Coagulation - Final Exam Flashcards
Normal Hemostasis is a balance b/w what 3 things?
- clot generation
- thrombus formation
- counter-regulatory mechanisms that inhibit uncontrolled thrombogenesis (clot formation) or premature thrombus degradation
What are the 3 goals of hemostasis?
- limit blood loss from vascular injury
- maintain intravascular blood flow
- promote revascularization after thrombosis
Stages of Hemostasis
What is primary hemostasis?
What does it lead to?
What kind of injury is it adequate for?
- immediate platelet deposition at the endovascular injury site
- leads to initial platelet plug formation
- minor injuries
Stages of Hemostasis
What is secondary hemostasis?
- where clotting factors are activated & a stabilized clot is formed w/ crosslinked fibrin
Hemostasis
Vascular endothelial cells have ________, ________, and ________ effects that inhibit clot formation.
- antiplatelet
- anticoagulant
- profibrinolytic
Hemostasis
Vascular endothelial cells are ________ charged to repel ________.
- negatively
- platelets
Hemostasis
What platelet inhibitors do vascular endotheloal cells produce?
- Prostacyclin
- Nitric Oxide
Hemostasis
What do vascular endothelial cells excrete that degrades ADP?
What is ADP’s role in hemostasis?
- they excrete adenosine diphosphatase
- ADP is a platelet activator
Hemostasis
True or False?
Vascular endothelial cells inactivate protein C?
- what is protein C’s role in anti-clotting?
False. They increase protein C, which is an anticoagulant
Hemostasis
True or False?
Vascular Endothelial cells produce tissue factor pathway inhibitor (TFPI).
What does TFPI inhibit?
- True
- TFPI inhibits factor Xa and TF-VIIa complex
Hemostasis
Where is tissue plasminogen activator (t-PA) synthesized?
in vascular endothelial cells
Hemostasis
Where are platelets derived from?
bone-marrow megakaryocytes
Hemostasis
What do inactive platelets circulate as? What is their lifespan?
- discoid anuclear cells
- lifespan: 8-12 days
Hemostasis
In normal conditions 10% of platelets are consumed to support ________ ________.
How many platelets are formed daily?
- vascular integrity
- 1.2-1.5 x 10^11 (1 billion)
Hemostasis
What does the platelet membrane contain that increases the surface area?
- numerous receptors
- surface canalicular system (channels in the membrane that help the platelet function)
Hemostasis
What expose the extracellular matrix?
Damage to the endothelium
Hemostasis
What 3 things are found in the extracellular matrix?
- collagen
- Von Willebrand’s Factor
- other platelet adhesive glycoproteins
Hemostasis
What are the 3 phases that platets undergo after exposure to the extracellular matrix?
- Adhesion
- Activation
- Aggregation
Platelet phases
What initiates adhesion of platelets?
- exposure to extracellular matrix proteins
Platelet phases
Activation of the platelet is stimulated when the platelet interacts with ________ & ________ ________.
What does activation of the platelet cause?
- Collagen & tissue factor (TF)
- Activation causes release of granular contents of the platelets
What are the 2 types of storage granules in platelets?
- alpha granules
- dense bodies
Platelets
What contents are release from alpha granules?
- fibrinogen
- Factors V & VIII
- vWF
- Plt-derived growth factor
- & more
Platelets
What contents are released from dense bodies?
- ADP
- ATP
- Calcium
- Serotonin
- Histamine
- Epinephrine
Platelet Phases
When does platelet aggregation occur?
What does this recruit and activate?
Then ________ ________ coagulation is propagated.
- Occurs when granular contents are released
- this recruits and activates more platelets
- plasma-mediated coagulation propagated
Platelet Aggregation
What binds to fibrinogen and promotes fibrin crosslinking?
- activated glycoprotein IIb/IIIa receptors on the platelet’s surface
Hemostasis
What does each stage of the clotting cascade require assembly of?
- membrane-bound activation tenase complexes
What 4 things are each membrane-bound activation tenase-complex composed of?
- substrate (inactive precursor)
- enzyme (activated coagulation factor)
- cofactor (accelerator or catalyst)
- calcium
Clotting Factors
Factor I
Fibrinogen
Clotting Factors
Factor II
Prothrombin
Clotting Factors
Factor III
Tissue Thromboplastin
Clotting Factors
Factor IV
Calcium Ions
Clotting Factors
Factor V
Labile Factor
Clotting Factors
Factor VII
Stable Factor
Clotting Factors
Factor VIII
Antihemophilic Factor
Clotting Factor
Factor IX
- Christmas Factor
or - Plasma Thromboplastin Component (PTC)
Clotting Factors
Factor X
Stuart-Prower Factor
Clotting Factors
Factor XI
Plasma Thromboplastin Antecedent (PTA)
Clotting Factors
Factor XII
Hageman Factor
Clotting Factors
Factor XIII
Fibrin Stabilizing Factor
Picture from Miller of Clotting Cascade
Which pathway is the initiation phase of plasma-mediated hemostasis?
Extrinsic Pathway
What does the extrinsic pathway begin with? What does this expose?
- endothelial injury
- exposes TF to the plasma
Extrinsic Pathway
After the TF is exposed to the plasma, what does TF form?
an active complex w/ VIIa (TF/VIIa complex)
Extrinsic Pathway
What 2 factors does the TF/VIIa complex bind to & activate?
- Factor X —– Factor Xa
- Factor IX —– Factor IXa (intrinsic path)
In the intrinsic pathway what does activated IXa and Calcium convert?
Factor X —- Factor Xa (intrinisc)
What factor begins the final common pathway?
Xa
Intrinsic Pathway
What factor does the intrinsic pathway begin with?
XIIa
Intrinsic Pathway
What was the intrinsic pathway initially thought to occur in response to?
endovascular contact w/ negatively charged substances (glass, dextran)
k
intrinsic Path
Current Understanding - the intrinsic path plays a more minor role in ____________________.
It is more of an amplification system to propagate what??
Initiation of hemostasis
- propagates thrombin generation initiated by the extrinsic path
Most thrombotic events follow which path?
What path do lab coag studies rely on to activate cascade?
- extrinsic path
- lab studies rely on intrinsic path
Intrinsic Path
What does the intrinsic path begin with?
What factor does this activate?
- contact w/ a negatively charged surface
- activates factor XII — factor XIIa
Intrinsic path
What does Factor XIIa convert?
Factor XI to XIa
Intrinsic Path
IXa + VIIIa + platelet membrane phospholipid + Ca… activate what?
Factor X to Xa
Intrinsic Pathway Propagation
What 4 factors does activated thrombin (IIa) activate?
What does this amplify?
- Factor V, VII, VIII, XI
- amplifies thrombin generation
Intrinsic Pathway Propagation
What is the powerhouse of clot formation?
- activated thrombin (IIa) activating factor V, VII, VIII, & XI – amplifying thrombin generation
- this process activates plts leading to propagation of the final common pathway
Common Pathway
Factor X becomes Xa & binds w/ Va to form “________ ________.”
prothrombinase complex
Common Pathway
What is the prothrombinase complex made of?
What does prothrombinase complex convert?
- (Xa + Va) + Calcium
Prothrombin (II) into thrombin (IIa)
Common Pathway
What does the thrombin (IIa) attach to & convert?
attaches to plts converts fibrinogen (I) to fibrin (Ia)
Common Pathway
What do fibrin molecules do?
Crosslink to form a mesh that stabilizes the clot
Common Pathway
Thrombin cleaves ____________ from fibrinogen. This generates ________ ________.
Fibrinopeptides A & B
Fibrin Monomers
Common Pathway
What do fibrin monomers do?
Polymerize into fibrin strands to form basic clot
Common Pathway
What factor crosslinks the fibrin strands to stabilize and make an insoluble clot that is resistant to fibrinolytic degradation?
XIIIa
What is the key step in regulating hemostasis?
Thrombin Generation
Image depicting thrombin generation & fibrin formation
What 4 things make up the intrinsic tenase complex?
- activator
- IXa
- VIIIa
- Calcium
What 4 things make up the Extrinsic Tenase Complex?
- injury
- TF
- VIIa
- Calcium
What initiates the intrinsic & extrinsic pathways?
- A catalyst
- Extrinsic: tissue injury
- Intrinsic: activator
Anticoagulation
What are the 4 major coagulation counter-mechanisms?
- Fibrinolysis
- Tissue Factor Pathway Inhibitor (TFPI)
- Protein C System
- Serine Protease Inhibitors (SERPINs)
Coagulation Counter-Mechanism
Fibrinolysis
Endovascular tissue plasminogen activator (tPA) & urokinase convert plasminogen into plasmin
Fibrinolysis
What does plasmin break down?
What does it degrade?
- breaks down clots enzymatically
- degrades V & VIII
Anticoagulation
What does Tissue Factor pathway inhibitor form?
- a complex w/ Xa that inhibitsTF/VIIa complex
- downregulating the extrinsic pathway
Anticoagulation
What 3 factors does the Protein C System inhibit?
- II
- Va
- VIIIa
Anticoagulation
What 3 things are Serine protease inhibitors (SERPINs)?
- Antithrombin (AT)
- Heparin
- Heparin cofactor II
SERPINs
What 5 factors does Antithrombin inhibit?
- thrombin
- IXa (9a)
- Xa (10a)
- XIa (11a)
- XIIa (12a)
SERPINs
What does heparin bind to?
What does that cause?
- Heparin binds to antithrombin
- causes a conformational change - accelerates AT activity
SERPINs
What does Heparin Cofactor II inhibit?
thrombin alone
Pre-op Eval
What is the most effective predictor of bleeding?
What things should we inquire about?
- carefully performed bleeding history
- inquire about nose bleeds, bleeding gums, easy bruising
Pre-op Eval
What procedures should we ask about for excessive bleeding?
- dental extractions
- surgery
- trauma
- child birth
- blood transfusion requirements
Pre-op Eval:
Common Blood Thinners
- ASA
- NSAIDs
- Vitamin E
- Gingko
- Ginger
- Garlic Supps
Pre-op Assessment
What 4 coexisting diseases lead to increased bleeding times?
- Renal Disease
- Liver Disease
- Thryoid Disease
- Bone Marrow Disorders
What are standard first-line labs if a bleeding disorder is suspected?
PT, aPTT
*address both extrinsic & intrinsic pathways
What is the most common inherited bleeding disorder?
Von Willebrand’s Disease
What does a deficiency in vWF cause?
What does vWF play a critical role in?
- defective platelet adhesion/aggregation
- plays a role in plt adhesion & prevents degradation of factor VIII
vWF
Are routine coag labs helpful?
What better tests are there?
- No - plts & PT normal. aPTT might be prolonged d/o Factor VIII
- vWF level
- vWF plt binding activity
- Factor VIII level
- plt function assay
vWF
Treatment (mild & intra-op bleeding)
- mild: DDAVP - increases vWF
- bleeding: vWF & Factor VIII
Hemophilia A
What is the factor deficiency?
Incidence?
- factor VIII deficiency
- 1:5,000
Hemophilia B
What factor deficiency?
Incidence?
IX
1:30,000
Hemophilia
What amount is genetic?
What amount is a new mutation w/o family Hx?
- 2/3 genetic
- 1/3 new mutation w/ no family Hx
Hemophilia
When does it present and how?
- in childhood as spontaneous hemorrhage involving joints & muscles
Hemophilia Labs
- normal PT, Plts, & bleeding time
- PTT normally prolonged
Hemophilia
Who ya gonna consult pre-op?
What drugs/Factors may be indicated before surgery?
- Hematology
- DDAVP/Factor VIII or IX
What meds are the most significant cause of intraoperative bleeding?
Anticoagulants duhhhh
What 8 drugs can lead to bleeding?
- Heparin
- Warfarin
- Direct Oral Anticoagulants
- Beta-lactam Abx
- Nitroprusside
- NTG
- NO
- SSRIs
What 8 supplements/herbals can cause bleeding?
- Cayenne
- Garlic
- Ginger
- Gingko Bilboa
- Grapeseed Oil
- St. John’s Wort
- Tumeric
- Vitamin E
What factors come from the Liver?
- I
- II
- V
- VII
- IX
- X
- XI
- XII
- protein C & S, antithrombin
What does liver disease lead to? (3 things)
- complex, multifactorial hemostatic issues
1. impaired synthesis of coagulation factors
2. quantitative and qualitative platelet dysfunction
3. impaired clearance of clotting and fibrinolytic proteins
Liver Disease
What do lab findings show?
what do these labs account for?
What do they not account for?
- prolonged PT & possible prolonged PTT
- they reflect lack of pro-coagulation factors
- don’t account for concurrent lack of anticoagulation factors
Liver Disease
Chronic liver pts displace a ________ ________. They also have sufficient amounts of ________ production.
But, they are still susceptible to disruption in ________.
- rebalanced hemostasis
- thrombin
- coagulation
** they are compensated but not optimized **
What are valuable guides for Liver Disease pts?
What do these labs tell you?
- TEG, ROTEM
- tell you what they are lacking/what blood products they need
