Coag Flashcards
What happens in Primary Hemostasis?
Platelet deposition at injury site
What is formed during Primary Hemostasis?
Initial platelet plug
What is Secondary Hemostasis?
Clotting factors activated
What stabilizes the clot in Secondary Hemostasis?
Crosslinked fibrin
What process is involved in secondary hemostasis?
Coagulation
What activates fibrin in the clotting process?
Factor Ia
What are some anti-clotting mechanisms of vascular endothelial cells?
Negatively charged, produce platelet inhibitors, excrete adenosine diphosphatase, increase protein C, produce TFPI, synthesize t-PA
What does vascular endothelial cells excrete to degrade adenosine diphosphate (ADP)?
Adenosine diphosphatase
What is the anticoagulant produced by vascular endothelial cells to inhibit factor Xa & TF-VIIa complex?
Tissue Factor Pathway Inhibitor (TFPI)
Where are platelets derived from?
Bone-marrow megakaryocytes
What is the lifespan of nonactivated platelets? How many new platelets are formed daily under normal conditions?
8 to 12 days.
1.2−1.5 × 10^11
What is present in the platelet membrane that increases surface area?
Surface canalicular system
What is exposed when there is damage to endothelium?
ECM containing collagen and platelet-adhesive glycoproteins
What are the 3 phases of alteration that platelets undergo upon exposure to ECM?
adhesion, activation, aggregation
What occurs when platelets interact with collagen and tissue factor?
Activation
What do alpha granules contain?
Fibrinogen, factors V & VIII, vWF, PDGF
What do dense bodies contain?
ADP, ATP, calcium, serotonin, histamine
What promotes fibrin crosslinking during aggregation?
Activated glycoprotein IIb/IIIa receptors
What is required for each stage of the cascade?
Membrane-bound activation tenase-complexes
What does each complex consist of?
Substrate, enzyme, cofactor, calcium
What is the Extrinsic Pathway?
Initiation phase of plasma-mediated hemostasis
What is formed when TF binds to VIIa?
TF/VIIa complex
What does the TF/VIIa complex activate?
Factor X
What does the TF/VIIa complex also activate in the intrinsic pathway?
IX→ IXa
What converts factor X to Xa in the intrinsic pathway?
IXa and calcium
Which factor begins the final common pathway?
Factor Xa
How was the intrinsic pathway initially thought to occur?
Thought to occur only in response to endovascular contact with negatively charged substances
What is the current understanding of the intrinsic pathway?
Amplification system to propagate thrombin generation initiated by extrinsic pathway.
What is the first step in intrinsic pathway hemostasis initiation?
Upon contact with negatively charged surface, Factor XII is activated
What converts XI to XIa in the intrinsic pathway?
Factor XIIa
Which components convert factor X to Xa in the intrinsic pathway?
XIa + VIIIa + plt-membrane phospholipid + Ca++
What initiates the final common pathway in the intrinsic pathway?
Xa
What does activated thrombin (IIa) do in the intrinsic pathway propagation?
Activates factors V, VIII, and XII to amplify extrinsic thrombin generation
What leads to the propagation of the final common pathway in hemostasis?
Platelet activation
What does Factor X become in the common pathway?
Xa
What does Xa bind with to form the prothrombinase complex”?”
Va
What is rapidly converted into thrombin by the prothrombinase complex?
prothrombin (II)
What does thrombin convert fibrinogen (I) into?
fibrin (Ia)
What stabilizes the clot by forming a mesh?
Fibrin molecules crosslink to form a mesh that stabilizes the clot.
Thrombin cleaves__________ from fibrinogen to generate __________?
Fibrinopeptides A & B
Fibrin Monomers
What crosslinks the fibrin strands to stabilize and form an insoluble clot?
Factor XIIIa
What is the key-step in regulating hemostasis?
Thrombin generation
What does the Common Pathway depict?
Thrombin generation and fibrin formation
Which complexes facilitate the formation of prothrombinase complexes?
Both intrinsic and extrinsic tenase-complexes
What components make up the Intrinsic Tenase Complex?
Activator, IXa, VIIIa, Ca²
What components make up the Extrinsic Tenase Complex?
Injury, TF, VIIa, Ca²
What are the three Serine Protease Inhibitors (SERPINs)
Antithrombin, Heparin and Heparin cofactor II
What is the role of fibrinolysis in anticoagulation?
endovascular TPA and urokinase convert plasminogen to plasmin
How does Plasmin contribute to anticoagulation?
Plasmin breaks down clots enzymatically and Degrades factors V & VIII
What does Tissue Factor Pathway Inhibitor (TFPI) do in anticoagulation?
Forms complex with Xa that Inhibits TF/7a complex along with Xa. This down-regulates the extrinsic pathway.
How does the Protein C system contribute to anticoagulation?
Inhibits factors II, Va, VIIIa
What is the role of Antithrombin (AT) in anticoagulation?
Inhibits thrombin and factor IXa, Xa, XIs and XIIa
How does Heparin enhance anticoagulation?
Heparin binds to Antithrombin and accelerates Antithrombin activity
What does Heparin cofactor II do in anticoagulation?
Inhibits thrombin alone
Why is preop identification and correction of hemostatic disorders vital?
Predicts bleeding risk
What is the most effective predictor of bleeding in preop assessment?
Carefully performing a Bleeding history is the most effective predictor of bleeding
What should be inquired about in a bleeding history for preop assessment?
Nose bleeds, bleeding gums, easy bruising
What should be asked about regarding excessive bleeding in preop assessment?
Dental extractions, surgery, trauma, childbirth, blood transfusion
What medications should be asked about in preop assessment?
Blood thinners: ASA, NSAIDs, vitamin E, Ginko, Ginger, Garlic
What coexisting disorders should be considered in preop assessment?
Renal, liver, thyroid, bone marrow disorders.
What are the standard first-line labs if a bleeding disorder is suspected?
PT, aPTT
What are some causes of bleeding disorders?
Von Willebrand’s, Hemophilia, Drug-induced bleeding, Liver disease, Chronic renal disease, Disseminated Intravascular Coagulation and Trauma-induced coagulopathy
What is the role of vWF?
It plays a critical role in platelet adhesion and prevents degradation of factor VIII
What is the most common inherited bleeding disorder? What percent of the population are affected by this dz?
Von Willebrand’s Disease
1% of population
What are the main characteristics of Von Willebrand’s Disease?
Deficiency in vWF, causing defective plt adhesion/aggregation
Why might routine coagulation labs not be helpful in diagnosing Von Willebrand’s Disease?
Platelets & PT will be normal; aPTT might be prolonged d/o level of factor 8
What are the better tests for diagnosing Von Willebrand’s Disease?
vWF level, vWF-plt binding activity, Factor 8 level, Plt function assay
How is mild von Willebrand’s Disease often managed?
Responsive to DDAVP (↑s vWF)
What may be required for intraoperative bleeding in Von Willebrand’s Disease?
Administration of vWF & Factor 8 concentrates
What is Hemophilia A? What is the incidence of Hemophilia A?
Factor 8 deficiency
1 in 5,000
What is Hemophilia B? What is the incidence rate of Hemophilia B?
Factor IX deficiency
1 in 30,000
How much of hemophilia cases are genetically inherited? What is the cause of the other 1/3 cases?
2/3
1/3-present as new mutations
When does hemophilia often present? What are the presenting signs?
Frequently presents in childhood as spontaneous hemorrhage in joints & muscles
What do the lab results show in hemophilia?
Normal PT, Plts, bleeding time; prolonged PTT
Who should be consulted preoperatively for hemophilia?
Hematologist
What may be indicated before surgery in hemophilia?
DDAVP and Factors 8/9
List the pharmacological anticoagulation drugs that a CRNA must be aware of?
Heparin, warfarin, Direct Oral Anticoags (DOACs), Beta-lactam abx, Nitroprusside, NTG, NO, SSRIs.
What is the most significant cause of intraoperative bleeding?
Anticoagulant meds
What must a CRNA understand regarding anticoagulant drugs?
Pharmacodynamics and how to reverse them
What are the primary coagulation factors synthesized by the liver?
Factors V, VII, IX, X, XI, XII
Besides coagulation factors, what other proteins are synthesized by the liver?
Protein C & Proteins S, antithrombin
What hemostatic issues can occur in liver disease?
Impaired synthesis of coagulation factors
Quantitative and qualitative platelet dysfunction
Impaired clearance of clotting and fibrinolytic proteins
What lab findings are often seen in liver disease in relation to clotting tests?
Prolonged PT and possible prolonged PTT
Why might traditional clotting tests not fully represent the coagulation status in liver disease?
Values only reflect lack of pro-coagulation factors, not accounting for lack of anticoagulation factors
How do chronic liver patients usually display hemostasis despite their condition?
Rebalanced hemostasis with sufficient thrombin production
Are chronic liver patients prone to disruptions in coagulation despite having a rebalanced hemostasis?
Yes, susceptible to disruption in coagulation
What other coagulation tests can be useful in the context of liver disease?
TEG & ROTEM
What is the cause of baseline anemia in CKD patients?
Lack of erythropoietin and platelet dysfunction (due to uremic environment)
How can dialysis and correction of anemia impact bleeding times in CKD patients?
Shorten bleeding times
What are treatment options for platelet dysfunction in CKD patients?
Cryoprecipitate, DDAVP, Conjugated estrogens
What is Disseminated Intravascular Coagulation?
Pathological hemostatic response to TF/7a complex, which causes excessive activation of the extrinsic pathway.
How does excessive activation of the extrinsic pathway in DIC increase bleeding?
The excessive activation of extrinisic pathway overwhelms the anticoagulation mechanisms and generates intravascular thrombin.
What causes depletion of coagulation factors and platelets in DIC?
Widespread microvascular thrombotic activity
What can precipitate DIC?
Trauma, amniotic fluid embolus, malignancy, sepsis, incompatible blood transfusion
What are some lab findings in DIC?
↓Plts, prolonged PT/PTT/Thrombin time, ↑soluble fibrin & fibrin degradation products
How should DIC be managed?
Correct underlying condition, administration of appropriate blood products
What is a common cause of trauma-related death?
Uncontrolled hemorrhage
What are the causes of coagulopathies in trauma?
Acidosis, hypothermia, hemodilution
What is Trauma Induced Coagulopathy (TIC)?
Independent acute coagulopathy in trauma pts. This is thought to be related to activated protein C decreasing thrombin generation.
What is thought to be the driving factor for protein C activation in TIC?
Hypoperfusion
How does the degradation of proteoglycan-containing endothelial glycocalyx in TIC cause excessive bleeding?
Proteoglycan-shedding results in auto-heparinization
What also contributes to the increased bleeding in TIC?
Platelet dysfunction
The most common inherited prothrombotic disease is caused by a mutation of ___________?
Factor V Leiden or PT
What does Factor V Leiden mutation lead to?
Activated protein C resistance
What percentage of the Caucasian population has the Factor V Leiden mutation?
5%
What does the prothrombin mutation cause?
↑PT concentration leading to hypercoagulation
What does thrombophilia refer to?
Inherited or acquired predisposition for thrombotic events
How does thrombophilia generally manifest?
Venous thrombosis
What are individuals with prothrombotic states highly susceptible to?
Virchow’s Triad
What are the components of Virchow’s Triad
blood stasis, endothelial injury, hypercoagulability
What is Antiphospholipid Syndrome?
autoimmune disorder with antibodies against the phospholipid-binding proteins in the coagulation system.
What is Antiphospholipid Syndrome characterized by?
Recurrent thrombosis and pregnancy loss
What is one of the treatments often required for patients with Antiphospholipid Syndrome?
Life-long anticoagulants
What factors greatly increase the risk of thrombosis in individuals with Antiphospholipid Syndrome?
Oral contraceptives, pregnancy, immobility, infection, surgery & trauma
What is HIT and when does it usually occur?
HIT is Mild-moderate thrombocytopenia associated with Heparin. Usually occurs 5-14 days after heparin tx
What can Heparin-Induced Thrombocytopenia result in?
Platelet count reduction, activation of remaining platelets, and potential thrombosis
What is a risk factor for Heparin-Induced Thrombocytopenia?
Women, high heparin doses such as with cardiopulmonary bypass. Unfractionated heparin has greater risk than LMWH.
What should be done if HIT is suspected?
D/C heparin, convert to alternative anticoagulant
What anticoagulant is contraindicated with HIT and why?
Warfarin is contraindicated since it decreases Protein C and Protein S synthesis.
How is HIT diagnosis confirmed?
HIT antibody testing
How long do HIT antibodies remain in circulation?
Typically cleared from circulation in 3 months.
What does Prothrombin Time (PT) assess?
Integrity of extrinsic & common pathways
Which factors’ deficiencies does PT reflect?
1, 2, 5, 7, 10 (II, V VII, X)
What is used to monitor Vitamin K antagonists like Warfarin?
PT. Factors II, VII and X are vit K dependent.
What does aPTT assess?
Intrinsic and common pathway.
What is Activated Partial Thromboplastin Time (aPTT) sensitive to?
Deficiencies in factor 8 & 9 (VIII, IX)
What can aPTT measure the effect of?
Heparin
What does the Anti-factor Xa activity assay assess?
Functional assessment of Heparin’s anticoagulant effect.
Can also be used to assess LMWH, Fondaparinux, and factor Xa inhibitors.
What is the purpose of the Platelet Count test? What is the normal Platelet count?
Coagulation testing
normal platelet count >100,000 platelets/microliter
What does the Activated Clotting Time (ACT) measure? What is the normal ACT result?
Addresses intrinsic and common pathways, it is used to assess responsiveness to heparin.
Normal 107 +/- 13 seconds.
What is the most popular point-of-care method to determine perioperative heparin concentration?
Protamine-concentration
How does 1mg protamine affect 1mg heparin?
Inhibit
What happens to the time to clot as increasing amounts of protamine are added to heparinized blood?
Decreases until protamine concentration > heparin concentration
What do Viscoelastic Coagulation Tests measure?
All aspects of clot formation from early fibrin generation to clot retraction and fibrinolysis. Coagulation diagrams are generated as a result of this test.
What are the benefits of TEG and ROTEM?
They allow for more precise blood product administration.
What is the normal range for R time on a thromboelastogram (TEG)?
5 - 10 minutes
What does the Alpha angle represent on a thromboelastogram (TEG)?
Maximum amplitude
What is MA in a thromboelastogram (TEG)?
Highest vertical amplitude
What does LY30 measure on a thromboelastogram (TEG)?
Percentage of amplitude reduction 30 minutes after maximum amplitude
What is the treatment for excess fibrinolysis on a thromboelastogram (TEG)?
Tranexemic Acid and/or Aminocaproic Acid
What do antiplatelet agents do?
Inhibit platelet aggregation and/or adhesion
What are the 3 main classes of Antiplatelet Agents?
COX Inhibitors, P2Y12 receptor antagonists, Platelet GIIb/IIIa Receptor antagonists.
What do Cyclooxygenase Inhibitors block in platelet aggregation?
Block Cox 1 from forming TxA₂
How long do the antiplatelet effects of ASA and NSAIDs last after discontinuation?
ASA: 7-10 days
NSAIDs: 3 days
How do P2Y12 receptor antagonists work?
Inhibit P2Y12-R, preventing GIIb/IIIa expression
What is the duration of antiplatelet effects for Clopidogrel after discontinuation? Ticlopidine? Ticagrelor and Cangrelor?
Clopidogrel: 7 days
Ticlopidine: 14-21 days
Ticagrelor and Cangrelor: Short-acting <24 hours
What do Platelet GIIb/IIIa receptor antagonists prevent?
vWF & fibrinogen from binding to GIIb/IIIa-R
Name three Platelet GIIb/IIIa receptor antagonists.
Abciximab, Eptifibatide, Tirofiban
What do Vitamin K antagonists inhibit the synthesis of?
Vit-K dependent factors 2, 7, 9, 10, Protein C & S
What is the most common Vitamin K antagonist?
Warfarin
What is the drug of choice for valvular Afib and valve replacements?
Warfarin
How long does it take for Warfarin to reach therapeutic INR (2-3)?
3-4 days due to long half-life of 40 hours.
What is often required until Warfarin reaches its therapeutic effect?
Heparin
What lab tests are frequently required for monitoring Warfarin therapy?
PT/INR
How can Warfarin’s anticoagulant effects be reversed?
Vitamin K
What is the mechanism of action of Heparin?
Binds to antithrombin, inhibits thrombin and Xa
What are some characteristics of Unfractionated Heparin?
Short half-life, given IV
Fully reversed with Protamine
Close monitoring required
What are the characteristics of LMWH?
longer half-life, dosed BID SQ
No coag test needed
Protamine only partially effective with LMWH
What is half-life of Fondaprinux? How often is Fondaparinux dosed?
Much longer half-life (17-21 hours) therefore it is dosed Once a day
*protamine ineffective
What is the mechanism of Direct Thrombin Inhibitors?
Bind/block thrombin in both soluble & fibrin-bound states
What is the natural source of Hirudin?
Leeches
What are some characteristics of Argatroban?
synthetic, reversibly binds to thrombin.
Half-life 45 mins.
Monitored intraop with PTT or ACT
What are some characteristics of Bivalirudin?
Bivalirudin is the synthetic Direct Thrombin Inhibitor that has the shortest half-life
DOC for renal/liver impairment
What is Dabigatran (Pradaxa)?
1st DOAC
DTI approved for CVA prevention and non-valvular A-fib
What are the key advantages of DOACs over Warfarin?
More predictable pharmacokinetics/dynamics, fewer drug interactions, fewer embolic events, fewer intracranial hemorrhages, lower mortality than heparin, dosed daily without lab monitoring
What is the efficacy of DOACs compared to Warfarin?
Similar efficacy with much shorter half-life
Name a Direct Thrombin Inhibitor.
Dabigatran (Pradaxa)
Name three Direct Xa Inhibitors.
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
What is the primary use of Thrombolytics? How are these drugs administered?
To dissolve blood clots
IV or directly into site of blockage.
What is the mechanism of action for most Thrombolytics?
Most of Serine Proteases that convert plasminogen to plasmin, breaking down fibrinogen to fibrin
Name a Fibrin-Specific Thrombolytic.
Altepase (tPA), Reteplase, Tenecteplase
Name a Non-Fibrin-Specific Thrombolytic. Why is this drug not commonly used?
Streptokinase. Decreased use due to allergic reactions.
Why is Streptokinase not widely used?
Allergic reactions
What are the concerns with surgery for patients on thrombolytics?
Surgery contraindicated within 10 days of thrombolytic treatment
What are some absolute contraindications for thrombolytics?
Vascular lesions, Severe, uncontrolled hypertension, Recent cranial surgery or trauma, Brain tumor, Ischemic stroke <3 months prior, Active bleeding
What are some relative contraindications for thrombolytics?
Ischemic stroke >3 months prior, Active peptic ulcer, Current use of anticoagulant drugs, Pregnancy, Prolonged/traumatic CPR <3 weeks prior, Major surgery <3 weeks prior
What is the benefit of procoagulants?
They mitigate blood loss
What are the two classes of procoagulants used to mitigate blood loss?
Antifibrinolytics & Factor Replacements
What are the two subclasses of antifibrinolytics?
Lysine analogues & SERPIN
Name two lysine analogues used as antifibrinolytics. What are lysine analogues MOA?
Epsilon-amino-caproic acid (EACA) & Tranexamic Acid (TXA)
MOA: Binds & inhibits plasminogen from binding to fibrin, impairing fibrinolysis
What class of drugs does Aprotinin belong to? Why was it removed from the market?
Aprotinin is a Serine protease inhibitor (SERPIN). Renal & cardio toxicity
List the 5 Factor replacements
Recombinant VIIa, Prothrombin complex Concentrate (PCC), Fibrinogen Concentrate, Cryoprecipitate and FFP
What does Recombinant VIIa (RfVIIa) do in factor replacements?
Increases thrombin generation via intrinsic & extrinsic paths
What does Prothrombin Complex Concentrate (PCC) contain?
Vitamin-K factors
What is Fibrinogen Concentrate derived from?
Pooled plasma
Why might Cryoprecipitate & FFP be preferable to more specific coag factor replacements?
Cheaper & contain more coag factors, but less specific composition
When should low risk patients discontinue warfarin before surgery? When should they restart warfarin?
D/C: 5 days prior to surgery
Restart: 12-24 hours post op
When should high risk patients discontinue warfarin before surgery? When should they restart warfarin?
D/C: 5 days prior to surgery.
They should not restart warfarin but rather bridge with unfractionated heparin or LMWH.
How should unfractionated heparin be managed pre-surgery?
d/c: 4-6h prior
Restart: no bolus, greater than or equal to 12 hours post op
When should LMWH be discontinued before surgery?
D/C: 24h prior to surgery
Restart: 24 hour post op
What is the guideline for aspirin use in moderate to high risk patients pre-surgery?
Continue
When should low risk patients stop aspirin before surgery?
7-10 days
How long to delay elective surgery after bare-metal stent placement?
6 weeks
How long to delay elective surgery after drug-eluding stent placement?
6 months
When is warfarin reversal indicated?
Excessive bleeding ro emergent surgery
What is the drug of choice for emergent coumadin reversal?
Prothrombin Complex Concentrates
What must be given concurrently when reversing warfarin?
Vitamin K must be given concurrently to restore carboxylation of vit K dependent factors by the liver for more sustained correction.
Why are direct thrombin inhibitors more difficult to reverse?
Most don’t have a reversal. The exception being Dabigatran (Pradaxa)
What is the antidote for Dabigatran (Pradaxa)?
Idarucizumab
How can Factor Xa Inhibitors be reversed?
Andexanet, a derivative of factor Xa
Reversal agent for ASA
Platelet transfusion
Reversal agent for P2Y12 receptor antagonists
GPIIb/IIIa antagonists
Stop before procedure days for P2Y12 receptor antagonists
7-14 days
Monitoring required for Warfarin
PT, INR
Reversal agents for Warfarin
PCC, FFP, vitamin K
Monitoring required for Unfractionated Heparin (UFH)
aPTT
Reversal agent for UFH
Protamine
Monitoring recommended for Low-molecular weight heparin (LMWH)
fXa levels
Reversal agent for LMWH
Partially reversed by protamine
Monitoring recommended for Fondaparinux
fXa levels
Monitoring required for Argatroban, Bivalirudin
aPTT or ACT
Reversal agent for Rivaroxaban and Apixaban
Andexanet alfa
