Exam 4 - Coagulation Flashcards
What are the 3 goals of hemostais?
- To limit blood loss from vascular injury
- Maintain intravascular blood flow
- Promote revascularization after thrombosis
What are the 2 stages of hemostatsis?
Primary - Platelet plug formation, adequate for minor injuries
Secondary - activation of clotting factors →stabilized crosslinked clot
Anti-clotting mechanisms of endothelial cells:
- are ____ to repel platelets
- produce platelet inhibitors ____ and ____
- excrete ____, which degrades ADP - a platelet activator
- increase ____, an anticoagulant
- produce ____, which inhibits factor Xa and TF-VIIa complex
- Synthesizes ____
- are negatively charged to repel platelets
- produce platelet inhibitors prostacyclin and nitric oxide
- excrete adenosine diphosphatase, which degrades ADP - a platelet activator
- increase protein C, an anticoagulant
- produce tissue factor pathway inhbitor (TFPI), which inhibits factor Xa and TF-VIIa complex
- Synthesizes tissue plasminogen activator (t-PA)
What are platelets derived from?
Bone-marrow megakaryocytes
Inactive platelet lifespan?
8-12 days
How many platelets are used just to maintain vascular integrity?
How many are made daily?
10%
120-150 billion
What increases the membrane surface area of platelets?
Numerous receptors and surface canalicular system
Damage to the endothelium exposes the underlying ECM which contains what?
What does this cause?
Collagen, vWf, glycoproteins
Platelet adhesion and activation
What happens when platelets are activated?
Release of alpha granules and dense bodies
What is contained within alpha granules?
fibrinogen, factor V, VIII, vWF, and PLT growth factors
What is contained within dense bodies?
ADP, ATP, Ca++, serotonin, histamine, and epinephrine
How does platelet aggregation occur?
Occurs when granular contents are released - activating additional platelets
Each stage of the clotting cascade require assembly of what?
membrane-bound activated tenase-complexes
Each membrane tenase complex is composed of?
- Substrate
- Enzyme
- Cofactor
- Calcium
Draw the clotting cascade
What are the common names for the clotting factors?
Foolish People Try Climbing Long Slopes After Christmas, Some People Have Fallen
The TF/VIIa complex activates what?
X to Xa
IX to IXa
What is the major role of the intrinsic pathway?
Amplifies coagulation to propagate thrombin generation initiated by the extrinsic pathway
What activates factor XII to start the intrinsic pathway?
Contact with a negatively charged surface
In the intrinsic pathway, what converts factor X to Xa?
IXa + VIIIa + Ca++
Intinisic tenase complex
What factors does activated thrombin (IIa) activate?
V, VII, VIII, and XI
What makes up the prothrombinase complex?
What does it do?
Xa + Va + Ca
Converts prothrombin (II) to thrombin (IIa)
How does thrombin generate fibrin?
Cleaves fibrinopeptides from fibrinogen to generate fibrin
Fibrin then polymerizes into strands to form basic clot
What does factor XIIIa do?
Crosslinks the fibrin strands to stablize the clot - making it resistant to degredation
What is the key step in regulating hemostasis?
Thrombin generation
What makes up the intrinsic and and extrisic tenase compexes?
What do these facilitate?
Formation of prothrombinase complex
What are the 4 major coagulation counter mechanisms?
- Fibrinolysis
- Tissue Factor Pathway Inhibitor (TFPI)
- Protein C system
- Serine Protease Inhibtors (SERPINs)
How does fibrinolysis occur?
Endovascular TPA & urokinase convert plasminogen to plasmin
How does plasmin cause fibrinolysis?
Plasmin breaks down clots enzymatically, and degrades factors V & VIII
How does TFPI function to counter the coagulation cascade?
- Forms complex w/ Xa that inhibits TF/7a complex
- Thereby downregulating the extrinsic pathway
What does protein C do?
Inhibits factors II, Va, and VIIIa
What are the 3 SERPINs and how do they work?
- Antithrombin (AT) inhibits thrombin, factors 9a (IXa), 10a (Xa), 11a (XIa), 12a (XIIa)
- Heparin binds to AT, causing a conformational change that accelerates AT activity
- Heparin cofactor II inhibits thrombin alone
If a bleeding disorder is suspected in a patient, what are the first line labs?
PT and aPTT
What is the most common inherited bleeding disorder?
Von Willebrands Disease
Patho of vWD?
- Deficiency in vWF, causing defective plt adhesion/aggregation
- vWF plays critical role in plt adhesion & prevents degradation of factor 8 (VIII)
Lab findings in vWD?
Normal PT and platelets
aPTT could be prolonged d/t decreased factor VIII
Treeatment for vWD?
DDAVP (increase vWF synthesis) or Factor VIII concentrates
What clotting factors are defiecent in hemophilia A and B?
A: Factor VIII deficient
B: Factor IX deficient
Lab findings in hemophilia?
PT, Plt, and bleeding time normal
PTT prolonged
What is the most significant cause of intraoperative bleeding?
Anticoagulant meds and supplements
What meds can increase bleeding that you may not consider?
- Beta-lactam abx
- Nitroprusside
- NO
- NTG
- SSRIs
Supplements that can cause bleeding?
- Cayenne
- Garlic
- Ginger
- Gingko
- Grapeseed oil
- SJW
- Turmeric
- Vitamin E
What clotting factors are NOT made in the liver?
I-IV, VIII, XIII
Coagulation lab findings in patients with liver disease?
Prolonged PT and PTT
Labs don’t show lack of anticoagulant factors
Why do CKD patients show a baseline anemia?
- Lack of EPO
- Plt dysfunction from uremia
Treatment of plt dysfunction in CKD?
- Cryo (rich in vWF)
- DDAVP
- Conjugated estrogens
DIC patho?
Depletion of coag factors and plts d/t excessive activation of the extrinsic pathway that overwhelms anticoagulant mechanisms - leading to large amounts of thrombin and microemboli
Lab findings in DIC?
↓Plts, prolonged PT/PTT/Thrombin time,↑soluble fibrin & fibrin degradation products
Cause of trauma induced coagulopathy?
Activated protein C (from hypoperfusion) decreases thrombin generation
What causes “auto heparinization” seen in TIC?
Proteoglycan shedding
Factor V leiden patho?
Genetic mutation of factor V leading to activated protien C resistance
What prothrombotic state generally presents with venous thrombi?
Thrombophilia
What is antiphospholipid syndrome?
Sx?
Tx?
- Autoimmune disorder w antibodies againest phospholipid binding proteins
- Recurrent thrombosis and miscarrage/spontaneous abortion
- Often requires life long anticoagulants
HIT patho?
Autoimmune response resulting in platelet count reduction as well as activation of the remaining platelets and potential thrombosis
What is contraindicated in HIT?
How long do the antibodies stay in the circulation?
- Warfarin - decreases protein C and S synthesis
- Clear within 3 months
What does Prothrombin Time measure?
- Assesses extrinsic and common pathways
- Reflectsdeficiencies in factors I, II, V, VII, X
- Used to monitor warfarin levels (WEPT)
What is activated Partial Thromboplastin Time (aPTT) measuring?
- Assesses intrinsic and common pathways
- Sensitive to factor VIII and IX deficiencies
- May be used to monitor heparin
What is an anti-factor Xa activity assay?
Provides assessment of heparin and other factor Xa inhibitors (LMWH, fondaparinux)
Normal PLT count?
- > 100 K
What does activated clotting time (ACT) measure?
- Measures intrinsic and extrinsic pathways - whole clotting time
- Normal is 107 +/- 13 secs
- Used to measure responsiveness to heparin
Fill in this chart
MOA of cyclooxygenase inhibitors?
Inhibit COX-1 from forming TXA2 - which is important in plt aggregation
What are the COX inhibitors?
How long do they affect platelets?
ASA - effects last 7-10 days after d/c
NSAIDS - effects last 3 days
What are the P2Y12 inhibitors?
MOA?
Clopidogrel, Ticlopidine, Ticagrelor, and Cangrelor
Inhibit P2Y12-R→preventing GIIb/IIIa expression
How long do the antiplatelets effects last for the P2Y12 inhibitors?
- Clopidogrel: anti-plt effects x 7 days after d/c
- Ticlopidine: anti-plt effects x 14-21 days after d/c
- Ticagrelor & Cangrelor: Short-acting, < 24h activity
How do GIIb/IIIa antagonisits work?
What drugs are in this class?
- Prevent vWF and fibrinogen from binding to the GIIb/IIIa receptors on platelets
- Abciximab, Eptifibatide, Tirofiban
Warfarin inhibts…?
Vitamin K dependent clotting factors (2, 7, 9, 10, Protein C & S)
What is the drug of choice for valvular afib and valve replacements?
Warfarin
Heparin MOA?
Binds to antithrombin (increasing it’s activity)→ directly inhibits soluble thrombin and Xa
Compare unfractionated heparin and LMWH?
Unfractionated: Short HL, given IV, Fully reversable w/Protamine, Close monitoring required
LMWH: Longer HL, dosed BID SQ, No coag testing needed, Protamine only partially effective
Can you reverse fondaparinux with protamine?
No
What are the direct thrombin inhibitors and their MOA?
- Hirudin, Argatroban, Bivalirudin, Dabigatran
- Bind/block thrombin in both soluble & fibrin-bound states
What anticoagulant is naturally occuring in leeches?
Hirudin
Which direct thrombin inhibitor has the shortest half life and is the DOC for liver/renal impairment?
Bivalirudin
What was the first direct oral anticoagulant?
Dabigatran (Pradaxa)
Which direct thrombin inhibitor reversibly binds thrombin?
What labs are monitored intraop?
Argatroban
PTT or ACT
What are the direct Xa inhibitors?
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
What are the 2 categories or thrombolytics and the drugs in each category?
- Fibrin-specific: Alteplase (tPA), Reteplase, Tenecteplase
- Non-fibrin specific: Streptokinase
How long should someone wait who hase received thrombolytic therapy?
10 days
What are the absolute contraindications to thrombolytic therapy?
What are the 2 subclasses of fibrinolytics oand the drugs in each?
- Lysine analogues: Epsilon-amino-caproic acid (EACA) & Tranexamic Acid (TXA)
- SERPIN: Aprotinin (removed from market d/t renal & cardio toxicity)
MOA of lysine analogues?
Binds & inhibits plasminogen from becoming plasmin→impairing fibrinolysis
What are the 4 factor replacements used to improve clotting?
- Recombinant VIIa
- Prothrombin Complex Concentrate (PCC)
- Fibrinogen concentratre
- Cryoprecipitate and FFP
Which factor replacement increases generation of thrombin?
RfVIIa
Which factor replacement contains Vit K factors?
Prothrombin Complex Concentrates
When should warfarin be stopped and restarted perioperatively?
Low risk pts: 5 days prior, resumed 12-24hr post op
High risk pts: 5 days prior, bridge with heparin through surgery
When should UFH and LMWH be stopped and restarted perioperatively?
UFH: stop 4-6h preop, resume >12 h post op
LMWH: stop 24 preop, resume 24h post op
When should ASA be stopped before surgery?
Moderate and high risk pts: continue ASA
Low risk: 7-10 days prior
How long should elective surgery be delayed for patients who have bare metal and drug eluting stents post PCI?
Bare metal - 6 weeks
Drug-eluting - 6 months
Which anticoagulants do we need to worry about when preforming neuraxial anesthesia?
Heparin TID SQ
Lovenox qD
Warfarin
What drug would you give for emergent reversal of warfarin?
PCC (short 1/2 life)
Vit K also for more sustained correction
Which DOAC has a reveral drug and what is it?
Dabigatran (Pradaxa) - reversed with Idarucizumab
Oral factor Xa inhibitors can be reversed with what?
Andexanet
