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1. HDS Cardiology > Coagulopathy > Flashcards

Coagulopathy Flashcards

1
Q

Normal

Platelet Count

A

Normal range:

150k - 450k platelets/microliter

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2
Q

Thrombocytopenia

A
  • Abnormally low platelet count
    • < 150k/microliter
  • Characterized by:
    • Easy bruising
    • Nose bleeds
    • Petechial rash
    • Spontaneous bleeding
      • Occurs below 20k platelets/microliter
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3
Q

Idiopathic Thrombocytopenic Purpura

(ITP)

A

Autoimmune disease where anti-platelet Ab destroy platelets.

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4
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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5
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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6
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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7
Q

Lambda (λ) Granules

A

Contains:

Lysosomal enzymes ⇒ clot resorption

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8
Q

Platelet

Surface Antigens/Receptors

A
  • Human platelet antigens (HPA) ⇒ glycoprotein receptors
    • GPIIb/IIIa
    • GPIb/IX/V
  • P2Y1/P2Y12 ⇒ binds ADP
  • PAR-1/PAR-4 ⇒ binds thrombin
  • Thromboxane A2 Receptor ⇒ binds TxA2
  • ABO antigens
  • HLA class I
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9
Q

von Willebrand Factor

(vWF)

A
  • Synthesized/stored in Weibel-Palade bodies of endothelium
  • Holds platelet GPIb/IX/V receptors to exposed collagen
  • Binds platelets to one another
  • Circulates bound to Factor VIII
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10
Q

Human Platelet Antigens

(HPA/glycoproteins)

A
  • GP Ib/IX/V ⇒ vWF ⇒ adhesion
  • GP Ia/IIa ⇒ collagen ⇒ adhesion/activation
  • GP IIb/IIIa ⇒ Fibrinogen ⇒ aggregation
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11
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 GP Ib receptors for vWF
  • Single layer of platelets forms @ site of endothelial damage

Aggregation

  • Adhered platelets secrete fibrinogen
  • Other platelets attracted to the site via GP IIb/IIIa receptors for fibrinogen
  • Fibrinogen links the platelets together
  • Forms a multilayered 1° hemostatic plug
    • Fills defect in 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 2° 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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12
Q

Blood Clotting

Overview

A

Initiated on the membranes of endothelial cells and platelets:

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

Functions through cascades of proteolytic cleavage or conformational changes.

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13
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
    • 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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14
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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15
Q

Tissue Factor (TF)

A

“Factor III”

  • 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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16
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).

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17
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, X, and Ca2+ on membrane ⇒ Tenase complex
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18
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
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19
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 i → insoluble hard clot
20
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
21
Q

Roles of Thrombin

22
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, 11, 8, and 5
    • Fibrinogen → Fibrin
    • XIII → XIIIa
23
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
24
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
25
Platelet Activation Regulation
* 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
26
Platelet Degranulation
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
27
Von Willebrand's Disease
* **Deficiency of von Willebrand's factor** * Results in _abnormal platelet adhesion_ * Most common inherited coagulopathy * AR
28
Bernard-Soulier Syndrome
* **Deficiency of platelet receptor for von Willebrand's factor** * GPIb receptor * Results in _abnormal platelet adhesion_
29
Glanzmann's Thrombasthenia
* **Deficiency of platelet receptor for fibrinogen** * GPIIb/IIIa complex * Results in _decreased platelet aggregation_
30
Immune thrombocytopenia
Autoimmune disorder caused by autoantibodies to platelet receptor for fibrinogen.
31
Antithrombin III | (AT-III)
* 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
32
Heparin
* Therapeutically used to **↓ clot formation** * IV administration * Rapid-onset * Short half-life
33
Activated Protein C Complex | (APC)
**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
34
Tissue Factor Pathway Inhibitor | (TFPI)
Protein that inhibits the extrinsic pathway shortly after its activation. Intrinsic path becomes dominant.
35
Fibrinolysis
* **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
36
Plasmin
* 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
37
Thrombophilia
**"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
38
Factor V Leiden
* **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
39
Virchow's Triad
Three broad categories thought to contribute to thrombophilia:
40
Coagulation Summary
* 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
41
Abnormal Clotting Summary
Disorders of vessels, platelets, and coagulation proteins ⇒ altered ability to clot * Vessels * Scurvy * Plaque formation * Hyper-Hcy * ↑ Lp(a) * Platelets * ↓ Number ⇒ thrombocytopenia * ↓ Function * Deficiency of vWF ⇒ VW disease * Deficiency of GPIb ⇒ Bernard-Soulier syndrome * Deficiency of CPIIb/IIIa ⇒ Glanzmann thrombasthenia * Coagulation proteins * VIII ⇒ Hemophilia A * IX ⇒ Hemophilia B * XI ⇒ Hemophilia C * Factor V Leiden
42
Clotting Clinical Tests
* _Platelets_ * Platelet counts * Platelet function tests * **Prothrombin time (PT)** * **Activated partial thromoplastin time (aPTT)**
43
Prothrombin time (PT)
* _Extrinsic through common path_ * Uses thromboplastin * Combination of PL + TF * Expressed as INR (international normalized ratio)
44
Activated partial thromoplastin time (aPTT)
* _Intrinsic through common path_ * Uses partial thromboplastin * Just the PL portion b/c TF isn't needed to activate intrinsic path
45
Vascular and Platelet Bleeding Disorders
46
Endothelium
Regulator of 1° hemostasis, 2° hemostasis, fibrinolysis. * **Heparan sulfate** on cell surface: aids activity ATIII * Secretes **PGI2** (COX pathway): vasodilator and plate activation inhibitor * Secretes **NO** (NO synthase)" vasodilator and plate activation inhibitor * **Protease-activated receptor Type 1 (PAR-1)**: binds thrombin aiding in platelet activation and release of tPA from endothelium * Synthesizes/secretes **tPA** (activates plasmin), **vWF,** and **FVIII** * **Thrombomodulin/Endothelial cell protein C receptor (EPCR)**: coordinate activation of protein C * Thrombomodulin is not found in the brain microvasculature

1. HDS Cardiology (7 decks)

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