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Physiology Block 2 > 9- Blood Clotting > Flashcards

9- Blood Clotting Flashcards

1
Q

Hemohrrhage/Bleeding Diathesis

A

pathological bleeding, inability to form clots

-hemophilia

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2
Q

thrombosis/thrombophilia

A

pathological formation of blood clots

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3
Q

innate immunity

A

ability of our blood to fight off toxins nonspecifically

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4
Q

anti-coagulants

A

stop blood clots (snakes have this to kill prey by bleeding out)

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5
Q

primary hemostasis vs secondary hemostasis

A

PRIMARY: rapid formation of cellular (platelet) plug at the site of a vascular injury

SECONDARY: formation of a stable proteinaceous (fibrin) clot , involves formation of fibrin clot (glue) that seals leak and uses an insoluble protein polymer that reinforces the primary hemostatic plug

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6
Q

platelet general structure and how it helps function

A
  • anucleate and very small (not dense)

- its better for them to be lighter so they can travel on the edges of the bloodstream as they flow and patrol the blood

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7
Q

platelet specific structures

A
  • a-granule: contain platelet factor 4, fibrinogen, thrombospondin, fibronectin, PDGF, other growth factors
  • dense granules: contrain ATP, ADP, Serotonin (5HT)
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8
Q

Megakaryocytes

A
  • located in bone marrow
  • produce blood platelets
  • HUGE and polyploid (N=64)
  • 1 megakaryocyte makes up to 1000 platelets
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9
Q

how is platelet production regulated?

A
  • by complex network of growth factors and cytokines

- mass of platelets is inversely related to the cytokine growth factor network (IL-3, Thrombopoietin)

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10
Q

Megakaryocyte differentiation and platelet production

A
  1. “baby” megakaryocyte with a and dense granules, DNA replicates and microtubules form array
  2. cytoplasm matures and evagination of membrane begins to occur to make platelets and they bud off as proplatelets then become platelets
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11
Q

Platelets in blood

A
  • normal circulation platelet count is 1 trillion (~2x10^5 per microliter)
  • platelet lifespan is 7 days
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12
Q

steps in platelet adhesion

A
  1. GP1b complex on platelet binds to von Willebrand Factor on sub-endothelial matrix and slows down
  2. Rolls until Integrin a2B1 binds to collagen the sub-epithelium and has firm adhesion and spreads out
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13
Q

von Willebrand Factor (vWF)

A
  • large glycoprotein synthesized by endothelial cells that line blood vessels and megakaryocytes
  • secreted by endothelial cells into plasma and carries coagulation Factor VIII
  • secreted from platelet granuels in response to hemostatic stress (cut or something)
  • one of largest proteins in nature (30,000 Kd)
  • binds collagen (A3 site) and GP1b complex (cause of A1 site)
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14
Q

vWD

A

genetic mutations in vWF cause hereditary bleeding disorder

  • Type 1: heterozygous null mutation
  • Type 2: a,b,c: mutations impair multimerization
  • Type 3: homozygous null mutation
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15
Q

vWF function regulation

A
  • regulated by stress and proteolytic processing
  • when stressed/injured vWF unfolds further and interacts with matrix collagen and with platelet GP1b complex to allow platelet tethering, rolling, and adhesion
  • defective processing by ADAMTS13 cause syndrome of severe microvascular thrombosis (TTP)
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16
Q

platelet activation

A
  • occurs after platelet adhesion
  • necessary for formation of stable platelet plug
  • induced by platelet agonists
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17
Q

platelet agonist general info

A
  • secreted from activated platelets and act as amplifiers
  • generated from blood/vessels during injury and can be initiators and amplifiers
  • act via GPCRs on platelet surface
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18
Q

platelet agonists secreted from activated platelets

A
  1. Thomboxane
    - phospholipase A2 cuts arachidonic acid
    - cyclo-oxygenase 1 (Cox1) acts on arachidonic acid to form endoperoxides PGH2 and PGG2
    - thromboxane synthetase then acts on endoperoxides to generate thromboxane A2
  • secreted from nearby activated platelets
    2. ADP and serotonin (5-HT)
  • released from platelet dense granules
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19
Q

Platelet agonists generated from/in blood or blood vessels by injury

A
  1. Thrombin
    - generated as part of blood coagulation cascade
  2. epinephrine
    - stress hormone
  3. collagen
    - element of sub-endothelial matrix exposed after an injury
20
Q

what is the proximate cause of heart attack and stroke?

A

aggregation of platelets that results in formation of occlusive thrombus

21
Q

what does platelet aggregation depend on?

A

fibrinogen binding to activated aIIbB3 integrin

fibrinogen is a long fibrillar dimer that is well suited to cross-link aIIbB3 receptors on adjacent platelets

22
Q

What does platelet activation result in?

A
  1. platelets changing shape
  2. Integrin-aB becomes functionally competent to bind fibrinogen and leads to platelet-platelet adhesion (aggregation)
  3. platelets secrete granules: stabilization, amplification, recruitment, wound healing (recruit more platelets/amplify and promote healing response)
  4. platelets lose membrane lipid asymmetry (phosphatidylserine exposed on outer surface promotes coagulation enzyme function)
23
Q

what happens if platelets do not function properly?

A
  • bleeding disorder
  • typically mucosal bleeding: nose bleeds, GI bleeds, minute skin hemorrhages (petechia)
  • can be platelet problem or with molecules they interact with (ex: vWF)
  • platelet hyper-reactivity can increase risk of arterial thrombosis: heart attacks and strokes
  • anti-platelet pharmacology is mainstay of secondary prevention of MI and stroke
24
Q

PFA100 system

A

mimics bleeding time assay to see how long it takes for blood to clot

25
Q

fibrinogen

A

precursor of fibrin which is a dimer of 2 trimers (product of 3 genes, Aa; BB; gamma)

  • synthesized by liver
  • circulates at high concentration in a soluble form

-undergoes proteolytic cleavage by vitamin-K-dependent serine protease (thrombin leads to fibrin)

26
Q

where does thrombin come from?

A

an enzymatically inactive precursor (zymogen) called prothrombin circulates at high concentrations in the blood

27
Q

How is thrombin generated?

A
  • cascade of enzymatic reactions: proteolytic cascades allow rapid generation of active thrombin from inactive prothrombin when needed
  • enzymes circulate in abundant quantities, but in an inactive state (zymogen)
  • limited proteolytic cleavage converts an inactive circulating zymogen (coagulation factor) to an active enzyme (active coagulation factor)- typically becomes active through cleavage resulting in a disulfide linked dimer
28
Q

most enzymes involved in coagulation…

A
  1. most enzymes are serine proteases made in the liver

2. most of the enzymes are vitamin K dependent

29
Q

how to make an enzyme more efficient

A 
zymogen = 1
cleaved zymogen = 100
add calcium = 500
add phospholipid = 5000
add protein cofactor (ex: factor VIIIa, Va, tissue factor) = 500,000
30
Q

vitamin K importance

A
  • fat soluble vitamin essential for synthesis of many coagulation factors
  • essential cofactor for gamma-carboxylase
  • creates gla residues from glu
  • glu are clustered at N-termini
  • Gla domain promotes association with calcium and membrane phospholipids
  • vitamin K must be recycled continuously by VKORC, which is inhibited by the commonly used anti-coagulant drug warfarin
31
Q

5 steps of coagulation

A
  1. Initiation
    - tissue factor (transmembrane protein found on all cells except endothelial and blood cells) meets factor VIIa (vitamin K dependent serine protease)
  2. Amplification
    - amplification of coagulation: thrombin
    - thrombin convertes fibriogen to fibrin
    - thrombin creates a feed forward loop so thrombin creates even more thrombin
    - co-factor activation accelerates kinetics of tenase and prothrombinase complexes
    - zymogen (factor XI) activation provides a positive feedback loop
  3. Stabilization
    - fibrin cross-linking by a trans-glutaminase enzyme (Factor XIIIa-active form from thrombin)
    - glutamine +lysine –(transglutaminase)–> cross-link
  4. Termination
    - blood flow
    - enzyme (protease) inhibitors bind to active site of coagulation enzymes and prevents the productive interaction of enzyme with substrate
    - cofactor destroyers proteolyze the key cofactors- factors V and VIII and renders them inactive
    - serine protease inhibitor (Serpin)
    - inhibits (IIa, Xa, IXa)
    - Haparan-dependent
    - -sulfated proteoglycan found on EC and in matrix
    - -carbohydrate chain length determines reactivity (minimum = 5)
    - Protein C –thrombin gets attached to thrombomodulin on the endothelial cell–> APC
    - tissue factor pathway inhibitor (TFPI) stops initiation phase
  5. Removal
    - fibrinolytic system (plasmin) dissolves the fibrin clot
    - fibrin degradation products form with breakdown of clot
    - a1-antiplasmin and a2-macroglobulin inactivate plasmin
    - lysine binding kringle domains
32
Q

most common form of hemophilia

A

genetic mutations in the initiation pathway (factors IX or VIII)

33
Q

extrinsic pathway

A
  • part of the initiation of coagulation where the key component is not found normally in blood (Tissue factor VIIa, which releases Ca2+)
  • assessed in the clinical lab by prothrombin time (PT) which measures time to clot re-calcified plasma after addition of tissue thromboplastin (i.e. Tissue factor)
34
Q

intrinsic pathway

A

factor XI can also be activated by an alternate enzyme system

  • contact activating system
  • assessed in clinical lab by activated partial thromboplastin time (aPTT)- add negatively charged “surface”, plus Ca2+ plus phospholipid
35
Q

clinical phenotype of Factor XIII deficiency?

A

Delayed bleeding after trauma (for example: bleeding from umbilical stump 2-3 days after taking baby home)

36
Q

which proteins are vitamin K dependent?

A

Protein C and S

37
Q

what does tissue factor pathway inhibitor (TFPI) do?

A

stops initiation phase

  • recruited by Factor Xa
  • TFPI is a “Kunitz” type protease inhibitor with specificity for the VIIa-Xa complex
38
Q

fibrin degradation products (FDP) or fibrin split products (FSP)

A

soluble fibrin fragments

39
Q

D-dimer

A

can be measured in plasma as evidence for both thrombin and plasmin generation

40
Q

Lysine binding kringle domains

A

Localize fibrinolytic enzymes to clot surface

  • protection from inhibitors
  • localizes action to the clot
  • accelerates tPA enzymatic activity
  • prevents systemic “lytic sate”: fibrinogenolysis
41
Q

function of thrombin

A
  • converts fibrinogen to fibrin
  • activates platelets and endothelial cells via protease activated receptors (PARs)- GPCRs
  • Accelerates its own formation by activating cofactors (V and VIII) and zymogens (XI)

-Activates the transglutaminase Factor XIII
to cross link and stabilize fibrin

-Initiates an important off switch of coagulation (Protein C)

42
Q

constitutive endothelium to activated endothelium

A

non-thrombin (anticoagulant) to thrombic (procoagulant)

43
Q

red and white cells contribute to hemostasis

A

• Red cells “push” platelets to the periphery of the flowing blood column where they can physically interact with the vessel wall

• White cells contribute in many ways:
– Activated blood monocytes express tissue factor
– Lymphocytes and monocytes can secrete factors that influence endothelial cells and platelets
– Neutrophils secrete “NETs” – neutrophil extracellular traps

44
Q

NET = neutrophil extracellular trap

A
  • neutrophils are “activated”, (ex: by bacterial components or cytokines) they release intracellular DNA with histone proteins
  • creating a fibrous extracellular network that traps bacteria and also traps other blood cells (platelets) and blood components (e.g. tissue factor).
  • These NETs strongly promote clot formation. Dissolving NETs may be a therapeutic option for treating or preventing blood clots.
45
Q

Testing Coagulation system

A
  • Collect blood into citrate (removes Ca++) and centrifuge to remove platelets and other blood cells – this fluid fraction of blood is called “plasma”
  • Initiate clotting of plasma in a test tube; measure time until solid fibrin gel (“clot”) forms
  1. Prothrombin Time/INR (PT)
    - Add phospholipid, Ca++, tissue factor, (“thromboplastin”) Estimates extrinsic and common pathways – VII, X, II: used to monitor warfarin (developed by Armand Quick/MCW)
  2. Activated Partial Thromboplastin Time (aPTT)
    -Add kaolin (“surface”), phospholipid, Ca++
    Estimates intrinsic factors –XII, XI, IX, VIII, and the common pathway; it diagnoses hemophilia A and B
  3. Thrombin time (TT)
    -Add thrombin, Ca++; mostly to test fibrinogen function
    Thrombin time:

Physiology Block 2 (21 decks)

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