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Blood & Host Defense > Week 3 > Flashcards

Week 3 Flashcards

1
Q

Define hemostasis

A

hemostasis is the physiologic process that maintains blood in a fluid state under normal conditions and arrests blood flow from an injured vessel by the rapid and localized formation of a hemostatic plug

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2
Q

Define hemorrhage

A

A hemorrhage is the failure to achieve hemostasis as a result of a defect in one or more hemostatic mechanisms

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3
Q

Define thrombosis

A

thrombosis is the pathologic formation and propagations of a clot within the vasculature resulting in obstruction of blood flow and tissue ischemia

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4
Q

Describe the role of endothelium in hemostasis [broad terms]

A

Endothelial cells have both antithrombotic and prothrombotic properties. Under normal conditions, the cells are primarily antithrombotic, but when damage occurs they become prothrombotic.

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5
Q

Name the components of the endothelium’s antithrombotic properties

A
  1. prostacyclin [PGI2] 2. heparan sulfate 3. thrombomodulin 4. tissue plasminogen activator [tPA]
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6
Q

Describe the function of prostacyclin [PGI2]

A

synthesized and released by endothelial cells. It is a potent inhibitor of platelet adhesion and aggregation; limits intravascular extension of the platelet plug

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7
Q

Describe the function of heparan sulfate

A

glycosaminoglycan; catalyzes antithrombin III-mediated inhibition of thrombin and other clotting factors. Expressed on surface membrane of endothelial cells

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8
Q

Describe the function of thrombomodulin

A

thrombomodulin binds thrombin, forming a complex that activates protein C. Expressed on surface membrane of endothelial cells.

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9
Q

Describe the function of protein C

A

Protein C is a natural anticoagulant protein

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10
Q

Describe the function of tissue plasminogen activator [tPA]

A

synthesized and released by endothelial cells. Activates fibrinolysis by converting plasminogen to plasmin; limits the size of the fibrin clot

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11
Q

Name the components of the endothelium’s prothrombotic properties

A
  1. subendothelial collagen 2. tissue factor 3. von Willebrand factor [vWF] 4. phospholipids 5. plasminogen activator inhibitors [PAIs]
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12
Q

Describe the function of subendothelial collagen

A

bind platelets [exposed after endothelial injury]

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13
Q

Describe the function of tissue factor

A

exposed after endothelial injury & synthesized by endothelial cells. Tissue factor complexes with factor VIIa to activated factor X and initiate coagulation

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14
Q

Describe the function of von Willebrand factor [vWF]

A

synthesized and released by endothelial cells; large multimeric protein required for platelet adhesion to subendothelial collagen

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15
Q

Describe the function of phospholipids in terms of being a prothrombotic factor

A

Phospholipids become exposed after endothelial injury. The negative charges of the phospholipids are able to bind clotting factors and provide a surface for coagulation reactions.

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16
Q

Describe the function of plasminogen activator inhibitors [PAIs]

A

Synthesized and released by endothelial cells. They inhibit fibrinolysis

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17
Q

What is the average life-span of a platelet in circulation?

A

7-10 days

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18
Q

Do platelets have nuclei?

A

NO!!!!

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19
Q

Describe platelet structure in both unstimulated and activated states

A

Unstimulated/resting: small, discoid shaped cell Activated: more spherical and extend long & short pseudopods [altered organization of their cytoskeleton]

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20
Q

List the integral membrane proteins on platelets

A

The integral membrane proteins founds on platelets are glycoprotein receptors. These include glycoprotein Ib [GPIb] and Glycoprotein IIb/IIIa [GPIIb/GPIIIa].

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21
Q

Describe the function of glycoprotein Ib [GPIb]

A

GPIb is the primary receptor for adhesion that binds vWF [which is bound to subendothelial collagen]

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22
Q

Describe the function of glycoprotein IIb/IIIa [GPIIb/IIIa]

A

GPIIb/IIIa is the receptor for fibrinogen

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23
Q

List the types of granules in platelets

A

Alpha granules and dense granules

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24
Q

Describe the function of alpha granules

A
  • 50-60 per platelet
  • they store many proteins including vWF, fibrinogen, factor V, platelet factor 4, fibronectin, platelet derived growth factor, P-selectin, Factor XIII, vitronectin, and high molecular weight kiniogen
  • these are more common than delta/dense granules
  • these granules give platelets their blue/purple color on H&E stains
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25
Q

Describe the function of dense granules

A
  • AKA: delta granules
  • 3-8 per platelet
  • They contain nucleotides and other substances such as serotonin, ADP, ATP, 5-HT, and calcium
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26
Q

List the four major functions of platelets [for hemostasis]

A
  1. Adhesion to damaged surfaces 2. Storage and release of agonists that promote platelet activation 3. Aggregation to form a platelet plug 4. Exposure of a phospholipid surface for coagulation
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27
Q

What happens during platelet adhesion?

A

vWF binds to subendothelial collagen and to platelets via the GPIb receptor, bringing the two together

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28
Q

What happens during platelet storage and release?

A

Platelets secrete the contents of alpha and dense granules. This release recruits and activates other platelets. Platelets also release arachidonic acid from their cell membrane which is converted to thromboxane A2 [TXA2]

29
Q

Describe the function of TXA2

A

TXA2 is a potent agonist and vasoconstrictor that activates platelets and potentiates aggregation

30
Q

What happens during platelet aggregation?

A

Platelet aggregation means the platelets need to bind together. When platelets are activated a conformational change in GPIIb/IIIa occurs that exposes binding sites for fibrinogen. Fibrinogen forms a bridge between activated platelets.

31
Q

What happens during exposure of negatively-charged phospholipids [exposure mediated by platelets]?

A

Activated platelets expose negatively-charged phospholipids that bind clotting factors. Activation of coagulation generates thrombin. Thrombin converts fibrinogen to fibrin - this creates a fibrin network that anchors and stabilizes the platelet plug.

32
Q

What is the difference between primary hemostasis and secondary hemostasis?

A

Primary = mediated by blood platelets and their adhesive proteins Secondary = formation of a fibrin clot by the coagulation cascade [occurs after the platelets adhere to the wound site]

33
Q

What type of enzyme is thrombin? What is it’s role?

A

serine protease. By cleaving four small peptides from the center of fibrinogen it converts fibrinogen to fibrin monomers [the monomers spontaneously polymerize to form fibrin].

34
Q

What is the function of factor XIII? How does it become activated?

A

Factor XIII is a transglutaminase zymogen. It is activated by thrombin cleavage to become XIIIa. XIIIa forms amide bonds between glutamine and lysine side chains in adjacent fibrin strands, stabilizing the clot.

35
Q

What do fibrin clots trap?

A

red blood cells and platelets

36
Q

Coagulation uses the strategy of protease zymogen activation. Describe this strategy.

A

In this strategy we have a series of inactive protease zymogens which are activated one after the other by other proteases in the pathway.

37
Q

What are the two advantages to using the protease zymogen activation strategy for coagulation?

A

Massive amplification and finely-tuned regulation.

38
Q

Name the type of enzyme that most coagulation factors are. How are they made more specific?

A

Most of the coagulation factors are inactive serine protease zymogens which are based on the enzyme trypsin. To become specific, extra domains are added to the amino terminus.

39
Q

List all the functions of thrombin [AKA activated factor II]

A
  • cleaves fibrinogen into fibrin
  • activates factor XIII
  • activates factors V, VIII, and XI
  • activates platelets [by cleaving the cell surface proteins PAR-1 and PAR-4 [protease-activated receptors 1 and 4]]
  • activates protein C
  • activates fibrinolysis
40
Q

Draw out the extrinisic pathway for coagulation. Why is it called the extrinsic pathway?

A

The extrinisic pathway is named as such “because something extrinsic to blood itself was needed to initiate it [the pathway]. That “something” is tissue factor [Dr. Farrel’s Study Guide].”

41
Q

Draw out the intrinsic pathway for coagulation. Why is it called the intrinsic pathway? What other name does this pathway go by? How is it activated?

A

The intrinsic pathway is so named because “all the components needed to clot the blood are intrinsic to the blood itself [Dr. Farrel’s Study Guide].”

Other name: contact pathway/activation

This pathway is activated by the cleavage reactions of thrombin that occured in the extrinsic pathway.

42
Q

Is Factor XII essential for the intrinsic pathway? How do we know?

A

Factor XII is not essential for the intrinsic pathway is no longer believed to initiate the pathway in vivo. This was determined since people with a deficiency in factor XII do not have any bleeding problems.

43
Q

Describe the aPTT assay

A

aPTT stands for activated partial thromboplastin time. This assay uses kaolin [clay-like substance providing a surface for contact] to initatie clotting. This assay is very sensitive in detecting the most common hemophilas.

44
Q

Why do we have the intrinsic pathway in addition to the extrinsic pathway since both generate thrombin?

A

One reason we have the intrinsic pathway in addition is because it provides more amplication. It is also important that we have the second pathway since the extrinsic pathway is shut off by the Tissue Factor Pathway Inhibitor [TFPI] very rapidly.

45
Q

Describe the difference between the “Old Pathway” and the “New Pathway.”

A

Old Pathway: Contact System [XII and XI] → IXa+VIIIa → Xa+Va → IIa → Clot

New Pathway: thrombin [IIa] activates factor XI; everything else is the same.

46
Q

Describe the four things required for the basic reaction mechanism for key steps in coagulation [the four things together are called the “Quaternary Complex”]

A
  1. Enzyme [Factors IIa, VIIa, IXa, Xa, and XIa]
  2. Cofactors [Factors Va, VIIIa, Tissue Factor] - these speed up the reactions greatly [bind directly to the serine protease coagulation factors]
  3. Calcium - binds protein to surfaces; interacts with Gla residues in clotting factors [Gla = Carboxyglutamic acid]
  4. Phospholipid surface - provides negative charges for calcium binding [the ones used for this purpose are typically in membrane surfaces]
47
Q

Describe gamma carboxylation and its role in coagulation.

A
  • Gamma carboxylation is a modification of specific glutamic acid residues in clotting factors that allow them to bind calcium.
  • This modification requires a consensus sequence in the clotting factor, a gamma carboxylase enzyme [in liver ER], vitamin K, CO2, O2, and an enzyme to recycle the Vitamin K after it gets oxidized in the reaction.
  • it makes the glutamic acid residues bidentate [have two negative charges so it can chelate the calcium ion]
48
Q

Name the clotting factors and cofactors that have Gla residues.

A

Remember: SC, 10972

  • Protein S
  • Protein C
  • Factor X
  • Factor IX
  • Factor VII
  • Factor II
49
Q

Name the three macromolecular complexes of coagulation that form on phospholipid membranes

A
  1. Extrinsic Xase
  2. Intrinsic Xase
  3. Prothrombinase
50
Q

Draw out the role of Vitamin K in coagulation. How does Warfarin affect this pathway?

A

Warfarin inhibits the reduction of Vitamin K by blocking VKORC1 [vitamin K epoxide reductase complex] enzyme. The blocking of reduction prevents synthesis of Gla residues which, therefore, prevents synthesis of active factors and proteins [SC, 10972].

51
Q

Describe the clinical uses of Warfarin and its side effects.

A

Clinical Uses

  • chronic anticoagulation:
    • venous thromboembolism prophylaxis
    • prevention of stroke in atrial fibrillation
  • DO NOT use in pregnant women [warfarin can cross the placenta]

Adverse Effects

  • bleeding
  • teratogenic
  • skin/tissue necrosis
    • “Proteins C and S have shorter half-lives than clotting factors II, VII, IX, and X, resulting in early transient hypercoagulability with warfarin use. Skin/tissue necrosis within first few days of large doses is believed to be due to small vessel microthrombosis [First Aid, 2017].
  • drug-drug interactions [CYP2C9]

Route of Administration = Oral

Site of Action = Liver

Onset of Action = slow; limited by halft-lives of normal clotting factors

Duration of Action = days

Agents for reversal = Vitamin K, FFP, PCC

Monitoring = PT/INR [extrinisic pathway]

Crosses placenta? = Yes [teratogenic]

52
Q

Describe how antithrombin works as an antithrombotic molecule.

A
  • Antithrombin is a glycoprotein synthesized in the liver
  • circulates in plasma; it is also found on the surface of endothelial cells where it binds to heparan sulfate
  • member of the serpin family: SERine Protease INhibitors
  • inhibits thrombin as well as several other activated coagulation enzymes [IXa, Xa, XIa]
  • Two functional sites:
    1. heparin binding site: allows reversible binding to physiologic heparan on the endothelial surface
    2. thrombin binding site: irreversible binding to thrombin which neutralizes its activity
53
Q

Describe the clinical uses of Heparin and its side effects.

A

All of these is taken from First Aid 2017:

Mechanism of Action: activates antithrombin which lowers the action of thrombin and factor Xa

Route of Administration: Parenteral [IV, SC]

Site of Action: blood

Onset of Action: rapid [seconds]

Duration of Action: hours

Agents for Reversal: protamine sulfate [positively charged molecule that binds negatively charged heparin]

Monitoring: PTT [intrinsic pathway]

Crosses placenta?: No

Clinical Uses:

  • immediate anticoagulation for pulmoary embolism, acute coronary syndrome, MI, deep venous thrombosis
  • can be used during pregnancy - does not cross the placenta

Adverse Effects:

  • bleeding
  • thrombocytopenia [HIT]
  • osteoporosis
  • drug-drug interactions
54
Q

Define heparin-induced thrombocytopenia [HIT]

A

development of IgG antibodies agains heparin-bound platelet factor 4 [PF4]. Antibody-heparin-PF4 complex activates platelets and the result is thrombosis and thrombocytopenia.

55
Q

Describe how protein C and protein S act as antithrombotic molecules.

A
  1. Protein C is converted to APC [activated protein C] by thrombin binding to thrombomodulin [cleavage event takes place].
    • thrombomodulin is an integral membrane protein on the surface of endothelial cell
  2. APC inactivates the two coagulation cofactors: Factor Va and Factor VIIIa via selective proteolysis
  3. Protein S is a required cofactor for these reactions. It binds APC, forming a complex which enables it to bind to phospholipid surfaces
    • only the free form of protein S can function as a cofactor for APC

Protein C is synthesized in the liver.

Protein S is primarily synthesized in the liver; it is also synthesized by endothelial cells and other tissues.

56
Q

Describe how Tissue Factor Pathway Inhibitor acts as a antithrombotic

A

TFPI inhibits the tissue factor/VIIa/Xa complex and blocks the initiation of coagulation

  • primarily synthesized by the microvascular endothelium
57
Q

Describe the function of prostacyclin I2 [PGI2] as an antithrombotic

A
  • PGI2 is a potent vasodilator and inhibitor of platelet aggregation [blocks recruitment of additionnal platelets to the vascular injury site]
  • made from arachidonic acid via the enzyme cyclooxygenase-1 [COX-1]
  • synthesized and released by stimulated endothelial cells [intact ones in proximity to area of injury]
58
Q

Describe the fibrinolytic system.

A
  • this system lyses fibrin clots
  • fibrinolysis is activated by relase of tissue plasminogen activator [TPA]
  • TPA is released from perturbed or activated endothelial cells near injury site
  • TPA converts plasminogen into plasmin
  • plasmin is the key fibrinolytic enzyme that lyses polymerized fibrin at multiple sites
  • plasminogen is synthesized in the liver
59
Q

List and describe the regulatory proteins that prevent uncontrolled fibrinolysis.

A
  • Plasminogen activator inhibitor-1 [PAI-1]
    • synthesized by endothelial cells and platelets
    • inhibits tPA
  • alpha2-antiplasmin
    • synthesized and secreted by liver
    • inactivates free plasmin released into circulation
    • bound plasmin is resistant to alpha2-antiplasmin
  • thrombin-activatable fibrinolysis inhibitor [TAFI]
    • protects newly-formed clot from premature fibrinolysis
    • activated by thrombin-thrombomodulin complex
    • inhibits fibrinolysis via plasmin
60
Q

Explain what happens to the coagulation pathway during sepsis/inflammation

A
  • The hemostatic balance is shifted to favor procoagulant pathways
  • tissue factor expression is upregulated
  • there is an increase in expression of negatively charged phospholipids
  • thrombomodulin expression is downregulated → impaired activation of protein C
  • lower amount of free protein S
  • may result in disseminated intravascular coagulation [DIC]
61
Q

Explain what happens to the coagulation pathway with extra estrogen [via oral contraceptive use or during pregnancy].

A
  • 3-6 fold increase risk of venous thrombosis when taking oral contraceptives [associated risk]
  • 6 fold increase risk of venous thrombosis during pregnancy
  • both during pregnancy and while using contraceptives there is an increase in several clotting factors and a lowering in free protein S levels [result in an acquired resistance to protein C]
  • Pregnancy: these changes reflect the physiologic preparation for the hemostatic challenge of delivery.
62
Q

What cells are the first responders of the hemostatic system?

A

platelets!

63
Q

Define megakaryopoiesis

A

This is the process of megakaryocyte maturation and differentiation

64
Q

Where are most clotting factors [& tPO] made?

A

The liver! So, people with liver disease may have major problems in their coagulation pathway

65
Q

Where are about 1/3 of platelets stored at any one time?

A

The Spleen!

66
Q

Where are platelets produced?

A

in the bone marrow

67
Q

List the functions of platelets

A
  • hemostasis
  • chemotaxis
  • cell growth
  • inflammation
  • vasomotor activities

These functions are carried out through direct cell-cell interactions and cell-cell signaling

68
Q

What does integrin alpha2beta1 and glycoprotein VI [both on platelets] bind to?

A

collagen

69
Q
A

Blood & Host Defense (5 decks)

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