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N929 - Anesthesia Pharmacology > Coagulation and Dissolution of a Blood Clot > Flashcards

Coagulation and Dissolution of a Blood Clot Flashcards

1
Q

normal hemostasis

A

balance between generation of hemostatic clots and uncontrolled thrombus formation; anticoagulants dominate

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2
Q

extrinsic pathway

A
  • plasma mediated, initiation of hemostasis
  • primary hemostasis
  • key –> tissue factor
  • activated when blood contacts cells outside the vascular endothelium
  • nonvascular cells express a membrane protein called tissue factor III which initiates this pathway
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3
Q

intrinsic pathway

A
  • amplifies and propagates hemostasis
  • secondary hemostasis
  • key –> thrombin
  • triggered when blood contacts a negatively charged surface (exposed sub-endothelial collagen)
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4
Q

common pathway

A
  • results in an insoluble fibrin clot; starts at Xa

- where intrinsic and extrinsic pathways converge with activation of factor X

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5
Q

How do you decide whether or not to get preoperative coagulation testing?

A
  • based on patient’s history and planned surgery

- balance between risk of surgical bleeding and risk of developing postoperative thromboembolism

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6
Q

mechanism of normal hemostasis

A
  • vasoconstriction
  • platelet plug
  • clot formation
  • clot dissolution
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7
Q

vasoconstriction in normal hemostasis

A
  • vascular endothelium provides nonthrombotic or antiplatelet surface (basically makes it so the blood doesn’t stick to the surface and clot)
  • damage to the endothelium exposes the underlying extracellular matrix and elicits contraction (vasoconstriction)
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8
Q

what other things can induce prothrombotic endothelial changes?

A
  • thrombin
  • hypoxia
  • high fluid sheer stress
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9
Q

formation of platelet plug in normal hemostasis

A

when platelets are exposed to the extracellular matrix in damaged endothelium they undergo a series of biochemical and physical alterations

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10
Q

3 major phases of platelet plug

A
  • adhesion
  • activation
  • aggregation
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11
Q

platelet normal concentration

A

150,000-400,000 per microliter
spontaneous bleeding can occur at <50,000
lethal is <10,000

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12
Q

what is the life of a platelet?

A

8-12 days

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13
Q

platelet adhesion

A

exposure to the subendothelial matrix proteins allows platelets to undergo a conformational change to adhere to the vascular wall; basically conformational change makes them more sticky

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14
Q

platelet activation

A
  • after platelets adhere to damaged endothelial cell wall, several intracellular signaling pathways are activated when ligands bind to platelet receptors and a series of physical and biochemical changes occur
  • platelets develop pseudopod-like membrane extensions to increase platelet surface area
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15
Q

platelet aggregation

A
  • plt recruitment
  • release granular contents resulting in recruitment and activation of additional platelets
  • completes the formation of a platelet plug
  • activators released during the activation phase recruit and amplify the response of additional platelets to the site of injury
  • newly activated GPIIb/IIIa receptors on the platelet surface bind fibrinogen to provide for cross-linking with adjacent platelets
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16
Q

Von Willebrand Factor (vWF)

A
  • produced in endothelium and platelets
  • released by endothelial cell and by activated plts
  • primary function is to bind other proteins
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17
Q

vWF primary function

A
  • important bridging molecule between subendothelial matrix and platelets forming cross links
  • Glycoprotein IIb/IIIa –> platelet to platelet
  • Glycoprotein Ib/factor IX/factor V receptor complex –> plt to endothelium
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18
Q

glycoprotein Ib-factor V-factor IX complex (GPIb-V-IX)

A
  • binds vWF allowing platelet adhesion and platelet plug formation at sites of vascular injury
  • absence of this complex = Bernard-Soulier syndrome
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19
Q

Von Willebrand Disease (vWD)

A
  • mainly activated in conditions of high blood flow and shear stress
  • 1 in 100 individuals, but clinically significant cases are 1 in 10,000
  • deficiency of vWF therefore show primarily in organs with small vessels such as skin, GI, and uterus
20
Q

vWD common presentation

A

woman with heavy periods, bleeding when flossing or brushing teeth

21
Q

vWD diagnosis

A

measure amount of vWF in a vWF antigen assay and the functionality of vWF with biding assays

22
Q

type 1 vWD

A
  • 60-80% of cases
  • failure to secrete vWF into circulation or vWF being cleared more quickly than normal
  • mild, often goes undiagnosed until bleeding following surgery, easy bruising, or menorrhagia
23
Q

type 2 vWD

A
  • 15-30%
  • qualitative defect and bleeding varies (4 subtypes)
  • decreased ability to bind to GPIb
  • decreased ability to bind to VIII
24
Q

type 3 vWD

A
  • most severe, homozygous defective gene, complete absence of production of vWF
  • leads to extremely low levels of factor VIII since it does not exist to protect VIII from proteolytic degradation
25
Q

platelet type or pseudo-vWD

A
  • defect of the platelets GPIb receptor

- vWF is normal but the platelet receptor GPIb is abnormal

26
Q

what medications do we use that are a GPIIb/IIIa inhibitor?

A
  • GPIIb/IIIa inhibitors (class of antiplatelet)
  • abcizimab (ReoPro)
  • eptifibatide (Integrilin)
  • tirofiban (Aggrastat)
  • blocks ability of fibrinogen to form around aggregated platelets
27
Q

which medications do we use that are a thromboxane A2 inhibitor?

A
  • aspirin - inhibits the ability of COX enzyme to synthesize the precursors of thromboxane within platelets
  • naproxen - nonselective COX inhibitor
28
Q

P2Y12 receptor

A

further amplify the response to ADP and draw the forth of the completion of aggregation

29
Q

formation of blood clot

A
  • follows platelet plug
  • fibrinogen breaks down to produce fibrin, which becomes cross-linked into a stable mesh
  • coagulation factors activated and initiate coagulation cascade
  • soluble fibrinogen converted to insoluble fibrin
  • converted by thrombin (IIa)
30
Q

what is the key step in blood clotting?

A

conversion of fibrinogen (I) to fibrin (Ia) by thrombin (IIa)

31
Q

coagulation factors

A
  • identified with roman numerals
  • most are glycoproteins
  • most synthesized in liver
  • circulate in an inactive state
  • lower case “a” indicates active enzyme
32
Q

which coagulation factors are not enzymes?

A
  • vWF
  • Tissue factor (III)
  • glycoprotein
33
Q

which coagulation factors are not synthesized in the liver?

A
  • calcium (from diet)

- vWF (synthesized in endothelial cells)

34
Q

Which factors are dependent on vitamin K for utilization?

A

factors II, VII, IX and X

35
Q

intrinsic pathway of coagulation

A
  • contact activation system
  • begins with damage to blood vessels
  • formation of primary complex on collagen and thrombin generation by way of factor XII and ultimately merges to the common pathway to activate factor X
36
Q

extrinsic pathway of coagulation

A
  • tissue factor pathway
  • initial step in plasma-mediated hemostasis
  • following damage to the blood vessel, factor VII comes into contact with tissue factor (which is prevalent in the sub-endothelial tissues surrounding vasculature) and forms an activated TF-VIIa complex
  • the TF-VIIa circulating the plasma activates factor X to promote the conversation of X to Xa
37
Q

common pathway of coagulation

A
  • common to both extrinsic and intrinsic
  • prothrombin (II) is cleaved by activated factor X to produce thrombin (IIa)
  • signal amplification
38
Q

blood clot

A
  • prothrombin gets activated to thrombin
  • thrombin activates fibrinogen to form fibrin
  • fibrin –> covalent bonds and cross-linking of fibers create a meshwork in all directions of blood cells, platelets and plasma which adhere to the surface of damaged blood vessel
  • after clot is formed, actin/myosin of platelets trapped in fibrin mesh and interact in a manner like that in muscle contraction
39
Q

dissolution of blood clot

A
  • clot lysis occurs when plasminogen is activated to plasmin
  • activation occurs by tissue plasminogen activator (t-PA) released from the tissue, vascular endothelium, plasma, and urine
  • plasmin is an enzyme which digests fibrin fibers, fibrinogen, Factor V, Factor VIII, prothrombin, and Factor XII
40
Q

prothrombin time (PT)

A
  • evaluation of extrinsic pathway
  • sample blood plasma incubated with tissue factor in the presence of excess Ca2+
  • particularly sensitive to three of the four vitamin K factors (II, VII, and X)
  • commercial prothrombin reagents vary markedly in their responsiveness to warfarin-induced decreases in clotting factors and are not interchangeable between laboratories
41
Q

partial thromboplastin time (PTT)

A
  • indicates performance of intrinsic pathway

- a sample of blood triggered by adding an activator surface plus phospholipid and Ca2+

42
Q

ACT

A
  • performed by mixing whole blood with an activated substance to initiate activation of the clotting cascade
  • widely used and is reliable for high heparin concentrations
  • influenced by hypothermia, thrombocytopenia, coagulation deficiencies
43
Q

viscoelastic testing

A
  • thromboelastometry (TEG)
  • rotational thromboelastometry (ROTEM)
  • global assay for whole blood clotting including coagulation factors, inhibitors, anticoagulant drugs, platelets, and fibrinolysis
44
Q

bleeding time

A
  • sensitive test of platelet function

- small incision made in underside of forearm and the amount of time it takes for bleeding to stop is recorded

45
Q

heparin concentration measurements

A
  • increasing concentrations of protamine added to samples of heparin containing blood
  • time to clot measured by the sample in which heparin and protamine are most closely matched will clot first
46
Q

platelet function tests

A

-classic method involves centrifugation of patient blood to obtain platelet rich plasma, which then analyzed in a cuvette at 37 degrees placed between light source and photocell

47
Q

ACT

A

80-150 seconds

N929 - Anesthesia Pharmacology (12 decks)

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