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Pathology - Quiz 1 > Thrombosis > Flashcards

Thrombosis Flashcards

1
Q

Diagram the in vitro coagulation pathways (intrinsic and extrinsic).

A

Intrinsic:
12 —> 11 —> 9 —(with 8 + Ca)—> [10 —(with 5 and Ca)—> 2 —(with Ca)—> fibrinogen to fibrin —(with 13)—> cross-linked fibrin]
(12, 11, 9 with 8 to [10, with 5 to 2, fibrinogen to fibrin, with 13 forms cross-links])

Extrinsic:
TF + 7 —> [10 —(with 5 and Ca)—> 2 —(with Ca)—> fibrinogen to fibrin —(with 13)—> cross-linked fibrin]

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2
Q

Diagram the in vivo (“new”) coagulation pathway.

A

TF + 7 —> 9 —(with 8)—> 10 —(with 5)—> 2(prothrombin to thrombin) —> fibrinogen —> fibrin monomers —> fibrin polymers —(with 13)—> fibrin clot

(TF and 7 to 9, with 8 to 10, with 5 to 2, fibrinogen to fibrin monomers then polymers, with 13 to fibrin clot)

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3
Q

Explain how PT tests are performed.

A

Measures EXTRINSIC pathway

Plasma + TF + Ca + phospholipids -> measure time to clot

Normal = 12-14 seconds

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4
Q

Explain how PTT tests are performed.

A

Measures INTRINSIC pathway

Plasma + contact activator + phospholipid -> wait 5 min -> add CaCl2 -> measure time to clot

Normal = 23-33 seconds

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5
Q

Name the four stages of hemostasis and explain what is occurring in each.

A
  1. Reflex vasoconstriction at site of injury
    - Neurogenic mechanism via local release of chemical mediators
  2. Platelets come to site of action
    - VWF (von Willebrand factor): platelets adhere to sub-endothelial matrix via VWF
    - Platelets become activated: increase surface area, aggregate
  3. Coagulation cascade forms a clot
    - Tissue factor starts the coagulation cascade
    - See thrombin activation and fibrin polymerization
  4. Thrombus and antithrombotic events
    - Endothelium releases t-PA, thrombomodulin, trapped neutrophils and RBCs
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6
Q

Explain the 3 A’s associated with the role of platelets in hemostasis.

A

Their role in primary hemostasis–
Adhesion - VWF mediates adhesion to subendothelium at site of injury

Activation - metabolic activity increases secretion, increases surface area, and results in surface protein GPIIb/IIIa alteration

Aggregation - fibrinogen cross-links the GPIIb/IIIa, mechanical contraction occurs via actomyosin, surface phospholipid exposed

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7
Q

Name three functions of von Willebrands factor.

A
  1. Adhesion - undergoes conformational change on binding to sub-endothelial collages -> binding to platelet GP1b
  2. Aggregation - binds platelet GPIIb/IIIa
  3. Factor 8 binding - binds factor 8 to site of hemorrhage, protects from cleavage
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8
Q

Explain the role of factor 13 in coagulation.

A

Stabliizes the fibrin clot by cross-linking the lysine and glutamine side chains

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9
Q

Name the three inherent anticoagulant systems/mechanisms in the blood.

A
  1. Antithrombin: binds heparin-like molecules, makes conformational change so they can bind thrombin (IIa)
    - Effect: neutralize master regulator -> neutralize everything
  2. Thrombomodulin: binds thrombin and protein c -> APC, which is antithrombotic
    - APC binds protein S -> inactivates factors 5 and 8
  3. Fibrinolytic system: functions in clot lysis
    - Plasminogen (from liver) activated by…
    - —Tissue plasminogen activator (from endothelial cells) at clot site, bound to fibrin
    - —Urokinase-PA
    - —Streptokinase
    - …to plasmin, a serine protease
    - —Cleaves fibrin –> D-D dimer, other fragments
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10
Q

Identify four types of hemophilia and the factors that are deficient in each.

A

von Willebrand’s disease: VWF
Hemophilia A: Factor 8
Hemophilia B: Factor 9
Hemophilia C: Factor 11

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11
Q

Name the three components of “Virchow’s triad” active in thrombosis.

A
  1. Endothelial injury
  2. Alterations in blood flow
  3. Hypercoagulability
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12
Q

Explain the abnormality present in factor V Leiden hypercoagulability.

A

AA change in Activated Protein C (APC) cleavage site on Factor 5a molecule -> APC cannot inactivate it

Factor 5 persists longer -> increased thrombin generation -> hypercoagulable state

Worsened with OCP

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13
Q

Discuss the etiological, clinical, and laboratory findings associated with DIC.

A

DIC: disseminated intravascular coagulation; a pathologic, consumptive coagulopathy

Widespread, inappropriate coagulation in microvessels -> thrombosis -> consumption of procoagulants -> hemorrhage

Laboratory:

  • -Thrombocytopenia
  • -Prolonged screening coagulation tests
  • -Elevated fibrin degradation products (D-dimer)
  • -Fragmented red blood cells
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14
Q

Calculate an INR from a patient’s PT value and the normalized PT value.

A

INR: international normalized ratio
—Target = 2-3

INR = (patient PT/mean normal PT for lab) ^ ISI

ISI = international sensitivity index
Higher ISI = less sensitive reagent

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15
Q

Explain the mechanism behind three forms of antiplatelet (may not need to know).

A

Aspirin: irreversibly inhibits COX-1 in platelets (would otherwise make thromboxane A2)
NSAIDs reversibly inhibit COX-1
Clopidogrel/Plavix block ADP receptor
Abciximag blocks GPIIb/IIIa

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16
Q

Hemostasis

A

Maintenance of blood in a fluid, thrombus-free state under normal conditions
Induce a rapid and localized hemostatic plug at a site of vessel injury

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17
Q

Thrombosis

A

Inappropriate clot formation, a pathologic process

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18
Q

Procoagulants

A

Clot promoting components of blood and blood vessels

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19
Q

Anticoagulants

A

Clot inhibiting or clot dissolving components of blood or blood vessels

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20
Q

Primary hemostatic plug

A

Initial phase of cessation of bleeding
Brought about at the site of vessel injury by adhesion and aggregation of platelets to vessel wall and to other platelets

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21
Q

Secondary hemostatic plug

A

The stabilization of the primary hemostatic plug by the generation of fibrin from plasma proteins

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22
Q

Coagulation cascade

A

A series of sequential, enzymatic conversions turning proenzymes into activated enzymes culminating in the formation of fibrin

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23
Q

Fibrinolysis

A

The controlled breakdown and remodeling of fibrin at the site of thrombus formation to reestablish blood flow in an affected blood vessel

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24
Q

Thrombophilia

A

Hereditary and acquired defects, primarily in anticoagulant components of the blood, which result in increased risk for thrombosis

25
Q

Describe the general process of hemostasis, from injury to healing and repair.

A
  1. Injury to vessel
  2. Platelet activation - plug
  3. Coagulation cascade - fibrin clot
    - Control of clot extension by antithrombotic mechanisms (clot must stay at site of injury)
    - Fibrinolysis and clot removal (when clot has done its work)
  4. Healing and repair
26
Q

Tissue factor

A

Anything the blood recognizes as non self

27
Q

Explain the roles of endothelial cells in thrombosis. (4)

A
  1. Maintain blood fluidity
    - Secrete endothelin -> vasoconstriction
    - Prevent platelet aggregation/promote vasodilation by secreting prostacyclin and NO
  2. Anticoagulant
    - Prevent interactions with adhesive proteins (collagen, VWF, TF)
    - Secrete membrane-associated heparin-like molecules heparin sulfate and thrombomodulin
  3. Modulate fibrinolysis
    - Make tissue plasminogen activator (tPA) and plasminogen activator inhibitors (PAI)
  4. Prothrombotic properties
    - Make/store/release VWF
    - Store/release Factor 8 in Weibel-Palade bodies
    - Make tissue factor - triggers initiation of coagulation
28
Q

Name the two unusual organelles found in platelets and what each contains.

A

Dense body: ATP, ADP, serotonin, calcium

Alpha granule: VWF, factor 5, platelet factor 4, fibrinogen

29
Q

Name the two sites of synthesis of VWF.

A

Weibel-palade body (endothelial cells, constituitive or stimulated secretion)

Platelet alpha-granule (platelet, stimulated secretion)

30
Q

What is the quaternary complex?

A

Collection of everything (enzyme [coag factor], cofactor, phospholipid, Ca2+) onto the phospholipid surface of the platelets

Makes it more efficient

31
Q

What is factor 1?

A

Fibrinogen

32
Q

What is factor 2?

A

Prothrombin

33
Q

What is factor 3?

A

Tissue factor/thromboplastin

34
Q

What is factor 4?

A

Calcium

35
Q

What is factor 8?

A

Antihemophilic A factor

36
Q

What is factor 9?

A

Antihemophilic B/Christmas factor

37
Q

What is factor 12?

A

Hageman factor

38
Q

Which four factors are vitamin K dependent?

A

2, 7, 9, 10

39
Q

What is the master conductor of coagulation?

A

Thrombin (IIa): activates 9, 8, and 5; also 13, fibrinolysis and platelets

40
Q

What systems are in place as a check on the fibrinolytic system?

A

Plasminogen activator inhibitor-1: inactivates excess t-PA that escapes into plasma
Alpha-2 antiplasmin: inactivates plasmin that escapes into plasma

41
Q

Name the three general causes of hemorrhage and examples of the two that we studied.

A
  1. Vessel wall abnormalities
  2. Primary hemostasis related abnormalities: -> mucosal bleeding
    - vWD, Bernard-Soulier, Glanzman Thrombasthenia
  3. Secondary hemostasis related abnormalities: -> bleeding into joints
    - Deficiency in factors (hemophilia, Christmas disease)
42
Q

What is the most common inherited hemorrhage disorder?

A

von Willebrand’s disease (0.1-1%)
See lots of bleeding
Give DDAVP

43
Q

Why would you test Factor 8 levels when testing for vWD?

A

Because vWF binds Factor 8 - problem could be with either one

44
Q

What is Bernard Soulier syndrome?

A

Deficiency of GPIb, which binds VWF to the platelet
Early childhood bruising
Give DDAVP

Diagnosis: increased bleeding time, giant platelets, thrombocytopenia, aggregation studies

45
Q

What is Glanzmann’s Thrombasthenia?

A

Big name, big molecule!!

Deficiency of GPIIv/IIIa - the big molecule that binds fibrinogen

Early childhood bruising, bleeding

46
Q

Causes of endothelial injury (6)

A 
MI
Valve problems
Atherosclerosis
Vasculitis
Bacterial toxins
Cigarette
47
Q

Signs of endothelial injury (3)

A

Exposure of sub-endothelial collagen
Platelet activation
Adherence of platelets -> clotting cascade -> thrombotic state

48
Q

Causes of alteration in blood flow (2)

A

Turbulence (arterial/cardiac thrombosis)

Stasis (venous thrombosis)

49
Q

Causes of hypercoagulability (10)

A 
Factor 5 Leiden
Antithrombin deficiency
Deficiency of anything in clotting factor pathway (protein C, protein S)
Bed rest
MI
Tissue damage
Cancer
DIC
Antiphospholipid antibody syndrome
Heparin-induced thrombocytopenia syndrome
50
Q

What is the result of the prothrombin 20210 mutation?

A

Increased prothrombin levels due to mRNA stabliity

51
Q

Name 5 causes of DIC.

A 
Bacterial sepsis
Viremia
Trauma
Malignancies
Obstetric accidencts
52
Q

What is antiphospholipid antibody syndrome? Distinguish between primary and secondary APS. Briefly, what are the diagnostic criteria?

A

Aka Hughes syndrome
-> Arterial/venous thrombosis, thrombocytopenia, frequent miscarriages

Antiphospholipid antibodies -> hypercoagulable state

  • -Secondary APS: underlying autoimmune, like SLE
  • -Primary APS: no underlying autoimmune

Must have symptoms AND consistent phospholipid antibodies for >6 weeks

53
Q

What is heparin-induced thrombocytopenia syndrome?

A

Abnormal reaction to unfractionated heparin -> antibodies against Platelet Factor 4 -> activation of platelets -> prothrombotic state

54
Q

How do alterations in blood flow lead to thrombosis?

A

Disruption of laminar flow
Failed dilution of activated factors
Retard clotting factor inhibitors
Promotion of endothelial cell activation

55
Q

What is thrombocytopenia?

A

Low platelet count

56
Q

What could cause a prolonged PT time? (6)

A

Deficiencies of 7, 10, 5, 2, fibrinogen

Warfarin administration

57
Q

What can cause a prolonged PTT time? (6)

A

Deficiencies in 8, 9, 11, 12

Heparin
Lupus

58
Q

What are mixing studies?

A

Differentiate between coagulation factor deficiencies or presence of circulating anticoagulants/inhibitors as a cause of prolonged PT/PTT

Mix with fresh pooled normal plasma

PTT/PT will CORRECT if cause is factor deficiency
PTT/PT will NOT correct if cause is anticoagulant/inhibitor

Pathology - Quiz 1 (11 decks)

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