Coagulation Flashcards
Exam 4
What is hemostasis?
the balance between clot generation, thrombus formation and regulation to inhibit uncontrolled thrombogenesis.
What are the two stages of hemostasis?
primary hemostasis: immediate platelet deposition at site of injury-> plt plug formation
secondary hemostasis: clotting factors are activated and clot secured w/ fibrin
Name a few anti-clotting mechanisms of endothelial cells…
- negative charge to repel plt
- produce prostacyclin and NO
- excrete adenosine diphosphatase
- increase protein C
- produce TFPI
- synthesize tPa
where are Plt derived from?
megakaryocytes in bone marrow
what is the lifespan of inactive plts?
8-12 days
How many plts are form daily?
120-150 billion
Describe what happens at the site of injury during primary hemostasis…
Endothelium is damages which exposes the extracellular matrix containing collagen and vWF. This triggers adhesion, activation and aggregation of the plts.
What causes platelet activation?
the interaction b/w the plt and the collagen and TF which causes the release of granular proteins.
What are the two types of storage granules that platelets contain?
- alpha granules
- dense bodies
what do alpha granules contain?
fibrinogen, factor V, VIII, vWF and platelet derived growth factor
what do dense bodies contain?
ADP, ATP, Ca, 5HT, histamine, Epi
What triggers aggregation of platelets?
the release of granular contents which activate additional plts.
what are the 4 components of tenase-complexes?
- a substrate
- an enzyme
- a cofactor
- calcium
what is the extrinsic pathway responsible for?
-initiation of plasma-mediated hemostasis
-tissue factor forms active complex w/ VIIa
-this complex can activate factor X (common pathway) and IX (intrinsic pathway)
what is the intrinsic pathway responsible for?
-responsible for amplification and propagation of thrombin generated by the extrinsic pathway
-lab coag studies rely in the intrinsic pathway to acitivate the clotting cascade
Describe the major components of the intrinsic pathway…
factor XIIa is activated by negatively charged surface which converts XI-> XIa which activates IXa which interacts w/ VIIIa to activate factor Xa
What factor is used to propagate the intrinsic pathway to further amplify thrombin generation?
Thrombin or factor IIa
Describe the common pathway…
Factor X becomes Xa which binds w/ Va to form a prothrombinase complex. This complex rapidly converts prothrombin to thrombin (IIa)
Thrombin attaches to the plts and converting fibrinogen to fibrin (Ia) Fibrin strands are used to stabilize clot
what factor is responsible for forming crosslinks between fibrin strands?
factor XIIIa
What is the key step in regulating hemostasis?
Thrombin generation
what are the two tenase-complexes that facilitate the formation of prothrombinase complexes?
intrinsic tenase complex: activator + IXa + VIIIa + Ca
extrinsic tenase complex: injury + TF + VIIa + Ca
What are the 4 major coagulation counter-mechanisms of anticoagulation?
- fibrinolysis
- tissue factor pathway inhibitor (TFPI)
- protein C system
- serine protease inhibitors (SERPINS)
What factors are involved in the protein C system?
Protein C inhibits factor II, Va and VIIIa
What are three examples of SERPINs?
- antithrombin
- heparin
- heparin cofactor II
which factors does antithrombin inhibit?
factors 9a, 10a, 11a, and 12a and thrombin
How does heparin work?
binds to antithrombin (AT) causing a conformational change that accelerates AT activity
If a bleeding disorder is suspected what are the first line labs to be ordered?
PT and aPTT
What is Von Willebrand’s disease?
-the most common inherited bleeding disorder
-caused by a deficiency in vWF causing defective plt adhesion and aggregation
vWF prevents degradation of which factor?
VIII
Which labs do you need to order to if VWD is suspected?
vWF level, vWF-plt binding activity, factor VIII level and a plt function assay
routine platelets and PT will be normal
What is the treatment for VWD?
DDAVP (increases vWF)
What is the difference between hemophilia A and B?
A: factor 8 deficiency
B: factor 9 deficiency (more rare)
Which lab is normally affected with hemophilia?
PTT is normally prolonged
PT, plts and BT are usually normal
What products may be indicated prior to surgery?
DDAVP
Factors 8 or 9
What are a few drugs that can cause increased bleeding?
heparin
warfarin
DOACs
Beta lactam ABx
nitroprusside
NTG
NO
SSRIs
What are a few homeopathic drugs that can increase the risk of bleeding?
cayenne
garlic
ginger
gingko biloba
grapeseed oil
St. John’s wort
turmeric
vitamin E
Which factors is the liver the primary source for?
5,7,9,10, 11,12
What other components of the coagulation cascade is the liver the primary source for?
proteins C and S and antithrombin
What causes CKD patients to be anemic?
-lack of EPO
-plt dysfunction
What are the treatment options for plt dysfunction r/t CKD?
-cryo
-DDAVP
-conjugated estrogens can be given 5 days preoperatively
What is DIC?
-the pathological hemostatic response to TF/7a complex causing excessive activation of the extrinsic pathway which overwhelms the anticoagulant mechanisms
-Coag factors and plts become depleted leading to MSOD
What are a few causes for DIC?
trauma, amniotic fluid embolus, malignancy, sepsis or incompatible blood transfusion
Which labs with be affected if you are in DIC?
decreased plts, prolonged PT/ PTT/TT, increased fibrin and increased fibrin degradation products
What is trauma induced coagulopathy?
acute coagulopathy seen in trauma patients r/t activated protein C which decreases thrombin generation–> increased bleeding
What is the driving force for protein C activation with trauma-induced coagulopathy?
hypoperfusion
What is the most common inherited prothrombotic disease?
factor V leiden mutation
what is factor V leiden?
genetic mutation of factor V the leads to activated protein C resistance leading to increased risk of clot formation
what is prothrombin mutation cause?
increases prothrombin concentration which leads to hypercoagulation
What is thrombophilia?
an inherited predisposition for thrombotic events like DVTs. These patients are highly susceptible to Virchow’s Triad
What is antiphospholipid syndrome?
an autoimmune disorder w/ antibodies against the phospholipid-binding proteins in the coagulation system. This disease is characterized by recurrent thrombosis and pregnancy loss
What is heparin induced thrombocytopenia?
a mild-moderate thrombocytopenia associated with Heparin that occurs about 5-14 days after heparin treatment is initiated
How long does it take to clear the HIT antibodies from circulation?
about 3 months
How is prothrombin time (PT) performed and what does it measure?
plasma is mixed with tissue factor and the seconds until a clot forms is measured
Assesses the integrity of the extrinsic and common pathways
good at measuring vit. K antagonists like Warfarin
What is the aPTT and what does it measure?
the activated partial thromboplastin time measures the sec until clot forms after mixing plasma w/ phospholipid, Ca, and an activator of the intrinsic pathway
Assesses the intrinsic and common pathways
Useful for measuring Heparin
What does an anti-Xa measure?
provides a functional assessment of heparin’s anticoagulant effect. Can also be used to assess LMWH and fondaparinux
What is a normal plt count?
greater the 100,000 plts/microliter
What is an ACT and what does it measure?
activated clotting time measures responsiveness to heparin. Assesses intrinsic and common pathways.
What is a normal ACT?
> 107s +/- 13 seconds
how much protamine do you need to neutralize 1 mg of heparin?
1 mg of protamine
What is a normal R time? What is the treatment?
5-10 min
FFP
What is a normal K time? What is the treatment?
1-3 min
Cryo
What is the normal alpha angle? What is the treatment?
53-72 degrees
cryo
What is the normal value for maximum amplitude? What is the treatment?
50-70mm
plts or DDAVP
What is the normal lysis at 30 minutes (LY30)? What is the treatment?
0-8%
TXA or amicar
What are the three main classes of antiplatelets?
- COX inhibitors (aspirin, nsaids)
- P2Y12 receptor antagonists (clopidogrel, ticagrelor, ticlopidine)
- Plt GIIa/IIIa receptor antagonists (abciximad, eptifibatide)
Warfarin is the DOC for what pathologies and how does it work?
DOC for valvular afib and valve replacements
inhibits the synthesis of vitamin K dependent factors
What are the vitamin K dependent factors?
2, 7, 9, 10
also, protein C and S
How does Heparin work?
binds to antithrombin and directly inhibits soluble thrombin and Xa
What are some differences between unfractionated heparin and LMWH?
UFH: shorter HL, fully reversible w/ protamine, coag testing needed
LMWH: longer HL, no caogs needed, only partially reversible w/ protamine
How do direct thrombin inhibitors work?
they bind to thrombin in both soluble and fibrin-bound states
Give some examples of direct thrombin inhibitors (DTI) …
Hirudin, Argatroban, Bivalirudin, and Dabigatran
Which DTI has the shortest HL and is the DOC for renal and liver impaired patients?
Bivalirudin
What are direct oral anticoagulants (DOAC)?
These are a newer class of drugs that have more predictable pharmacokinetics and dynamics. They have a similar efficacy to Warfarin but fewer drug interactions, embolic events, ICH, and mortality than Warfarin.
Give three examples of DOAC’s…
DTI: Dabigatran
Xa inhibitors: Xarelto, Eliquis and Savaysa
How do thrombolytics work?
these dissolve clots directly. They are usually serine proteases that convert plasminogen to plasmin (which breaks down fibrin).
What are the two categories of thrombolytics?
fibrin specific: alteplase (tPA), tenecteplase
non-fibrin specific: streptokinase
How long does surgery need to wait after giving a thrombolytic?
10 days
What are some contraindications for thrombolytics?
vascular lesions, uncontrolled HTN, recent cranial surgery or trauma, brain tumors, recent ischemic stroke (w/i 3 mos), peptic ulcers, pregnancy, major surgery in the last 3wks
Name a few antifibrinolytics…
- Lysine analogues (EACA, TXA)
- SERPINs (removed from the market d/t cardiotoxicity)
What are some factor replacements?
- recombinant VIIa
- prothrombin complex concentrate (PCC)–> contain vit. K factors
- fibrinogen (from pooled plasma)
- cryo and FFP (cheaper but less specific)
When should patients stop taking Warfarin?
dc 5 days prior to surgery
low risk: restart 12-24h postop
high risk: bridge to UFH or LMWH
When should patients stop taking heparins?
UFH: dc 4-6hr prior to surgery
LMWH: dc 24hr prior to surgery
When should surgical patients stop taking aspirin?
low risk patients dc 7-10 days prior
mod/high risk: do NOT dc
How long should surgery be delayed for patients with bare metal stents?
6 weeks after placement
How long should surgery be delayed for patients with drug-eluding stents (DES)?
6 months after placement
How long do you need to wait to do neuraxial anesthesia on patients who are on NSAIDS? Aspirin? Heparin BID? TID?
NSAIDS/aspirin: no restrictions
Heparin SQ BID: no restrictions
Heparin SQ TID: 4hr
How long do you need to wait to given neuraxial anesthesia to patients who are on Lovenox? Warfarin?
Lovenox: 12 hr
Warfarin: 5 days (INR <1.5)
What is the DOC for warfarin reversal?
Give PCC’s first for emergent coumadin reversal (short HL)
Give vit. K for sustained correction
What is the reversal drug for Dabigatran?
Idarucizumab
What is the reversal agent for Factor Xa Inhibitors?
Andexanet (a derivative of factor Xa)
What is the reversal agent for antiplatelet drugs like aspirin, clopidogrel, or cangrelor?
Platelets :)
