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Heme/Lymph Exam > Principles of Hemostasis > Flashcards

Principles of Hemostasis Flashcards

1
Q

tissue factor

A

*the trigger for hemostasis
*transmembrane protein
*found everywhere except in the bloodstream
*deletion is lethal
*cofactor for factor VIIa activity
*TF-VIIa is rapidly inhibited by TFPI (tissue factor pathway inhibitor)

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2
Q

fibrin clot formation

A

*requires THROMBIN [recall: thrombin is the result of the coagulation cascade, and it made when factor II (prothrombin) becomes activated]
*major coagulation effector enzyme
*thrombin converts fibrinogen to fibrin
*activates factor XIII (factor XIIIa crosslinks fibrin)
*activates (more) platelets

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3
Q

fibrinogen

A

*soluble protein, digested by plasmin
*NOT a clot
*converted into fibrin by thrombin

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4
Q

fibrin

A

*insoluble, easily digested by plasmin
*“weak” clot
*formed from fibrinogen when thrombin is present

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5
Q

fibrin vs. cross-linked fibrin

A

*cross-linked fibrin is not as easily digested by plasmin as fibrin is
*note - fibrin is cross-linked by factor XIIIa
*i.e. cross-linked fibrin forms a “strong” clot

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6
Q

coagulation cascade (in words)

A
  1. tissue factor (TF) binds factor VIIa
  2. TF-VIIa complex enzymatically cleaves factor IX, converting it to its active form (FIXa)
  3. factor IXa converts factor X into factor Xa
  4. factor Xa binds factor II (factor II is prothrombin)
  5. prothrombin (factor II) is converted into THROMBIN
  6. thrombin has multiple “jobs””
    a. converts fibrinogen into fibrin!
    b. catalyzes conversion of factor VIII into FVIIIa (which dramatically increases conversion of FX into FXa (“thrombin burst”
    c. converts factor V into FVa (which increases the speed and efficiency of prothrombin -> thrombin)
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7
Q

coagulation cascade - image

A
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8
Q

which factor is factor II

A

prothrombin

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9
Q

natural anticoagulation - “systems”

A
  1. antithrombin 3 (aka heparin cofactor, antithrombin, or serpin C1)
  2. Protein C System (includes protein S + thrombomodulin)

note - anticoagulation is turning off the coagulation cascade

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10
Q

protein C system of anticoagulation

A
  1. circulating thrombomodulin (TM) binds thrombin (FIIa), forming TM-IIa complex
  2. TM-IIa enzymatically activates protein C (aPC is the abbreviation for activated protein C)
  3. aPC enzymatically cleaves factor Va into an inactivated form (FVi)
  4. protein S serves as a key cofactor that speeds up the cleavage of FVa -> FVi
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11
Q

fibrinolysis vs. anticoagulation

A

*breaking down the clot formed by coagulation
*contrast fibrinolysis to anticoagulation, which is turning off the cascade, rather than breaking down the clot

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12
Q

fibrinolysis

A

*triggered by aPC (activated protein C)
*plasmin is the effector enzyme
*plasmin is a relatively non-specific serine protease
*fibrin specificity is conferred by activation mechanism

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13
Q

fibrinolytic system - steps

A
  1. aPC (activated protein C) binds endothelial cells, resulting in the release of tPA (tissue plasminogen activator)
  2. tPA converts plasminogen into plasmin
  3. plasmin degrades fibrin into fibrin degradation products (FDP), including D-dimer
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14
Q

where does D-dimer come from

A

*D-dimer is one of the primary breakdown products of fibrin (when it is degraded by plasmin)

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15
Q

blood flow characteristic: hydraulic forces

A

*pressure difference across the vascular defect
*pressure gradient (between intravascular and extravascular space)
*assumes external pressure = 0
*ignores the effect of gravity

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16
Q

blood flow characteristic: shear forces

A

*flow velocity
*laminar versus turbulent
*vessel diameter
*blood viscosity

17
Q

tamponade

A

*tamponade is holding pressure (on a wound or body cavity) to stop bleeding

*in a closed space, as bleeding continues, external pressure rises to match internal pressure
*effectiveness depends on pressure difference
*if external pressure rises above a critical value, all blood flow ceases and other structures are compromised, giving a “compartment syndrome”

18
Q

shear forces increase as…

A

*linear velocity increases (activated coagulation factors are washed away)
*viscosity increases
*vessel radius decreases
*flow changes from laminar to turbulent (high flow rates; vessel irregularities)

19
Q

platelets and vWF - under high shear forces

A

*platelets are activated by thrombin (in addition to other methods)
*activated platelets:
1. promote coagulation and bind to subendothelial collagen/subendothelial bound vWF
2. stick to each other
3. “stickiness” of platelets AND vWF increases with shear rate

therefore - platelets and vWF are really important for arterial bleeding especially

20
Q

thrombosis - simplified

A

*conceptualize this as hemostasis (formation of a clot) WITHIN the vessel, rather than outside the vessel
*the biochemistry is pretty much the same as hemostasis
*usually triggered by localized “patch” of exposed Tissue Factor
*thrombosis requires thrombin activity to exceed plasmin activity

21
Q

venous thrombosis - Virchow’s Triad

A
  1. endothelial injury
  2. stasis of blood flow
  3. hypercoagulability
22
Q

arterial thrombosis

A

*atherosclerotic plaques as focus
*platelets are central:
-high shear setting
-vWF involved
*coagulation is involved in thrombus growth

23
Q

thrombophilic factors

A
  1. inherited:
    -protein C, protein S, antithrombin 3 deficiencies
    -FV Leiden, prothrombin (G20210A) mutations
  2. congenital (factors II, VII, VIII, IX, XI, vWF, or homocysteine mutations)
  3. acquired:
    -age
    -lupus anticoagulant, DIC
    -obesity, sedentary lifestyle, smoking
    -malignancy, surgery, pregnancy
    -HIT/HITT
24
Q

tissue factor - locations

A

*TF on extravascular smooth muscle: constitutive -> hemostatic plug
*TF patch on luminal vessel wall: endothelial damage -> thrombosis
*TF on circulating monocytes: activation by lipopolysaccharide - sepsis (DIC)

25
Q

disseminated intravascular coagulation (DIC) - Stage 1 [the hypercoagulable state]

A

*antithrombin 3 is adequate to control the coagulation cascade, BUT:
-factors V and VIII are being activated to FVa and FVIIIa by thrombin:
~procoagulant effectiveness increases
~more thrombin produced for a given stimulus
-circulating platelets are activated
*RISK OF THROMBOSIS IS INCREASED

26
Q

treating DIC stage 1

A

*control coagulation to regulate process
*low dose heparin, low dose low molecular weight heparin:
-amplifies AT3 effectiveness
-shuts down / rebalances THROMBIN GENERATION
-reduces risk of thrombosis
*anti-platelet agents (sometimes)

27
Q

disseminated intravascular coagulation (DIC) - Stage 2 [early or mild DIC/consumption coagulopathy]

A

*AT3 has been consumed:
-excess thrombin is produced
-protein C system becomes activated
-aPC inactivates FVa and FVIIIa (FV and FVIII deficiencies result)
*activated platelets are removed from circulation (thrombocytopenia)
*RISK OF BLEEDING IS INCREASED

28
Q

treating DIC stage 2

A

*replace missing coagulation factors V and VIII (use cryoprecipitate and platelets)
*replace AT3 (concentrate or bank plasma)
*BUT THERE IS EXCESS THROMBIN:
-after repletion of V and VIII, add low dose heparin to control thrombin generation

29
Q

disseminated intravascular coagulation (DIC) - Stage 3

A

*aPC inhibitor has been consumed
*fibrinolysis has been activated
*free plasmin circulates [dissolves hemostatic plugs, reduces the thrombin/plasmin ratio, digests most coagulation factors, digests fibrinogen, digests platelet surface receptors]
*DEFECTIVE HEMOSTASIS AND RE-BLEEDING OF OLD WOUNDS

30
Q

treating DIC stage 3

A
  1. need to inhibit plasmin (amicaproic acid)
  2. need to inhibit thrombin (heparin)
  3. need to replace coagulation factors (plasma, cryo, platelets, AT3, prothrombin complex)
31
Q

clinical presentation of DIC

A

hypercoagulability -> thrombocytopenia / hypofibrinogenemia -> transition to bleeding -> dramatic bleeding

32
Q

intrinsic pathway of coagulation cascade

A

*note - activated independent of tissue factor (not really relevant in humans physiologically)

  1. surface contact factors (HMWK collagen, platelets, Kallikrein) activate factor XII
  2. FXIIa activates factor XI
  3. FXIa activates factor IX
  4. FIX activates factor X
33
Q

PT (prothrombin time) lab test

A

extrinsic + common pathways

“Play Tennis Outside” = PT is extrinsic

34
Q

PTT (partial thromboplastin time) lab test

A

intrinsic + common pathways

“Play Table Tennis Inside” = PTT is intrinsic

Heme/Lymph Exam (38 decks)

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