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Coagulation > Platelet Structure and Function > Flashcards

Platelet Structure and Function Flashcards

1
Q

What is the division of megakaryocytes called ?

A
  • Endomitosis
  • it is an increase in the cellular DNA content without proliferation
    • polyploid DNA content may reach 32 to 64 times that of a normal diploid cell
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2
Q

What is the most immature form of

Megakaryocytes and what are characteristic features ?

A
  • Megakaryoblasts
  • present in low numbers
  • small cells with high N:C ratios often with cytoplasmic blebs
  • Express:
    • CD34, CD41, thrombopoietin receptor (c-MPL) and the alpha chemokine receptor CXCR4
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3
Q

When megakaryocytes express this surface marker

they become less responsive to which cytokine ?

A
  • GPIb/IX/V [vWF receptor]
  • become less responsive to thrombopoietin
    • undergo fewer endomitotic cycles
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4
Q

What surface proteins are expressed on Megakaryocytes

when they become committed to the lineage ?

A
  • CD61, CD41
  • GPIIb/IIIa
  • c-Mpl (thrombopoietin receptor)
  • GPIb/IX/V
    • this comes at an even later stage and causes the cells to be less responsive to TPO

Note: the alpha and dense granules form when the megakaryocytic cytoplasm becomes filled with platelet specific organelles and proteins

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5
Q

What factors when expressed by Megakaryocytes

can lead to bone marrow fibrosis development ?

A
  • Transforming growth factor beta 1 (TGFB1)
  • Platelet-derived growth factor (PDGF)
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6
Q

What is the specific mechanism of the megakaryocytic

pathology seen in Wiskott Aldridge Syndrome ?

A
  • megakaryocytes lose their ability to extend protoplatelets into the blood stream
  • platelets are abnormally released into the bone marrow
  • leads to thrombocytopenia and bleeding diathesis
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7
Q

What are some of the receptors that are found on

normal platelets ?

A
  • glycoprotein surface receptors:
    • GPIIb/IIIa -Fibrinogen receptor
    • GPIa/IIa and GPVI- Collagen receptor
    • GPIV- Thrombospondin
    • GPIb/IX/V- vWF receptor
    • GPIc/IIa- Fibronectin
  • ADP receptors: P2Y1, P2Y12, P2X1
  • Thrombin receptors: PAR-1 and PAR-4
  • Thromboxane and aderenergic receptors
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8
Q

What is the role of the vW receptor GPIb/IX/V ?

A
  • secreted by endothelial cells into the extracellular matrix
  • facilitates platelet adhesion to the endothelial surface ***
    • binding of vWF to GPI/IX/V initiated by the conformational change brought about by shear stress or simulated by Ristocetin
    • exposes GPIb binding epitope
  • IMP: also serves as one of the thrombin receptors on the platelet surface
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9
Q

What are the two collagen receptors on platelets ?

A
  • GPVI and GPIa/IIa
  • collagen helps platelets bind during initial platelet plug formation, but also collagen is a potent platelet activator
  • Polymorphisms if GPIa/IIa exist
    • lead to altered binding to collagen
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10
Q

What are the two ADP platelet receptors ?

A
  • P2Y1
    • classic 7 transmembrane G-coupled protein, only 150 copies per platelet
      • distributed in many other tissues
    • involved in the initial platelet shape change with mobilization of intracytoplasmic Ca++
    • but not able to support the full platelet aggregation response
  • P2Y12
    • activates PI3K pathway, completes platelet aggregation
    • potentiates platlet secretion and clot stabilization
    • leads to inhibition of adenylate cyclase
    • IMP: only found on platelets, no other tissues
  • P2X1 receptor
    • ATP-gated cation channel that raises cytoplasmic calcium levels
    • can also bind to collagen under shear stress
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11
Q

What is the adrenergic receptor on platelets and

how does it function ?

A
  • platelets can take up and store epinephrine in their dense granules
  • alpha2A-adrenergic receptor on platelets
    • expressed in low numbers
  • epinephrine is a weak activator of platelets
    • leads to platelet secretion and aggregation
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12
Q

What are the thrombin receptors on platelets

and what is their function ?

A
  • PAR-1 and PAR-4
    • protease activated receptors
  • Because thrombin enzymatically cleaves these receptors they are not easily inactivated
    • down regulation occurs by internalization of the receptors
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13
Q

What are the thromboxane and prostaglandin receptors

on platelets and how do they function ?

A
  • Thromboxane A2
    • metabolic product of cyclooxygenase
    • released from platelets and interacts with TxA2 receptors on adjacent platelets
      • stimulates platelet activation via calcium mobilization
  • Prostaglandin D2 receptors
    • lead to decreased platelet activation
    • release of cAMP
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14
Q

What is the platelet receptor for Fibrinogen ?

A
  • GPIIb/IIIa
  • most abundant surface protein on platelets
  • its expression is limited to megakaryocytes and platelets
  • it is an integrin that requires Ca++ and Mg++ for use
  • in resting platelets it is in an inactivated conformation and does not interact with fibrinogen
    • becomes activated when vWF binds GPIb/IX/V or some other platelet agonist
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15
Q

What is the CD36 receptor and its ligands ?

A
  • CD36 is also known as GPIV
  • broad ligand specificity and one of the most abundant surface proteins on platelets
    • receptor for Thrombospondin 1 (TSP-1)
    • released from alpha granules
    • reinforces the molecular bridge formed between platelets and fibrinogen
  • Also a scavenger receptor for oxidized lipids and apoptotic cells on macrophages
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16
Q

What is CD31 and how does it function on platelets ?

A
  • also known as Platelet endothelial cell adhesion molecule-1 (PECAM-1)
  • abundantly expressed protein on the platelets surface
    • note: platelets deficient in PECAM-1 are capable of activation and aggregation
  • CD31 reduces activation of platelets when it is stimulated by Thrombin and ADP
  • CD31 enhances platelet spreading on fibrinogen and clot retraction
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17
Q

What organelles are found within the platelet cytoplasm ?

A
  • mitochondira
  • lysosomes
  • glycogen
  • alpha granules
  • dense granules
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18
Q

What is stored in alpha granules ?

A
  • granules are abundant in platelets, carry proteins
  • contain 2 morphologically distinct compartments
  • Contain MANY things including:
    • Platelet factor 4 (PF4)
    • Fibronectin
    • vWF
    • Coagulation factors: Fibrinogen, V, VII, XI, XIII, protein S, plasminogen
    • Cellulalar mitogens: PDGF, TGFB, VEGF
    • Protease inhibitors: alpha 2 antitrypsin, PAI-1, TFPI, TAFI
    • Immunoglobulins, Albumin, amyloid precursor protein
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19
Q

What is stored in dense granules ?

A
  • small granules, few in number (<10 per platelet)
  • fuse with plasma membrane for release
  • Contents include:
    • ADP, ATP
    • Serotonin, Histamine
    • Calcium, Magnesium
    • Polyphosphates, glutamate, sphingosine, I-phosphate, epinephrine
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20
Q

How do platelets promote hemostasis ?

A
  • adhere to sites of vascular injury
  • undergo an activation process leading to the release of compounds from their granules
  • aggregate to form a hemostatic platelet plug
  • provide a procoagulant surface for activated coagulation protein complexes on their phospholipid membrane
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21
Q

What are the platelet inhibiting factors produced by

the endothelium to prevent not necessary adhesion ?

A
  • ecto-ADPase
  • Nitrous oxide
  • Prostaglandin I2
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22
Q

What is the initial step in binding/platelet adhesion to the endothelium?

A
  • vWF becomes exposed from the subendothelial matrix
    • either by injury, shear stress, collagen exposure or ristocetin
  • binds platelets in the shear stream
    • allos platelets to roll and transiently bind
    • transiently is bound to platelet GPIb/IX/V receptor
  • binding activates intracytoplasmic calcium release
    • leads to activation of GPIIb/IIIA receptor
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23
Q

What is the next step in platelet adhesion

after vWF transiently binds ?

A
  • extracellular matrix collagen binds to the platelet receptors GPVI and GPIa/IIa
  • a stronger bond to collagen and weaker bond to vWF allow the platelet to roll along the damaged endothelium

Note: with longer adhesion times the actin cytoskeleton restructures itself to extend filopodia where eventually the adherent platelets forma a pancake like layer

24
Q

After platelet adhesion, what are essential steps

to further platelet activation ?

A
  • production of thrombin during coagulation
  • release of ADP from dense granules
  • and platlet production of Thromboxane A2
25
Q

What happens as a consequence of platelets binding to

the subendothelium ?

A
  • the platelets then get stimulated by thrombin and ADP
    • ADP binds to P2Y1 and P2Y12
    • allows calcium release
  • thrombin binds to receptors PAR-1 and PAR-4 which leads to activation of receptors and ultimately increases in cytoplasmic calcium
    • this results in re-organization of GPIIb/IIIa
    • allows binding of Fibrinogen to the receptor and causes platelet aggregation
26
Q

Which pathway in platelet activation is thought to be

essential in amplification of platelet activation and aggregation?

A
  • Cyclooxygenase pathway –> production of Thromboxane A2 from Arachadonic acid
  • TXA2 binds to it’s receptors on adjacent platelets and induces activation and aggregation
  • this process works in parallel to the others
27
Q

What is the process for platelet granule release ?

A
  • increase in cytoplasmic calcium leads to platelet granule release
  • it is a processes of exocytosis
  • alpha granules
    • degranulate directly into the channels
  • dense granules
    • merge with the plasma membrane
28
Q

What are platelet microparticles and why are they important ?

A
  • they are tiny, membrane bound particles shed by platelets
  • they are rich in surface glycoproteins, GPIIb/IIIa receptors, and phospholipids
    • further amplify thrombotic process
    • Fibrinogen binds to GPIIb/IIIa
    • Coagulation cascade gets activated with phospholipids
  • represent 70-90% of all microparticles
29
Q

What is essential for platelet aggregation ?

A
  • Fibrinogen must bind to the GPIIb/IIIa receptor on platelets/between platelets and forms a bridge
    • conformation change of the receptor is induced by increase in cytoplasmic calcium and release/binding of ADP to receptors
30
Q

Other than ADP, what other molecules can

initiate platelet aggregation ?

A
  • epinephrine
  • thrombin
  • collagen
  • platelet activating factor
31
Q

What molecular found in alpha granules and expressed

on activated platelets binds monocytes ?

A
  • P-selectin
  • serves to localize monocytes to areas of tissue damage
  • alos helps with tissue factor expression and inflammatory changes
32
Q

What is a frequent cause of

pseudothrombocytopenia ?

A
  • it is a lab phenomenon, caused by EDTA
    • often due to cold reactive platelet agglutinins or platelets binding neutrophils (platelet satellitism)
    • agglutinins are often seen in patients with high immunoglobulins or infections
    • IMP: usually only bind platelets when calcium is chelated (EDTA)
    • Note: Abciximab (anti-GP IIb/IIIa) pseudothrombocytopenia has been reported
  • better to collect in citrate or heparin tubes
  • the mean platelet volume would be increased size of the platelets because the platelets are stuck together as they go through the automated cell counter

Note: peripheral platelet destruction or a primary marrow process can also lead to large platelet production.

33
Q

What is true about the PFA-100 ?

A
  • it has a high negative predictive value
  • normal results support normally functioning platelets

Exceptions:

  • platelet secretion defects
  • platelet storage pool disorders
  • mild type I vWD
34
Q

What is the gold standard for

evaluating platelet disorders?

A
  • light transmission platelet aggregometry
    • specimen must be run within 4 hours of collection
  • uses platelet rich plasma
  • very labor intensive and time consuming
  • Intereference from:
    • hyperlipidemia
    • hemolysis
    • thombocytopenia
    • anticoagulation
35
Q

What are the usual agonists used

in platelet aggregometry ?

A
  • ADP, Epinephrine and collagen
  • AA
    • can be used
    • helps exclude the effect of aspirin and or NSAIDS
36
Q

What does the mean platelet volume (MPV)

tell you ?

A
  • it is an indication of the platelet size
  • can be an indication of platelet turnover
    • newly released platelets from the bone marrow are larger and tend to decrease in size with age in circutlation

Note: platelets live for 7-10 days before being cleared

average platelet loss per day is 7000

37
Q

What are the specimens that can be used for

platelet aggregation studies ?

A
  • whole blood using impedence
  • platelet rich plasma using turbidimetric techniques
    • measured by spectrophotometry
38
Q

How is platelet aggregometry interpreted ?

A
  • optimal aggregomtry:
    • biphasic pattern for ADP and Epinephrine
      • initial increase is due to primary aggregation via GP IIb/IIIa
      • second wave is due to platelet degranulation
    • AA, Thrombin, and collagen
      • usually single wave agonist
39
Q

How is ristocetin used in evaluating

platelet aggregation ?

A
  • ristocetin is an antibiotic
  • facilitates binding of vWF to the glycoprotein IB/IX/V
  • use various concentrations of ristocetin
  • for a normal result the patient must have functional vWF and normal GP IB/IX/V
    • allows detection of Bernard Soulier syndrome as well as vWD
40
Q

What is the basis of the of the PFA-100

test of platelet function ?

A
  • device that measures platelet-related primary hemostasis within a citrated whole blood specimen
  • membrane with a central aperature
  • uses collagen and epinephrine as well as collagen and ADP
  • the instrument measures closure time
41
Q

In the PFA-100, what is the primary

screening cartridge and what do the results mean?

A
  • collagen-epinephrine cartridge
  • detects platelet dysfunction induced by intrinsic platelet defects, vWD, or platelet inhibiting agents
  • abnormal results with:
    • intrinsic platelet defects
    • vWD
    • platelet inhibiting agents
42
Q

When would you expect to see an abnormal

result on PFA-100 with collagen-ADP ?

A
  • abnormal result with:
    • platelet disorders
    • vWD
  • normal results with
    • aspirin like drugs
    • high concentration of ADP overcomes them
43
Q

What conditions produce abnormal results

with both collagen-epinephrine and collagen-ADP

cartridges ?

A
  • vWD
  • intrinsic platelet dysfunction
  • non-aspirin drugs

Note: sample must be run within 5 hours,

  • affected by:
    • low platelet counts
    • low hematocrit
    • BUT not affected by heparin
44
Q

How is the reticulated platelet count performed ?

A
  • flow cytometry essentially
    • measures platelets based on increased RNA content
  • thiazole orange dye binds RNA and DNA
  • helps evaluate whether thrombocytopenia is due to decreased platelet destruction or increased platelet production
    • platelets newly released from bone marrow usually have more RNA content
45
Q

What technique is used to evaluate the

ultrastructural components of platelets ?

A
  • EM
  • used for evaluation of cytoplasmic granules mostly
46
Q

What is Glanzmann thrombasthenia ?

A
  • congenital deficiency or dysfunction of GP IIb/IIIa
    • receptor for fibrinogen
  • autosomal recessive disorder
  • manifests as lifelong mucocutaneous bleeding
47
Q

What is the pattern of abnormality seen with

platelet testing for Glanzmann thrombasthenia ?

A
  • PFA- abnormal
  • LTA
    • no aggregation with ADP, collagen, epinephrine or AA
    • ristocetin aggregation will be normal
48
Q

Which disorder can present similarly

to Glanzmann thrombasthenia ?

A
  • Afibrinogeniemia
  • rare deficiency of fibrinogen
  • can present with similar aggregation results, but the results should correct with the addition of fibrinogen to the specimen
49
Q

What is Bernard Soulier disease ?

A
  • congenital deficiency of the platelet glycoprotein GP Ib/IX/V
    • receptor for vWF mediated aggregation in primary hemostasis
  • incomplete autosomal recessive
  • presents with severe bleeding
  • moderate to severe thrombocytopenia and large platelets
50
Q

What are the platelet study findings in

Bernard Soulier disease ?

A
  • normal aggregation on LTA to
    • ADP, collagen, epinephrine and AA
  • abnormal aggregation
    • ristocetin

Note: the abnormality can be confirmed with flow cytometry

51
Q

What is the pattern seen on LTA

for dense granule disease ?

A
  • decreased aggregation response to ADP, epinephrine and collagen
  • normal aggregation to AA and Ristocetin

Note: acquired platelet disorders can be seen with myeloproliferative disorders

52
Q

What situations can mimic platelet storage

pool disorders due to ongoing platelet activation ?

A
  • cardiopulmonary bypass
  • DIC
  • TTP/HUS
53
Q

What is Scott Syndrome ?

A
  • defect in a phospholipid flipase
  • patients will have normal platelet aggregation studies
  • abnormal platelet procoagulant activity
    • phosphilipid is needed for clotting cascade to effectively work
54
Q

What finding is usually seen on platelet

aggregation for a myeloproliferative disorder ?

A
  • epinephrine aggregation is reduced or absent altogether
    • possibly due to down regulation of alpha 2 adrenergic receptors

see pg. 142 for additional findings.

55
Q

What is Wiskott Aldrich Syndrome ?

A
  • condition with thrombocytopenia and small platelets
  • X-linked recessive
  • characterized by recurrent infections, eczema, and thrombocytopenia
    • also a T lymphocyte function
    • MPV is often low and lymphocytes are often low in CD43
  • platelet dysfunction is severe
    • platelets cannot aggregate and looks like a storage pool disorder
56
Q

When would you expect to see post

transfusion pupura ?

A
  • 5-12 days after transfusion
  • it is an immune mediated destruction of platelets (both native and transfused)
    • patients often have abnormal platelet antigens
57
Q

Where does thrombopoietin originate ?

A
  • liver

Coagulation (17 decks)

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