Hematology & Anticoagulant Drugs Flashcards
Hemophilia - pathophysiology
Coagulation factor deficiency –> impaired ability to form clots –> excessive bleeding
Hemophilia A involves a deficiency in:
factor VIII
hemophilia B involves a deficiency in:
factor IX
What % of hemoglobin is normal in mild hemophilia? In moderate? In severe?
mild = 6-49% is normal
moderate = 1-5% is normal
severe <1% is normal
Medications for treating hemophilia A
factor VIII concentrate
DDAVP - desmopressin
antibody therapy
gene therapy
Factor VIII Concentrate
Dose by % increase in factor desired & body weight
Desmopressin
a synthetic analog of ADH, releases stored factor VIII from endothelium, used for mild hemophilia A
Antibody therapy
Monoclonal antibody (an antibody that has been cloned from a WBC) works by binding together 2 factors in the clotting cascade (IXa & X) that would normally be where factor VIII would work, prophylactic
Gene therapy
very expensive, reconstruction / repair of genetic material in patient’s body
Treatment for Hemophilia B
Factor IX concentrate - dose by % increase in factor desired & body weight
Microcytic anemias
iron deficiency, anemia of chronic disease, thalassemia, sideroblastic anemia
Normocytic anemias
corrected reticulocyte count
Macrocytic anemias
- megaloblastic: folate deficiency, Vit B12 deficiency
- nonmegaloblastic: liver disease, alcoholism, reticulocytosis, drugs
Iron
- absorbed in small intestine, stored as ferratin or binds transferrin for distribution
- goes to bone marrow for use in HgB
- recycled, very minimal leaves body
Iron deficiency
- due to uptake / demand imbalance
- results in decreased O2 carrying capacity (fatigue, pallor, tachycardia)
Iron supplementation
- PO or parenteral (PO unless unable to absorb / tolerate PO iron)
PO iron side effects
- GI disturbances (nausea, heartburn, bloating); take w/ food & water
- leading cause of poisoning fatalities in young children
- treat for 1-2 months or until HgB normalizes
Vit B12
- required for DNA synthesis & cell growth / division
- catalyzes folic acid to active form
- requires intrinsic factor (parietal cells of stomach) for absorption
- storage in liver, slow elimination
B12 deficiency causes:
bone marrow suppression
decreased GI tract mucosa
*neuronal demyelination of the CNS
When are B12 injections preferred?
If neurologic deficits (d/t neuronal demyelination of the CNS)
Adverse effect of B12 supplementation
hypokalemia due to increased erythrocyte production
Folic acid
- required for DNA synthesis & cell division / growth
- must be converted to active form, 2 pathways (1 includes B12)
- absorbed in small intestine, stored in liver, extensive enterohepatic recirculation
Consequences of folic acid deficiency
bone marrow suppression
GI tract mucosa decrease
fetal neural tube defects
can increase colorectal CA & atherosclerosis risk
is folic acid or folinic acid replacement preferred
folic acid (the folinic acid active form is more expensive & not any more effective)
Why is B12 given in severe folic acid deficiency?
B12 is utilized in converting folic acid to its active form
**folic acid can also be converted to its active form via a different pathway too!
erythropoietin (EPO) results in:
stimulation of RBC production in bone marrow
Uses for hematopoietic agents
- anemia due to kidney disease
- chemo induced anemia (only for palliation)
- anemia pre-operatively
adverse effects of exogenous EPO
HTN
CV events
what increases the risk of CV events with exogenous EPO?
Hgb>11
or
Hgb increase >1 in 2 weeks
formulations of exogenous EPO
epoetin alfa
darbepoetin (longer 1/2 life, slower clearance, can admin less frequently)
What are leukopoietic growth factors?
substances that stimulate WBC proliferation
Uses for leukopoietic growth factors
- patients undergoing myelosuppressive chemo
- patients undergoing bone marrow transplant
- sever chronic neutropenia
adverse effects of leukopoietic growth factors?
leukocytosis
bone pain
formulations of leukopoietic growth factors
G-CSF: filgrastim
GM-CSF: sargramostim
What do thrombopoietin receptor agonists do?
stimulate platelet production
Uses for throbopoietin receptor agonists
- idiopathic thrombocytopenic purpura (immune mediated destruction of platelets & impaired platelet production)
- thrombocytopenia w/ liver disease pre op
Two main steps in forming a clot
- platelet plug
- fibrin mesh
fibrinogen connects activated platelets by binding:
GPIIb/IIIa receptors
platelet activation occurs upon exposure to an agonist such as:
ADP
TXA2
thrombin
collagen
platelet activation factor
What is fibrin?
threadlike protein that reinforces the platelet plug
Pathways to produce fibrin
- intrinsic: triggered by collagen contact (injured BV)
- extrinsic: triggered by thromboplastin (released by vascular wall trauma)
What does antithrombin do?
inhibits some of the coagulation factors so clotting doesn’t get out of control
Which factors depend on vitamin K for their synthesis?
II, VII, IX, X
what degrades the fibrin mesh?
plasmin
What happens with arteriole thrombosis formation?
Lack of adequate blood flow (oxygenation) to distal tissues
What happens with venous thrombosis formation?
Possibility of pieces breaking off (emboli) and traveling to lungs/brain.
Which drugs activate antithrombin?
heparin
LMWH (enoxaparin, dalteparin)
How does heparin work?
activates antithrombin –>
increased inhibition of some clotting factors (= suppression of thrombin & factor Xa)
–> decreased ability to create fibrin mesh
Which major step in coagulation does heparin inhibit?
Fibrin mesh formation
LMWH
greater suppression of factor Xa than thrombin
Fondaparinux
only suppression of factor Xa, no thrombin suppression –> decreased fibrin formation
What type of drug is warfarin?
Anticoagulant
Vitamin K antagonist
How does warfarin work?
inhibits VKORC1 (vitK epoxie reductase complex 1)
vitK cannot be converted to active form
factors II, VII, IX, X are decreased = fibrin mesh formation is decreased
Which major step in coagulation does warfarin inhibit?
fibrin mesh formation
How do direct thrombin inhibitors work?
Bind & inhibit thrombin
Thus fibrin can’t be formed & factor XIII can’t be activated.
Decreased fibrin mesh formation
What major step in coagulation do direct thrombin inhibitors inhbit?
Fibrin mesh formation
Name a couple direct thrombin inhibitors
dapigatran
desirudin
bivalrudin
argatroban
How do direct factor Xa inhibitors work?
bind & inhibit factor Xa = decreased thrombin production
= decreased fibrin mesh formation
What major step in coagulation do direct factor Xa inhibitors inhibit?
fibrin mesh formation
List a couple direct factor Xa inhibitors
rivaroxaban
apixaban
What is the primary source of thrombi in veins?
fibrin
*thus anti-fibrin drugs are especially helpful for preventing DVTs
How is heparin administered?
IV or subQ
Why do IV infusions of heparin have to be monitored with PTT checks?
widely variable protein binding, so effects amongst various patients are unpredictable
What is normal PTT
40 sec
What is often the therapeutic goal of heparin infusion?
PTT 60-80sec
antidote for heparin
protamine
How does protamine work?
binds heparin, inactivating it
adverse effects of high dose heparin?
hemorrhage
heparin induced thrombocytopenia
hypersensitivity reactions
spinal / epidural hematoma
Heparin - therapeutic uses
- situations that require rapid anticoagulation (PE, DVT)
- open heart surgery or dialysis prevent device coagulation
- low dose SubQ for DVT prevention
- treatment of DIC
- adjunct in acute MI
What is HIT (heparin induced thrombocytopenia)?
immune response against heparin: antibodies are produced against heparin-platelet complexes
What does HIT result in?
consumption of platelets (decreased platelets available to clot) = thrombocytopenia
increased platelet activation = increased thromboembolic events
What lab values might you expect to change in heparin induced thrombocytopenia?
PTT increase
platelet decrease (drastically)
Treatment for heparin induced thrombocytopenia?
d/c heparin
use alternative anticoagulant
Why don’t LMWH require PTT monitoring?
decreased protein binding & slower clearance: predictable pharmacokinetics
LMWH
- Enoxaparin & dalteparin = more Xa than thrombin inhibition
- AE = bleeding (less common than w/ heparin)
How is warfarin given?
PO only
Warfarin - mechanism
- Vitamin K antagonist
- decreases production of factors II, VII, IX & X
- results in decreased fibrin formation
What might occur if another highly protein bound drug is given to your patient on warfarin?
Increased free warfarin = overdose
Increased bleeding risk
What lab value is monitored during warfarin administration?
PT/INR
What is the normal INR value?
0.8-1.1
What is the goal INR in warfarin therapy?
2-3
Warfarin PK
PO, 99% protein bound, free drug crosses membranes, CYP450 metabolism, renal/fecal excretion
Why is warfarin not used for acute clotting issues?
Doesn’t inhibit the vitK factors that are already synthesized - thus effects take a few days
(just inhibits the formation of future vitK factors)
Warfarin - therapeutic uses
- long term prevention of thrombosis: DVT/PE, thromboembolism in prosthetic heart valves, thrombosis in chronic a fib, those at risk of recurrent MI/TIA
Adverse effects of warfarin
hemorrhage
fetal hemorrhage (contraindicated in pregnancy)
infant hemorrhage (caution in breasfeeding)
antidote of warfarin
vitamin K (phenytonadione)
FFP
plasma concentrates of factor II, VII, IX, X
Dietary guidance for a patient being prescribed warfarin:
caution with excessive dietary vitK:
- leafy green veggies
- mayo
- canola oil
Warfarin / drug interactions: increase anticoagulant effects
- highly protein bound drugs (displacement of warfarin)
- CYP450 inhibitors
- decreased synthesis of clotting factors
- acetaminophen?
Warfarin / drug interactions - promote bleeding
- inhibition of platelet aggregation
- inhibition of clotting factors
- generation of GI ulcers
- heparin, aspirin, many OTC supps
Warfarin drug/food interactions - decrease coagulant effects
- CYP450 inducers
- increased synthesis of clotting factors
- inhibition of warfarin absorption
- increased dietary vit K intake
Direct thrombin inhibitors
dabigatran, desirudin, bivalrudin, argatrobin
Mechanism of direct thrombin inhibitors
- binds / inhibits thrombin that is already bound to clots –> decreased conversion of fibrinogen to fibrin, decreased activation of factor XIII
End result of direct thrombin inhibitors
decreased conversion of soluble to insoluble fibrin
Pros of direct thrombin inhibitors
- rapid onset
- no need to monitor lab values, predictable responses = reliable dosing
- few drug food interactions
- lower risk of major bleeding
Direct thrombin inhibitors - PK
- PO
- peak 1-3 hrs (food affects absorption rate)
- low protein binding
- renal elimination, no liver metabolism
- 1/2 life = 13 hrs (norm renal function), 18 hrs (mod renal dysfunction)
What is unique about bivalrudin (compared with the other direct thrombin inhibitors)?
IV only (continuous infusion)
immediate onset
short duration
eliminated by renal excretion & proteolytic cleavage
Therapeutic uses of direct thrombin inhibitors
- A fib
- tx for DVT / PE
- prevention of thrombosis
- knee / hip replacement
adverse effects of direct thrombin inhibitors
hemorrhage (less than warfarin)
GI disturbances
bivalrudin can cause back pain, hypotension, and headache
Do you need to monitor lab values for direct thrombin inhibitors or direct factor Xa inhibitors?
no
Mechanism of Rivaroxaban
- selective binding & inhibition of factor Xa
- decreased production of thrombin
- inhibition of fibrin mesh formation
Advantages of rivaroxaban
rapid onset, fixed dosage, lower bleeding risk, few drug interactions, no lab monitoring required
Rivaroxaban - PK
PO, peak 2-4 hrs, CYP450, 35% unchanged in urine
Rivaroxaban - therapeutic uses
- PE/DVT prevention after ortho procedures
- stroke prevention w/ a fib
- DVT/PE prevention
- tx of DVT/PE
adverse effects of rivaroxaban
hemorrhage (less than warfarin)
maternal hemorrhage risk + fetal effects (avoid in pregnancy)
“Antidote” of rivaroxaban
- can give activated charcoal to avoid further absorption
- hemorrhage = factor VIIa or factor II (prothrombin)
Factor Xa inhibitors
apixaban, betrixaban, endoxaban, rivaroxaban
How does aspirin decrease clotting?
irreversibly inhibits cyclooxygenase = decreased thromboxane A2 (TXA2) formation
(TXA2 agonizes platelet activation & aggregation)
What major step in clotting does aspirin inhibit?
platelet activation & aggregation
what class of medication is aspirin?
COX inhibitor
Aspirin - PK
effects last lifetime of platelet (7-10 days)
Aspirin indications & AE
- indications: CVA, TIA, chronic stable angina, stents, acute MI
- AE: GI bleeding, hemorrhagic stroke
How do P2Y12 ADP receptor antagonists work?
block P2Y12 ADP receptors on platelet surface –> decreased activation and aggregation
What major step in clotting do P2Y12 ADP receptor antagonists inhibit?
platelet activation & aggregation
List some P2Y12 ADP receptor antagonists
clopidogrel (irreversible)
prasugrel (irreversible)
ticagrelor (reversible)
PK, use & AE for P2Y12 ADP antagonists
- PK: PO, hepatic met, effects in 2 hrs, 7-10 days = duration
- use = prevention of stent thrombosis & thrombotic events
- adverse = same as aspirin (bleeding TTP)
How do PAR-1 antagonists work?
inhibit PAR1 receptors on platelet surface = decreased platelet activation/aggregation; mediate effects of thrombin
What major step in coagulation do PAR1 antagonists inhibit?
platelet activation/aggregation
Name a PAR1 antagonist
vorapaxar
PAR 1 PK, uses, AE
- PK: PO, effects in 1 hr, hepatic met, fecal excretion, 8 days = 1/2 life
- uses = w/ aspirin/clopidogrel in reduction of thrombotic events
- AE = bleeding
How do GP IIb/IIIa receptor antagonists work?
block GPIIb/IIIa receptors on platelet surface = inhibit FINAL COMMON STEP in platelet aggregation
(thus making them the MOST effective antiplatelet drug)
list some GPIIb/IIIa receptor antagonists
abciximab
tirofiban
eptifibatide
Which antiplatelet drug is most effective
GP IIb/IIIa receptor antagonists
(like abciximab)
duration of action of single dose of aspirin
7-10 days (lifetime of platelet due to irreversible binding)
duration of action of single dose clopidogrel (Plavix)
7-10 days (lifetime of platelet due to irreversible binding)
Why are GPIIb/IIIa receptor antagonists the most powerful antiplatelet drug?
all other platelet activating/aggregating agonists (TXA2, etc.) require the GP IIb/IIIa receptor
What do thrombolytic drugs do?
break down thrombi that have already formed
list some thrombolytics
alteplase (tPA)
reteplase
tenecteplase
how do thrombolytic drugs work?
activate plasmin which breaks down fibrin mesh
also degrades clotting factors
route of administration of thrombolytic drugs
IV
uses for thrombolytic drugs
acute MI, CVA, PE
adverse effects of thrombolytic drugs
hemorrhage!
How to prevent hemorrhage when administering thrombolytic drugs
- minimize patient manipulations
- avoid invasive procedures (even PIV placement!)
- avoid subQ/IM injections
- minimize concurrent use of other blood thinners
