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Hemostasis & transfusion > Physiology > Flashcards

Physiology Flashcards

1
Q

What is the most abundant platelet integrin

A

αIIbβ3

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2
Q

Where are integrins and glycoproteins mainly localized in the platelet membrane

A

Lipid rafts

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3
Q

Describe the 3 phases of platelet activation

A
  1. Initiation:
    - Vascular injury -> exposure of subendothelial collagen and vWF
    - Shear stress increases binding affinity of vWF for GP1bα receptor
    - Plasma vWF gets immobilized on collagen and captures platelets
    - Binding of vWF and platelet GP1bα leads to tethering and rolling of platelets then adhesion and formation of platelet monolayer
    - Binding of platelets to collagen and vWF triggers platelet activation
  2. Extension:
    - Platelet activation leads to shape change, formation of procoagulant membrane, integrin activation
    - Local accumulation of thrombin and secretion of thromboxane A2 and ADP activate nearby platelets
    - Agonists trigger inside-out signaling (eg. binding of fibrinogen to αIIbβ3 -> activates integrins -> conformation change to high-affinity state
  3. Stabilization:
    - Adhesion of platelet integrins to fibrinogen -> outside-in signaling
    - Platelet integrins migrate to complexes linked to actin/myosin filament -> contraction strengthening platelet-to-platelet interactions
    - Activators stay trapped in this tight platelet aggregation -> local procoagulant microenvironment
    - Clot retracts when fibrin gets deposited
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4
Q

What cells contribute to secondary hemostasis

A

Platelets, leukocytes, fibroblasts + microparticles

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5
Q

What coagulation factors / proteins are vitamin K dependent and why

A
  • Clotting factors II, VII, IX, X, protein C, protein S
  • Vitamin K allows the action of the carboxylase in charge of γ-carboxylation of the glutamic acid of these factors / proteins in the liver. This allows them to bind to calcium, which then enables them to interact with phosphatidylserine on cell membranes
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6
Q

What membrane change is required for activation of secondary hemostasis

A

Disruption of membrane symmetry with exposure of phosphatidylserine (negatively charged) on the surface thanks to the action of scramblase

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7
Q

Draw the coagulation cascade (traditional model)

A

See picture

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8
Q

Described the phases of the cell-based model of coagulation

A
  1. Initiation:
    - FVII is converted to FVIIa in the blood (without stimulus)
    - Vascular injury -> exposure of tissue-factor bound fibroblasts to FVIIa
    - Complex FVIIa-TF activates small amounts of FIX and FX
    - FXa activates FV -> FXa-FVa complex = prothrombinase complex
    - FXa-FVa complex activates small amounts of FII (prothrombin) -> FIIa
  2. Amplification
    - Activated platelets have procoagulant membrane surfaces and release partially activated FV
    - FIIa maximizes platelet aggregation and activation
    - FIIa activates FXI, FV, and FVIII
    *Small amounts of thrombin formed
  3. Propagation:
    P for P –> platelets come to the area
    - Formation of FIXa-FVIIIa (tenase) and FXa-FVa (prothrombinase) complexes on activated platelets
    - FXIa bound to platelets generates more FIXa
    - FIXa-FVIIIa complex facilitates generation of FXa -> more FXa-FVa complex formation -> formation of FIIa (thrombin)
    - Thrombin cleaves fibrinogen into fibrin monomers
    - Fibrin monomers polymerize to form a fibrin clot
    - FXIII gets activated by FIIa
    - FXIIIa causes crosslinking of fibrin monomers to stabilize fibrin clot
    * Lots of thrombin formed
  4. Termination:
    - Tissue factor pathway inhibitor (TFPI) is secreted by endothelium and inhibits FVIIa-TF bound to FXa
    - Antithrombin (AT) produced by the liver inhibits thrombin formation by forming complexes with FIIa, FIXa, FXa, FXIa, FXIIa (facilitated by heparin and heparan sulfate)
    - Protein C is activated by thrombin bound to thrombomodulin (expressed on endothelial cells). Protein C bound with protein S lyse FVa and FVIIIa
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9
Q

What platelet conformation change triggered by their activation is crucial for the rest of the coagulation process

A

Externalization of phosphatidylserine on the membrane surface

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10
Q

What complex leads to the activation of prothrombin into thrombin

A

Prothrombinase complex = FXa-FVa

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11
Q

What factor leads to crosslinking of thrombin? What activates it?

A

FXIIIa, activated by thrombin FIIa

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12
Q

What is the initial reaction and last reaction of intrinsic, extrinsic, and common pathways of coagulation

A
  1. Intrinsic pathway: starts by FXII -> FXIIa, ends with FIXa and FVIIIa activating FX
  2. Extrinsic pathway: FVIIa forms complex with TF, FVIIa-TF leads to activation of FX
  3. Common pathway: starts with FXa-FVa activating FII to FIIa and ends with crosslinking of fibrin

(FX is considered as part of common pathway)

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13
Q

What are the actions of thrombin? Which ones are pro-clot and which ones are anti-clot?

A
  • Platelet activation (pro-clot) - degranulate alpha granules, activate GpIIb
  • Cleavage of fibrinogen to fibrin (pro-clot)
  • Activation of FXIII (for crosslinking of fibrin) (pro-clot)
  • Amplification of its own production by activation of FXI, FV, and FVIII-vWF (pro-clot)
  • Activation of FVII (pro-clot)
  • Activation of TAFI (pro-clot)
  • Activation of protein C (after binding to thrombomodulin) (anti-clot)
  • Secretion of tPA from endothelium (anti-clot)
  • Promotes binding of platelets to the endothelium (via PAR-1) (pro-clot)
  • Also stimulates leukocytes to produce IL-1, IL-6, TNF-alpha through NF-kB pathway
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14
Q

What 2 complexes lead to the activation of FX

A
  • FVIIa-TF
  • FIXa-FVIIIa (tenase complex)
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15
Q

What is required for activation of plasminogen

A
  • tPA (tissue-type plasminogen activator): Released under the action of thrombin, FXa, beta-adrenergic agents, histamine, bradykinin)
  • Fibrin: lysine group binds on plasminogen and allows the activation by tPA
  • uPA (urinary-type plasminogen activator): Can also activate plasminogen but only when cell-bound, does not require fibrin
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16
Q

What are endogenous inhibitors of fibrinolysis and their mechanisms of action

A
  • Plasminogen activator inhibitor 1 (PAI-1): forms complexes with tPA and uPA
  • Alpha-2 antiplasmin: binds to plasminogen and prevent its activation binding to fibrin OR cross-links fibrin which neutralizes the activity of plasmin
  • Thrombin-activatable fibrinolysis inhibitor (TAFI): removes lysin residues from fibrin (once activated by thrombin-thrombomodulin complex and plasmin)
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17
Q

What proteins are responsible for termination of secondary hemostasis

A
  • Tissue factor pathway inhibitor - secreted by endothelium
  • Antithrombin (activated by heparin) - produced by liver
  • Protein C (activated by thombin-thrombomodulin) and cofactor protein S - produced by liver (vitamin K dependent)
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18
Q

At which steps of the coagulation cascade is Ca2+ required

A

At each step involving factors II, VII, IX, X (vitamin-K dependent factors)

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19
Q

What molecules contributing to anticoagulation / pro coagulation can be found in the endothelium

A
  1. Anticoagulation
    - Tissue factor pathway inhibitor
    - Thrombomodulin
    - Heparin / heparan sulfate

(- tPA and uPA, which are pro-fibrinolytic)

+ endothelial cells secrete prostacyclins and NO

  1. Procoagulation
    - vWF
    - Plasminogen activator inhibitor 1 (PAI-1)
20
Q

What is contained in platelet alpha-granules

A
  • Factor V
  • Factor VIII
  • Fibrinogen
  • P-selectin
  • vWF in cats
  • Integrins: GPIIbIIIa (= alpha-IIb-beta-3), GPIb-IX-V

(large peptides)

21
Q

What is contained in platelet dense granules

A
  • ADP
  • ATP
  • Serotonin
  • Histamine
  • Ca2+

(low molecular weight compounds)

22
Q

What are the roles of activated protein C

A
  • Inhibits factor Va
  • Inhibits factor VIIIa
  • Inhibits PAI-1
  • Inhibits TAFI
23
Q

Which coagulation factor preferentially binds to vWF

A

Factor VIII

24
Q

What coagulation factors are contained in platelet granules

A

Factor V, factor VIII, fibrinogen

25
Q

What does TFPI inhibit

A
  • TF-FVIIa
  • FXa
26
Q

What does antithrombin inhibit

A
  • FXa
  • FIIa (thrombin)
  • When bound to heparin, FXIIa, FXIa, FIXa, FVIIa
27
Q

What triggers the secretion of tPA

A
  • Thrombin, FXa
  • Bradykinin
  • Histamine
  • Beta-adrenergic agents
28
Q

Name some platelet agonists and their receptors

A

Via G protein coupled receptors:
- Thromboxane A2 -> TXA2 receptor

  • ADP -> P2Y1 and P2Y12 receptors
  • Vasopressin -> V1
  • Thrombin -> PARs (= protease-activated receptors)
  • Serotonin -> 5-HT2A
  • Epinephrine -> beta2-adrenergic

Via others:
- Fibrinogen -> integrin αIIbβ3 ( = glycoprotein IIbIIIa)

  • vWF -> glycoprotein GP1b-IX-V (leucine-rich receptor) + integrin αIIbβ3 ( = glycoprotein IIbIIIa)
  • Collagen -> integrin α2β1 (= glycoprotein IaIIa) + GPVI (Ig superfamily)
  • P-selectin -> glycoprotein GP1b-IX-V (leucine-rich receptor)
29
Q

What are the components of platelet membranes?

A
  • Glycoproteins - repulses adherence to normal endothelium and yet causes adherence to injured areas of the vessel wall
  • Phospholipids
30
Q

What is the normal half-life of platelets in the blood?

A

8 to 12 days

31
Q

What are the 3 major mechanisms of hemostasis following vascular injury?

A
  1. Vascular constriction
    - Local myogenic spasm
    - Local autacoid factors from the traumatized tissues and blood platelets (thromboxane A2)
    - Nervous reflexes
  2. Formation of a platelet plug
  3. Formation of a blood clot
32
Q

How is clotting prevented in the normal vascular system?

A
  1. Smoothness of the endothelialial surface
  2. Glycocalyx
  3. Thrombomodulin which binds to thrombin
    –> also activates protein C (inactivates F V and VIII)
33
Q

Blood enzyme that destroys injected heparin?

A

Heparinase

34
Q

Where does hemostasis take place in vivo?

A

on phospholipids on the external leaflet of intact cells (platelets, leukocytes, fibroblasts)

35
Q

What is immunothrombosis?

A

Increased fibrin formation in the vasculature in the face of pathogen invasion as a first line of defense as it prevents dissemination of pathogens via circulation.
–> can become dysregulated in disease –> excessive clot formation or consumptive coagulopathy

  • NETs play a key role
36
Q

How does TF perpetuate inflammation?

A

Through the activation of nuclear factor κB, leading to the production of TNF-α

37
Q

Name a few functions/roles of glycocalyx in anticoagulation

A
  • Heparin sulfate (50-90% of EGs proteoglycans) facilitates binding of antithrombin
  • Binding of anticoagulants such as heparin cofactor II and thrombomodulin –> protein C
  • Binding of TFPI
  • Release of NO in conditions of shear stress –> NO affects leukocyte adhesion, platelet aggregation etc
38
Q

Role of UL- vWF and what enzyme cleaves it into smaller vWF?

A

Role: bind platelet GP1bα receptors –> platelet activation and aggregation

ADAMTS13

39
Q

List ways that inflammation can lead to a hypercoagulable state?

A

Endothelial disturbances:
- Decreased synthesis of GAGs on the EG –> decreased function of anticoagulants that rely on the EG

  • Activation of endothelial cells by inflammatory cytokines (TNF-α, bradykinin, vascular endothelial growth factor + thrombin and histamine) –> release of ultra-large vWF

Increased pro-coagulant elements:
- Endothelial disruption –> exposure of TF and platelets

  • Release of NETs from activated neutrophils –> activation of contact pathway, direct platelet activation, impairment of fibrinolysis

Decreased endogenous anticoagulants:
- Decrease of AT from consumption, decreased production or degradation

  • Decreased hepatic synthesis of protein C and S
  • Downregulation of the expression of TM by TNF-α

Perturbations in fibrinolysis:
- TNF-α + IL1b –> increase in PAI-1 –> decreased fibrinolysis

40
Q

What are the 3 primary anticoagulant proteins?

A
  • AT
  • Protein C
  • TFPI
41
Q

What is the effect of ADP binding on P2Y1 and P2Y12 receptors

A
  • P2Y1 -> platelet shape change and mild reversible aggregation
  • P2Y12 -> integrin activation and granule secretion
42
Q

What COX enzyme is present in platelets? What is its main function in these cells?

A

COX-1 -> production of thromboxane-A2 from arachidonic acid

43
Q

What is the difference between clots formed in arterial system vs venous system

A
  • Arterial -> high shear conditions -> mostly platelets held together by fibrin strands (“white clots”)
  • Venous -> low shear conditions -> mostly fibrin and red blood cells (“red clots”)
44
Q

What are the different products of the degradation of fibrin / fibrinogen

A
  • Fibrinogen and non-cross-linked fibrin: fragment X -> fragment Y -> fragments D and E
  • Cross-linked fibrin -> D-dimer/E complex + fragments D and E
45
Q

Which anti-fibrinolytic factors are produced in the liver?

A
  • Alpha-2 antiplasmin
  • TAFI

PAI-1 –> platelets

46
Q

What are roles of antithrombin?

A
  • Prevents pro-coagulant activity of thrombin
  • Causes prostacyclin release from endothelial cells –> inhibit platelet activation and aggregation + decreased secretion of cytokines and tethering of neutrophils
47
Q
A

Hemostasis & transfusion (3 decks)

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