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MI Immuno/Heme > Hemostasis > Flashcards

Hemostasis Flashcards

1
Q

Plasma vs. serum

A

Plasma - blood from which the cellular componenets have been removed

Serum - Plasma from which the clotting factors have been removed

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2
Q

Fibrinogen

A

Soluble protein converted to insoluble fibrin by thrombin

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3
Q

Vitamin K-dependent factors

A

Require vitamin K for the process of gamma-carboxylation that changes some Glu resides to Gla (γ-carboxy glutamate) with an extra negative charge necessary for the binding of Ca+2 and to phospholipid membrane surfaces

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4
Q

Nitric oxide

A

Inhibits the activation of platelets

NO stimulates the production of cGMP dependent protein kinase (G-kinase), which inhibits signaling and Ca²⁺ mobilization, preventing platelet activation.

Secreted by endothelial cells

Also a potent vasodilator

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5
Q

Prostacyclin (PGI2)

A

Prostaglandin member of the eicosanoid family of lipid molecules

Inhibits platelet activation similarly to NO

Secreted by endothelial cells

Also a potent vasodilator

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6
Q

Heparan sulfate

A

Glycosaminoglycan surface receptor on endothelial cells

Negatively charged and binds to anti-thrombin III (AT3)

Heparin is a stronger negatively charged glycosaminoglycan

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7
Q

Anti-thrombin III (AT3)

A

Degrades clotting factors II (aka thrombin), IX, and X

Binds to heparan sulfate and heparin

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8
Q

Heparin

A

Negatively charged, sulfated glycosaminoglycan, free-flowing in blood, produced by mast cells and basophils.

Binds to AT3 (like heparan), causing a conformational change, activating AT3 and inhibiting thrombin (factor II), factor X, and other factors.

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9
Q

Where is heparan sulfate located?

Cellular level

A

It is a glycosaminoglycan surface receptor on endothelial cells

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10
Q

Thrombomodulin

A

Endothelial membrane surface protein binds to thrombin (factor II), preventing thrombin from converting soluble fibrinogen to insoluble fibrin (part of the platelet plug).

While bound to thrombomodulin, thrombin activates protein C, which, along with protein S, degrades cofactors V and VII.

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11
Q

Steps of hemostasis

A
  1. Vascular spasm
  2. Platelet plug formation
  3. Coagulation
  4. Clot retraction and repair
  5. Fibrinolysis (clot busting)
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12
Q

Vascular spasm

A
  1. Endothelin release - endothelial cells secrete endothelin (21-AA peptide) which binds to receptors (various cells, including smooth muscle) leading to Ca2+ mobilization and muscle contraction causing vasoconstriction
  2. Myogenic mechanism - direct injury to smooth muscle cells triggers contraction by the myocyte itself, not external stimuli, helping maintain constant renal blood flow in response to BP changes
  3. Pro-inflammatory signals (i.e. histamine) are released subsequent to vessel/tissue damage along with endothelin - initially engage the nociceptor activation that leads to pain reflex and smooth muscle contraction

Proinflammatory signals also tends to lead to vasodilation over time

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13
Q

Platelet plug formation

A

Upon injury to vessel walls - platelets aggregate and adhere, forming a plug to prevent blood loss (primary hemostasis)

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14
Q

Von Willebrand factor and platelet plug formation.

A

vWF release - endothelial cells release vWF - large multimeric glycoprotein

vWF binds to factor VIII - prolonging its life

vWF naturally binds to exposed collagen - platelets passing by bind to vWF via their glycoprotein 1b receptors (Gp1b)

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15
Q

Once platelets become activated, what three signals do they release?

A

ADP - attracts more platelets

Thromboxane A2 (TxA2) - assists in platelet activation/aggregation, vasoconstriction, and degranulation

Serotonin - vasoconstrictor

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16
Q

Secondary hemostasis

A

The extrinsic and intrinsic pathways of the coagulation cascade

Both ex/in paths lead to fibrin formation - they converge

Intrinsic pathway is aka the contact activation pathway

Extrinsic pathway is aka the tissue factor pathway

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17
Q

What is the primary pathway for the initiation of coagulation?

A

The extrinsic pathway (tissue factor pathway)

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18
Q

What causes blood to coagulate in vitro?

A

The intrinsic pathway

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19
Q

Intrinsic pathway

A

Serine proteases become activated beginning w/ factor XII

Factor XII interacts w/ negative charges on platelets and becomes activated (factor XIIa)

Factor XIIa activated XI to XIa

XIa activates IX to IXa

With the help of cofactor VIII and Ca2+, IXa activates X to Xa of the common pathway

13-11-9(8)-10 (factor steps)

Takes 4-6 min. for Fx

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20
Q

Exrinsic pathway

A

Initiated by cell damage

Endothelial cells secrete tissue factor (aka factor III) when damaged

factor III acts as a cofactor for factor VII to VIIa - which then activates factor X of the common pathway

Quicker than intrinsic (~30s)

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21
Q

Common pathway

A

Factor Xa and V (and platelet factor) activate factor II (prothrombin) to factor IIa (thrombin)

Thrombin is a serine protease that polymerizes soluble fibrinogen molecules together to form insoluble fibrin

Thrombin also activates XIII to XIIIa - which crosslinks fibrin to create the fibrin mesh that holds the platelet plug down preventing it from getting loose and causing a distant thrombotic event

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22
Q

Clot retraction and repair

A

While in the plug formation platelets contract to close the injury and secrete PDGF to trigger mitosis in damaged smooth muscle cells, regenerating collagen fibers. They also produce VEGF to help regenerate the endothelial lining.

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23
Q

Fibrinolysis

A

Endothelial receptor tissue plasminogen activator (t-PA) - converts plasminogen in the plasma into plasmin

Plasmin - digest fibrin mesh into degradation products (D-dimer)

24
Q

What regulator mechanisms keep platelet activation and coagulation cascade in check?

A
  1. Protein C
  2. Anti-thrombin
  3. Tissue factor pathway inhibitor
  4. Plasmin
  5. Prostacyclin
25
Q

Protein C

A

Anticoagulant

Vitamin K-dependent serine protease - becomes activated by thrombin when bound to thrombomodulin on endothelium

Activated protein C (along with protein S) degrades cofactors V and VII

Deficiencies in proteins C or S may lead to thrombophilia (tendency to develop thrombosis)

26
Q

Anti-thrombin

A

Serine protease inhibitor (serpin) that degrades serine proteases: thrombin, along with factors IXa, Xa, XIa, and XIIa

27
Q

Tissue Factor Pathway Inhibitor (TFPI)

A

Limits the action of tusse factor (factor III) - in turn inhibits VIIa and Xa

28
Q

Plasmin

A

Generated by proteolytic cleavage of plasminogen (plasma protein produced by liver) - catalyzed by tissue plasminogen activator (t-PA), which is produced by endothelium

Plasmin proteolytically cleaves fibrin into fibrin degradation products (including D-Dimers)

29
Q

Prostacyclin

A

Is released by endothelium and it keeps platelets in an inactive state by preventing the Ca2+ mobilization w/i platelets

30
Q

Prothrombin time (PT)

A

Measures extrinsic pathway

Primarily inhibited by warfarin

Warfarin blocks the gamma-carboxylation of the certain Glu’s

PT uses plasma rather than whole blood - does not measure platelet Fx

31
Q

Partial thromboplastin time (PTT)

A

Measures intrinsic pathway

PT uses plasma rather than whole blood - does not measure platelet Fx

32
Q

What activates antithrombin 3 and slows aPTT?

A

Heparin (primarily) and heparan

33
Q

Blood clotting made simple…

A
34
Q

Xarelto

A

Inhibits factor Xa

So does Eliquis

35
Q

Pradaxa

A

Inhibits IIa

36
Q

Endothelial cell contributions to thrombosis

A

Tissue factor (III) to initiate the extrinsic pathway

vWF that binds platelets to collagen at the injury site

vWF binds factor VII and protects VIII

37
Q

Endothelial cell contributions to hemostasis

A

Surface heparan and plasma heparin (from mast cells) molecules activate anti-thrombin III (AT3) to prevent clotting

Thrombomodulin/throbmin complex activates protein C, which along w/ protein S (cofactor) degrades factors Va and VIIIa to slow clotting

Adenosine diphosphatase cleaves ADP; reducing platelet adhesion

Production of NO

Production of prostacyclin (PGI2); inhibits platelet aggregation

38
Q

Vit K role in clotting

A

Vit K is needed for the post-translational modification of some of the clotting factors in the liver

Helps carboxylate 10-12 glu AA’s of factors II, VII, IX, and X to yield γ-carboxyglutamic acid (Gla)

The extra negative charges of Gla bind Ca2+ so the coagulation factors can stick to the phosphatidylserine on the sruface of activated platelets

Phosphatidylserine is normally in the cytoplasmic side of lipid bilayers, but it appears on the outside of activated platelets

39
Q

Warfarin

A

Vit K antagonist - inhibits vit K epoxide reductase (VKOR) - the enzyme responsible for reduction of vit K to its active form

Without reduced vit K - Gla residues cannot be formed from the Glu residues of factors II, VII, IX, and X such that they are less negatively charged and less likely to form the Ca2+ bridge w/ phosphatidylserine of activated platelets

40
Q

Von Willebrand Disease

A

Most common bleeding disorder (~1% of pop.)

If vWF is absent/reduced - 50% cases - prolonged aPTT due to factor VII not being protected - defect in intrinsic pathway

41
Q

Hemophilia

A

A - factor 8 def

B - factor 9 def

Both A/B deficits in intrinsic path

42
Q

Healthy endothelial cell

A
43
Q

Endothelial injury

A
44
Q

Unactivated platelets

A

Dense bodies - procoagulants thromboxane A2 (TXA2), ADP, and calcium

TXA2 and ADP bind to the TXA2 receptor (TXA2-R) and the ADP receptor, specifically P2Y12, respectively

45
Q

The clotting cascade

A
46
Q

How would defect in the common clotting pathway affect PT/aPTT

A

Elevation in both PT and PTT

47
Q

In normal blood flow processes, endothelial cells secrete which of the following modulators that functions to keep vessels dilated?

A. Endothelin
B. Anti-thrombin III
C. Prostacyclin
D. Thrombomodulin
E. Thromboxane A2

A

C. Prostacyclin

48
Q

A patient is started on warfarin for atrial fibrillation. Which of the following coagulation factors will be affected due to the inhibition of vitamin K?

A

Factors II, VII, IX, and X

49
Q

In the extrinsic pathway of coagulation, which factor secreted by endothelial cells activates factor VII leading to the entry into the common pathway?

A

Tissue factor

50
Q

Endothelial cells express the surface receptor thrombomodulin, which leads to the activation of which factor that degrades factors Va and VIIIa to slow clotting?

A

Protein C

51
Q

A 42-year-old man is undergoing surgery and develops excessive bleeding. His prothrombin time (PT) is prolonged, but his aPTT is normal. Which pathway is most likely impaired?

A

Extrinsic

52
Q

As part of the platelet plug formation, platelets bind to one another via which combination of receptor ligands?

A

Glycoprotein IIb/IIIa and fibrinogen

53
Q
A

C. Thrombomodulin and thrombin

Heparan sulfate receptor is another modulator

54
Q
A

B. GpIIb/IIIa (aka integrin)

55
Q

Endothelial cell modulators

A
56
Q

Hemophilia C

A

Deficiency of Factor XI

Autosomal recessive

MI Immuno/Heme (24 decks)

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