Hematology Flashcards
What are the three main components of Virchow’s Triad?
- Hypercoagulable state
- Vascular wall injury
- Circulatory stasis
What is the number one reason people are on anticoagulation?
Atrial fibrillation
What is released from damaged cells after damage occurs outside the blood vessels?
Thromboplastin
What does thromboplastin activate?
Factor VII
Trauma to the blood itself or exposure of the blood to collagen activates what factor?
XII (XIIa)
XIIa activates what factor?
XI-XIa and XIa activates IX-IXa
Xa, when complexed on the platelet surface with Va and factor IV, converts ______ to _____?
Prothombin (II) to thrombin (IIa
IIa converts _____ to _____ ?
fibrinogen (I) to fibrin (Ia)
MOA of Heparin?
Acts as a catalyst to markedly accelerate the rate at which ATIII (heparin cofactor) neutralizes thrombin (II) and Factor Xa
What is heparin made out of?
Porcine intestinal mucosa (no longer made out of bovine)
T/F: Heparin induces a confirmational change in the ATIII that makes the reactive site less accessible to the protease?
False; makes it more accessible to the protease
Uses of heparin?
- Px and tx of VTE
- Px and tx of postop DVT and PE
- Tx of emboli from afib or heart valves
- Dx and tx of DIC
- Px and tx periph arteral embolism
- During arterial or cardiac surgery
- Unstable angina, non-Q wave MI, acute MI, PCI
- Complications of pregnancy
At what plasma concentration of heparin is Thombin (IIa), IXa, and Xa inhibited rapidly by ATIII?
0.1 to 1 unit/ml
Does heparin act on bound or unbound factors?
Unbound. It does not break down clots that have already been formed
Onset of action of heparin IV? Heparin SQ?
IV= immediate
SQ=1-2 hours
How is half life related to dose of heparin?
The more you give the longer the half life
100u/kg=1 hr
400u/kg=2.5 hrs
800u/kg=5 hrs
How is heparin metabolized?
Cleared by the reticuloendothelial system and then excreted by the kidneys
What type of cells is the reticuloendothelial system comprised of?
Phagocytes
Does heparin cross the placenta?
No
What are reasons for heparin resistance?
- Increased concentration of Factor VIII
- Accelerated clearance of the drug with massive PE
- Inherited ATIII deficiency
- Acquired ATIII deficiency
What are examples of causes for acquired ATIII deficiency?
- Cirrhosis
- Nephrotic syndrome
- DIC
Are patients with inherited or acquired ATIII deficiency more likely to have normal response to heparin?
Inherited ATIII Deficiency patients.
Acquired ATIII deficiency patients will require 2 units FFP and/or ATIII concentrate administration
What is the risk of bleeding with heparin?
1-33%
What are the 4 issues with heparin toxicity?
- Bleeding
- Thrombocytopenia (HIT)
- Abnormal LFTs
- Risk of osteoporosis and spontaneous vertebral fractures
Does HIT occur immediately after heparin adminstration?
No; 7-14 days after initiation of full dose or low dose heparin therapy (includes heparin flush solution)
Type I or II HIT due to heparin dependent antiplately IgG antibodies?
Type II HIT.
Type I is direct or nonimmunogenic effect on platelets
If patient previously exposes to heparin, can thrombocytopenia occur earlier or later?
Occur earlier
MOA of Protamine Sulfate?
Acts as heparin antagonist by complexing with strongly acidic and anionic heparin to form a stable salt. The complexes are removed by the reticuloendothelial system
Onset and duration of Protamine sulfate?
Rapid onset 5 min or less and duration around 2 hours
Protamine has no effect on reversing LMWH?
False; if emergency reversal is needed, protamine will neutralize about 65% of Anti-Xa activity of LMWH
If heparin was given within 30-60mins, what is the dose of protamine reversal?
0.5-0.75mg/100u Heparin
If heparin was given 2 hours ago or more, what is the dose of protamine reversal?
0.25-0.375mg/100u Heparine
If heparin infusion is stopped, what is the dose of protamine reversal?
25-50mg
If heparin reversal is needed immediately following heparin administration for surgery, what is the protamine reversal dose?
1-1.5mg/100u heparin
How should protamine be administered?
Slow IV 10mg/ml over 1-3 mins.
Up to 50mg/10min maximum
What are adverse effects to rapid IV injection of protamine sulfate?
Acute Histamine related- hypotension, bradycardia, pulmonary hypertension, transient flushing, dyspnea.
Hypersensitivty reaction for protamine can result in what?
- Uticaria
- Angioedema
- Acute Pulmonary Hypertension
- Anaphylactoid Reaction
- Anaphylaxis
What four things predispose a patient to having a hypersensitivity reaction to protamine administration?
- Fish allergy
- Previous protamine reversal of heparin
- NPH Insulin
- Previous vasectomy
What are examples of insulin that predispose patients to protamine hypersensitivity reactions?
Humulin N and Novolin N
What is heparin rebound?
Re-anticoagulation after protamine administered
When does heparin rebound typically occur?
Usually 8-9hours after protamine administration (has been reported 30min-18hours after CPB).
What can overdose of protamine cause?
Protamine overdose may result in bleeding d/t it having anticoagulant and anti-platelet effects when given alone or in excess of heparin dose.
What has a higher risk of thrombocytopenia- Heparin or Low-molecular weight heparin?
Heparin
What lab value would indicate HIT?
PLT <100K
T/F
HIT is reversible with stopping heparin
True
What is the name of the thrombotic complication that can occur in a minority of patients with HIT?
White clots (HITTS)
basically arterial thrombosis with PLT-Fibrin clots
What 3 drugs are LMWH?
Dalteparin Sodium (Fragmin®) Enoxaparin Sodium (Lovenox®) Tinzaparin Sodium (Innohep®)
What is the MOA of LMWH?
Inhibition of Factor Xa by antithrombin.
They do have some Factor IIa inhibition effect.
According to the JAMA article, does LMHW reduce rate of VTE?
No
Other target sites, such as PLT, may be needed to be blocked
What lab value should be monitored with LMWH’s?
Anti-Xa levels
T/F
aPTT and PT relatively insensitive with LMWH therapy.
True
What are the adverse effects with LMWH’s?
Thrombocytopenia (<1%)
Do not use in patients with HIT
Decrease dose in patients with chronic renal insufficiency
How is Fondaparinux (Arixtra) different from LMWH’s?
No effect on Factor IIa or PLT function
Can give Arixta if pt has hx of HIT (no risk of HIT b/c the rate of thrombocytopenia is so low)
T/F
Hemodialysis will help with bleeding complications from dabigatran, but not with xarelto and eliquis
True
Out of coumadin, xarleto, eliquis, and dabagratan (pradaxa), which one’s pre-op cessation time is not half-life related?
Coumadin
this is the reason coumadin has a longer cessation time than the other ones.
Out of coumadin, xarleto, eliquis, and dabagratan (pradaxa), which one is dependent on kidney function?
Dabagratan
What are two specific antidotes for dabigatran?
idarucizumab, ciraparantag
T/F
Giving too much coumadin initially can result in VTE formation
True
B/C Coumadin inhibits proteins C& S first (natural anticoagulants) before inhibiting factors 2,7,9,10
What is the relationship b/w Vit K and factors II, VII, IX, and X?
These factors are biologically inactive. Vit K activates them via a carboxylation reaction.
If giving Vit K for coumadin reversal, how long does it take before the body makes new factors II, VII, IX, and X?
24 hours
What is the most common anticoagulant used?
Heparin
Is heparin’s MOA direct or indirect? Is it reversible or irreversible?
Indirect (it is a catalyst of ATIII)
Reversible
Does heparin cross the placenta?
No, hence it is the SAFEST anticoagulant to give to pregnant pts
T/F
With HIT, you have a risk of clots even though it results in in thrombocytopenia
True
will see drop in PLT levels and clumping of pts (slide 17)
What is the pathophysiology of HIT?
PLT’s have PF4 which binds with heparin. IgG complex recognizes heparin/PF4 and binds it up, results in a large complex
Anaphylactoid reaction from protamine is due to ____ activation
compliment
what is the DOA of protamine?
2 hrs (at best)
T/F
Fondaparinux has the same risk of spinal and epidural hematoma as LMWH
True
What are two unique features of Betrixaban (Bevyxxa)
Can only give PO and it is only used in the hospital setting
T/F
Danaparoid Sodium (Orgaran) has no risk of HIT
FALSE
still has a risk of HIT, buts very low.
Why do patients with massive PE’s have increased resistance to heparin?
the PE causes activation of the reticuloendothelial system, speeds up metabolism of heparin
When evaluating HIT, is it more beneficial to look at PLT level or how fast PLT levels are dropping?
How fast PLT’s drop.
HIT could be present if there is a rapid drop in PLT’s (ex. 300K to 150K)
If a patient has ARF or is on dialysis, what is the best oral Xa inhibitor to give them?
Edoxaban (Savaysa)
Does oral Xa inhibitors have a reversal agent?
Previously no, but two reversal agents are Andexanet and Ciraparantag
Which drugs is Andexanet alpha approved for?
rivaroxabam (Xarelto) and apixaban (Eliquis)
Which drugs is Ciraparantag approved for?
Xa inhibitors, IIa inhibitors, Fondaparinux, and heparin
MOA of Andexanet alpha
Reverses Factor Xa inhibitors- recombinant human Factor Xa (basically just giving more Xa, will bind up inhibitors)
Binds COMPETITIVELY to Factor Xa inhibitors for complete reversal
MOA of Ciraparantag
Binds to anticoagulants through a hydrogen bond
What is the only direct thrombin inhibitor that has a reversal agent?
dabigatran
agatraban and hirudin analogs do not
Hirudin analogs binds ______ to the active catalytic and substrate-recognition sites of both ______ and ______ thrombin (Factor IIa).
- irreversibly
- circulating
- clot bound
When are hirudin analogs indicated?
for thrombosis assoc. with HIT
What is a disadvantage of hirudin analogs?
Because they come from a natural products, Antihirudin antibodies form n~40% of patients and may be associated with an increased anticoagulant effect of
lepirudin.
What is the only oral direct thrombin inhibitor?
dabigatran (pradaxa)
this is not a Xa inhibitor even though it has “xa” in its name
What are the 2 reversal agents for dabigatran?
Idarucizumab (Praxibind) and Ciraparantag
If bleeding or toxicity occurs, what are 2 major benefits of dabigratan compared to the other direct thrombin inhibitors?
- It has reversal agents
- Hemodialysis will help remove dabigatran, whereas HD has no benefit with the other direct thrombin inhibitors
How long will dabigatran (Pradaxa) reversal occur after administration of Idarucizumab (Praxibind)?
10 mins
How long after a procedure can direct thrombin inhibitors be resumed?
as soon as adequate hemostasis has been achieved
she stressed this in the lecture
For direct thrombin inhibitors, how many life-lives need to pass before it is safe to proceed with surgery
2 half-lives (usually 1-2 days)
holding med for at least 1 day is safe to proceed for minor procedures
2-4 days for major procedures
hold times for these meds are based on kidney function and type of procedure
If a patient accidentally took a direct thrombin inhibitor within 2 hours prior to surgery, what can be done?
give activated charcoal
When would agatroban be a good choice?
Used for the prevention and treatment of thrombosis in patients with HIT or HITTS
What is lab monitoring goal for agatroban?
Goal: aPTT 1.5 to 3 times baseline (<100 sec.)
Will see increases in EVERYTHING (aPTT, ACT, PT, and TT)
T/F
Dabigatran has no CYP3A4 interactions, only PgP interactions
True
If a pt is on a DOAC and bleeding, when is the only time a reversal agent is recommended?
Life threatening, critical organ, or major bleeding not responding to maximal supportive effort
If a pt is on a DOAC and not bleeding, when is the only time a reversal agent is recommended?
Only when an invasive procedure cannot be safely performed while anticoagulated and cannot be delayed
Trauma and drug overdose are not reasons to give a reversal agent for DOAC’s
Why are DOAC reversal agents given cautiously?
b/c once anticoagulation is reversed, it is even harder to get them re-anticoagulated again
Coumadin decreases the total amount of each Vit. K dependent coagulation factor made by the liver by ____ %.
In addition, the factors made are _______ resulting in diminished biological activity (10-40% normal).
30-50%
undercarboxylated
You DO NOT want completely block all the Vit K factors, only decrease them slightly
What route of Vit K administration is recommended?
PO
What route of Vit K administration is never recommended (according to Emily)?
SQ
Does coumadin have a lot of drug interactions? What drugs are of most concern for interaction?
YES! (Emily said to file coumadin along with digoxin, amiodarone, diltiazem as a drug that has many interactions)
- Antibiotics
- Acetaminophen (causes an interaction with 2D1)
- Supplements (the ones that begin with “g”)
- NSAIDS and other blood thinners
- Seizure meds
Bridge therapy is recommended for what medication?
Coumadin only. No need for oral direct thrombin inhibitors bc you only need to hold them for a day or two
T/F
There is no reduction in thromboembolic events and increased risk of bleeding with bridge therapy
True
Only bridge if pt is very high risk (slide 61)
Indwelling neuraxial catheters should be removed ____ hours after the last heparin dose and after evaluating the patient’s coagulation status.
2-4 hrs
T/F
ASA and NSAIDs do not appear to be associated with an increased risk of epidural hematoma.
True
For LMWH use, Needle placement should occur at least _____hours after last LMWH dose. High doses of LMWH require a delay of at least ____ hours.
10-12 hours
24 hours
remembering 12 hour increments makes it easy to remember
For LMWH…If epidural cath inserted, it should be done ____ hours prior to any dose of postoperative LMWH (single daily dosing) and ____ hours for twice daily dosing
6-8hours
24 hours
Removal of epidural catheter should be done ____ hours before any dose of LMWH
2-4hours
Removal should occur ____ hours after any dose of LMWH and __ hours before a subsequent dose.
10-12 hours
2 hours
D/C DOAC prior to neuraxial procedures ___ days for dabigatran and 3-5D for Xa inhibitors
4-5 days
3-5 days
4 days is easier to remember
How soon after surgery can DOAC’s be restarted?
24 hours for low-bleed risk and 72 hours for high-bled risk
