoagulation with non-heparin anticoagulant
    > no prophylactic PLT transfusions
70
Q

when blood vessels and PLTs respond to vascular injury

A 
primary hemostasis
- blood vessels contract (vasoconstriction)
- PLTs become activated
 > adhere to site of injury
 > secrete granule contents
 > aggregate to form PLT plug
71
Q

the vascular system is supported by internal elastic lamina and connective tissue

A
  • collagen
  • fibroblasts
  • smooth muscle cells (in arteries/arterioles)
72
Q

endothelial and subendothelial structures and substances in the blood vessels have hemostatic properties: (3)

A
  • anticoagulant (prevent clotting)
  • procoagulant (promote clotting)
  • fibrinolysis (promote clot lysis)
73
Q

anticoagulant properties of the vascular system

A
  • intact endothelium prevents thrombosis
  • repels PLTs when intact
  • non-reactive to coagulation factors
  • thromboresistance achieved by substances and/or released by the endothelium
  • enhances fibrinolysis
  • barrier between blood and collagen/tissue factor
74
Q

Procoagulant Properties

A
  • vasoconstriction: decreease blood flow to site of injury
  • exposure of subendothelial collagen and secretion of vWF by endothelial cells: allows for PLT adhesion (primary hemostasis)
  • endothelial release of tissue factor (TF): activates the extrinsic coagulation pathway
  • exposure of collagen: initiates activation of the intrinsic coagulation pathway
75
Q

endothelial substances that promote clotting

A
  • collagen: activates PLTs, PLT adhesion
  • vWF: required for PLT adhesion
  • tissue factor: activates ciagulation with factor VII
76
Q

Fibrinolytic properties

A
  • tissue plasminogen activator (TPA): released by endothelial cells
    > during clot formation, TPA and plasminogen bind to the clot
    > TPA activates plasminogen to plasmin
    > plsmin breaks down fibrin and restores blood flow
77
Q

platelet roles in hemostasis

A
  • maintain vascular integrity
  • platelet plug formation for initial stopping of bleeding
  • promoting fibrin formation to stabilize the clot

must be normal in number and function to do these

78
Q

these nourish the endothelial cells lining the vascular system

A
  • PLTs!
  • help with maontoanong vascular integrity
  • accomplished by releasing platelet-derived growth factor (PDGF) from alpha granules
79
Q

what does platelet plug formation inolve?

A
  • adhesion
  • shape change
  • release rxn/secretion
  • aggregation
80
Q

adhesion of PLTs

A
  • sitck to foreign surface; blood vessel injury expose collagen
  • requires GP Ib/IX/V on PLT surface & vWF (from endothelial cells + megs)
81
Q

PLT shape change

A
  • normally discoid
  • agonists = collagen, ADP, and thromboxane A2 alter levels of Ca 2+ promoting shape change
  • activated PLTs = spherical
82
Q

PLT dense granules

A

PLT activating molecules; small molecules

  • ADP
  • ATP
  • Ca 2+
  • serotonin
  • epinephrine
83
Q

PLT dense granules

A

PLT activating molecules; small molecules

  • ADP
  • ATP
  • Ca 2+
  • serotonin
  • epinephrine
84
Q

PLT alpha granules

A

PLT-specific proteins

  • PDGF
  • platelet factors

procoagulants

  • fibrinogen
  • vWF
  • factor V
85
Q

T or F. alpha granules are released first

A

F! dense then alpha

86
Q

where do PLTs aadhered to exposed subendothelium release their granular contents into?

A

open canalicular system

87
Q

serotonin

A

vasoconstrictor

88
Q

ADP cause PLTs to __________

A

aggregate

89
Q

Ca 2+

A

aplifies aggregation by activating PLT membrane phopholipases which lead to formation of thromboxane A2

90
Q

thromboxane A2

A

enhances release rxn and aggregation, powerful vasoconstrictor

91
Q

Role of TXA2

A
  • TXA2 binds membrane receptors, deceases conctn of cyclic AMP by suppressing adenylate cyclase
  • allows release of ionic calcium from DTS
  • increased calcium = contraction of actin microfilaments, activating PLT = degranulation
92
Q

PLT aggregation

A

PLTs sitcking to each other

  • ADP released from dense granules causes initial aggregation of PLTs
  • requires GPIIb/IIIa, fibrinogen, and Ca 2+
93
Q

a stable platelet plug is required to stop bleeding

A

procoagulation comes in
> fibrinogen bound to PLTs must be converted to fibrin
> role of PLTs in fibrin formation = provide phospholipids required for intrinsic coagulation system

94
Q

what is PF3?

A
  • platelet membrane phospholipid exposd when PLts are activated
  • provides a charged surface for conctn and activation of coagulation factors
  • results in localization of the rxn to the injury site and increases the rate of rxn
  • interacts with vit K-dependent coagulation factors (II, VII, IX, X)

MLSCI 230 (36 decks)

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