Anticoagulants / Hematology Flashcards
Anticoagulants versus Antiplatelets versus Fibrinolytics
Anticoagulants: prevention of clot FORMUTION
-TX of VTE (includes PE or DVT)
-Immediate TX of STEMI or NON-STEMI (Acute Coronary Syndrome) due to plaque from rupturing and forming blood clots –> goal to prevent clot expansion
-Cardioembolic stroke prophylaxis
-Other conditions with increased risk of bleeding (ex. mitral valve pts)
Antiplatelets: interfere with platelets binding together, more for prevention of ischemic stroke/TIA or coronary artery disease
Fibrinolytics: BREAKDOWN of clots
-Higher risk of bleeding than anticogulants
Explain the process of anticoagulation:
-Virchow Triad
-Coagulation cascade
Virchow triad: factors that lead to coagulation process (blood vessel injury, blood statis, or pro-thrombotic conditions)
Coagulation pathway:
-an “a” on the factor number means it has been activated which will activate another factor
-factors primarily made in liver, especially vitamin K dependent ones (VII, IX, X, II)
-intrinsic pathway: from body’s natural mechanism of blood clots; extrinsic pathway: from tissue injury –> both have a common pathway that startes with factor X –> IIa (thrombin) –> converts fibrinogen to fibrin
-body has a natural anticoagulant: antithrombin
Why are anticoagulants considered high alert medications? What are some side effects to watch out for?
BLEEDING especially with dosing errors
Signs of bleeding:
-Epistaxis: nose bleeds
-Gums: new or worse than usual bleeds from gingivitis (pt may use softer toothbrush to avoid or reduce)
-Brusing, hematoma
-Acute drop in hemoglobin (by 2 g/dL or more)
-Hematemesis (may be red or coffee-ground appearance; other causes: varices w/ liver cirrhosis or bleeding veins, chronic reflux such as Barrett’s or esophagitis, NSAID-induced ulcer or H.pylori)
-Hematuria (lighter red in urine indicates less bood possibly from rectal tear or hemorrhoid, darker than sool or dark and tarry-looking could be GI bleedling; other caues: UTI, kidney stones, prostatitis, kidney disease)
-Hematochezia: blood from anus (other causes: diverticulosis, colon cancer, IBD, colon polyps, bloody diarrhea from infection like C. diff or Shigella)
DOACs versus Warfarin
DOACs = “Direct-acting Oral Anticoagulants): oral factor Xa inhibitors (apixiban, rivaroxaban, edoxaban) and thrombin inhibitors (dabigatran)
-DOACS are preferred for stroke prevent in AF and VTE TX
-Benefits: less DDIs, bleeding risk, shorter onset and duration of action (more quick to see results)
Warfarin: used when DOACs cannot (moderate-to-severe mitral stenosis, mechnical heart valve, or triple-positive antiphospholipid syndrome)
Unfractionated Heparin (UFH):
-MOA
-AVEs
-Warning
-CIs
-Monitoring
MOA: pentasaccharide sequence of UFH binds to antithrombin to cause a confirmation change that increases its activity by 1,000 fold which causes equal (1:1) anti-Xa and IIa activity (from longer oligosaccharide chain to inactivate IIa)
-Indirect inhibition of conversion of fibronogen to fibrin
AVEs: BLEEDING, THROMBOCYTOPENIA, HYPERKALEMIA, HIT (Heparin-induced thrombocytopenia), alopecia, osteoporosis (long-term usage)
Warning: FATAL MEDICATION ERRORS - verify correct concentration is choosen since there are many and similar looking
-Available as: 1,000 units/mL, 5,000 units/mL, or 10,000 units/mL
-Heparin lock-flushes (HepFlush): 10 units/mL or 100 units/mL –> ONLY used for keeping IV lines open
CIs: uncontrolled ACTIVE bleed (ex. intracranial hemorrhage), severe thrombocytopenia, hx of HIT
-Some contain benzyl alcohol as preservative: AVOID in neonates, infants, pregnancy, and breastfeeding
-Some derived from animal tissue: avoid in pork allergy
Monitoring:
-aPTT or anti-Xa level: check 6 hours after initiation and Q6H until therapeutic then Q24H with dosage change
-aPTT therapeutic range: 1.5-2.5x control (per institutional protocol)
-anti-Xa therapeutic range: typically 0.3-0.7 units/mL
-PLTs, Hgb, and Hct: at baseline and daily (decrease in PLTs >50% indicates possible HIT)
UFH Dosing:
-VTE prophylaxis
-VTE TX=
-ACS/STEMI TX
What are dosing considerations (calculation, ROAs, and reversal agent)?
VTE prophylaxis: 5,000 units SQ Q8-12H
VTE TX:
-Bolus: 80 units/kg IV
-Infusion: 18 units/kg/hr CIV
ACS/STEMI TX:
-Bolus: 60 units/kg IV
-Infusion: 12 units/kg/hr CIV
Dose Considerations:
-When calculating, use TOTAL BODY WEIGHT for dosing
-do NOT administer IM due to hematoma risk
-CIV infusion used since rapid onset, but short T1/2 (1.5 hours)
-SQ onset longer (20-30 minutes)
-Reversal agent: protamine
Enoxaparin Dosing:
-VTE prevention
-VTE and unstable angina/NSTEMI TX
-STEMI TX in pt <75 yo
-STEMI TX in pt 75 yo or older
What are dosing considerations (calculation, ROAs)?
VTE and unstable agina/NTSEMI TX: 1mg/kg SQ Q12H or 1.5mg/kg SQ QD (for inpatient only)
-CrCl <30mL./min: 1mg/kg SQ QD
STEMI TX <75 yo: 30mg IV bolus then 1mg/kg SQ Q12H (max 100mg for first two SQ doses only)
-CrCl <30mL/min: 30mg IV bolus plus 1mg/kg dose followed by 1mg/kg SQ QD
STEMI TX 75 yo or older: 0.75mg/kg SQ Q12H (NO bolus)
-CrCl <30ml/min: 1mg/kg SQ QD
Dosing Considerations:
-When calculating, use TOTAL body weight
-Calculate CrCl to determine how to dose ALWAYS prior
-Prefilled syringes: available as 30mg, 40mg, 60mg, 80mg, 100mg, 120mg, or 150mg
-Vial (inpatient): 300mg/3mL for unique doses
-do NOT administer IM
Low Molecular Weight Heparins (LMWHs):
-Drugs (Brands)
-MOA
-AVEs
-CIs
-BBW
-Monitoring
Drugs: enoxaparin (Lovenox), dalteparin (Fragmin)
MOA: binds to antithrombin to cause a confirmation change that increases its activity by 1,000 fold which causes UNEQUAL (4-2:1) anti-Xa and IIa activity (from varying length, but SHORTER oligosaccharide chain compared to UFH)
-Indirect inhibition of conversion of fibronogen to fibrin
AVEs: BLEEDING, ANEMIA, DECREASED PLTs (thrombocytopenia, including HIT –> HIT antibodies have cross-reactivity with UFH and LMWHs), INJECTION SITE RXNS (pain, bruising, hematomas)
CIs: uncontrolled ACTIVE bleed (ex. intracranial hemorrhage), hx of HIT
-Some derived from animal tissue: avoid in pork allergy
BBW: pt receiving simultaneous neuraxial anesthesia (epidural or spinal injection) or undergoing spinal puncture at risk for hematomas and subsequent paralysis
Monitoring: NOT routinely done since LMWHs have more predictable response than UFH
-PLTs, Hgb, Hct, SCr
-In high risk pts (extremes of body weight either obesity or underweight, reduced kidney fxn, PREGNANCY, pediatrics, elderly): anti-Xa to obtain 4 hours after SQ dose
**Low body weight, reduced kidney fxn can have increased anti-Xa activity (bleeding); obesity, pregnancy can have decreased anti-Xa activity (less clotting)
Heparin-Induced Thrombocytopenia (HIT):
-Pathophysiology
-Diagnosis: 4 Ts Score
-Labs
Pathophysiology: immune IgG reaction that forms antibodies against heparin bound to platelet four (PF4), causing platelet activation and increasing risk of thrombosis (complications: amputation, post-thrombotic syndrome, death)
Diagnosis: “4 Ts”
-Thrombocytopenia: >50% drop
-Timing of platelet fall: typically 5-10 days after start of heparin or even within hours if pt has been exposed to heparin within past three months
-Thrombosis: suspected or confirmed thrombosis or skin lesion that are necrotizing or non-necrotizing
-oTher causes: rule out other potential causes
Labs: Hepain-PF4 antibody enzyme-linked immunosorbent assay (ELISA)–> results may be confirmed w/ functional assay (serotonin release asay = SRA or heparin-induced platelet aggregation assay)
Management of Heparin-Induced Thrombocytopenia (HIT)
Management: follow even when suspected and NOT confirmed
-D/C all heparin products (UFH, heparin flushes, heparin-coated catheters, LMWHs)
-Reverse warfarin w/ vitamin K and do NOT restart until PLTs have recovered >/= 150,000/mm3 (low PLTs w/ warfarin: risk of warfarin-induced limb gangrene and necrosis)
-Start a non-heparin anticoagulant (argatroban or if urgent cardiac surgery or PCI is required, bivalirudin preferred); off-label: fondaparinux, Xarelto
Restarting warfarin if D/C:
-Start back at low dose (5mg max)
-Overlap with non-heparin anticoagulant for 5 days and until INR at target (measure for at least 2 consecutive days: argatroban can increase INR)
Enoxaparin Counseling
- Wash and dry hands.
- Select and clean an injection site on the abdomen at least 2 inches away from the belly button (avoid sites from tenderness, scars, bruising). Let alcohol dry to avoid stinging.
- Remove needle cap. Do NOT expel air bubble in syringe as this can lead to loss of drug.
- Pinch as least 1-inch fold of skin and while holding, insert full length of needle at 90 degree angle. Press plunger down while holding skin.
- Pull needle out all drug administered, and release the skin. Point needle away from self and push down on plunger to activate safety shield. Dispose of syringe in sharps container.
- Do NOT rub the injection site (bruising risk).
- For future injections, rotate the site at least one inch away from previous site.
-Can inject on right side on “even days” and left side on “odd days”, circle where you have injected w/ date
Direct Factor Xa Inhibitors:
-Drugs
-ROA
-AVEs
-Warnings/CIs
-BBW
-Monitoring
Drugs: apiXAban (Eliquis), edoXAban (Savaysa), rivaroXAban (Xarelto)
ROA: PO
AVEs: generally well tolerated UNLESS bleeding occurs
-Edoxaban: increased rash and LFTs
Warnings/CIs:
-NOT recommended w/ prosthetic heart valves or triple-positive antiphospholipid syndrome (higher risk of bleeding than warfarin)
-Avoid in moderate to severe hepatic impairment
-CI in ACTIVE pathological bleeding
-Edoxaban: reduced efficacy in nonvalvular AF patients w/ CrCl >95mL/min (do NOT use)
BBW:
-Pt receiving neuraxial anesthesia (epidural or spinal) or undergoing spinal puncture - risk of hemotoma and subsequent paralysis (same as LMWHs)
-Premature D/C increases risk of thrombotic events
Monitoring: NO MONITORING for efficacy
-Hgb, Hct, SCr, LFTs
Direct Factor Xa Inhibitors:
-Reversal Agent
-Administration considerations
-When should these be discontinued if a patient is undergoing surgery?
Reversal for apixiban and rivaroxaban: andexanet alfa (Andexxa) –> NOT FDA approved for edoxaban
Administration considerations:
-ALL can be crushed and put on applesauce or suspending in water to administer as NG tube
-Apixiban: can be crushed and mixed in water, D5W, or apple juice
Surgery:
-Rivaroxaban, edoxaban: D/C 24 hours prior
-Apixiban: D/C 48 hours prior if moderate-high bleeding risk or 24 hours if low bleeding risk
Apixiban (Eliquis) Dosing:
-Stroke prophylaxis in nonvalvular Afib
-VTE TX
Stroke prophylaxis in NON-valvular Afib
-Typical dose: 5mg PO BID
-Dose adjust to 2.5mg PO BID if pt has TWO risk factors** of bleeding or more
**Risk factors:
-Age 80 yo or older
-Body weight 60kg or less
-SCr 1.5 mg/dL or higher
VTE TX: 10mg PO BID x7D then 5mg PO BID
-Can use starter pack to help with dosing
-Extended phase >/=6 months: 2.5mg PO BID
Rivaroxaban (Xarelto) Dosing:
-Stroke prophylaxis in nonvalvular Afib
-VTE TX
Stroke prophylaxis in NON-valvular Afib:
-CrCl >50 mL/min: 20mg PO with evening meal
-CrCl 15-50mL/min: 15mg PO with evening meal
-CrCl <15mL/min: AVOID use
VTE TX: 15mg PO BID x21D then 20mg PO CF
-CrCl <30mL/min: AVOID use
Doses >/= 15mg must be taken with food (how was studied in trial and may lead to better safety/efficacy)
Edoxaban (Savaysa) Dosing:
-Stroke prophylaxis in nonvalvular Afib: Avoid use if CrCl is?
-VTE TX
Stroke prophylaxis in NON-valvular Afib: avoid in CrCl >95mL/min (not effective since it would be cleared too quickly)
VTE TX: 60mg PO QD after 5-10 days of parenteral anticoagulation (how trial was designed and FDA-approved)
*Direct Factor Xa Inhibitor: what should be done if a pt misses a dose? *
Apixiban, Edoxaban: take STAT on the same day then resume normal schedule
-Dose should NOT be doubled
Rivaroxaban:
-Taking 15mg BID: take STAT on same day (two tablets may be taken at once)
-Taking 10mg, 15mg, or 20mg QD: take STAT on the same day, otherwise skip the missed dose
Fondaparinux
-Brand
-MOA
-ROA
-TX
-AVEs
Brand: Arixtra
MOA: synthetic pentasaccharide that selectively inhibits factor Xa via binding to antithrombin (indirect factor Xa inhibitor)
ROA: subcutaneous
TX: VTE TX and prophylaxis
-Off-label: HIT
AVEs: BLEEDING, anemia, local injection site rxns, thrombocyotpenia
Fondaparinux (Arixtra):
-CIs
-BBW
-Monitoring
-Administration considerations
CIs:
-SEVERE RENAL IMPAIRMENT (CrCl <30mL/min)
-ACTIVE major bleed
-Bacterial endocarditis
-Thrombocytopenia w/ (+) test for anti-PLT antibodies in presence of fondaparinux
BBW: pt receiving neuraxial anesthesia (epidural or spinal) or undergoing spinal puncture - risk of hematomas and subsequent paralysis
Monitoring: routine NOT required
-3 hours post-dose: PLTs, Hgb, Hct, SCr, anti-Xa levels
Administration Considerations:
-do NOT expel air bubble from syringe prior to injecting
-NO antidote / reversal agent
-do NOT administer IM
Apixiban and Rivaroxaban DDIs
-These are substrates of _________ and _______.
-What are recommendations when used with drugs that are strong dual inducers or inhibitors?
Substrates of CYP3A4 and P-gp
Strong dual inducer: less drug, less effects –> try to avoid use (ex. w/ carbamaezpine, phenytoin, rifampin, St. John’s Wort)
Strong dual inhibitor: more drug, more bleeding risk (ex. w/ itraconazole, ketoconazole, ritonavir)
-Apixiban: if dose >2.5mg BID, lower dose; if dose = 2.5mg BID, avoid
-Rivaroxaban: avoid use (benefit must outweight risk) + avoid use w/ cobicostat which can increase exposure to factor Xa inhibitors
Dabigatran
-Brand
-MOA
-ROA
-TX
-AVEs
Brand: Pradaxa
MOA: direct thrombin inhibitor
ROA: PO
TX: TX and prophylaxis of VTE, stroke prophylaxis in pt w/ non-valvular Afib
AVEs: BLEEDING (including GI bleeding), DYSPEPSIA, GASTRITIS-LIKE SYMPTOMS, increased INR/PT/aPTT
Dabigatrin (Pradaxa):
-Warnings/CIs
-BBW
-Reversal agent
-Administration Considerations (inpatient and outpatient)
Warnings/CIs:
-NOT recommended in triple-positive antiphospholipid syndrome
-CI: ACTIVE pathological bleeding, mechanical prosthetic heart valves
BBW: neuraxial anesthesia (epidural or spinal) or spinal puncture –> risk of hematoma and subsequent paralysis
-Premature D/C can increase risk of thrombotic events
Reversal Agent: idarucizumab (Praxbind)
Administration Considerations:
-MOISTURE SENSITIVE: dispense in original packaging and discard 4 months after opening (blister packs: good until date on package) –> only open one bottle at a time
-do NOT administer by NG tube
-Swallow capsules whole (do NOT break, crush, or open) with a full glass of water
-For TX of DVT/PE, start 5-10 days after parenteral coagulation
-Missed dose: take STAT unless within 6 hours of next dose (do NOT double dose)
-D/C if undergoing invasive surgery
IV Direct Thrombin Inhibitors
-Drugs/Brands
-TX
-AVEs
-CIs
-Monitoring
Drugs: agatroban, bivalirudin (Angiomax)
TX:
-Agatroban: HIT (safe, no cross-sensitivity, pt at risk or w/ HIT undergoing percutaneous coronary intervention (PCI)
-Bivalirudin: undergoing PCI, including those at risk for HIT
AVEs: BLEEDING (mild to severe), anemia, can increase INR
CIs: ACTIVE major bleeding
Monitoring: aPTT and/or activated clotting time, PLT, Hgb, Hct, renal function
**There is NO antidote, but short T1/2 so D/C
Conversion between anticoagulants
-Oral Factor Xa inhibitors –> warfarin
-Dabigatran –> warfarin
-Warfarin –> Dabigatrin or Oral Factor Xa inhibitors (Remember: “READ”)
Oral Factor Xa Inhibitors –> warfarin: stop Xa inhibitor, start parenteral anticoagulant and warfarin at next scheduled dose
-Edoxaban only: refer to package labeling
Dabigatran –> warfarin: start warfarin 1-3 days before D/C dabigatran (determined by renal function, refer to labeling)
Warfarin –> Other anticoagulants: stop warfarin and convert to ________ (remember: READ)
-R: Rivaroxaban when INR <3
-E: Edoxaban when INR < or = 2.5
-A: Apixiban when INR <2
-D: Dabigatran when INR <2
*Warfarin: *
-Brand
-MOA (Remember: “SNOT”)
-ROA
-Onset of Action
-Isomers
-AVEs
Brand: Coumadin (D/C Brand), Jantoven
MOA: competitively inhibits C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, reducing the production of vitamin K-dependent inactive clotting factors (II, VII, IX, and X) and anticoagulants protein C and S
-Indirect inhibition of clotting cascade
-To remember clotting factors: “SNOT” S: Seven, N: Nine, O: 0 in 10, T: TWO (also the order of the factors in the cascade) –> in first 24 hours see rapid depletion of VII, IX, and protein C and S with slight INR increase
ROA: PO
Onset of Action: 5 days (to finally see all clotting factors depleted and about 90% of INR reduction)
Isomers: racemic mixture (S-warfarin which is 3-5x more potent and is metabolized by CYP2C9; R-warfarin metabolized from CYP3A4)
AVEs: BLEEDING/BRUISING (mild to severe), SKIN NECROSIS
Warfarin:
-Warnings/Pharmacogenics Considerations
-CIs
-Monitoring (why is it important?, goals based on indications)
-Reversal Agent
Warnings: tissue necrosis/gangrene, HIT (CI if monotherapy in initial TX of active HIT until PLT >150,000 cells/mm3), purple toe syndrome (rare from embolization of cholesterol cyrstals)
Pharmacogenomics: presence of CYP2C9*2 or *3 alleles and/or polymorphism of VKORC1 gene –> increases bleed risk
CIs: pregnancy (except w/ mechnical heart valves)
Monitoring: NARROW THERAPEUTIC INDEX (NTI) drug
-INR: if increased, more risk of bleeding; if decreased, risk of clots –> take after initial 2-3 doses then when stable Q4-12 weeks
-Goal INR 2-3 (target: 2.5): Afib, bioprosthetic mitral valve, clotting disorder (ex. Factor V Leiden), mechnical aortic valve, VTE
-Goal INR 2.5-3.5 (target 3): mechnical mitral valve, 2 mechanical heart valves
-Hct, Hgb, s/sx of bleeding
Reversal Agent: vitamin K
Warfarin Metabolism and DDIs
-Metabolism
-DDIs interfering with main mechnanism of metabolism
-DDIs interfering with distribution of warfarin
Warfarin is a racemic mixture where S-warfarin is 3-5x more potent
-S-warfarin: metabolized by CYP2C9
-R-warfarin: metabolzied by CYP3A4 and others
S-warfarin:
-CYP2C9 inducers: decrease INR (“Review Patient Profiles and Counsel Soon): Rifampin, Phenytoin, Phenobarbital, Carbamazepine, St. John’s Wort
-CYP2C9 inhibitors: increase INR (“AAA”: Amiodarone, Azole Antifungals, Anti-infectives –> metronidazole, Bactrim)
Warfarin is HIGHLY protein bound –> drugs that are also highly protein bound may displace warfarin (ex. phenytoin, valproic acid)
Warfarin DDIs:
-Drugs with additive bleed risk
-Drugs with increased clotting risk
-Supplements that increase risk of bleeding
-What supplement can decrease the efficacy of warfarin?
-Dietary interactions
Additive bleeding risk: NSAIDs, antiplatelets, anticoagulants, SSRIs, SNRIs
Increase clotting risk: estrogen, SERMs (avoid use w/ tamoxifen)
Supplements with bleed risk: chamomile, chondroitin, dong quai, high doses of fish oils, vitamin E, willow bark (plant salicylate), 5 G’s (garlic, ginger, ginkgo, gingseng, glucosamine)
Supplement that can decrease efficay: St. John’s Wort
Dietary Interactions: vitamin K consumption can decrease INR –> STAY CONSISTENT in diet
-Foods high in vitamin K: spinach (cooked), broccoli, brussel sprouts, collard greens, kale, turnip greens, swiss chard, parsley, other greens, canola oil, some teas
Warfarin Dosing:
-Available as what strengths/colors associated with strengths (Remember: “Please Let Greg Brown Bring Peaches To Your Wedding”)
-Typical Initial Dose
-Who would require a lower dose and why?
-General method of adjusting for maintenance dose
Available as: “Please Let Greg Brown Bring Peaches to Your Wedding”
-P: Pink (1mg), L: Lavender (2mg), G: Green (2.5mg), B: Brown/Tan (3mg), B: Blue (4mg), P: Peach (5mg), T: Teal (6mg), Y: Yellow (7.5mg), W: White (10mg)
Initial Doses: 10mg or less for 2 days then adjust per INR
-TX of active DVT/PE, start warfarin WHILE on parenteral anticoagulant for at least 5 days on both until INR is 2 or higher for at least 24 hours
Lowering Doses: 5mg or less
-Elderly, liver diease pt: decreased liver fxn and production of vitamin-K dependent clotting factors
-Malnourished: less intake of vitamin K
-HF: liver congestion, decreased clotting factor synthesis
-CYP inhibitor use: increased warfarin serum levels
-Taking select ABXs (PCNs, cephalosporins, quinolones, tetracyhclines): alteration of intestinal flora
Maintenance dose: take weekly dose / 7 to see typical average daily dose and consider INR
-Consider DDIs, dietary intake, and pt risk factors
-Follow institutional protocol of how to adjust (pts can take two different strengths to achieve “one” dose, take different doses each day –> lots of customization)
Warfarin: when to hold versus reverse warfarin?
-Consider INR
-Consider surgery
INR <4.5, NO bleeding: hold or decrease dose
INR 4.5-10:, NO bleeding: hold 1-2 doses of warfarin
INR >10, NO bleeding: hold and administer 2.5-5mg PO vitamin K
ANY INR with MAJOR bleeding: hold and administer 5-10mg IV vitamink K and 4-PCC (Four Factor Prothrombin Complex Concentrate)
Surgery:
-Planned surgery: hold dose for 5 days prior (if INR still elevated, consider low dose PO vitamin K)
-Planned surgery, HIGH risk for thromboembolism: bridge w/ LMWH (D/C 24 hours before surgery) or UFH (D/C 4-6 hours prior to surgery)
-Abrupt surgery: reverse warfarin w/ vitamin K
Four-Factor Prothrombin Complex Concentrate:
-Brand
-MOA
-ROA
-TX
-General dosing considerations
Brand: Kcentra, Balfaxar
MOA: human blood containing factors VII, IX, X, II, Protein C, and Protein S
ROA: IV
TX: Reversal of warfarin –> only acts for about 8-12 hours so MUST BE GIVEN WITH VITAMIN K
Dosing:
-do NOT repeat dose
-Dosing calculation has different vial concentrations for each factor, BUT dosing is based on factor IX per kg of pt’s body weight and INR
Vitamin K or Phytonadione
-Brand
-ROA
-TX
-Administration considerations
-AVEs
-BBW
Brand: Mephyton
ROA: PO or IV
TX: warfarin reversal (PO for no bleeding, but INR >10 and IV for major bleed any INR)
Administration Considerations:
-SQ NOT recommended due to risk of variable absorption
-IM NOT recommended due to risk of hematoma
-REQUIRES light protection during administration
AVEs: anaphylaxis (dilute dose to avoid risk and infuse slowly over at least 20 minutes), flushing, rash, dizziness
BBW: severe rxns resembling hypersensitivity rxns after IV
NovoSeven RT is factor ____ recombinant that is used off-label for warfarin reversal. What is its BBW?
VIIa (another brand called Sevenfact)- BBW for severe thrombotic events
Protamine sulfate:
-MOA
-TX / Dosing
-AVEs
-BBW
-Monitoring
MOA: mixture of proteins derived from fish sperm that combines with heparins to form stable salt complex, neutralizing the anticoagulant activity
TX/Dosing:
-UFH Reversal: 1mg IV for 100 units of heparin reversal in the last 2-2.5 hours (heparin has very short T1/2), max: 50mg
-LMWH Reversal: 1mg IV per 1mg of enoxaparin (LESS effective since shorter chain and reverses what was given in last 8 hours by about 60%)
AVEs: hypotension (from rapid IV infusion - administer over 10 minutes), bradycardia, flushing, anaphylaxis
BBW: hypersensitivity (due to fish sperm derivation)
Monitoring: aPTT, anti-Xa levels, cardiac monitoring (ECG, BP, HR)
Andexanet alfa:
-Brand
-MOA
-ROA
-TX
-Warnings
Brand: Andexxa
MOA: recombinent modified human factor Xa protein
ROA: bolus followed by infusion
TX: apixiban or rivaroxaban reversal
Warnings: THROMBOEMBOLIC RISKS, ischemic events, cardiac arrest, sudden death
Idarucizumab
-Brand
-MOA
-ROA
-TX
-Drug on look alike/sound alike list to this one
-Warnings
Brand: Praxbind
MOA/TX: humanized monoclonal antibody fragment that binds and reverses effects of dabigatran
ROA: IV
Look alike/sound alike: idarubicin
Warnings: THROMBOEMBOLIC RISK, serious rxns from sorbitol excipient
Venous Thromboembolism (VTE)
-Types and diagnosis
-Modifiable risk factors
-Non-modifiable risk factors
Types and Diagnosis:
-General diagnosis: D-dimer (protein released to breakdown blood clots) test (low sensitivity) –> if positive, use high sensitivity test to diagnose (ex. ultrasound for DVT and pulmonary CT angiogram for PE)
-Deep Vein Thrombosis (DVT): clot in leg, causing unilateral lower extremity swelling and pain
-Pulmonary Embolism (PE): clot that has broken off and traveled to lungs causing SOB and chest pain
Modifiable risk factors (can go away): acute medical illness, imobility, obesity, pregnancy/postpartum period, recent surgery/trauma
-MEDICATIONS: estrogen-containing, SERMs, erythropoiesis-stimulating agents (ESAs)
Non-modifiable risk factors: increasing age, cancer/chemotherapy, previous VTE, certain disease states (HF, nephrotic syndrome, respiratory failure), inherited or acquired thrombophilia (antithrombin deficiency, factor V Leiden, anti-phospholipid syndrome, protein C or S deficiency)
Venous Thrombembolism (VTE):
-Non-pharmacologic VTE prophylaxis
-VTE Treatment (general)
-Drug choice in VTE TX
Non-pharmacologic VTE prophylaxis: intermittent pneumatic compression (IPC) devices, graduated compression stockings (higher pressure at bottom to help blood flow and avoid DVT, use w/ 15-30mmHg), frequent ambulatoin, calf-muscle exercises
VTE Treatment:
-D/C: estrogen-containing medications, SERMs
-Provoked VTE (surgery or reversible risk factor): 3 months of TX
-Unprovoked VTE (unknown cause): extended phase therapy (potentially 6 months or more) using apixiban or rivaroxaban unless high risk of bleeding (3 months)
-Two unprovoked VTE episodes: extended TX phase
-If unprovoked VTE and D/C anticoagulant, recommended to continue ASA if no CIs
Drug choice in VTE TX:
-W/o cancer: DOAC (oral factor Xa inhibitors or dabigatran) for first 3 months > warfarin (sometimes used w/ longer duration for cost)
-With cancer: oral factor Xa inhibitors preferred (others: oral anticoagulants, LMWHs)
Why is a warfarin bridge needed in active VTE treatment?
Warfarin depletes factors II, VII, IX, and X which are procagulants AND protein C and S which are ANTI-coagulants.
Warfarin depletes protein C and S FASTER than the clotting factors which means in the first few days patients are still at a potential risk for clotting until after 5-7 days have passed where warfarin depletes more protein C and S.
During the first few days up to 5 days or at least until INR has stabilized for >24 hours, LMWH or UFH is used to close this gab of procoagulation risk.
Anticoagulation in Pregnancy
Preferred: LMWH, intermittent pneumatic compresion devices
-Monitoring with anti-Xa levels recommended
Warfarin: teratogenic, but can be used in mechanical heart valve high risk or inherted thrombophilias –> consider converting from LMWH back to warfarin after 13th week of pregnancy and when close to delivery switch to LMWH since warfarin takes longer to D/C
NOT recommended: oral factor Xa inhibitors and direct thrombin inhibitors (not been adequately studied)
Anticoagulation and Atrial fibrillation pts
-Why are pts for Afib sometimes placed on anticoagulants?
-Anticoagulation selection
-Duration of anticoagulation therapy
-Recommendations on anticoagulations for cardioversion
Reason for anticoagulant: heart is NOT adequately pumping and blood pools which can lead to clots, potentially causing cardioembolic stroke
Anticoagulation Selection:
-Nonvalvular Afib: DOAC > warfarin
-Mechanical heart valve: HIGHEST RISK –> warfarin (DOACs have NOT been approved)
Duration: usually for life
Cardioversion (attempt to convert Afib to normal sinus rhythm w/ electricty or medications):
-Have risk of blood clot dislodging during transition
-If pt Afib </=48 hours, initiate anticoagulant at diagnosis and 4 weeks after cardioversion
-If pt Afib >48 hours, initiate anticoagulant for 3 weeks PRIOR to cardioversion then 4 weeks after cardioversion
Anticoagulants and Afib patients: Using CHA2DS-VASc Scoring System, determine when a pt should be placed on an anticoagulant if cardioversion was NOT done
Risk factors:
-1 point for: CHF, HTN, DM, Vascular disease (prior MI, PAD, aortic plaque), age 65-74 yo, female
-2 points for: age >/=75 yo, prior stroke/TIA/thromboembolism
Recommendations based on score:
-No anticoagulant if 0 points in men or 1 point in women
-Oral anticoagulant considered if 1 point in men or 2 points in women
-Oral anticoagulant recommended (DOACs > warfarin): 2 or more points in men, 3 or more points in women
Atrial fibrillation: HAS-BLED Scoring System
Assess bleeding risk in AF pts on anticoagulants
H: HTN (SBP >160mmHg) 1 point
A: Abnormal liver or kidney functoin: 1-2 points
S: Stroke 1 point
B: Bleeding tendency or predisposition: 1 point
L: Labile INR (if on warfarin): 1 point
E: Elderly (>65 yo): 1 point
D: Drugs (ASA, NSAIDs), excess alcohol use: 1-2 points
**May NOT need to know this entire scoring system, but in general, more points = more bleeding risk
Anemia
-Define
-Causes
-S/Sx
Anemia: decrease in RBCs, hemoglobin, and/or hematocrit
Causes:
-Impaired RBC or Hgb production (nutritional deficiencies - iron, folate, vitamin B12), complications of a medical disorder (CKD, malignancy)
-Increased RBC destruction (hemolysis, mechanical such as valves) or blood loss
-Genetic predispositions (sickle cell disease)
S/Sx: mild can be asymptomatic
-Reduced oxygen delivery: fatigue, weakness, SOB, exercise intolerance, HA, dizziness, pallor (pale skin)
-Chronic anemia: tachycardia (to compensate for reduced oxygen) which can lead to ventricular hypertrophy
-Sudden blood loss: chest pain, syncope, palpitations, tachycardia
Anemia: Microcytic MCV versus Normocytic MCV versus Macrocytic MCV
-What are the causes of each type?
MCV (Meancorpuscular volume): size or average volume of RBCs
Microcytic MCV: low MCV <80fl
-Likely from iron deficiency (use iron studies to further investigate)
Normocytic MCV: 80-100 fl
-Likely from acute blood loss (reticulocytes, immature RBCs, would be high), malignancy, CKD, bone marrow failure (aplastic anemia), or hemolysis
Macrocytic MCV: high MCV >100 fl
-Likely from vitamin B12 or folate deficiency (reticulocyte, immature RBCs would be low in these deficiencies w/ bone marrow suppression)
Iron Deficiency Anemia
-Particular s/sx to iron deficiency besides typical anemia s/sx
-Heme versus non-heme iron
-Causes
S/Sx: glossitis (inflammed sore tongue), kolionychia (thin, concave, spoon-shaped nails), pica (craving and eating non-foods such as ice or clay)
-Labs: decreased Hgb, MCV (<80), reticulocytes, serum iron (iron in blood), ferritin (iron stores), and TSAT (% transferrin bound to iron); increased TIBC (total iron binding capacity: available amount of transferrin available to bind to iron)
Heme iron: from meat and seafood; READILY MORE ABSORBED
Non-heme iron: from nuts, benas, vegetables, fortified grains; LESS absorable (which is why vegan/vegetarian diet is more suspectable to anemia)
Causes:
-Low iron intake from diet
-Blood loss: hemorrhage, heavy menses, PUD, IBD, drug-induced (NSAIDs, antiplatelets, anticoagulants)
-Decreased absorption: high gastric pH (PPIs), GI disorders (celiac disease, IBD), gastric bypass
-Increased iron requirements: pregnancy, lactation, infants, adolescents
True or False: All pregnant patients are recommended for an iron supplement to prevent iron deficiency anemia.
True
Percentages of iron in:
-Ferrous gluconate
-Ferrous sulfate
-Ferrous sulfate, dried
-Ferrous fumarate
-Ferric maltol
Gluconate: 12%
Sulfate: 20%; dried: 30%
Fumarate: 33%
Ferric maltol: 100%
Oral Iron:
-Why is this preferred TX in iron deficiency anemia?
-Dosing
-AVEs
-BBWs
Preferred since there is no differences in effiacy between other ROAs, cheap (OTC), and less side effects
Dosing: 1 tablet QD or QOD (QOD still shows same Hgb increases with less AVEs)
-Ferrous sulfate: 325mg (65mg elemental iron)
AVEs: GI in up to 70% (constipation; dark, tarry stools; nausea/stomach upset)
BBW: accidental overdose of especially fatal in <6 yo
-Child if taken iron and asymptomatic should go to ED or call poison control
-Antidote: deferoxamine (Desferal)
Oral Iron: Counseling / DDIs
- Take OES (improves absorption), but can be taken CF if GI AVEs occur
- SR or EC NOT recommended due to poor absorption (advertised for less GI AVEs)
- If child ingests (risk of overdose), ED or call poison center
DDIs:
-Avoid H2RAs and PPIs, separate 2 hours before or 4 hours after antacids: decrease absorption due to making environment less acidic
-Vitamin C: may increase absorption by increasing acidic environment
-Iron is a polyvalent ion that will decrease absorption of other drugs through chelation, separate from:
Quinolone and tetracycline ABXs: 2 hours before or 4-8 hours after
Bisphosphonates: >/=60 minutes away from PO ibandronate or >/= 30 minutes away from risedronate or alendronate
Levothyroxine: separate by 4 hours
Integrase strand transfer inhibitors (INSTIs)
**For NAPLEX, more likely to know whichs drugs to seperate than exact timing
Intravenous Iron
-When to use
-Types/Brands
-AVEs
-BBW
When to use: typically restricted to pts that need faster rates and potentially with single dose, but has more cost:
-CKD on hemodialysis and/or receiving ESAs
-Unable to tolerate iron from GI AVEs (ex. H, pylori, celiac disease, IBD)
-Severe anemia (also pts who do NOT accept blood transfusions)
Types: iron sucrose (Venofor), ferumoxytol (Faraheme), iron dextran complex (Infed)
AVEs: N/V/D, hypotension, dizziness, dyspnea, chest pain, muscle aches, peripheral edema, injection site rxns
BBW: iron dextran and ferumoxytol can cause serious and sometimes fata anaphylatic rxns (dextran REQUIRES test dose )
-Warning for anaphylaxis/hypersensitivity for others –> sometimes premedicate to help (Medrol, Benadryl) AND SLOW INFUSION TO HELP
Macrocytic Anemia: Vitamin B12 deficiency
-What is pernicious anema?
-Other causes of vitamin B12 deficiency
-S/Sx
-TX
Pernicious Anemia: autoimmune condition caused by antibodies binding to intrinsic facot which is needed for vitamin B12 absorption
Other causes: low intake, alcohol use disorder, GI disease or surgery, drug-induced (metformin, PPIs, H2RAs)
S/Sx: neurologic dysfunction (cognitive impairment and peripheral neuropathy - can be IRREVERSABLE after 3 months of no TX), visual disturbances, psychiatric symptoms
-Labs: MCV >100; decreased reticulocytes, serum vitamin B12, and serum folate; elevated homocysteine (metabolized by vitamin B12 and folate) and methylmalonic acid (metabolized by vitamin B12)
TX: severe or neurologic symptoms - vitamin B12 injections
Macrocytic Anemia: Folate deficiency
-Causes
-S/Sx
-TX
Causes: low intake, alcohol use disorder, GI disease or surgery, drug-induced (methotrexate)
S/Sx: ulcerations of tongue/oral mucosa, hair and fingernail pigmentation
-Labs: MCV >100; decreased reticulocytes, serum vitamin B12, and serum folate; elevated homocysteine (metabolized by vitamin B12 and folate)
TX: PO folic acid usually sufficient
Cyanocobalamin:
-Brands/ROAs/dose frequency
-AVEs
-Warnings/CIs
Brands/ROA:
-Nascobal (nasal spray): spray in ONE nostril Qweek
-Physcians EZ Use B-12 (injection): IM or deep SQ QD or Qweek or Qmonth
-Others: lozenge, tablet, SL liquid
AVEs: injection site rxns, polycthemia vera, pulmonary edema
-All side effects besides injection pain are RARE
Warnings/CIs:
-Warning: parenteral products may contain aluminum which can accumulate and cause CNS/bone toxicity if renal fxn impaired or benzyl alcohol which can cause fatal toxicity and “gasping syndrome” in neonates
-CI: allergy to cobalt or vitamin B12 (intradermal test for any suspected sensitivity prior to intranasal or injection recommended)
Folic acid, folate, vitamin B9
-Brand
-ROA
-AVEs
-Warnings
Brand: FA-8
ROA: PO, injection
AVEs: bronchospasm, flushing, rash, pruritus, malaise (ALL RARE)
Warnings: parenteral products may contain aluminum which can accumulate and cause CNS/bone toxicity if renal fxn impaired or benzyl alcohol which can cause fatal toxicity and “gasping syndrome” in neonates
Normocytic Anemia (“Anemia of Chronic Disease)
-What is the role of erythropoietin?
-Causes
-General TX recommendations
Erythropoietin (EPO): hormone produced from kidneys that stimulate bone marrow to produce RBCs
Causes of normocytic anemia: CKD, malignancy
General TX Recommendations:
-Kidney Disease Improving Global Outcomes (KDIGO): all iron therapy in CKD if TSAT </=30% and ferritin </=500 ng/mL –> IV iron preferred, but PO iron can be used if NOT on HD (if other causes have been corrected and Hgb <10g/dL, ESA)
-Erythropoeisis-stimualting agents (ESAs): require iron stores to function, recommended to decrease dose or D/C when Hgb approaches or exceeds >11 g/dL due to RISK OF DEATH AND THROMBOSIS
Erythropoeisis-Stimulating Agents (ESAs)
-Drugs/Brands
-ROA/frequency given
-MOA
-Administration Considerations
Drugs: epoetin alfa (Epogen, Procrit, biosimilar: Retacrit), darbepoetin (Aranesp)
ROA: IV of SQ (IV recommended in HD)
-Epoetin: given three times weekly
-Darbopoetin: given weekly in HD
MOA: act like natural hormone erythropoietin, increasing RBC production in bone marrow
-does NOT stimulate production of erythropoietin
Administration considerations:
-IV recommended in HD
-Store in refrigerator: discard vial after 21 days
-do NOT shake (prevent degradation of protein)
-Darbopoetin half life is 3x longer than epoetin, allowing weekly administration
Epoetin and Darbopoetin:
-AVEs
-Warnings
-BBW
-Monitoring
AVEs: arthralgia/bone pain (from direct stimulation of bone marrow)
Warnings: HTN
-Epoetin alfa: contains albumin from human blood (remote risk for transmission of viral diseases)
BBW: increased risk of death, MI, stroke, or thrombosis
-CKD: further increased risk of death if Hgb >11 g/dL
-Cancer: decreased survival - NOT intended to cure (palliative care is an option)
-Use lowest effective dose
Monitoring: Hgb, Hct, TSAT, serum ferritin, BP
Drug-induced hemolytic anemia:
-Mechanism
-Drugs that induce
-S/Sx of hemolysis
-Actions to take when this occur
Immune-mediated hemolysis: medication binds to RBC surface and triggers antibody development, identified w/ (+) direct Coombs test
-Drugs: PCNs, cephalosporins, isoniazid,, rifampin, sulfonamides, levodopa/methyldopa, quinidine/quinine
Hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency: inherited disorder where G6PD is deficient - enzyme that protects RBCs from oxidation
-Drugs: primaquine/quinidine/quinine, sulfonamides, dapsone, nitrofurantoin, methylene blue, pegloticase, rasburicase
S/Sx of hemolysis: jaundice, dark urine, splenomegaly
Actions:
-D/C causative drug
-Immune-mediated: list causative drug as an allergy
-G6PD deficiency: avoid ALL potential causative drugs, note pt is G6PD deficient on chart
Sickle Cell Disease (SCD):
-Define
-S/Sx, complications
-Which population is more likely to have SCD?
SCD: group of inherited (autosomal recessive) RBC disorders where RBCs contain sickle hemoglobin (HgbS) which is misshapen with rigid, concacer shape (shorted life span of 10-20 days, unable to carry oxygen, and can stick together)
S/Sx: do NOT usually occur until 2-3 months after birth due to having fetal hemoglobin (HgbF) which is protective
-Acute: vasoocclusive crises (VOC: ischemic pain): ACUTE CHEST SYNDROME (leading cause of death in SCD), anemia, infections, priapism, stroke, acute pain criss, cholecystitis
-Chronic: avascular necrosis (bone death), leg ulcers, gallstones, pain, pregnancy complications, pulmonary HTN, renal impairment, retinopathy, priapism
Population more likely to have SCD: African Americans
Sickle Cell Disease (SCD):
-Why are pts w/ SCD at increased risk for infections?
-Immunization recommendations
-Antibiotic recommendations
Infection risk: healthy spleen removes old and damaged RBCs, stores WBCs and helps immune function, and clears bacteria from body (S. pneumoniae, H. influenzae, N. meningitidis)
-Asplenia: RBC sickling causes infarction of spleen, spleen shrinks and becomes fibrotic w/ increased infection risk
-Encourage pt to seek help ASAP w/ fever >101.3F
Immunizations: goal to prevent sepsis and pnuemonia
-Routine Childhood Series: Haemophilus influenzae type B (Hib), pneuomococcal conjugate (PCV13 or Prevnar 13)
-Additional vaccines for Asplenia: meningococcal conjugate series + routine boosters, meningooccal serogroup B (Bexsero, Trumenba), pneuomococcal (Prevnar 20 x1 OR PCV15 x1 then PPSV23 x1 >/= 8 weeks later)
Antibiotics: oral PCN VK BID until age 5 yo (if spleen removed, may be longer)
Sickle Cell Disease (SCD):
-When to give blood transfusions and its considerations
-What is the only CURE for SCD?
-Recommendations for pain control
-What are the drugs given for disease-modficiation?
Blood transfusions: helps supply HgbA, BUT risk of iron overload (can damage organs)–> maintain serum Hgb at 10 g/dL or less
-Chelation therapy can be used to remove exces iron stores (PO options: deferasirox - Exjade, Jadenu; deferiprone - Ferroprox)
Only cure for SCD: bone marrow transplantation (can be untolerable and COSTLY)
Pain control: IV opioids (PCA - pain-controlled analgesia)
-Avoid seeing multiple providers for pain control to avoid overdose
Disease-modifiying therapy: PRIMARILY hydroxyurea
-Others: L-glutamine, voxelotor, crizanlizumab (alone or in combo w/ hydroxyurea)
Hydroxyurea
-Brand
-MOA
-ROA
-TX
-How long does it take to achieve clinical response?
-AVEs
Brand: Droxia, Hydrea, Siklos
MOA: stimulates production of hemoglobin F (HgbF)
ROA: PO
TX: sickle cell disease
-ALL pts w/ 1 or more moderate-pain crisis or acute chest pain syndrome in one year or in chronic pain
-ALL pediatric pts between 9 months and 18 yo regardless of disease severity
Clinical response: can take 3-6 months
AVEs: increased LFTs, uric acid, BUN, and SCr; N/V/D, alopecia, hyperpigmentation or atrophy of skin and nails. low sperm counts (men)
Hydroxyurea:
-Warnings
-BBW
-Monitoring
Warnings:
-FETAL TOXICITY: MUST use contraception during TX and for 6 (females) or 12 (males) months after D/C, do NOT breastfeed during TX)
-AVOID LIVE VACCINES
-Hazardous drug: teratogenic, chemotherapy-like drug (handle gloves when handling, wash hands)
-Folic acid supplementation may be needed for macrocytosis
-Others: skin ulcers, pulmonary toxicity, pancreatitis risk, hepatotoxicity, peripheral neuropathy
BBW: MYLEOSUPPRESSION (decreased WBCs and PLTs), malignancy (leukemia, skin cancer)
-Additive risk when used w/ other drugs that cause myloesuppression
-Can increase risk of infection
Monitoring: HgbF, LFTs, uric acid, renal function, baseline pregnancy test
-CBC w/ differential Q2-4 weeks after initiation and titration then Q2-3 months after once stable dose achieved
-If ANC <2,000 cells/mm3 or PLTs <80,0000 cells/mm3: HOLD dose until recovery
L-Glutamine:
-Brand
-MOA
-ROA
-TX
-AVEs
-Administration considerations
Brand: Endari
MOA: amion acid that is thought to have antioxidant properties
ROA: PO
TX: sickle cell disease (reduces acute complications: pain crises, hospitalizations, occurance of acute chest pain syndrome)
-Approved for 5 yo and older
AVEs: constipation, flatulence, HA, nausea, pain (abdominal, extremeties, back, chest, cough)
-Safer profile than hydroxyurea
Administration: mix each dose (5 grams of powder per packet) with 8 oz of cold or room temperature beverage (water, milk, apple juice) or 4-6 oz of food (applesauce, yogurt)
-does NOT need to completely dissolve before administration
Voxelotor
-Brand
-MOA
-ROA
-TX
-AVEs
-Warnings
-Administration considerations
Brand: Oxbryta
MOA: inhibits hemoglobin S (HgbS) polymerization, which prevents RBC sickling
ROA: PO
TX: sickle cell disease
AVEs: HA, fatigue, abdominal pain, diarrhea, nausea
Warnings: hypersensitivity rxns (lab test interference w/ measurement of Hgb subtypes - A, F, and S)
Administration: swallow tablets whole (do NOT cut, crush, or chew)
***Manufacturer voluntarily wtihdrew from market saying recent data does NOT show a benefit over risk, causing higher rates of voco-occlusive crisis (severe pain from sickle cell RBCs blocking blood flow and oxygen delivery to tissues)
Crizanlizumab
-Brand
-MOA
-ROA
-TX
-AVEs
-Warnings
Brand: Adakveo
MOA: MAB that binds and inhibits P-selectin, involved in adhesion of sickled erythrocytes to vessels
ROA: injection
TX: sickle cell disease - reduces frequency of vaso-occlusions
AVEs: nausea, fever, arthralgias
Warnings: infusion-related rxns, lab test interference w/ PLT counts
