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CMBM Exam 3: Immunology > Thrombosis > Flashcards

Thrombosis Flashcards

1
Q

Define hemophilia

A

Tendency to bleed

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2
Q

Define thrombophilia

A

Tendency to clot

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3
Q

Define hemostasis

A

The stoppage of blood flow

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4
Q

What is the goal of hemostasis?

A

To produce a platelet and fibrin plug (thrombosis) in order to seal an injured blood vessel wall

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5
Q

The tunica intima plays a role in ___________
The endothelium plays a role in ___________
The tunica adventitia/collagen play a role in ___________

A

Hemostasis
Inhibiting coagulation
Adhesion of platelets

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6
Q

What 3 events occur after a vessel wall is injured?

A
  1. Vascular spasm causing vasoconstriction
  2. Formation of the platelet plug
  3. Blood coagulation (fibrin formed via thrombin)
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7
Q

How are RBCs involved in clotting? What about WBCs?

A

RBCs play no role in clotting, however they do stick to the clot and give it its red appearance.
WBCs that become injured can serve as a surface for the clot

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8
Q

What 3 mechanism/cell types cause vasoconstriction after vessel injury?

A
  1. Reflex neurogenic mechanisms
  2. Endothelial cell secrete endothelin
  3. Platelets secrete thromboxane A2 and serotonin
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9
Q

Once the platelet plug is formed what is the next step in the hemostatic process?

A

Clotting factors induce the production of fibrin “mesh” to form around the platelet plug thus forming a “hard clot” which completely stops the loss of blood

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10
Q

Name 6 characteristics of platelets (thrombocytes)? Such as their size, where they are derived from, lifespan, etc.

A
  1. Small, disk shaped clear cell fragments
  2. No nucleus
  3. 2-3 micrometers in diameter
  4. Derived from fragmentation of precursor megakaryocytes
  5. Lifespan of 5 to 9 days
  6. They are a source of growth factors
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11
Q

Another component of hemostasis found in the blood are platelet microparticles (PMPs). From what two cells are they derived from and what properties do they have?

A
  1. Platelets (~90%): have procoagulant property

2. Apoptotic monocytes: contain encrypted (inactive state) tissue factor

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12
Q

Once platelets become activated by outside signals what 5 things do they do?

A
  1. Undergo abrupt shape change
  2. Spill granule contents into surround area
  3. Adhere/Aggregate
  4. Synthesize prostaglandins (target of ibuprofen)
  5. Get a negatively charged surface (helps to bind clotting factors)
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13
Q

What is thrombopoietin (TPO)? What does it target? In what organ(s) is it produced?

A

TPO is a hematopoietic growth factor/cytokine/hormone
It targets megakaryocytes to fragement into platelets
Mostly produced in the liver but also in the kidney

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14
Q

How is TPO negatively regulated?

A

By binding to platelets which removes TPO from circulation

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15
Q

What is the normal concentration of platelets in the blood?

A

150,000 to 300,000 per microliter

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16
Q

Activated platelets change their shape and release granule contents? Specifically how does their shape change and how do the granules get released?

A
  1. Begin to swell
  2. Assume irregular forms with numerous irradiating pseduopods
  3. Contractile proteins contract forcefully releasing granules that contain multiple active factors
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17
Q

Platelets contain 2 types of granules. What are they and what is stored in them?

A

Alpha granules: fibrinogen, vWF, thrombospondin, beta-thromboglobulin, platelet factor 4, PDGF
Dense granules: serotonin, ADP, ATP, calcium

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18
Q

What is Gray Platelet Syndrome?

A

Condition in which there are little to no alpha granules

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19
Q

Where are Weibel-Palade bodies found and what do they store?

A

Found in the cytoplasm of endothelial cells and they store vWF

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20
Q

What is the function of each of the molecules stored within the dense granules of platelets?

A

ADP: recruits more platelets
Serotonin: causes vasoconstriction
Calcium: contains a positive charge which binds to the negative charge on the platelet cell membrane

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21
Q

Arachidonic acid derived from cell membrane phospholipids/linoleic acid (omega 6 FA) serves as a precursor for what 2 types of molecules?

A
  1. Prostaglandins

2. Leukotrienes

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22
Q

What are the 4 steps involved in arachidonic acid metabolism? Note the enzymes involved, the intermediate(s) and the product(s) as well as the cell types that it occurs in.

A
  1. Phospholipase A2 cleaves arachidonic acid from the cell membrane phospholipids
  2. PGH synthase (COX-1 or COX-2) converts arachidonic acid to prostaglandin H2 (PGH2)
  3. PGH2 serves as a common intermediate for both platelets and endothelial cells
  4. Platelets synthesize thromboxane A2 (TxA2) and endothelial cells synthesize prostacyclin (PGI2)
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23
Q

PGH synthase has two main isozymes involved in the metabolism of arachidonic acid called cyclooxygenase (COX); COX-1 and COX-2. What, if anything, regulates each their expressions?

A

COX-1 is constitutively expressed

COX-2 is inflammation induced

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24
Q

What drugs can target COX, do they do it reversibly or irreversibly?

A

Aspirin targets COX irreversibly

NSAIDS target COX reversibly

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25
Q

What 2 vasodilatory compounds do endothelial cells secrete?

A
  1. Nitric oxide (NO)
  2. Prostacyclin (PGI2)
    * Factor 7a converts prekalikrein to kalikrein which cleaves high molecular weight kininogen (HMWK) to produce bradykinin which has vasodilatory activity.
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26
Q

Cleavage of cell membrane phospholipids by PLA2 creates arachidonic acid as well as a phospholipid byproduct. What happens to this byproduct

A

Phospholipids that do not contain arachidonic acid will flip from the inner leaflet of the cell membrane to the outer leaflet giving the platelet surface a negative charge. The negative charge helps facilitate clot formation.

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27
Q

The negatively charged surface of the activated platelet bind clotting factors via what?

A

Clotting factors bind to calcium (which is bound to the negatively charged platelet surface) via glycosylation

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28
Q

The surface-bound reactions of the activated platelet help to do what 3 things?

A
  1. Concentrate clotting factors
  2. Achieve 2-dimensional diffusion of factors via a lipid raft
  3. Orient the reactants for the enzymatic reactions
29
Q

What are the 7 steps in platelet recruitment to the site of injury? Be specific and note which proteins and chemicals are involved in this process

A
  1. Collagen gets exposed on the injured vessel and binds platelets directly via glycoprotein (Gp) IV (GpIV) receptor which is expressed on the platelet.
  2. Platelets degranulate releasing serotonin (vasoconstrictor), ADP (promotes receptor expression on other platelets to encourage aggregation/induces conformational change of Gp2b-3a receptor), and TxA2 (promotes aggregation, degranulation, and vasoconstriction)
  3. vWF produced by endothelial cells is released from the Weibel-Palade bodies and the vWF binds to exposed collagen
  4. vWF bound to collagen is exposed to a sheer stress that causes vWF to unfold and become active.
  5. Active vWF binds to Gp1b-9-5 receptor on the platelet
  6. Phosphatidylserine (PS) gets exposed on dying cells and activated platelets; PS binds more platelets
  7. Platelets bind to one another via Gp2b-3a receptor using 3 fibrinogen molecules as an intermediate (this also helps to concentrate fibrinogen)
30
Q

Deficiency in the following molecules results in what diseases?

  1. Gp2b-3a
  2. Gp1b
  3. vWF
A
  1. Glanzmann thrombasthenia
  2. Bernard-Soulier syndrome
  3. von Willebrand disease
31
Q

Both Glanzmann and Bernard-Soulier syndrome are thrombasthenia’s that bind receptors via what motif? What factors is this motif found on?

A

Both bind receptors via RGD (Arg-Gly-Asp) amino acid sequence which is found on fibrinogen and vWF

32
Q

How does von Willebrand disease present both symptoms and epidemiologically?

A

It is the most common hereditary coagulation disorder. Symptoms include: nose bleeds, skin bruises, and hematomas

33
Q

Aside from mediating adhesion of platelets to collagen, what is the other function of vWF?

A

Protects factor 8 from being degraded. Thus a deficiency of vWF means that factor 8 will also be deficient. This is because they normally float around complexed to one another

34
Q

A Disintegrin And Metalloproteinase with ThromboSpondin-1-like domains (ADAMTS-13) plays what role in clotting?

A

It is a metalloproteinase that cleave vWF under high sheer stress thus regulating the final size of vWF in plasma
This ultimately protects against uncontrolled platelet adhesion

35
Q

What condition is caused by a congenital deficiency in ADAMTS-13?

A

Thrombotic thrombocytopenia purpura (TTP)

36
Q

Ticlopidine and clopidogrel (Plavix) both target what? How does this function?

A

Both are ADP receptor inhibitors which serve to inhibit ADP-induced expression of Gp2b-3a.
This causes platelets to stop adhering to one another. Commonly used in pts that cannot tolerate aspirin or need dual therapy

37
Q

What does Abciximab (ReoPro) act on?

A

Directly inhibits Gp2b-3a

38
Q

Aside from secreting vWF, what other compound do damaged endothelial cells release/expose to promote thrombosis?

A

Tissue Factor (TF)

39
Q

Most clotting factors are ____________ and some are ___________

A

Most are enzymes and some are cofactors

40
Q

Clotting factors require what 2 things to function?

A

All require calcium and some require vitamin K

41
Q

How do clotting factors bind to the the surface of the platelets?

A

Phospholipids of platelets have a negatively charged surface which binds to calcium. The calcium then binds to certain clotting factors which contain extra carbonyl groups, thus bridging the clotting factors and the platelets

42
Q

How are the extra carbonyl groups present on certain clotting factors synthesized?

A

Carboxylate groups are added to glutamate residues using a vitamin K cofactor during clotting factor synthesis and processing in the liver

43
Q

Which clotting factors require vitamin K?

A

Factor 2 (prothrombin), 7, 9, and 10. As well as protein C and S

44
Q

What is the function of protein C?

A

Protein C is present at the end of coagulation to end the process. (Protein S is similar but we do not discuss it)

45
Q

How does warfarin (Coumadin) function?

A

Inhibits the addition of the extra/gamma carboxyl group to glutamate residues on certain clotting factors by blocking the reductases that allow vitamin K to be recycled and participate in further reactions

46
Q

What is thrombin and what does it do?

A

Thrombin is a serine protease
Thrombin alone activates clotting factors: 5, 8, 11, and 13 as well as platelets
Thrombin complexed with thrombomodulin activates protein C
Most importantly it converts fibrinogen to fibrin monomers to form the fibrin clot

47
Q

What are the 4 steps involved in initiation (activation) of the coagulation cascade?

A
  1. Injured fibroblast, monocyte, etc. expresses TF on it’s surface.
  2. Factor 7 binds to TF and is converted to F7a by either thrombin, factors 9a, 10a, 12a, or even another TF-F7a complex which are all serine proteases
  3. TF-7a converts F9 and F10 to F9a and F10a (F9a diffuses to activated platelets)
  4. F10a contains the enzymatic activity and binds to F5a to form the prothrombinase which converts prothrombin to thrombin
48
Q

What are the 2 steps involved in the amplification phase of the coagulation cascade?

A 
1. Thrombin converts the following:
F8+vWF => F8a and free floating vWF
F5 => F5a
F11 => F11a
Platelets => activated platelets
2. F11a can then convert more F9 to F9a
49
Q

What are the 4 steps involved in the propagation phase of the coagulation cascade?

A
  1. F8a (from thrombin) and F9a (comes from the both F11a and TF-F7a) and complex on the surface of the platelet and are called TENASE
  2. TENASE converts F10 to F10a
  3. F10a (from the TENASE) and F5a (from the thrombin in the amplification step) complex on the platelet surface to form more prothrombinase
  4. Significantly more prothrombinase is present now and creates a large burst of thrombin
50
Q

How is factor 5 activated and how does it function/what is it’s purpose? How is F5a inactivated?

A

Factor 5 is a cofactor (no enzymatic activity) which is converted to F5a by thrombin.
F5a binds to receptors on the platelet surface and facilitates alignment of all of the compounds
It is inactivated to FVi by an activated protein C (APC)

51
Q

Following the propagation phase what is the last step to creating a stable blood clot?

A

Thrombin converts fibrinogen to fibrin monomers
Thrombin converts F13 (aka fibrin stabilizing factor) to F13a
F13a causes the fibrin monomers to crosslink thus forming the “hard clot”

52
Q

What is Hemophilia A and B? What does it affect? What does it result in both mechanistically and symptomatically? How is it treated?

A

It is an X-linked disorder of coagulation
It affects clotting factors 8 or 9 (doesn’t matter whether it’s A or B because the outcome is the same in every way)
Results in decreased clotting which produces symptoms such as: bleeding into soft tissues, muscle, weight bearing joints, which starts hours to days after trauma and continues for days to weeks.
Treatment is IV replacement therapy of the deficient factor

53
Q

What are the 4 steps to inhibiting thrombosis?

A
  1. Endothelial cells produce thrombomodulin (TM)
  2. TM complexes with thrombin and modifies the enzymatic activity of thrombin
  3. Thrombin-TM complex activates protein C to active protein C (APC)
  4. APC cleaves and inactivates F5a and F8a (double hit because 8 activates 10 and 5 cannot function without 10, this turns off the prothrombinase)
54
Q

How does proteolysis of the clot occur?

A
  1. Plasminogen is converted by plasminogen activator (PA) to plasmin, which is a protease.
  2. Plasmin degrades the cross linked fibrin monomers
55
Q

What 2 things can inhibit the degradation of the clot?

A
  1. Plasminogen activator inhibitor (PAI) which targets PA

2. alpha-2 Antiplasmin (alpha2-AP) which directly targets activated plasmin

56
Q

How does plasmin specifically destroy the clot? What is formed in the process which can be measured and indicates that a patient has had a recent blood clot?

A

Plasmin cleaves at two ends of adjacent fibrin molecules which happen to be covalently linked.
This cleavage product is called a D-dimer and indicates that a patient has had a recent blood clot

57
Q

What 4 drugs are currently used to dissolve clots?

A
  1. Streptokinase (SK)
  2. Urokinase
  3. Alteplase (tissue PA (t-PA))
  4. Recombinant t-PA
    * Usually delivered directly to clot via a catheter and contraindicated for PE
58
Q

What domain does plasminogen/plasmin use to bind to fibrin? What other component in the body has this domain and why is that bad?

A

Binding is via a Kringle domain which is also found on lipoprotein A.
This makes lipoprotein A a competitive inhibitor for plasmin binding to fibrin thus reducing fibrinolysis. This makes lipoprotein A a risk factor for atherosclerotic disease such as coronary heart disease and stroke

59
Q

What is the name of a family of inhibitors of serine proteases? Where are they produced? How do they function?

A

Serpins, which are produced in the liver
They function by inactivating/trapping serine proteases by behaving as a suicide substrate and binding irreversibly to the active site of the enzyme

60
Q

Serpins differ in their functional capacity modulate hemostasis/thrombosis. What are 3 mechanism by which they achieve this? Give examples of specific serpins associated with each method.

A
  1. Inhibitors that block clotting: AT3, C1 inhibitor, alpha-1 protease inhibitor
  2. Inhibitors that block fibrinolysis: PAI and plasmin inhibitors
  3. Inhibitors that shift reactions: tissue factor pathway inhibitor (TFPI)
61
Q

Where does TFPI come from and how does it function?

A

Secreted by endothelial cells and is a serpin which inactivates TF, F7a, and F10a

62
Q

How does heparin function and where is it found?

A

Herparin is a mucopolysaccharide chain found on endothelial cells (or can be administered exogenously)
It works by binding to and enhancing the activity of AT3 which is a serpin that cleaves F9a, F10a, F11a, F12a, and Thrombin

63
Q

How does fondaparinux (Arixtra) function?

A

It is a synthetic indirect inhibitor of F10a but not when F10a is in the prothrombinase (F5a/F10a complex). It is administered SQ

64
Q

How does rivaroxaban (Xarelto) function?

A

Direct inhibitor of F10a both free and F10a of the prothrombinase. It has a rapid onset of action (compared to warfarin which acts on clotting factors being produced not ones that are already circulating). It is administered orally

65
Q

What 4 things do primary hemostasis tests test for?

A
  1. Platelet count
  2. Platelet aggregation assay
  3. vWF function studies
  4. Bleeding time (test of platelet-vessel wall interaction)
66
Q

What does a secondary hemostasis test check for? What 2 tests are normally performed and what do they specifically test?

A

Secondary hemostasis test assesses the function of clotting factor pathway.

  1. Partial thromboplastin time (PTT): Factors 1, 2, 5, 8, 9, 10, 11, and 12 (PTT used for monitoring heparin therapy)
  2. Prothrombin time (PT): Factors 1, 2, 5, 7, and 10 (PT used for monitoring warfarin therapy)
67
Q

What are the normal PTT and PT times, what is the ideal time for patients on heparin and warfarin therapy respectively, and what reactants are required for each?

A

PTT: Normally 25-27 seconds; heparin therapy the time is 50-64 seconds
PT: Normally 10-12 seconds; warfarin therapy the time is 20-30 seconds
Both PTT and PT require the patient’s plasma, phospholipid and calcium, however PTT uses kaolin and PT uses tissue factor.

68
Q

What is the purpose of the International Normalized Ratio (INR)?
How is INR calculated?

A

Used to standardize PT from various labs
INR = ratio of (PT patient/ PT normal mean)
This means that INR = 1 is normal (pre-warfarin therapy) and INR = 2 is good for patient on warfarin therapy

CMBM Exam 3: Immunology (21 decks)

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