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Foundations of Disease > Exam 2: Platelets and Coagulation > Flashcards

Exam 2: Platelets and Coagulation Flashcards

1
Q

Platelet

Functions

A
  • Limit bleeding after injury to a blood vessel
  • Promote vessel repair
  • Regular maintenance of an intact endothelium
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2
Q

Platelet Count

A

Normal range: 150,000 - 450,000 platelets/microliter

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3
Q

Thrombocytopenia

A
  • Abnormally low platelet count
    • < 150,000/microliter
  • Characterized by:
    • Easy bruising
    • Nose bleeds
    • Petechial rash
    • Spontaneous bleeding
      • Occurs below 20,000 platelets/microliter
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4
Q

Idiopathic Thrombocytopenic Purpura

(ITP)

A

Autoimmune disease where anti-platelet Ab destroy platelets.

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5
Q

Platelet

Lifecycle

A
  • Derived from bone marrow cells called megakaryocytes
  • Lifespan ~ 8-10 days
  • Removed by sleen or via clotting process
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6
Q

Platelet

Morphology

A

Small, flat, disc-shaped membrane-enclosed bits of cytoplasm.

Hyalomere

  • Clear outer region
  • Contains bundles of microtubules
    • Helps maintain discoid shape
  • Contains actin & myosin
    • Involved in shape change of activated platelets

Granulomere

  • Central region with basophilic stippling
  • Contains usual cytoplasmic organelles
  • Contains at least 3 types of granules
    • Alpha, Delta, and Lambda

2 systems of membrane bound channels:

  • Open canalicular system
    • Invaginations of the plasma membrane
    • Facilitates rapid exocytosis of granules
  • Dense tubular system
    • Stores Ca2+ needed for exocytosis
    • Not continuous with the plasma membrane
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7
Q

Alpha (α) Granules

A

Contains:

Platelet-derived growth factor (PDGF) ⇒ mitogen for vessel repair

von Willebrand Factor (vWF) ⇒ mediates platelet adhesion to endothelium (collagen and laminin)

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8
Q

Delta (δ) Granules

A

Contains:

Ca2+, ATP, ADP ⇒ all enhance platelet aggregation

Serotonin ⇒ vasoconstriction

(Picked up by platelets in circulation)

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9
Q

Lambda (λ) Granules

A

Contains:

Lysosomal enzymes ⇒ clot resorption

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10
Q

Vessel Repair

Process

A

Adhesion

  • vWF binds to components of the damaged basement membrane (collagen, laminin)
    • vWF can be secreted by many cells including platelets
  • vWF attracts platelets which have surface receptor for vWF
  • Single layer of platelets forms @ site of endothelial damage

Aggregation

  • Adhered platelets secrete fibrinogen
  • Other platelets attracted to the site via cell surface receptors for fibrinogen
  • Fibrinogen links the platelets together
  • Forms a multilayered primary hemostatic plug
    • Fills the defect in the vessel wall

Activation

  • Aggregation causes platelet activation
  • Results in:
    • Secretion of granule mediators
    • Synthesis and release of aracidonic acid derivatives
      • Thromboxane A2 (TXA2)
    • ​Change of platelet shape
      • Mediated by the hyalomere
  • Released mediators cause:
    • Further platelet aggregation
      • TXA2, serotonin, and Ca2+
    • Vasoconstriction (limits bleeding)
      • Serotonin and TXA2
    • Blood coagulation
      • Platelets release several coagulating factors from α-granules
      • Meshwork of fibrin formed which stabilizes the platelet plug forming the secondary hemostatic plug

Clot Retraction

  • After ~ 1 hr, platelets contract due to actin-myosin interaction
    • Platelet plug ↓ in size & flattens against vessel wall
    • Helps to re-establish smooth blood flow

Clot Resorption

  • Mediated partially by lysosomal enzymes from λ-granules

Vessel Repair

  • Mediated by platelet-derived growth factor (PDGF) from α-granules
  • PDGF is strongly mitogenic for cells needed to rebuild the vessel wall including:
    • Endothelial cells
    • Fibroblasts
    • Smooth muscle
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11
Q

Platelet Activation

Regulation

A
  • Platelets activated upon binding to collagen and laminin of damaged basement membrane
    • Not exposed in healthy vessels
  • Healthy endothelial cells produce factors that inhibit platelet aggregation
    • Ex. Prostacyclin I2 (PGI2) from arachidonic acid
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12
Q

Aspirin

A

Inhibits cyclooxygenase activity

  • ↓ platelet function
  • Prolongs bleeding times
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13
Q

Thrombosis

A

Formation of a clot (thrombus)

  • Can cause serious damage
  • Can lead to death if vessel occluded
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14
Q

Thrombus

Charactertistics

A
  • Meshwork of fibrin + plug of activated platelets
  • Clotting occurs in association with membranes
  • Pathology:
    • In coronary arteries ⇒ MI
    • In cerebral arteries ⇒ ischemic stroke
    • In peripheral arteries ⇒ claudication (leg pain with exercise) or amputation
    • In deep veins ⇒ DVT
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15
Q

Embolus

A

A mass traveling through the circulation.

Can be a thrombus broken off a site of coagulation.

If thrombus lodges in the lung ⇒ pulmonary embolism (PE)

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16
Q

Blood Clotting

Overview

A

Initiated on the membranes of endothelial cells and platelets:

  1. Formation of a fibrin clot
  2. Formation of a platelet plug
  3. Vasoconstriction (eicosanoids, PGs, Txs)
  4. Limits to the process (anticoagulation)
  5. Clot dissolution (fibrinolysis)
  6. Wound repair

Functions through cascade of proteolytic cleavage or conformational changes.

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17
Q

Fibrin Clot Formation

Charactertistics

A
  • Intrinsic and extrinsic pathways converge on the final common pathway
  • Major factors
    • Named by Roman numerals & common names
      • Factor IX = Christmas factor
    • Are glycoproteins synthesized primarily by the liver
  • Functions using cascades
    • Activation primarily by proteolytic cleavage
    • Successive proteins are serine proteases
      • Cleaves peptide bond on carboxyl side of Arg or Lys
    • Activation can also be caused by conformational changes
    • Facilitates acceleration and amplification of process
  • Non-proteolytic proteins also needed ⇒ accessory proteins (cofactors)
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18
Q

Clotting Effectors

A

Presence accelerates the rate of certain steps in fibrin clot formation:

  • Negatively charged phospholipids (PS, PI)
    • Normally found on inner leaflet of plasma membrane
    • Exposure signals injury
  • Ca2+
    • Binds negatively charged γ-carboxyglutamate (Gla) residues on certain clotting proteins
    • Facilitates binding of these proteins to exposed negatively charged phospholipids
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19
Q

Gla Proteins

A

Factors II, VII, IX, X

  • Contains negatively charged γ-carboxyglutamate (Gla) residues
  • γ-carboxylation
    • Post-translational modification
      • 9-12 Glu residues @ N-terminus carboxylated to Gla residues by glutamyl carboxylase
    • Occurs in lumen of RER in hepatocytes
    • Vit K required as co-enzyme
      • Oxidized in reaction to epoxide
      • Must be reduced back to hydroquinone form to continue
        • Done by Vitamin K epoxide reductase (VKOR)
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20
Q

Dicumarol

&

Warfarin (Coumadin)

A

⊗ reduction of Vit K by VKOR

  • Inhibits clotting by depleting pool of Vit K
  • Oral administration
    • Slow onset
    • Long half-life
  • Polymorphisms in cytochrom P450 and VKOR isozymes results in varied dosing
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21
Q

Tissue Factor

(TF)

A
  • Transmembrane glycoprotein
    • Abundant in vascular subendothelium
  • Released by damaged tissue ⇒ extravascular
  • Key protein in the extrinsic pathway
    • Pathway is quickly shut down by tissue factor pathways inhibitors (TFPI)
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22
Q

Extrinsic Pathway

A

“Tissue Factor Pathway”

  1. Vascular injury exposes extravascular TF (Factor III) to Factor VII
  2. TF binding causes conformation change of VII activating it to VIIa
    • VII can also be activated by Factor XIIa from intrinsic path or thrombin (IIa) from common path
  3. VIIa is a serine protease which activates factor X
  4. Factor Xa enters the common pathway

Extrinsic pathway is quickly shut down by tissue factor pathway inhibitors (TFPI).

23
Q

Intrinsic Pathway

A

“Contact Pathway”

All protein factors are found in the blood ⇒ intravascular

Contact Phase

Results in the activation of factor XII → XIIa

  1. Contact of blood with a negatively charged surface ⇒ conformational change & activation of factor XII → XIIa
    • In vitro ⇒ glass blood vials
      • Sodium citrate/oxalate added to chelate Ca2+ and prevent clotting
    • In vivo ⇒ ⊖ PL on damaged endothelium or an abnormal surface
      • E.g. mechanical heart valve, stent, knee/hip replacements
  2. Amplification of contact phase
    • Factor XIIa cleaves Prekallikrein-HMWK at an anionic surface producing Kallikrein
      • HMWK = High molecular weight kininogen
    • Kallikrein can then proteolytically cleave additional Factor XII ⇒ amplification

No known bleeding disorders associated with factor deficiencies of the contact phase.

X Activation Phase

  1. Factor XIIa cleaves XI-HMWK at an anionic surface to produce Factor XIa
    • Factor XI can also be activated by Thrombin from common pathway
    • Defective Factor XI → Hemophilia C
  2. Factor XIa cleaves Factor IX (Christmas factor) → IXa
    • Defective Factor IX → Hemophilia B
    • Can also be cleaved by Factor VIIa from extrinsic pathway
  3. Factor IXa combines with Factor VIIIa
    • Interaction with VIIIa ↑↑↑ rxn rate
    • Factor VIII found in the blood bound to von Willebrand factor (vWF)
      • vWF protects VIII from degradation
      • Thrombin from common pathway cleaves vWF off VIII activating it
    • Defective Factor VIII → Hemophilia A
  4. IXa:VIIIa complex cleaves Factor X → Xa
    • Factors VIIIa, IXa, 10, and Ca2+ on membrane ⇒ Tenase complex
24
Q

Hemophilia

A
  • Coagulopathy caused by clotting factor deficiencies
    • Factor VIII ⇒ Hemophilia A
      • 6x more common than B
      • Found on chromosome Xq
    • Factor IX ⇒ Hemophilia B
      • Found on chromosome Xq
    • Factor XI ⇒ Hemophilia C
      • Autosomal recessive
  • Manifestations
    • Decreased/delayed ability to clot
    • Formation of abnormally friable clots
  • Severity related to residual activity
    • Effects seen if < 30% activity
    • Severe form if < 1% activity
      • Spontaneous, prolonged bleeding particularly into joints and muscle
  • Treatment
    • Recombinant factor replacement
    • Somatic gene therapy in development
25
Q

Common Pathway

A

Factor Xa to Fibrin:

  1. Factor Xa from both intrinsic and extrinsic paths associates with Factor Va(accessory protein) forming Xa-Va ⇒ Prothrombinase complex
    • Binding of Va ⇒ 20x ↑ in Xa activity
  2. Binding of Ca2+ to Gla residue on Prothrombin (Factor II) facilitates binding of Prothrombin to membrane and to Xa-Va complex
  3. Xa-Va complex cleaves Prothrombin (II) → Thrombin (IIa)
    • Excises Gla region releasing Thrombin from the membrane
      • Only time Gla excised
      • Gla-peptide remains bound to membrane surface
        • Taken up by the liver
  4. Thrombinplasma cleaves Fibrinogen (Factor I) → Fibrin (Ia)
  5. Fibrin forms the fibrin soft clot
  6. Thrombinplasma activates Factor XIII → XIIIa
  7. Factor XIIIa (transglutaminase) cross-links Gln from one fibrin with Lys of another ⇒ isopeptide bond
    • Converts soft clot into an insoluble hard clot
26
Q

Fibrin

A
  • Fibrinogen
    • Soluble glycoprotein made by the liver
    • Dimers of three different polypeptides held together at N-termini by disulfide bonds
  • N-termini of the chains form “tufts” on the central three globular domains (D, E, D)
  • Thrombin cleaves the negatively charged tufts producing fibrinopeptides:
    • Fibrinogen → fibrin monomers
    • Solubility decreases
    • Fibrin monomers associate laterally
    • Soft fibrin clot formed
27
Q

Roles of Thrombin

28
Q

Blood Clotting

Complete Pathway

A

Pathway Interconnections:

  • Factor VIIa of extrinsic path activates factor IX of intrinsic path
  • Factor XIIa of intrinsic path activates factor VII of extrinsic path
  • Thrombin (IIa) of common path activates factors of intrinsic and extrinsic paths
    • Factors 7, 12, 11, 8, and 5
29
Q

Clotting Factors

Classifications

30
Q

Platelet plug provides…

A

primary hemostasis

31
Q

Fibrin net provides…

A

secondary hemostasis

32
Q

Platelet Plug

Formation

A
  1. vWF binds exposed collagen on endothelial surface
  2. Platelets bind:
    • To vWF via GP1b
      • Part of the membrane receptor complex (GP1b/V/IX)
        • vWF made by endothelial cells and megakaryocytes
    • Directly to collagen via GPVI
  3. Binding stops forward movement of platelets causing adherence
  4. Platelet activation causes degranulation
    • Thrombin is the most potent activator
      • Required for platelet activation and fibrin formation
    • Also exposes anionic PL which allows formation of tenase complex on surface of platelets
  5. Conformational Δ following activation leads to platelet aggregation
    • Forms the platelet plug ⇒ primary hemostasis
  6. Conformational Δ in GPIIb/IIIa receptor exposes fibrinogen binding sites
  7. Fibrinogen binds & links activated platelets to one another
    • Fibrinogen → Fibrin by Thrombin (IIa)
    • Cross linkage by Factor XIIIa from plasma and platelets
    • Fibrin net strengthens platelet plug to resist shear forces
      • Achieves secondary hemostasis
33
Q

Platelet Activation

A
  1. Thrombin binds to and activates protease-activated receptors (PARs) on the surface of platelets & endothelial cells
    • Type of Gq receptor
  2. Receptor activates PLC which cleaves PIP2 → DAG and IP3
  3. DAG activates PKC leading to degranulation
  4. IP3 causes release of Ca2+ from delta granules
  5. Calcium causes:
    • Shape changes in platelet
      • Ca2+ activates MLCK which phosphorylates MLC
      • Favors association with actin
    • Activation of PLA2
      • Synthesis of TXA2
        • Platelet degranulation
        • Vasoconstriction
          • Via serotonin
        • Activation of additional platelets
          • By binding to GPCR on platelet membrane
34
Q

Platelet Activation

Regulation

A
  • Vascular wall is separated from blood by endothelial cells
    • Components like collagen and laminin are not exposed
  • Endothelial cells synthesize the vasodilators PGI2 and NO
  • Endothelial cells have a cell surface ADPase that converts ADP → AMP
35
Q

Platelet Degranulation

A

Degranulation releases:

  • Delta granules
    • Serotonin: causes vasocontriction
    • ADP: activates additional platelets
      • Plavix blocks ADP receptors preventing ability to activate platelets
  • Alpha granules:
    • PDGF: helps in wound healing
    • Factor Va
    • vWF
    • Fibrinogen
    • Many more
36
Q

Von Willebrand’s

Disease

A
  • Deficiency of von Willebrand’s factor
  • Results in abnormal platelet adhesion
  • Most common inherited coagulopathy
    • AR
37
Q

Bernard-Soulier

Syndrome

A
  • Deficiency of platelet receptor for von Willebrand’s factor
    • GP1b receptor
  • Results in abnormal platelet adhesion
38
Q

Glanzmann’s Thrombasthenia

A
  • Deficiency of platelet receptor for fibrinogen
    • GPIIb/IIIa complex
  • Results in decreased platelet aggregation
39
Q

Immune thrombocytopenia

A

Autoimmune disorder caused by autoantibodies to platelet receptor for fibrinogen.

40
Q

Pathways of Coagulation

Interrelationships

A
  • TF—VIIa of extrinsic path activates IX of intrinsic path
  • XIIa of intrinsic path activates VII of extrinsic path
  • Thrombin (IIa) of common path activates components of both the intrinsic and extrinsic paths and also activates platelets
  • Tenase complex of intrinsic path forms on the surface of activated platelets and damaged endothelium
  • One fifth of total Va is released by activated platelets
  • XIIIa and vWF present in both plasma and platelets
41
Q

Antithrombin III

(AT-III)

A
  • Made by the liver
  • Serine protease inhibitor (serpin)
  • ATIII binds to and inactivates:
    • Thrombin (most important)
      • Binding makes catalytic domain of thrombin inaccessible
    • Factor IXa through XIIa
      • Inactivation of X is key
    • Factor VIIa-TF complex
  • Complexes removed by liver
  • AT-III : Thrombin binding is greatly increased by heparin
    • Sulfated GAG released by mast cells in response to injury
42
Q

Heparin

A
  • Therapeutically used to ↓ clot formation
  • IV administration
    • Rapid-onset
    • Short half-life
43
Q

Activated Protein C Complex

(APC)

A

Protein C-Protein S complex inactivates Va and VIIIa by proteolysis.

  • Protein C(Gla) activated by thrombin-thrombomodulin complex
    • Thrombomodulin expressed on the surface of undamaged endothelial cells
      • Binds thrombin
      • ↓ thrombin’s affinity for fibrinogen
      • ↑ thrombin’s affinity for Protein C
  • Protein C complexes with Protein S(Gla) ⇒ activated Protein C complex (APC)
  • APC cleaves Va and VIIIa
    • Protein S helps achor Protein C to the clot
44
Q

Tissue Factor Pathway Inhibitor

(TFPI)

A

Protein that inhibits the extrinsic pathway shortly after its activation.

Intrinsic path becomes dominant.

45
Q

Fibrinolysis

A
  • Plasminogen binds to fibrin & incorporated into clots during formation
  • Physiological activators of plasminogen bind and cleave plasminogen → plasmin
    • Tissue plasminogen activator (t-PA or TPA)
      • Made by endothelial cells
      • Secreted in inactive form in response to thrombin
      • Becomes active when bound to fibrin-plasminogen
    • Urokinase (u-PA)
      • Made in the kidney
  • Plasmin hydrolyzes fibrin clot
    • Bound plasmin and TPA protected from inhibitors
    • When fibrin clot is dissolved, they are exposed and inactivated
      • α-2 antiplasmin ⇒ ⊗ plasmin
      • PAI (plasminogen activator inhibitor) ⇒ ⊗ TPA
46
Q

Plasmin

A
  • Serine protease which degrades fibrin
  • Plasminogen made by the liver & released into the blood
  • Binds to fibrin and is incorportated into clots as they are formed
  • Activated by TPA or u-PA
47
Q

Therapeutic Fibrinolysis

A

Treat patients with TPA or u-PA

48
Q

Thrombophilia

A

“Hypercoagulability”

Caused by:

  • Factor V Leiden
  • G20210A prothrombin gene mutation
    • ↑ factor II activity
    • Most prevalent genetic risk factor for venous thrombosis in Spanish populations
  • Deficiencies of proteins C, S, and ATIII
  • Excess lipoprotein A
  • Hyperhomocysteinemia
  • Anti-phospholipid Ab ⇒ referred to as Lupus anticoagulant
49
Q

Factor V Leiden

A
  • Mutant form of factor V ⇒ resistant to APC cleavage
  • Most commonly inherited thrombophilic condition
    • Esp. Caucasians, specifically Scandinavians
  • Heterozygotes have a 7x increased risk of forming clots
  • Homozygotes have 80x increased risk
50
Q

Virchow’s Triad

A

Three broad categories thought to contribute to thrombophilia:

51
Q

Coagulation

Summary

A
  • Tissue injury ⇒ blood vessel damage ⇒ collagen exposure
  • Platelets bind collagen
    • Mediated by vWF
  • Platelet activation
    • Thrombin is key
  • Platelet degranulation and synthesis of arachidonic acid products
    • Vasoconstriction
    • Platelet recruitment
    • Support the clotting cascade
  • Factors of intrinsic, extrinsic, and common paths of clotting cascade + Ca2+ + anionic surface ⇒ fibrin clot formation
    • Initial platelet plug ⇒ primary hemostasis
    • Fibrin mesh ⇒ secondary hemostasis
  • Clotting limited to injured site
    • Proteins that inactivate thrombin ⇒ AT-III, heparin
    • Proteins that degrade V & VIII ⇒ APC
  • After wound is healed, fibrin clot degraded by plasmin
    • Plasmin inactivated by α-2 antiplasmin
    • TPA inactivated by PAI
52
Q

Abnormal Clotting

Summary

A

Disorders of vessels, platelets, and coagulation proteins ⇒ deviations in ability to clot.

  • Vessels
    • Scurvy
    • Plaque formation
    • Hyper-Hcy
    • ↑ Lp(a)
  • Platelets
    • ↓ number ⇒ thrombocytopenia
    • ↓ function
      • Deficiency of vWF ⇒ VW disease
      • Deficiency of GP1b ⇒ Bernard-Soulier syndrome
      • Deficiency of CPIIb/IIIa ⇒ Glanzmann thrombasthenia
  • Coagulation proteins
    • VIII ⇒ Hemophilia A
    • IX ⇒ Hemophilia B
    • XI ⇒ Hemophilia C
    • Factor V Leiden
53
Q

Clotting

Clinical Tests

A
  • Platelets
    • Platelet counts
    • Platelet function tests
  • Extrinsic through common path
    • Prothrombin time (PT)
      • Uses thromboplastin
        • Combination of PL + TF
      • Expressed as INR (international normalized ratio)
  • Intrinsic through common path
    • Activated partial thromoplastin time (aPTT)
      • Uses partial thromboplastin
        • Just the PL portion b/c TF isn’t needed to activate intrinsic path

Foundations of Disease (46 decks)

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