Coagulation (4) Flashcards
How does hemostasis normally control bleeding?
Balance btw clot generation, thrombus formation, and regulatory mechanisms that inhibit uncontrolled thrombogenesis
What are the goals of hemostasis?
- Limit blood loss from vascular injury
- Maintain intravascular blood flow
- Promote revascularization after thrombosis
What are the 2 stages of hemostasis?
- Primary hemostasis
- Secondary hemostasis
What is primary hemostasis?
- Immediate platelet deposition at the endovascular injury site
- Leads to the initial platelet plug formation
- Only adequate for minor injury
What is secondary homeostasis?
- Clotting factors activated
- Stabilized clot formed and secured with crosslinked fibrin
What is the role of vascular endothelial cells?
- antiplatelet, anticoagulant, and fibrinolytic effects to inhibit clot formation
How do vascular endothelial cells function as an antiplatelet?
- Endothelial cells are negatively charged to repel platelets
- Produce platelet inhibitors such as prostacyclin and nitric oxide
- Excrete adenosine diphosphatase
- Increase protein C
- Produce tissue factor pathway inhibitor
- Synthesize tPA
What is the function of adenosine diphosphatase?
Degrades adenosine diphosphate (ADP), a platelet activator
What is the MOA of tissue factor pathway inhibitor?
Inhibits factor Xa & TF-VIIa complex
What are platelets derived from?
Bone-marrow megakaryocytes
What are the characteristics of inactive platelets?
- Disc shaped
- Anuclear (no nucleus)
- 8-12 day lifespan
Approximately ____% of platelets are consumes to support vascular integrity
10%
_________ new platelets are formed daily
120-150 billion
What is the function of the platelet membrane?
- Contains numerous receptors
- Surface canalicular system → increases membrane surface area
How does damage to endothelium signal for clotting cascade?
Damaged endothelium exposes underlying extracellular matrix (ECM): contains vWF, collagen, glycoproteins
What happens to platelets when extracellular matrix is exposed?
3 phases of alteration:
- Adhesion
- Activation
- Aggregation
When does platelet activation occur?
- Stimulated when platelets interact with collagen and tissue factor
- Causes release of granular contents
What are the 2 types of granules that platelets contain?
- Alpha granules: contain fibrinogen, factors V & VIII, vWF, Plt-derived growth factor & more
- Dense bodies: contain ADP, ATP, calcium, serotonin, histamine, epinephrine
When does platelet aggregation occur?
When the granular contents are released→ activate additional platelets and propagate plasma-mediated coagulation
Each stage of the clotting cascade requires assembly of membrane bound activated __________ complexes
Tenase
What is each activated tenase-complex composed of?
- Substrate (Inactive)
- Enzyme (activated coag factor)
- Cofactor (accelerator of catalyst)
- Calcium
The _________ pathway is the initiation phase of plasma mediated hemostasis
Extrinsic
What are steps of the extrinsic pathway?
1) Endothelial injury→ expose tissue factor to plasma
2) Tissue factor/VIIa complex
3) TF/VIIa complex binds and activates Factor X→ becomes Xa (activated)
4) TF/VIIa also activates IX→IXa
5) IXa and calcium convert X →Xa (intrinsic pathway)
6) Xa starts the common pathway
What factor is the start of the common pathway?
Factor Xa
What factor starts the intrinsic pathway?
Factor XIIa
What is the role of the intrinsic pathway?
- Minor role in the initiation of homeostasis
- Functions as an AMPLIFICATION system→ propagate thrombin generation initiated from extrinsic path
Most thrombotic events follow ___________ pathway
Extrinsic
Lab coag studies rely on _________ pathway to activate the cascade (hemostasis initiation)
Intrinsic
Explain how intrinsic pathway initiated hemostasis:
1) Factor XII is activated when it contacts (-) charged endothelial cells
2) Factor XIIa converts XI→XIa
3) XIa + VIIIa + plt membrane + Ca2+: converts X→Xa
4) Xa initiates final common pathway
Which factors in the intrinsic pathway convert factor X to Xa?
- XIa
- VIIIa
- plt-membrane phospholipid
- Ca++
For intrinsic pathway propagation, activated thromin (IIa) activates which factors?
- Factor V
- Factor VII
- Factor VIII
- Factor XI
all these factors amplify thrombin generation and activates platelets to lead to common pathway
What happens in the common pathway?
1) Factor X→Xa
2) Xa binds with Va→ prothrombinase complex
3) Prothrombinase complex converts Prothrombin (II)→ thrombin (IIa)
4) IIa attaches to plts and converts fibrinogen (I)→ fibrin (Ia)
5) Fibrin crosslink to form mesh/stabilize clot
What is the function of thrombin?
- Converts fibrinogen (I) to Fibrin (Ia)
(Cleaves fibrinopeptides from fibrinogen to generate fibrin)
How does fibrin form a stabilized clot?
Fibrin polymerizes into strands to form a basic clot
Which factor crosslinks the fibrin strands to stabilize and make an insoluble clot that is resistant to fibrinolytics?
Factor XIIIa
_________ generation is the key-step in regulating hemostasis
Thrombin
Both intrinsic and extrinsic tenase complexes facilitate the formation of __________ __________
Prothrombinase complexes
What are the 4 major coagulation counter-mechanisms?
- Fibrinolysis
- Tissue factor pathway inhibitor (TFPI)
- Protein C
- Serine protease inhibitors (SERPINs)
What is the MOA of fibrinolysis?
- TPA and urokinase→ convert plasminogen to plasmin which breaks down the clot enzymatically
Which factors does plasmin degrade?
Factor V and VIII
What is the MOA of tissue factor pathway inhibitor?
Forms complex with Xa→ inhibits tissue factor/VIIa complex, Xa, and downregulates the extrinsic pathway
What is the MOA of protein C?
Inhibits factors:
- 2
- 5
- 8
What are examples of serine protease inhibitors?
- Antithrombin
- Heparin
- Heparin Cofactor II
What factors does an antithrombin inhibit?
- Thrombin
- 9, 10, 11, 12
What is the MOA of heparin and what factors does heparin inhibit?
- Binds to antithrombin causing conformational change
- accelerates antithrombin
What is MOA of heparin cofactor II?
Inhibits thrombin alone
What test is the most effective predictor of bleeding?
Bleeding time
What should be asked about to assess bleeding risk in preop?
- Nose bleeds
- Bleeding gums
- easy bruising
- excessive bleeding w/dental extraction
- excessive bleeding with past surgery
- trauma
- childbirth
- blood transfusions
- fam hx
- use of blood thinners
- co-morbidities (liver, renal, thyroid, bone marrow disorders)
What should you do if you suspect bleeding disorder?
PT and aPTT are standard first-line labs
What is the most common inherited bleeding disorder?
Von Willebrands Disease: effects 1% of population
What lab tests are good for detecting vWD?
- vWF level
- vWF plt binding activity
- Factor 8 level
- Plt function test
What is a common medical treatment for mild vWD?
DDAVP (increases vWF)
If a patient with vWD has intraop bleeding, what way be required?
vWF administration and factor 8 concentrates
vWF plays a critical role in platelet adhesion and prevents degradation of factor ____.
8
What is hemophilia A?
Factor 8 deficiency
occurs 1:5,000
What is hemophilia B?
Factor 9 deficiency
Occurs 1: 30,000
Is hemophilia genetic?
- 2/3 genetic
- 1/3 mutation with no family history
How does hemophilia usually present?
In childhood as spontaneous hemorrhage involving joints and muscles
What do labs show with hemophilia?
- Normal PT, Plt, and bleeding time
- PTT prolonged
What can be used in preop to prophylactically treat patient with hemophilia?
- DDAVP
- Factor 8
- Factor 9
______ meds are the most significant cause of intraoperative bleeding
Anticoagulants
What herb can prolong bleeding time?
Garlic
* d/c 7-10 days before surgery
Common herbs/supplements that impact bleeding risk:
The liver is the primary source of which factors?
5, 7, 9, 10, 11, 12
How does liver disease lead to hemostatic issues?
- Impaired coagulation factor synthesis
- Platelet dysfunction (quantity and quality)
- Impaired clearance of clotting and fibrinolytic proteins
What are common lab findings in pts with liver disease?
- Prolonged PT
- possible prolonged PTT
Only accounting for lack of pro-coagulation factors no accounting for lack of anticoagulation factors
Do chronic liver patients suffer from insufficient thrombin production?
No, they often have rebalanced hemostasis as well as sufficient amounts of thrombin
Compensated but not optimal (susceptible to disruption in coagulation)
What tests are valuable guides for patient with chronic liver disease to assess risk for bleeding?
- TEG
- ROTEM (rotational thromboelastometry)
What causes baseline anemia in pts with CKD?
- Lack EPO
- Platelet dysfunction (d/t uremic environment)
_________ and correction of anemia are both shown to shorted bleeding times
Dialysis
What are treatments for platelet dysfunction associated with CKD?
- Cryo
- DDAVP
- Conjugated estrogens given preop (x5 days)
What is DIC?
- Pathological hemostatic response to TF/7a complex causing excessive activation of the extrinsic pathway, which overwhelms the anticoagulant mechanisms and generates intravascular thrombin
- Coagulation factors & platelets become depleted during widespread microvascular thrombotic activity, causing multi-organ dysfunction
What may precipitate DIC?
- Trauma
- Amniotic fluid embolus
- Malignancy
- Sepsis
- Incompatible blood transfusion
What are lab findings indicative of DIC?
- Low platelets
- prolonged PT/PTT/thrombin time
- increased soluble fibrin
- fibrin degradation products
What are primary actions in management of a pt in DIC/
- Correct underlying condition
- Administer appropriate blood products
Uncontrolled _____________ is a common cause of trauma related death
hemorrhage
What are common reasons for coagulopathies to occur in the trauma patient?
- Acidosis
- Hypothermia
- Hemodilution
What is Trauma induced coagulopathy (TIC)? What is thought to cause it?
- Acute coagulopathy seen in trauma
- Thought to be related to activated protein C decreasing thrombin generation
What is the driving factor for protein C activation associated with trauma induced coagulopathy?
- Hypoperfusion causing endothelial glycocalyx to degrade
- proteoglycan-shedding results in “auto-heparinization”
- platelet dysfunction contributes to the increased bleeding
The most common inherited prothrombotic diseases are cause by a mutation in factor ______ or ______
V or Prothrombin
What mutation leads to activated protein C resistance?
Factor V Leiden mutation
- present in 5% caucasion population
What mutation causes increase prothrombin concentration leading to hypercoagulation?
Prothrombin mutation
Inherited or acquired predisposition for thrombotic events:
Thrombophilia
What is a typical presentation of thrombophilia?
- Manifests as venous thrombosis
- Highly susceptible to Virchows Triad (stasis, endothelial injury, hypercoagulability)
Autoimmune disorder with antibodies against the phospholipid-binding proteins in the coagulation system:
Antiphospholipid Syndrome
How is antiphospholipid syndrome characterized and what is often required?
- Characterized by recurrent thrombosis and pregnancy loss
- Often require life-long anticoagulants
When is HIT likely to occur?
5-14 days after heparin treatment
What is the MOA of HIT?
Autoimmune response occurring in up to 5% of pts receiving heparin
What happens to platelets with HIT?
Platelet count reduction and activation of remaining platelets causing potential thrombosis
If HIT is occurring: If a patient received a prior heparin dose __________ or __________ may occur with in 1 day of a subsequent dose
Thrombocytopenia
Thrombosis
What are risk factors for development of HIT?
- Women
- Pt on high dose heparin (cardiopulm bypass)
- unfractionated heparin carried higher risk than LMWH
What are the step if HIT is suspected?
- D/C all heparin
- Convert to alternative AC (warfarin contraindicated because it decreases protein C and S synthesis)
How is HIT diagnosis confirmed?
HIT antibody testing
antibodies typically cleared from circulation in 3 months
How is Prothrombin time (PT) measured?
Plasma is mixed with TF and the number of seconds is measured until a clot forms
What are PT measurements used to assess?
- Assess integrity of extrinsic and common pathways
- Used to monitor vitamin K antagonists s/a warfarin
PT measurements can show deficiencies in which factors?
1, 2, 5, 7, 10
What is activated partial thromboplastin time (aPTT) measuring?
Measures seconds until clot forms after mixing plasma w/ phospholipid, Ca, and an activator of the intrinsic pathway
What are aPTT measurements used to assess?
- Assess integrity of intrinsic and common pathways
- May be used to measure the effect of heparin
aPTT measurements are more sensitive to deficiencies in what factors?
8 and 9
How is anti-factor Xa activity assay measured?
Plasma combined with Xa and an artificial substrate that releases a colorimetric signal after factor Xa is cleaved
What are anti-factor Xa activity assays used to assess?
- Functional assessment of heparin’s anticoagulant effect
- Can also be used to assess effect of LMWH, fondaparinux, factor Xa inhibitors
What is a normal platelet count?
> 100,000 plts/microliter
(POC testing is available)
How is Activated Clotting Time (ACT) measured?
Variation of whole blood clotting time, with the addition of a clotting activator to accelerate clotting time
What is ACT measurements used to assess?
- Intrinsic and common pathway
- Used to measure responsiveness to heparin
What is a normal ACT?
107 +/- 13 seconds
1 mg of protamine will inhibit ___ heparin
1 mg
What happens to heparin concentration if more protamine is added?
As increasing amounts of protamine are added to heparinized blood, time to clot decreases until protamine concentration > heparin concentration
What is heparin concentration measurement used for?
- Determines perioperative heparin concentration
- Estimates plasma heparin concentration
What does viscoelastic coagulation tests measure?
Measures all aspects clot formation from early fibrin generation to clot retraction and fibrinolysis - coagulation diagrams generated
Why are viscoelastic coagulation test used? What are they?
Allows for more precise blood product administration
- TEG
- ROTEM (rotational thromboelastometry)
What are the 3 main classes of antiplatelet agents?
- Cyclooxygenase inhibitors
- P2Y12 receptor antagonists
- Platelet GIIb/IIIa R antagonists
How do cyclooxygenase inhibitors work?
Block Cox1 from forming TxA2, which is important in platelet aggregation
What are examples of COX inhibitors?
- ASA: anti-platelets x 7-10 days after d/c
- NSAIDs: anti-platelet effects x3 days
How do P2Y12 receptor antagonists work?
Inhibit P2Y12-R→ preventing GIIb/IIIa expression
What are some examples of P2Y12 antagonists?
- Clopidogrel: anti-plt effects x7 days after d/c
- Ticlopidine: anti-plt effects x14-21 days after d/c
- Ticagrelor & Cangrelor: short acting, <24h activity
How do Platelet GIIb/IIIa R antagonists work?
Prevent vWF & fibrinogen from binding to GIIb/IIIa-R
What are examples of Platelet GIIb/IIIa R antagonists?
- Abciximab
- Eptifibatide
- Tirofiban
How do vitamin k antagonists work?
Inhibit synthesis of vit-k dependent factors 2, 7, 9, 10, protein C & S
What is the most common vitamin k antagonist?
Warfarin
Warfarin is the drug of choice for what?
Valvular Afib and valve replacements
How long is the half life for warfarin?
40 hours - can take 3-4 days to reach therapeutic INR (2-3)
- Usually requires heparin until therapeutic effect achieved
Considerations for patients on warfarin:
- Need frequent lab monitoring required (PT/INR)
- Reversable w/ vitamin K
How does heparin work?
Binds to antithrombin→ directly inhibits soluble thrombin and Xa
Unfractionated heparin:
- Short half life, given IV
- Fully reversable with protamine
- Close monitoring required
LMWH:
- Longer half life than unfractionated
- Dosed BID SQ
- No coag testing needed
- Protamine only partially effective
Fondaparinux:
- Much longer half life (17-21h), dosed once/day
- Protamine not effective
How do direct thrombin inhibitors work?
Bind/block thrombin in both soluble & fibrin-bound states
What are examples of direct thrombin inhibitors?
- Hirudin
- Argatroban
- Bivalirudin
- Dabigatran (pradaxa)
Where is hirudin naturally found?
Leeches
How is argatroban monitored?
Intraop with PTT or ACT
Half life of argatroban:
45 minutes
Which direct thrombin inhibitor has the shortest half life?
Bivalirudin
What is bivalirudin the drug of choice for?
Renal or liver impairment
What is the first direct oral anticoagulant?
Dabigatran (Pradaxa)
What is dabigatran approved for?
CVA prevention and non-valvular a-fib
What are the benefits to direct oral anticoagulants?
- Have more predictable pharmacokinetics/dynamics
- Fewer drug interactions
- Dosed daily w/o lab monitoring
- Efficacy similar to warfarin, but much shorter half-life
- Fewer embolic events, intracranial hemorrhages, and lower mortality than warfarin
What are examples of Direct Xa inhibitors?
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
What are most thrombolytics?
Serine proteases that convert plasminogen to plasmin, which breaks down fibrinogen to fibrin
What are the 2 categories of thrombolytics?
- Fibrin-specific: Altepase (tPA), Tenecteplase
- Non-fibrin-specific: Streptokinase (not widely used d/t allergic reaction)
Surgery is contraindicated within ___ days of thrombolytic tx
10
Absolute and relative contraindications for thrombolytics:
What are procoagulants used for?
To mitigate blood loss
What are the 2 classes of procoagulants?
Antifibrinolytics and factor replacements
What are the 2 subclasses of antifibrinolytics?
- Lysine analogues
- SERPIN
What do lysine analogues do?
What are the lysine analogues?
Bind and inhibit plasminogen from binding to fibrin and impairs fibrinolysis
- Epsilon-amino-caprioc acid (EACA) & tranexamic acid (TXA)
What is an example of a SERPIN?
Aprotinin (removed from market d/t renal & cardio toxicity)
What are the factor replacements?
- Recombinant VIIa
- Prothrombin Complex Concentrate (PCC)
- Fibrinogen concentrate
- Cryoprecipitate and FFP
What does recombinant VIIa do?
Increases thrombin generation via intrinsic and extrinsic pathways
What does Prothrombin complex concentrate contain?
Contain vitamin-k factors
One negative and positive of crycoprecipitate and FFP:
- Cheaper and contain more coag factors
- Less specific composition
When to stop Warfarin prior to surgery:
- Low rx pts should d/c 5 days prior to surgery & restart 12-24 hours postop
- High rx pts should d/c 5 days prior & bridge w/ UFH or LMWH
When to stop heparins prior to surgery:
- UFH should be d/c’d 4-6h prior to surgery & resumed (no bolus) > 12h postop
- LMWH should be d/c’d 24h prior to surgery & resumed 24h postop
When to stop aspirin prior to surgery:
*not as defined
- Mod/high rx pts - current recommendation is to continue ASA
- Low rx pts - stop 7-10 days prior to surgery
Preop guidelines for pts post coronary stent placement:
- Bare-metal stents→ delay elective surgery 6 weeks after placement
- Drug-eluding stents→ delay elective surgery 6 months after placement
When might warfarin reversal be required?
For excessive bleeding or emergent surgery
What is the drug of choice for emergent coumadin reversal?
Prothrombin complex concentrates
What does vitamin k restore for reversal?
Vitamin K restores liver carboxylation of vit-k dependent factors for more sustained correction
Is there a reversal for direct thrombin inhibitors?
No reversal for most, but half life is short
What is the antidote for Dabigatran?
Idarucizumab
What can direct factor Xa inhibitors be reversed by?
Andexanet - a derivative of factor Xa
Common anticoagulants graph:
