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Foundations Exam 2 > Hemostasis and Coagulation > Flashcards

Hemostasis and Coagulation Flashcards

1
Q

thrombomodulin, protein C, and protein S are…

A

anti-coagulant factors

thrombo-modulin MODULATES THROMBOSIS so we can have Safe (protein S) Coagulation (protein C)

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2
Q

the 4 basic steps of hemostasis:

A
  1. arteriolar vasoconstriction
  2. primary hemostasis: platelet function
  3. secondary hemostasis: clotting cascade
  4. regulation of thrombus activity: antithrombotics
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3
Q

most powerful endothelial-released vasoconstrictor

A

endothelin

very important for first step of hemostasis: local vasoconstriction

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4
Q

primary hemostasis, the 2nd step of hemostasis, is when _____ forms

A

platelet plug:
1. platelets adhere
2. TXA2 (thromboxane) release
3. aggregation/plug formation

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5
Q

platelets are part of what cell line?

A

made from megakaryocytes of myeloid lineage

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6
Q

_____ binds to platelets to degrade platelet mass

A

thrombopoietin (TPO): produced by liver constitutively

it is degraded with platelet mass

so TPO levels are determined by platelet mass —> when there is high TPO, platelet production increases to balance

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7
Q

describe endomitosis of megakarcyotes

A

as megakaryocytes mature, they stop dividing but DNA continues to replicate (endomitosis)

nucleus MUST be polypoid to produce platelets

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8
Q

when blood vessel endothelium is injured, what becomes exposed that platelets can now bind to (in subendothelial basement membrane)? (2)

A
  1. collagen
  2. von Willebrand Factor (vWF)

—> platelet plug formation

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9
Q

This large circulating multimer is synthesized in endothelial cells and megakaryocytes, and stored in Weibel-Pallade bodies. It is cleaved from endothelium via ADAMTS13 (enzyme) to initiate primary hemostasis (platelet binding). What is?

A

Von Willebrand Factor (VWF): adheres to exposed collagen at sites of injury, and platelets adhere to vWF via glycoprotein Ib (GpIb) receptor

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10
Q

a deficiency in Von Willebrand Factor (VWF) due to lack of the enzyme ____ which cleaves it from endothelium or its receptor _____ can cause a defect in primary hemostasis

A

enzyme: ADAMTS13 (—> von Willebrand disease)

receptor: glycoprotein Ib (GpIb) (—> Bernard-Soulier syndrome)

remember that primary hemostasis is the second step of hemostasis in which platelets bind

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11
Q

what are 3 soluble mediators of platelet shape change and granule release in hemostasis?

A
  1. ADP
  2. Thrombin (clotting cascade protein)
  3. Thromboxane A2 (prostanoid)

granules released include: VWF, fibrinogen, factor V, platelet factor 4, ADP, calcium, serotonin, epinephrine

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12
Q

This positively charged molecule (of 4 identical subunits) is found in alpha granules of platelets and circulating in the plasma. It contributes to hemostasis and can bind heparin (neg charge) to form ultra large multimers. What is?

A

platelet factor 4

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13
Q

the inside-out activation of ____ receptor and its subsequent interaction with ____ creates a bridge between platelets

A

GpIIb/IIIa receptor activated via inside-out signaling

followed by interaction with fibrinogen —> creates bridge between platelets —> platelet aggregation

(part of primary hemostasis, second step of hemostasis)

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14
Q

Glanzmann thrombasthenia is a clotting disorder due to a deficiency in the platelet receptor _____

A

GpIIb/IIIa

GpIIb/IIIa-fibrinogen interaction mediates platelet aggregation (primary hemostasis)

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15
Q

what are some signs of a defect in primary hemostasis (due to decreased platelet number or functioning)?

A

bleeding occurs immediately after injury

  • petechiae: tiny bruises due to RCB deposited in skin (lower extremities)
  • scattered ecchymoses (sites of minor trauma)
  • nose bleeds
  • menorrhagia (heavy menses)
  • GI/urinary bleeding
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16
Q

secondary hemostasis is the process in which cross-linked ____ is formed

A

cross-linked fibrin

secondary hemostasis = clotting cascade, when fibrin self-assembles from fibrinogen (via thrombin)

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17
Q

which clotting factors are circulating zymogen serine proteases? (roman numerals, looking for 6)

what are 3 soluble cofactors that accelerate the process?

A

Factors: 2, 7, 9, 10-12
II (2)
VII (7)
IX (9)
X (10)
XI (11)
XII (12)

Cofactors: 5, 8, VWF
V (5)
VIII (8) - NOT made in liver
Von Willebrand (VWF) - NOT made in liver

*note that most pro-coagulant proteins are made by liver, but factor VIII (8) and VWF are made by endothelium

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18
Q

which three pro-coagulation proteins are NOT made by the liver?

A

most pro-coagulant proteins are made by liver, but factor VIII (8) and VWF are made by endothelium (VWF is the chaperone of VIII)

tissue factor (cell-associated cofactor) is also not made by liver

19
Q

most coagulation factors are ____ that circulate as zymogens

A

serine proteases

when activated, add an “a” for “activated”
(example: Factor X—> Factor Xa)

20
Q

which clotting factors make up the common clotting cascade, where intrinsic and extrinsic converge?

A

Factors X —> V (cofactor) —> II —> fibrinogen

21
Q

which clotting factors make up the intrinsic pathway, and what lab test is used to evaluate the intrinsic pathway?

A

Factors XII —> XI —> IX —> VIII (cofactor)

activated partial thromboplastin time (aPTT) used to test intrinsic pathway

*note that results will be abnormal if a factors in common pathway (X, V, II, fibrinogen) are not functioning normally, as well

22
Q

which clotting factors make up the extrinsic pathway and what test is used to evaluate extrinsic pathway?

A

Factors VII, tissue factor

evaluate with prothrombin time (PT) - note that this will evaluate common pathway, as well, which extrinsic pathway feeds into
(factors X, V, II, fibrinogen)

23
Q

if a patient as a normal aPTT but a long PT, where is the problem in their clotting pathway?

A

aPTT evaluates intrinsic
PT evaluates extrinsic

normal aPTT = normal intrinsic and common pathway

long PT = problem with extrinsic pathway (Factor VII)

*note that if there was a problem in the common pathway, both test results would be long

24
Q

if a patient has a long aPTT and long PT, what is the problem in their clotting pathway?

A

common pathway problem, which intrinsic and extrinsic feed into (Factors II, V, X, fibrinogen)

remember aPTT measures intrinsic, PT measures extrinsic

25
Q

_____ is a transmembrane protein in endothelial cells and monocytes that is not normally accessible, but exposed by blood vessel injury and triggers the first step of the extrinsic pathway of coagulation

A

tissue factor: bound by circulating Factor VII (extrinsic pathway)

activated endothelial cells also express additional tissue factor

26
Q

describe the steps of the extrinsic pathway of coagulation (4)

A
  1. circulating factor VII (7) binds tissue factor and is activated (VIIa)

then feeds into common pathway:
2. VIIa activates Factor X
3. Factor Xa activates prothrombin (Factor II) —> thrombin (Factor IIa)
4. thrombin (Factor IIa) cleaves fibrinogen to fibrin

27
Q

At end of clotting cascade, thrombin cleaves fibrinogen to fibrin. Thrombin causes amplification of the clotting cascade in 2 ways, the first through Factor IX and Factor VIII. Explain.

A

thrombin also activates more Factor IX and Factor VIII (cofactor)

Factor VIII circulates in the plasma in a complex with VWF (its chaperone, extends its life)
so VWF is key for primary and secondary hemostasis

Factor IXa and VIIIa together accelerate Factor X activation (beginning of common cascade)

28
Q

the most common inherited disorders of coagulation are…. (2)

and which coagulation factors are deficient in these disorders? What is the significance of a deficiency in these?

A

Hemophilia A: Factor VIII deficiency
Hemophilia B: Factor IX deficiency

remember that VIIIa and IXa together cause accelerated activation of Factor X, the first step of the common pathway of coagulation

29
Q

At end of clotting cascade, thrombin cleaves fibrinogen to fibrin. Thrombin causes amplification of the clotting cascade in 2 ways, the second through Factor V. Explain.

A

thrombin activates Factor V —> Factor Va

Factor Va (cofactor) with Factor Xa accelerate prothrombin —> thrombin activation (WAYYY faster)

30
Q

what do these complexes activate?
a. tissue factor::Factor VIIa
b. Factor IXa::VIIIa
c. Factor Xa::Va

A

a. tissue factor::Factor VIIa —> Factor X activation (extrinsic pathway)

b. Factor IXa::VIIIa —> Factor X activation (via thrombin amplification) [8, 9, 10]

c. Factor Xa::Va —> Factor II (prothrombin) activation (via thrombin amplification) [10/5 = 2]

these complexes are essential for driving coagulation

31
Q

What coagulation factors are dependent on vitamin K? What is vitamin K used for?

A

Prothrombin (Factor II), Factors VII (7), IX (9), X (10)

vitamin K catalyzes carboxylation that provides negative charges essential for being in Ca2+ (creates docking station) —> allows factor activation

32
Q

reduced vitamin K =
oxidized vitamin K =

which form of vitamin K is needed to activate coagulation Factors II (prothrombin), VII, IX, X?

A

reduced vitamin K = hydroquinone
—> carboxylates coagulation factors

oxidized vitamin K = epoxide (epOXide is OXidized)

warfarin targets vitamin K redactase —> anticoagulation

33
Q

describe the steps of the intrinsic clotting pathway (4)

A
  1. Factor XII (12) is activated by contact with neg charged surface and binds
  2. XIIa recruits HMKG, which allows XI (11) to bind
  3. XIa activates IX (9)
  4. VIIIa (8) binds and with IXa activates Factor X —> common pathway
34
Q

Hemophilia C is caused by a deficiency in…

A

Factor XI (11) - intrinsic pathway

minor bleeding phenotype but can be clinically silent

35
Q

This clotting factor is a transglutaminase that cross-links fibrin chains, creating D-dimers and stabilizing clot formation. Deficiency in this Factor is rare but can cause increased bleeding. Who am i?

A

Factor XIII (8)

36
Q

describe how a defect in secondary hemostasis presents

A

bleeding within tissues and joints, can be immediate or delayed

due to decreased clotting factor production

37
Q

2 things that limit coagulation in hemostasis

A
  1. dilution - when blood flows out it washes away coagulation factors
  2. activate fibrinolytic cascade - initiated by plasminogen activation
38
Q

how is plasminogen activated to regulate clot formation?

A

thrombin activates tPA (tissue plasminogen activator)

tPA activates plasminogen —> plasmin, which regulates size of clot

39
Q

fibrin degradation products such as _____ are indicators of recent coagulation in the vasculature which has been degraded by plasmin

A

D-dimers

can help evaluate DVT, pulmonary embolism, arterial thrombosis, DIC

40
Q

how does thrombomodulin regulate coagulation?

A

thrombomodulin: high affinity receptor for thrombin (II) and neutralizes it, activates Protein C

Protein C then inactivates Factor Va (prevents acceleration of prothrombin—>thrombin) and Factor VIIIa (prevents acceleration of Factor X activation)

41
Q

how does Activated Protein C (APC) regulate coagulation?

A

Protein C inactivates Factor Va (prevents acceleration of prothrombin—>thrombin) and Factor VIIIa (prevents acceleration of Factor X activation)

42
Q

how does antithrombin regulate coagulation?

A

antithrombin: present in plasma, binds endothelial cells and inactivates thrombin when it tries to bind

*binding to endogenous heparins on cell surfaces increases antithrombin activity (so the drug Heparan also increases antithrombin activity)

43
Q

what do tissue factor pathway inhibitors bind to?

A

remember that tissue factor binds Factor VIIa to begin extrinsic coagulation pathway (and feed into common pathway via Factor X binding)

tissue factor pathway inhibitors bind this complex (TF::VIIa)

Foundations Exam 2 (42 decks)

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