Principles of Hemostasis Flashcards
tissue factor
*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)
fibrin clot formation
*requires THROMBIN [recall: thrombin is the result of the coagulation cascade, and is 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
fibrinogen
*soluble protein, digested by plasmin
*NOT a clot
*converted into fibrin by thrombin
fibrin
*insoluble, easily digested by plasmin
*“weak” clot
*formed from fibrinogen when thrombin is present
fibrin vs. cross-linked fibrin
*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
coagulation cascade (in words)
- tissue factor (TF) binds factor VIIa
- TF-VIIa complex enzymatically cleaves factor IX, converting it to its active form (FIXa)
- factor IXa converts factor X into factor Xa
- factor Xa binds factor II (factor II is prothrombin)
- prothrombin (factor II) is converted into THROMBIN
- 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)
coagulation cascade - image
which factor is factor II
prothrombin
natural anticoagulation - “systems”
- antithrombin 3 (aka heparin cofactor, antithrombin, or serpin C1)
- Protein C System (includes protein S + thrombomodulin)
note - anticoagulation is turning off the coagulation cascade
protein C system of anticoagulation
- circulating thrombomodulin (TM) binds thrombin (FIIa), forming TM-IIa complex
- TM-IIa enzymatically activates protein C (aPC is the abbreviation for activated protein C)
- aPC enzymatically cleaves factor Va into an inactivated form (FVi)
- protein S serves as a key cofactor that speeds up the cleavage of FVa -> FVi
fibrinolysis vs. anticoagulation
*fibrinolysis: breaking down the clot formed by coagulation
*anticoagulation: turning off the coagulation cascade, rather than breaking down the clot
fibrinolysis
*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
fibrinolytic system - steps
- aPC (activated protein C) binds endothelial cells, resulting in the release of tPA (tissue plasminogen activator)
- tPA converts plasminogen into plasmin
- plasmin degrades fibrin into fibrin degradation products (FDP), including D-dimer
where does D-dimer come from
*D-dimer is one of the primary breakdown products of fibrin (when it is degraded by plasmin)
blood flow characteristic: hydraulic forces
*pressure difference across the vascular defect
*pressure gradient (between intravascular and extravascular space)
*assumes external pressure = 0
*ignores the effect of gravity
blood flow characteristic: shear forces
*flow velocity
*laminar versus turbulent
*vessel diameter
*blood viscosity
tamponade
*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”
shear forces increase as…
*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)
platelets and vWF - under high shear forces
*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
thrombosis - simplified
*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
venous thrombosis - Virchow’s Triad
- endothelial injury
- stasis of blood flow
- hypercoagulability
arterial thrombosis
*atherosclerotic plaques as focus
*platelets are central:
-high shear setting
-vWF involved
*coagulation is involved in thrombus growth
thrombophilic factors
- inherited:
-protein C, protein S, antithrombin 3 deficiencies
-FV Leiden, prothrombin (G20210A) mutations - congenital (factors II, VII, VIII, IX, XI, vWF, or homocysteine mutations)
- acquired:
-age
-lupus anticoagulant, DIC
-obesity, sedentary lifestyle, smoking
-malignancy, surgery, pregnancy
-HIT/HITT
tissue factor - locations
*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)
disseminated intravascular coagulation (DIC) - Stage 1 [the hypercoagulable state]
*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
treating DIC stage 1
*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)
disseminated intravascular coagulation (DIC) - Stage 2 [early or mild DIC/consumption coagulopathy]
*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
treating DIC stage 2
*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
disseminated intravascular coagulation (DIC) - Stage 3
*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
treating DIC stage 3
- need to inhibit plasmin (amicaproic acid)
- need to inhibit thrombin (heparin)
- need to replace coagulation factors (plasma, cryo, platelets, AT3, prothrombin complex)
clinical presentation of DIC
hypercoagulability → thrombocytopenia / hypofibrinogenemia → transition to bleeding → dramatic bleeding
intrinsic pathway of coagulation cascade
*includes factors: 12, 11, 9, and 8
*lab measure: PTT
*note - activated independent of tissue factor (not really relevant in humans physiologically)
- surface contact factors (HMWK collagen, platelets, Kallikrein) activate factor XII
- FXIIa activates factor XI
- FXIa activates factor IX
- FIX activates factor X
PT (prothrombin time) lab test
extrinsic + common pathways
“Play Tennis Outside” = PT is extrinsic
PTT (partial thromboplastin time) lab test
intrinsic + common pathways
“Play Table Tennis Inside” = PTT is intrinsic
