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Coagulation

Hematology 

• Coagulation is how the blood clots, this is a many step process that happens very quickly 

• The formation of a clot happens because of a process that leads to a lattice/mesh 

Antiplatelets, Anticoagulants, Fibrinolytics 

• Prevention of an MI, CVA, TIA, PE, DVT, and other vascular disorders

• The treatments are all based on conditions; it's all risks versus benefits… there is always bleeding risk associated (ADR/SE)

• For certain conditions, certain drug classes have a better risk v benefit profile comparatively to other conditions and medications 

• We should focus on “this condition” and “what drugs are appropriate to treat this condition”, otherwise things start sound a lot alike and get confusing 

  • Start by categorizing drugs with conditions

Normal Coagulation 

• Coagulation starts upon damage, then we get platelet aggregation 

  • Platelets are donut shaped normally, when they become activated they get projections on their surfaces to better grab onto other platelets for form a platelet plug

  • Platelet plug is designed to slow whatever bleeding is taking place 

    • Then we have tissue factors that firm the platelet plug and starts the clotting cascade 

• 4 steps involved in this process: 

  • Vasospasm (to constrict and reduce blood flow/loss) 

  • Formation of a platelet plug 

    • Drugs can work here

  • Fibrin clot 

    • Fibrin is a substance that hardens and condenses the clot (turns platelet plug into finalized clot) 

    • Drugs can work here

  • Fibrinolysis 

    • The body’s way to break down clots

    • Drugs can work here 

• Clots can be beneficial; however, we don’t want them in the body forever and ever amen 

• Glycoprotein IIb/IIIa receptor on activated platelets 

  • Also called IIb/IIIa receptor 

  • Allows fibrin to pull platelets together/aggregation 

Platelet Activation (Primary Homeostasis) 

• Serotonin plays a role in how platelets are activated 

• Thromboxane A2 plays a role in how platelets are activated 

  • Both are associated with some bleeding risks

Coagulation Cascade (Secondary Homeostasis)

• The coagulation cascade has 2 initial pathways which lead to fibrin formation: extrinsic and intrinsic

  • Extrinsic pathway 

    • Activated by a complex tissue factor called thromboplastin (Factor III)

  • Intrinsic pathway 

    • Activated by surface contact with a foreign body or extravascular tissue 

• Both pathways meet at one factor… 

  • Factor X is the rate limiting step for the coagulation cascade 

    • Factor X leads to the formation of Thrombin 

      • Thrombin catalyzes the formation of fibrin from fibrinogen 

        • Fibrin is what gets into platelet plug and pulls them together to make a hardened/firm blood clot 

• Drugs that work at Factor X

 → Xarelto, Eliquis, Savaysa 

• Drugs that work at Thrombin (IIa) 

→ Pradaxa, Refludan, Angiomax

Extrinsic (Tissue Factor) Pathway/Steps

• Starts with tissue factor (foreign substances in the body = damage) 

• Factors involved in this pathway are III, VII, IV, X

• FXa = Factor X (activated), in coagulation cascade a little a means the activated form 

Intrinsic (Contact Activation) Pathway/Steps 

• Activation happens through different factors 

• XII, XI, IX, VIII, IV, X 

• Monitoring parameters are slightly different

  • Intrinsic pathway we should monitor → PTT (partial thromboplastin time) 

Common Pathway 

• We have to have good and appropriate minerals to support these clotting factors 

  • Not important to know fine details, but if a patient has some sort of faulty making of nutrients… you may see clotting difficulties because they are involved in the clotting cascade 

• Once we get to the point that we have a fully hardened fibrin clot = it takes a while to break up (longish duration of therapy to undo this)

Cofactors

• Various substances are required for the proper functioning of the coagulation cascade: 

  • Calcium, Phospholipid, and Vitamin K 

    • Patients not able to process these cofactors put them at a higher bleeding risk 

Hematology

• One of the things we fail to consider is that pooling of blood (stagnant blood) is more likely to clot 

  • If we think about A-Fib, blood kinda just sits there and becomes stale because it is not being pumped through the body… 

    • It is very likely to form a clot because it is just sitting there 

  • Similarly, to varicose veins = this blood is more likely to clot 

• Arterial thrombi (white thrombi) 

  • Primarily platelet aggregation 

• Venous thrombi (red thrombi) 

  • Coagulation predominates 

• The thought is that the venous side of things (DVT, PE) is more associated with the coagulation process and what we would target in our treatment

Oral Anticoagulants 

• Warfarin (Coumadin)

  • Was originally found in the sweet clover plant (think about the dead cows… RIP 🐮 🪦 🥩 🌱) 

  • This was our first oral, long-term option for slowing down or stopping the coagulation cascade

    • This medication works on all of the Vitamin K dependent clotting factors (4 of them) 

      • Factor II, VII, IX, X

  • It crosses the placenta and can cause fetal hemorrhage and malformation (fetal warfarin syndrome)

    • C/I IN PREGNANCY 

  • It takes several days to get everything lined out (max effect in 3-5 days after starting) 

    • When starting a patient on Warfarin it takes 3-5 days to have things stabilized/minimized after starting the medication 

      • So if we decide that Warfarin is our treatment of choice and we have an acute situation, we have to use something else in the meantime = bridge therapy (must use something else that works fast while Warfarin is getting to its therapeutic levels) 

        • Patients with acute thromboembolism are usually treated with a LMWH and Warfarin 

          • LMWH is withdrawn after Warfarin becomes effective 

  • ADR/SE: 

    • LOTS of drug interactions 

      • Most of the time, these interactions are going to make Warfarin more effective = increases bleeding risk 

    • Bleeding risk is very high with Warfarin especially with other medications 

      • Most common interactions are antibiotics and antivirals 

        • Trimethoprim/Sulfamethoxazole (Bactrim) 

        • Metronidazole (Flagyl)

        • Fluconazole (Diflucan)

        • Levofloxacin (Levaquin)

          • These 4 drugs inhibit the metabolism of Warfarin 

          • Automatically adjust the Warfarin dose if you have to prescribe any of these medications to a patient that is on Warfarin 

            • He said to be sure that we know these

    • Any antibiotic can suppress our production of Vitamin K by the GI microbiota→ this causes increased bleeding risk 

    • Binge drinking (alcohol 🍺) decreases the metabolism of Warfarin → increases PT/INR → increased bleeding risk 

    • Chronic alcohol use increases the metabolism of Warfarin → decreases PT/INR → decreases bleeding risk 

      • Just know overall you may have to adjust Warfarin dosing based on alcohol consumption 

    • Induced skin necrosis (seen in the LE the most)

      • Increased in patients with protein C or S deficiency (Warfarin inhibits these proteins)

    • “Purple toes syndrome” often painful 

    • Hepatic dysfunction

  • Why do we use Warfarin?  

    • Our first oral anticoagulant (slows down the coagulation cascade) 

      • Warfarin CANNOT and DOES NOT bust up the blood clot 

      • It prevents the clot from forming, getting tighter or stronger (prevents the clot from getting bigger)

        • The body has to bust up the clot 

      • Warfarin is NOT AN ACUTE QUICK FIX

  • Indications 

    • DVT

    • PE

    • Atrial Fibrillation 

    • Patients that have an artificial (mechanical/bioprosthetic) heart valve 

      • Mechanical and bioprosthetic heart valves… especially if they have A-Fib on top of it (Warfarin is the only current approved medication for these patients and this indication) 

      • Warfarin is the only option for these patients 

  • Starting dose 

    • 5 mg QDay 

      • If INR is too high, bring the dose DOWN

      • INR is checked daily until we get to our target range (within therapeutic range) 

      • Once stabilized, adjustments should be made by 10-15% of the weekly dose reduction in INR is higher than goal → you should not EVER double Warfarin dosing 

        • After dose reduction, recheck INR in ONE WEEK

        • He will gibb slap you if you double a Warfarin dose 

  • Monitoring 

    • For most indications, INR should be 2-3 (normal is 0.9-1) 

    • For patients with mechanical/bioprosthetic heart valves and for those with recurrent systemic embolization, INR should be 2.5-3.5 

      • The higher the INR the more likely we are to bleed (higher bleeding risk) 

    • Concurrent heparin therapy can cause increase 10-20% of the patient’s PT, target PT/INR should be increased by the same amount 

    • Once stabilized, it should be monitored q4 weeks at the MOST

      • Considerations: stability of the dose and patient compliance 

        • All leafy vegetables have Vitamin K = at the end of harvest season, this may cause their INR to decrease dramatically after being controlled 

Management of Bleeding with Warfarin 

• Examples 

  • Nosebleeds that are difficult to stop bleeding 

  • You look at them the wrong way and they bruise 

• Treatment of bleeding can include a reduction in Warfarin dose and the administration of Vitamin K1 (phytonadione) 

• INR <6 No significant bleeding occurring

  • Not easy bruising, stuff like that 

  • Just reduce the dose of Warfarin until INR <5 

• INR >6 but <8 → no significant bleeding occurring 

  • Hold the dose for 1-2 days until INR <5 then resume lower dose 

• INR >8: No significant bleeding occurring 

  • But you’re concerned about the patient being a high fall risk or something to do with bleeding risk 

  • Hold Warfarin until INR <5 then resume lower dose 

  • Give low doses of ORAL Vitamin K (if high risk for bleeding) 5-10mg ORALLY or 0.5 mg IV 

• Any INR elevation + serious bleeding 

  • Hold Warfarin, give Vitamin K 10 mg SLOW IV infusion, supplement with fresh plasma transfusion or prothrombin complex concentrate (Factor X complex) 

Vitamin K and Warfarin 

• High doses of Vitamin K may cause resistance to Warfarin for more than a week 

• Heparin or LMWH can be given until the patient becomes responsive to Warfarin again

Warfarin and Food 

• Effects of Warfarin may be decreased if taken with foods rich in Vitamin K 

  • Liver, green tea, and leafy green vegetables 

• Vitamin E may increase Warfarin effect 

• Cranberry juice may increase Warfarin effect 

Oral Anticoagulants (most other than Warfarin are BID drugs) 

• Dabigatran etexilate (Pradaxa)

  • The first attempt after Warfarin → to be more predictable 

  • Direct thrombin inhibitor (works just downstream of factor X)

    • May also hear it referred to as a novel oral anticoagulant (NOAC)

      • May also hear it referred to as a direct-acting oral anticoagulant (DOAC) 

        • = a little bit for targeted in it’s approach (working directly on thrombin) 

  • We still have bleeding risks, but they have improved a little because of its predictability 

  • Pro-drug

    • Has to be converted to its active form in the GI tract 

      • This process causes some GI upset 

        • = #1 SE is Dyspepsia, gastritis

  • Carries a higher risk of GI bleeding 

    • If you have a patient with Barrett’s esophagus, PUD, H. pylori… Dabigatran may not be the best choice 

  • The overall bleeding risk is lower, but the GI bleed risk is higher 

  • There are fewer drug interactions 

  • Can be used for A-fib, DVT, PE, H/O these conditions and trying to prevent recurrence, surgery and will be immobile for a while… → you can use this drug 

  • You cannot use this drug in valvular A-fib patients 

  • Dosed BID 

    • Don’t have to do routine INR monitoring 

  • Praxibind (idarucizumab) → monoclonal antidote

• Rivaroxaban (Xarelto) 

  • Factor Xa inhibitors (reversibly prevent X converting into Xa) 

  • NOAC, DOAC “class” 

    • Easy to recognize, all have “Xa” in their name 

  • Used for VTE prophylaxis b/c surgery, traditional A-fib (no heart valve) for stroke risk reduction, DVT, and PE 

    • Really low doses (2.5mg) have been used for patients that have had an MI and cannot tolerate aspirin 

  • Dosed daily unless you have an active DVT or PE → in that case do BID dosing for a while and then go back down to once daily dosing 

  • RENAL ELIMINATION 

    • If a patient has really bad renal function → Warfarin is the best choice 

      • If a patient is on dialysis and needs an anticoag → Warfarin (liver elimination)

  • Compared to Warfarin: 

    • Lower risks of bleeding overall 

    • More predictable = much more convenient 

  • Compared to Pradaxa: 

    • Lower GI bleeding risk 

  • Drug interactions

  • ADR/SE: 

    • Bleeding

    • MSK pain

    • Wound secretions 

    • Pruritus, blisters

    • Upper abdominal pain 

    • Syncope 

• Apixaban (Eliquis)  

  • Probably our safest oral anticoagulant 

  • NOAC, DOAC “class”

  • Factor Xa inhibitor, as well as prothombinase activity

  • Indications: 

    • Non-valvular A-fib, DVT prophylaxis, PE

  • Dosing BID (regardless of the indication) 

  • ADR/SE: 

    • Bleeding, low incidence of GI symptoms (nausea and hepatic transaminitis)

    • Rare: syncope, drug hypersensitivity (rashes), and anaphylactic reactions 

• Edoxaban (Savaysa)

  • Factor Xa

  • NOAC, DOAC “class” 

  • Black box warning 

    • Efficacy is greatly reduced in A-fib patients with CrCl > 95 mL/min 

  • If you have bad renal function, you have to worry about dose and bleeding risk 

  • Quite frankly, just don’t use it

    • There is no advantage, it’s just a dumb drug

NOAC: Clinical Pearls

• If you have someone with fairly decent renal function = you can use them all 

  • Apixaban is the best with worsening renal function (safest/least varied in it’s results based on renal function) 

• Very few drug interactions with any of these meds 

NOAC Disadvantages 

• Black box warning 

  • Premature discontinuation increases the risk of thrombotic events 

    • If you abruptly take these away (too soon after treatment), clot can form again = additional thrombotic events 

• Generally for a DVT or a PE

  • You’re looking at about 3 months minimum of treatment, maybe 6 months for the first one 

• If you have A-fib that is continual or chronic, you’re on these until the bleeding risk outweighs the benefits 

• If you’ve previously had a DVT and have a second DVT, you’ll be on an anticoagulant for life 

• You have to have been on these medications long enough to treat your thrombotic event 

NOACs and Surgery 

• Whether Warfarin or NOAC, if surgery is planned, you would need to consider holding or stopping or reversing the medication depending on the bleeding risk 

• Low risk 

  • Having a tooth pulled → hold at least 24 hours prior 

• Moderate-high risk → hold at least 48 hours prior

  • His example: having an open cholecystectomy procedure → may need to hold for 5 days prior 

• Andexa is the antidote for significant bleeding on Xa inhibitors 

• Vitamin K is the antidote for significant bleeding on Warfarin

Choosing an Oral Anticoagulant 

• You have to decide what’s best for the patient 

  • 1st look at the indication

    • If you have patient with A-fib with a valve replacement/mechanical heart valves = Warfarin

    • Just A-fib, DVT, surgery prophylaxis d/t immobility → any oral anticoagulants can work 

• All Xa inhibitors = $$$

• Dabigatran 

  • Avoided in patients with ulcer/non-ulcer dyspepsia, recent GI bleeding

Know the starred indication dosings

Parenteral Anticoagulants 

• Heparin family 

  • Unfractionated, low molecular weight, heparinoid drug, fondaparinux (Arixtra) 

• Unfractionated heparin 

  • Really large molecule, less predictable 

• LMWH 

  • Cut large molecule into small predictable pieces 

• Generally given IV or SQ

  • SQ in more preventative in nature (good for prophylaxis) 

  • If undergoing surgical procedure, dosage is determined by monitoring the aPTT (1.5-2 times normal)

• Indications of Heparin 

  • Bridge therapy (prevention or treatment of DVT/PE)

  • Need something that acts very quickly (life-threatening PE)

  • Safe to use in pregnant women (unlike Warfarin), still not the preferred option

• Disadvantages 

  • Requires frequent monitoring unless just using it for prophylaxis 

• Antidote of Heparin→ Protamine sulfate

• Heparin-induced thrombocytopenia (HIT)

  • Immune-mediated response that causes platelets to trend downward daily after treatment for a few days 

    • All heparin products can cause this, but unfractionated Heparin has the highest risk of HIT

    • Once the product is stopped = platelets trend back upwards 

• aPTT → intrinsic pathway

• ADR/SE: 

  • Bleeding risk 

  • HIT 

    • LMWH have the lowest occurrence 

• Heparin indications: 

  • Acute thromboembolic disorders→ DVT, PE, DIC 

  • Arterial and heart surgery

  • Blood transfusions

  • Renal dialysis and blood sample collection 

  • Acute atrial fibrillation

  • Unstable angina (to prevent ischemic complications) or NSTEMI

• Low dose of Heparin SQ to prevent DVT and PE

Unfractionated Heparin 

• Parenteral (faster acting) anticoagulant 

• Inhibits thrombin and a LOT of other factors (IXa, Xa, XIa, XIIa) 

  • Little bit more unpredictable 

LMWH

• Primarily inhibits factor Xa 

• Lower incidence of HIT 

• No need for monitoring because affecting factor Xa 

• Administer SQ

  • Typically once daily injections (Heparin is BID-TID SQ)

• Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep), and danaparoid (Orgaran)

• Antidote is still protamine 

• Regardless of what product is used (fresh frozen plasma) FFP is an option

• These are the medications often used for bridge therapy

• Enoxaparin (Lovenox)

  • The most commonly used 

  • It is a much more predictable dose and response 

  • We have to know the dosing of this one 

    • Preventative dosing → 40 mg SQ QDay 

    • Treatment dosing → 1 mg/kg SQ BID (active DVT or PE)

Fondaparinux (Arixtra) 

• Another Factor Xa inhibitor 

• It is ungodly expensive 

• The HIT risk of this medication is substantially lower than LMWH or unfractionated 

  • Because LMWH is generic and more affordable, this isn’t used as commonly 

• Could use this as an alternative possibly 

• Some providers prefer this medication for knee and hip surgeries (b/c of the lower risk of HIT) 

Heparin-Induced Thrombocytopenia

• Hirudin medications 

  • Found in the salivary glands of medical leeches (bloodletting) 

• Lepirudin (Refludan) → D/C

• Bivalirudin (Angiomax) 

  • Synthetic 

  • Used in a lot of angiocaths and procedural type indications b/c it’s available IV and it’s a heparinoid… not high risk for HIT

• These are really only used as alternatives for patients who have HIT 

Fibrinolytic Drugs 

• Also called plasminogen activators 

• Thrombolytic drugs are used to dissolve blood clots 

• Convert plasminogen to plasmin 

  • Plasmin degrades fibrin and fibrinogen and thereby causes clot dissolution 

• Causes a bleeding risk and arrhythmias 

• These drugs have strict protocols and contraindications 

• Tissue plasminogen activator (tPA) 

  • Seen when we know a clot has occurred in a definitive timeline 

  • Only used in really severe situations with time limit and dosage protocols 

• You have to be cautions; very strict protocols 

  • Can only be used in a thrombotic stroke, DO NOT USE IN A HEMORRHAGIC STROKE = ☠ ⚰

• Some of the tPA drugs came from streptokinase 🦠

• Recombinant forms of human tPA: 

  • Alteplase (Activase, rtPA)

  • Reteplase (Retavase) 

  • Tenecteplase (TNKase)

    • These drugs generally work very quickly; usually within minutes 

      • Used in patients in which clot dissolution is needed and if it does not happen, long-term damage may occur 

    • Very useful drugs if we can know timeline and if we can verify that the stroke is thrombotic in nature 

• Streptokinase 

  • Really isn’t used a lot anymore; b/c patients can develop an antibody reaction 

  • If the patient has had a recent strep infections which can quickly react to Streptokinase and cause it to be inactivated in the body and no longer work 

• Urokinase (Abbokinase)

  • Can from certain enzymes within urine; there was no benefit, it was greater cost 

Thrombolytics

• Current thrombolytic agents being used:  

  • Alteplase, Reteplase, and Tenecteplase 

• Indications 

  • Significant thrombotic events to reverse those effects: 

    • Myocardial infarction 

    • Thrombotic stroke 

    • Pulmonary embolism 

• Antidote (although, he’s not sure how effective it would be): 

  • Aminocaproic acid is used to inhibit fibrinolysis

Antiplatelets

 Antiplatelet Drugs 

• Intended to prevent and/or reverse platelet aggregation in arterial thrombosis 

• Antiplatelet drugs try to reduce the point of recruiting in more platelets to aggregate 

• This is most useful in conditions where we have a foreign body (stent)

  • Very good at preventing something from happening, but will not prevent super high risk stuff… 

    • Wouldn’t be used alone in A-fib, would still need an anticoagulant

    • Useful in preventing MI (NSTEMI and STEMI)

    • Useful in preventing future thrombotic strokes (PAD, CAD where arteries and veins are full of junk)... will not treat a current, but will prevent a future event 

Aspirin

• Inhibits the activation/aggregation of platelets through cyclo-oxidase enzymes (part of thromboxane activation) 

  • Thromboxane causes platelets to aggregate together 

• Aspirin works upstream to prevent the activation of these platelets 

• Irreversible inhibitor; works for a really long time 

• COX-1 is where aspirin works 

  • Prevents us from making the mucoprotective layer over the stomach but is also is what inactivates platelets 

• Of all the drugs working on the COX enzyme, Aspirin has the highest risk of GI irritation 

Aspirin 

• Indications 

  • MI (you may get aspirin and other antiplatelets for a long period of time)

  • Unstable angina or maybe even stable angina to prevent an MI 

  • Ischemic heart disease

  • CVA related to ischemia 

• Has been used in patients with heart valves; but this is not the standard and he will not test us on that 

  • Considered to be alternatives in patients that really can’t have or tolerate an anticoagulant = dual antiplatelet therapy 

• If you’ve had an MI you’re generally on aspirin indefinitely 

Dipyridamole (Persantine) 

• Has some vasodilatory activity  (often thought to be most useful for an ischemic stroke)

• Indications:

  • Thought to be better at prevent subsequent ischemic (thrombotic) stroke in patients 

  • Stroke prevention 

• Aggrenox (Dipyridamole/Aspirin) 

  • This combination product is superior to aspirin alone, and to clopidogrel

  • This drug is a combination of aspirin and extended release (ER) dipyridamole

  • Used in patients that need prevention of future stroke (have a history of strokes or CVA)

  • Causes HA, some patients cannot tolerate this 

• ADR/SE: 

  • GI irritation 

  • Headache (d/t vasodilatory properties) 

• Won’t use if: 

  • Migraines

  • Hypotensive 

• Maybe just a TINY bit stronger than aspirin b/c of vasodilatory and antiplatelet

  • Gamechanger are the ADP-inhibitors

• Antiplatelets are often used for patients who have CAD (junk in their arteries)

  • For the exam = really focus on (do I need an antiplatelet or anticoagulant?) 

    • Should always be our first question 

    • Anticoagulant needed = A-fib, already have a clot 

    • Antiplatelets needed = 

Adenosine Diphosphate Inhibitors 

• Clopidogrel (Plavix), Prasugrel (Effient), Ticagrelor (Brilinta), Ticlopidine (Ticlid), Cangrelor (Kengreal)

• Blocks ADP P2Y receptor = irreversible blockade

• Used IN PLACE of aspirin or IN ADDITION to aspirin for the same conditions 

• Ticlopidine was the very first of these ADP-i = can cause agranulocytosis 

  • BID product w/ NO added benefit

  • Black Box warning: causes agranulocytosis

• Prolongs bleeding time

• Inhibits platelet function for the life of the platelet 

Classes of ADP-i 

• Thienopyridines 

  • Clopidogrel, Prasugreal, Ticlopidine 

    • Oral formulations 

    • These bind very irreversibly, lasts about 5-6 days in the body 

• Nucleoside analogs 

  • Ticagrelor → PO 

  • Cangrelor (Kengreal) → IV applications 

    • These are reversible, quick on and quick off = BID dosing 

Clopidogrel (Plavix) 

• The most commonly used antiplatelet 

• Indications

  • Alternative to aspirin in patients who cannot tolerate aspirin

  • Most frequently used in patients who have had an MI (STEMI or NSTEMI) 

  • Also used in PAD (intermittent claudication), some sort of difficulty with platelets through occluded arteries 

  • Used to prevent thrombotic stroke 

• Dosing

  • 75 mg PO QDay dosing (d/t irreversible action) 

    • You have to know this dosing 

• Prodrug (the drug we’re giving is not active, must be activated) 

  • Requires 2 different enzymes! 

    • Therefore, there is variability in patients b/c of this 2 step process 

  • Requires hepatic-biotransformation = lot of opportunity for drug interactions 

    • If either enzyme is inhibited, clopidogrel can not be activated to become effective within the body 

• Drug interactions 

  • Omeprazole (Prilosec) 

    • NOT ALL PPIs, but omeprazole is the worst

      • There was a huge push previously to d/c omeprazole in patients with the need for Clopidogrel… 

        • Change to Pantoprazole!

• In order to take care of platelet aggregation because of percutaneous intervention (cath lab) following an occlusion related to a thrombotic stroke or MI… we give Clopidogrel (Plavix) as a loading dose

  • This is done to get the drug to its active level faster 

  • 300mg or 600 mg loading dose (he doesn’t expect us to know this dose, but just to know that you would do a loading dose)

Prasugrel (Effient)

• 1st step of enzymatic activation has already happened; but it’s still a prodrug 

  • Requires 1 step of enzymatic activation in the body 

    • = less drug interactions, a lot more predictable than Clopidogrel 

• Requires a loading dose 

• Indications 

  • Prevention of MI (following a previous one)

  • Can’t do all the same indications that is seen with Clopidogrel 

Ticagrelor (Brilinta) 

• Reversible inhibition = BID dosing

  • Patients must be diligent with this dosing regimen = half-life of 12 hours for platelets to become active again 

• Good for if you’re high bleeding risk, we can come off of this medication much more quickly 

• Loses its effectiveness if a patient takes more than 100 mg of aspirin

  • Not a horrible problem or most people, for people that use aspirin for pain management this becomes an issue 

  • He’s not a huge fan because of this 

• Quick on and quick off for patients who have a higher bleeding risk or a history of bleeding 

GP IIb/IIa-inhibitors

• Abcizimab (Reopro), Eptifabatide (Integrilin), and Tirofiban (Aggrastat) 

• Used parenterally in patients with ACS 

• These drugs are NOT used in an outpatient setting by non-specialists 

• ADR/SE: 

  • Major bleeding

  • ….

  • ….

Anagrelide (Agrylin) 

• Indications 

  • Thrombocythemia 

  • Secondary to myeloproliferative disorders

• Contraindicated in severe hepatic impairment 

• Never first line 

Vorapaxar (Zontivity)

• Works on the PAR-1 receptor type to prevent platelets from being activated 

• Inhibits thrombin-related platelet aggregation 

• Would really only be used for patients who have contraindication, maximized therapy, or huge bleeding risk on other medications or if intolerant to the other medications 

• Indications 

  • Reduction of thrombotic CV events in patients with a history of MI or with PAD 

CHADS2 Score & CHA2DS2-VASC Score 

• Used to estimate the risk of stroke in patients with non-rheumatic atrial fibrillation

• Used to determine whether or not treatment is required with anticoagulation therapy or antiplatelet therapy 

• A high score = greater risk of stroke

• A low score = lower risk of stroke

• Age considerations: (this was the difference between the two scores, CHA2DS2-VASC includes age while CHADS1 does not)

> 75 years = 2 points 

65-72 years = 1 point 

< 65 years = 0 points 

• The older the patient is, the more at risk they are for having a stroke

• If you have a score of 2 or greater, you need an oral anticoagulant 

• If you are a male with 1 point, oral anticoagulant should be considered 

• If you are a male with 0 points or a female with 1 point, no anticoagulant therapy is warranted

Antiplatelet Dosing 

• Post-MI 

  • Aspirin 81mg QD

  • Clopidogrel 75 mg QD 

  • Prasugrel 10 mg QD 

  • Ticagrelor 90 mg BID x12 months, then 60 mg BID

• Post-MI Management 

  • Long-term ASA use

  • Dual-antiplatelet usage for: 

    • At least 1 month with Bare-metal stent (he said to know this)

    • At least 12 months with Drug-eluting stent 

  • If the patient has just had a CVA… we decide to just do drug therapy, no stent

    • These patients need DAPT therapy x21-90 days 

• DAPT

  • No long-term benefit compared to SAPT but higher risk of bleeding for patient with CVA 

    • Use no longer than 90 days 

  • Has been used for patients who cannot tolerate or cannot afford anticoagulants

    • Not equivalent; but the the other option available 

  • Patients can be on an anticoagulant, aspirin, and clopidogrel 

    • Greatly increases bleeding risk 

• SAPT = single antiplatelet therapy

  • Aspirin 81 mg QD 

  • Aggrenox (Aspirin/Dipyridamole) BID 

  • Clopidogrel 75 mg QD 

• DAPT 

  • Aspirin 81 mg QD PLUS

  • Clopidogrel 75 mg QD 

    • Duration 21-90 days 

      • After 90 days, you can return to SAPT 

HAS-BLED 

• System used to assess the 1-year risk of major bleeding 

  • Intracranial bleedings, hospitalization, hemoglobin decreases >2 g/dL, and/or transfusion 

  • Developed in 2010 

• HAS-BLED 

  • HTN, Abnormal renal/liver function, Stroke, Bleeding (hx), Labile INRs, Elderly (>65), and Drug therapies (NSAIDS, antiplatelets, or alcohol [1 point for each]) 

  • All categories are 1 point with the exception of Drug therapy (1 point for drugs, 1 point for alcohol) 

• The higher the HAS-BLED score, the higher the risk of a bleeding event 

• If you have a patient that is 90 with a hx of A-fib, haven’t been in A-fib in 5 years though. HAS-BLED score is 5 though… Do you really need an anticoagulant at that point or is the risk of bleeding outweighing the benefit of continuing this drug at this time? 

  • He doesn’t know, but that’s something that you need to talk to your patients about and formulate a decision from that level 

Antineoplastic Therapies

Antineoplastics 

• Any designated drug or interventional treatment that kills or stops tumor cells from growing (National Comprehensive Cancer Network) 

  • Could also be chemotherapy, ionized radiation, or immunotherapy 

History of Chemotherapy 

• World War II (1940s)

  • Mustard (Mustine) gasses exposed individuals to destruction/depletion of bone marrow and lymphoid tissue 

• Foodman & Gilman (1942) 

  • Testing mustine against tumor-bearing mice 

Chemotherapy 

• Cell cycle phase specific (CCS) 

  • Targets a specific part of the cellular process, direct action against proliferation, schedule dependent (duration and timing of treatment) 

• Cell cycle non-specific (CCNS) 

  • Both proliferating and non-proliferating cells get killed, dose dependent (rather than timing or duration) 

Combination Chemotherapy 

• Initial resistance to any single agent is common; therefore regimens often have multiple drugs involved 

  • Different types of drugs → different regimen (trying to outsmart the cancer cells) 

Chemotherapy Toxicities 

• Weird effect from chemotherapy drugs

  • Activity and rapidly dividing cells [cancer and healthy cells] (you will also impact healthy cells, see some effects in hair follicles, GI tract, and bone marrow) 

• Dose-limiting toxicitiies: 

  • Myelosuppression (neutropenia, anemia, thrombocytopenia) 

  • Diarrhea, N/V

  • Mucositis 

Chemotherapy-Induced Neutropenia 

• Prevention is key 

  • Granulocyte colony stimulating growth factor is used to increase the production of WBC (G-CSGF) 

  • This product is naturally produced in the body and can be used to treat this neutropenia 

• Pegfilgrastim 

  • Long acting G-CSGF product

  • SQ injection 

  • Cannot be given within 24 hours after chemotherapy or 14 days prior to chemotherapy 

  • Neulasta OnPro: adhesive device, auto-injected ~27 hours after placement (helps with adherence overall) 

• Filgrastim 

  • Short-acting G-CSGF

  • Cannot be given within 24 hours after chemotherapy or 24 hours before chemotherapy 

  • Ideal in regimens where 14-day window required with pegfilgrastim is not possible 

Febrile Neutropenia 

• Quite regularly occurring 

• Infection risk increases when ANC <500 cells/mm3 

• Clinicians rely on fever as hallmark sign of infection 

• Risk factors: 

  • ANC <500 cells/mm3 

  • Prolonged duration of neutropenia (>10 days) 

  • Immune dysfunction (disease, immunocompromising drug) 

  • Malnutrition, non-ambulation 

Febrile Neutropenia Treatment 

• Considered to be an emergency (depleted the body’s ability to respond to any time of infection)

• Look at: 

  • CBC w/ diff, CMP, CXR, blood cultures, hepatic function panel 

• Causative bugs cultures <50% of the time of neutropenic fever episodes (contributing but not the cause of the condition) 

• Prompt initiation of empiric antibodies 

  • Chosen based on most likely organisms, institution sensitivities, allergies, and cost 

  • Empiric gram negative must cover Pseudomonas aeruginosa 

  • Consider Vancomycin if: 

    • Hemodynamic instability 

    • XR indicates pneumonia 

    • Suspected cath-related infection or skin/soft tissue infection 

Tumor Lysis Syndrome 

• Prevention is key 

  • IV hydration (mainstay of prevention) → to increase renal perfusion 

  • Hypouricemic medications → Allopurinol 

  • Rasburicase 

  • Treat electrolyte imbalances 

  • Dialysis (considered last option) 

• Associated with: 

  • Hyperuricemia 

  • Hyperkalemia 

  • Hyperphosphatemia 

  • Hypocalcemia 

• Considered an oncologic emergency 

CINV 

• Acute → within the first 24 hours following chemotherapy 

• Delayed → after 24 hours following chemotherapy 

• Anticipatory → conditioned response 

• Breakthrough → occurs despite prophylaxis 

• The higher the risk (>90%) of N/V with chemotherapy agents, the more drugs used to target the CINV

• If the chemotherapy drug being used is a class 4, we load them up on antiemetic medications 

Alkylating Agents 

• Prevent cell division by cross-linking DNA strands and covalent binding of alkyl groups to DNA base pairs

• Mainstays of treatment in a variety of cancer types 

• CCNS drug

Alkylating Agent: Cyclophosphamide

• Hallmark therapy in breast, lung, ovarian, lymphomas, and leukemias 

• Toxicities: 

  • Myelosuppression 

    • Most contain growth factor support 

  • N/V

    • High emetic potential with dose 

  • CV 

    • Can occur within 48=72 hours 

    • Baseline and repeat EKG (q3-6 months) 

  • Mucositis 

  • Alopecia

Platinum-Based Alkylating Agents 

• Preferentially bind purine DNA bases forming intra- and interstrand crosslinks and inhibiting DNA repair and/or synthesis 

Alkylating Agent: Cisplatin

• Hallmark therapy in bladder, lung, ovarian, testicular, and H&N (head and neck) cancer 

• Toxicities 

  • Myelosuppression 

    • Most regimens contain growth factor support 

  • N/V 

    • High emetic potential (gets 4 drugs) 

  • Ototoxicity 

    • Bilateral, symmetrical high frequency hearing loss 

    • Can be irreversible 

  • Peripheral neuropathy 

    • Loss vibration sensation, ankle jerks, painful sensation in hands/feet 

  • Nephrotoxicity* (* = dose limiting toxicity, why we can’t just use more of the drug)

    • Usually reversible 

    • Risk factors: age >60, GFR <75 mL/min, large doses, low albumin 

    • Prevention is key: 

      • Pre- and post-hydration, extended infusion, magnesium supplementation 

Alkylating Agent: Carboplatin 

• Hallmark therapy in lung, ovarian, and H&N (head and neck) cancer 

• Dosed to AUC (Calvert Equation) = GFR plays a role in the dose 

• Toxicities 

  • Myelosuppression*

    • More so than Cisplatin → neutropenia, thrombocytopenia, and anemia 

  • N/V

    • Moderate emetic potential 

  • Hepatotoxicity 

    • Generally associated w/ higher doses 

  • Nephrotoxicities 

Alkylating Agent: Oxaliplatin 

• Hallmark therapy in colorectal cancer

  • FOLFOX, CAPOX combination regimens 

• Toxicities 

  • N/V 

    • Moderate emetic potential 

  • Hypersensitivity reactions 

    • Mold, subdue after d/c 

  • Peripheral neuropathy* 

    • Hot/cold sensitivities 

    • Acute or delayed 

    • Prevention: 

      • Avoid anything hot/cold, including drinks 

      • Prolong infusion times 

Antimetabolites 

• Induced cell death in the S phase of cell dose 

• Classes: 

  • Purine analogs 

  • Folate antagonists 

  • Topoisomerase I inhibitors 

Antimetabolite Agent: Cytarabine

• Hallmark treatment in AML, ALL, and CML 

• Toxicities 

  • Myelosuppression* 

    • Neutropenia, thrombocytopenia, anemia 

  • N/V

    • Moderate emetic potential 

  • Hand-foot syndrome 

    • Skiing sloughing of palmar and plantar surfaces 

  • Mucositis 

  • Ocular toxicity 

    • Prophylactic corticosteroid eye drops given 24-48 hours after last dose 

  • Neurotoxicity 

    • Acute cerebellar syndrome 

    • Most often between days 3-8 after initiation 

    • Mary be irreversible 

Antimetabolite Agent: 5-Fluorouracil (5-FU) MOA 

• Inhibits TS, incorporating into RNA/DNA and preventing proliferation

• Severe toxicity (death) in patients dihydropyridium dehydrogenase (DpD) deficient

Antimetabolite Agent:  5-Fluorouracil (5-FU) 

• Hallmark treatment in colorectal, pancreatic, H&N cancer 

  • FOLIFOX, FOLFIRI combinations 

• Bolus dosing + continuous infusion 

• Toxicities 

  • Hand-foot syndrome 

  • Diarrhea

  • Mucositis 

  • N/V

    • Low emetic potential 

  • Hyperbilirubinemia 

Antimetabolite Agent: Capecitabine (Xeloda) 

• Hallmark treatment in colorectal, breast, and other cancers 

• Prodrug of 5-FU 

• Toxicities 

  • Diarrhea

  • Hyperbilirubinemia 

  • Hand-foot syndrome 

    • Redness, swelling of palms/soles 

    • Dryness, itching, pain 

    • Prevention: hydration, lotions, diclofenac* 

Vinca Alkaloids 

• Binds to dimeric tubulin, terminating microtubule assembly, resulting in apoptosis 

• Works in the Mitosis phase 

Vinca Alkaloid: Vincristine 

• Hallmark treatment in ALL, CML, Hodgkin & Non-Hodgkin lymphoma 

• Fatal if given intrathecally 

• Toxicities 

  • Neurotoxicity 

    • Peripheral neuropathy* 

      • Reversible 

    • Motor nerve impairment 

      • Loss of tendon reflexes, foot/wrist drop, irreversible 

  • Autonomic dysfunction 

    • Constipation, paralytic ileus, orthostatic hypotension, incontinence

  • Extravasation

Taxanes

• Preferentially bind to microtubules during the M phase, stabilizing microtubule polymer, and preventing disassembly → apoptosis 

Taxane: Paclitaxel 

• Hallmark treatment in breast, ovarian, lung, and pancreatic cancer 

  • Carboplatin/paclitaxel combination 

• Toxicities 

  • Myelosuppression* 

  • Peripheral neuropathy 

  • N/V

    • Low emetic potential 

  • Alopecia 

  • Hypersensitivity 

    • Formulated w/ polyoxyethylated castor oil 

    • Premedicate w/ diphenhydramine, famotidine, and dexamethasone 

    • Nab_paclitaxel (Abraxane) now available 

Taxane: Docetaxel 

• Hallmark treatment in breast, lung, and ovarian cancer 

• Toxicities 

  • Myelosuppression* 

    • Grade 4 neutropenia (--> usually admitted) 

  • Peripheral neuropathy 

  • Fluid retention 

  • Epiphora 

    • Anatomic narrowing of the canaliculi 

    • Excessive tearing 

    • Monthly ophthalmologist exams recommended 

  • Alopecia 

  • Nail disorder 

Topoisomerase Inhibitors 

• Topoisomerase I inhibitors: Bind to topo I/DNA complex preventing reannealing of the cleaved strand

  • Irinotecan, topotecan 

• Topoisomerase II inhibitors: bind to topo II/DNA complex, preventing relegation during replication and causing DNA strand breaks 

  • Etoposide, doxorubicin 

Topoisomerase I Inhibitor: Irinotecan

• Hallmark treatment in colorectal and lung cancer 

  • FOLFIRI, FOLFIRINOX combinations 

• Toxicities 

  • Myelosuppression* 

  • N/V 

    • Moderate to high emetic potential 

  • Diarrhea**

    • Early onset (during infusion or within hours) 

      • Prevention: Atropine 

    • Late onset (>12 hours after infusion) 

      • Loperamide

Topoisomerase II Inhibitor: Etoposide 

• Hallmark treatment in lung and testicular cancer 

• Toxicities 

  • Myelosuppression 

  • Hypotension 

  • Ethanol intoxication 

    • 33% alcohol content → caution in alcoholics, epileptics, cirrhotic, children 

  • Mucositis 

  • Alopecia 

Topoisomerase II Inhibitor: Doxorubicin 

• Hallmark treatment in breast cancer, sarcomas, leukemia, and others 

  • AC (Adriamycin/Cyclophosphamide) combination 

• Toxicities 

  • Myelosuppression 

  • N/V 

    • Moderate emetic potential (high with cyclophosphamide) 

  • Red urine discoloration 

  • Radiation recall

    • Acute inflammation 

    • Radiation should be given after doxorubicin 

  • Alopecia 

  • Extravasation → tissue necrosis 

  • Cardiotoxicity 

    • Mediated by free radical formation and oxidative stress/damage 

      • Acute → EKG changes, pericarditis syndrome 

      • Chronic → cardiomyopathy 

    • Risk factors 

      • Female 

      • Prior irradiation 

      • Concomitant cardiotoxins (cyclophosphamide, trastuzumab, paclitaxel) 

      • Underlying CVD 

    • Prevention 

      • Cardiac ECHO prior to start, routinely thereafter 

      • Lifetime cumulative dose (400 mg/m2)

        • 400 → 3-5% incidence cardiotoxicity 

        • 550 → 7-26% incidence cardiotoxicity 

        • 700 → 18-48% incidence cardiotoxicity 

Targeted Therapies 

• May target a specific biomarker related to the cancer type or a specific mutation = better response and less systemic effects 

• Often oral products

Monoclonal Antibodies 

• Man-made proteins, targeting immune system pathways, that mimic human antibodies 

• 4 primary types: 

  • Murine 

    • Mouse proteins (end in -omab) 

  • Chimeric 

    • Combination of part-mouse proteins, part-human proteins (end in -ximab) 

  • Humanized 

    • Small parts of mouse protein attached to human proteins (end in -zumab) 

  • Human 

    • Fully human proteins (end in -umab) 

      • He prefers this one, says the body responds better to the one it recognizes as it… more SE with mouse derived

Pembrolizumab (Keytruda) 

• #1 drug expenditure in the U.S. 

• Highly selected monoclonal antibody against programmed cell death ligand 1 (PDL1) receptors 

• Approved first for melanoma, how has over 20 indications 

  • Wide variety in cancer types 

  • Neoadjuvant, adjuvant (can be used before or after surgery) 

• Patients have a really good outcome as long as caught early (can even be curable if caught early enough) 

• IV treatment (either q3 weekly or q6 weekly) 

• Often used in combination w/ traditional chemotherapy agents 

• Toxicities 

  • Diarrhea

  • Skin reactions → rash 

  • Pneumonitis 

  • Hepatotoxicity 

  • Nephrotoxicity 

  • Fatigue 

• Patients often report no therapy if this is used alone, patients tend to tolerate this medication really well 

Trastuzumab (Herceptin) 

• Used primarily in breast cancer 

  • Can also be used is gastric cancer or gastroesophageal cancer 

• Highly selective monoclonal antibody against HER2 

• Toxicities 

  • Infusion reactions 

    • Itching, rash, chills 

  • Diarrhea 

  • Cardiotoxicity 

    • Obtain baseline ECHO and repeat routinely thereafter 

Cetuximab (Erbitux) 

• Highly selective monoclonal antibody against epidermal growth factor receptor (EGFR) 

• Hallmark treatment in H&N and metastatic colon cancer (K-RAS wild type) 

• Toxicities 

  • Infusion reactions 

  • Diarrhea 

  • Hypomagnesemia 

  • Acneiform rash 

    • Mild → treat w/ topical clindamycin, hydrocortisone 

    • Moderate → add doxycycline >4 weeks 

    • Severe → withhold treatment 1 week 

Bevacizumab (Avastin) 

• Highly selective monoclonal antibody against vascular endothelial growth factor (VEGF) ligand 

  • Inhibits formation of blood vessels to the tumor

• Hallmark treatment in metastatic colon, lung, and glioblastoma multiforme cancers 

• Often used in combination w/ traditional chemotherapy regimens 

  • FOLFOX + Bevacizumab in metastatic colon cancer 

CDK4/6 Inhibitors 

• Inhibit cyclin-dependent kinase 4 and 6, proteins in the nucleus of the cell that tell the cell to divide; slow or stop cell growth 

• Mainstay of treatment in HR+, HER2- metastatic breast cancer 

• Ribociclib (Kisqali) 

  • Monitor LFTs

  • Neutropenia, thrombocytopenia 

  • N/V 

• Abemaciclin (Verzenio) 

  • Diarrhea* 

  • Neutropenia, thrombocytopenia 

  • N/V

Bruton Tyrosine Kinase (BTK) Inhibitors 

• Inhibit BTK, an enzyme in the nucleus of cancerous B cells that tell the cell to divide; slow or stop cell growth 

• Mainstay of treatment in CLL 

• Ibrutinib (Imbruvica) 

  • Bruising, bleeding (thrombocytopenia) 

  • Diarrhea 

  • Muscle aches, fatigue 

• Zanubrutinib (Brukinsa) 

  • Rash 

  • Bruising, bleeding (thrombocytopenia) 

  • Diarrhea

  • Muscle aches, fatigue 

Abiraterone (Zytiga) 

• Anti-androgen therapy, inhibiting the production of testosterone 

• Toxicities 

  • Adrenocortical insufficiency 

    • Must be given with prednisone (5 mg BID) 

  • Fatigue 

  • Peripheral edema 

  • Hot flashes 

    • He uses Venlafaxine off-label here 

Enzalutamide (Xtandi) 

• Androgen deprivation therapy (ADT), inhibits testosterone receptors in prostate cells 

  • He prefers this drug 

• Toxicities 

  • Fatigue 

  • Headache

  • Constipation 

  • Hot flashes 

    • Venlafaxine off-label use 

  • Seizures 

    • Risk is low, but observed in the trial 

For the Exam 

• NO dosing 

• He wants us to know: 

  • SE that are specific to certain drugs 

• If drugs are in the same class, what are the differences between them (SE) 

• Anything that is uber-drug specific → more than drug specific, but monitoring parameters 

• Recognize what are oncolytic emergencies and know how to manage these 

• How do we look at the management of N/V, how do we approach that based on the type of different products we use 

Hematopoietic Drugs

Iron

• Indications 

  • Pregnant women have the greatest need for iron supplementation 

  • Women who are menstruating 

• Forms 

  • Ferrous salts 

  • Ferrous sulfate 

    • Gets you the most amount of iron

  • Ferrous gluconate 

    • Gets you the most tolerable iron (lower amount, but doesn’t have the SE)

  • Ferrous fumarate 

    • Most expensive; middle ground between gluconate and sulfate 

• ADR/SE: 

  • GI distress 

    • Heaviness, constipation, dyspepsia 

  • Liquid iron can stain the teeth 

  • Stool can be very dark or black in color 

• Food can retard iron absorption by 40-60%, need high acidity to break it down and absorb = adding Vitamin C with each dose may help absorption and side effect 

• Pulse dosing iron two-three time a week may be just as beneficial dosing with fewer side effects 

  • Dosing BID-TID, loses a lot of iron in the feces = pulse dosing improves this 

• H2RA and PPIs would decrease the absorption of iron supplementation 

  • Would be best to dose these medications after these medications 

• Iron polysaccharide complex (Ferrex-150) 

  • Prescription only product 

  • May provide more iron with less GI SE 

  • Generally dosed BID 

• Start with the OTC stuff if you need iron, best do these OTC products with pulse dosing

  • If no benefit at this point, switch to prescription 

• If a patient is already taking iron, go ahead and have them take vitamin C 

• Takes 4-6 months of oral iron therapy to reverse uncomplicated IDA 

• IV formulation → Iron dextran

  • Very high risks of infusion reactions and allergic reactions that can be life-threatening 

  • Only given at infusion centers 

Folic Acid 

• Requirement for the brain stem and good neural tube development

• Indications 

  • Pregnant women 

• If patients with megaloblastic anemia, Vitamin B12 deficiency, must be ruled out before treatment with folic acid is begun 

  • Severe B12 deficiency leads to neurotoxicity 

• Treatment with folic acid may partly correct the anemia caused by vitamin B12 deficiency but will not correct other problems associated with it 

  • Irreversible neurological damage can occur if a B12 deficiency is incorrectly treated with folic acid 

Vitamin B12 

• Essential for growth, cell replication, hematopoiesis, and myelin sheaths 

• Must have intrinsic factor and calcium to be absorbed from the gut 

• Sublingual formulations will help some with absorption issues, but not in pernicious anemia or severe deficiency

• An inadequate secretion of intrinsic factor leads to vitamin B12 deficiency and eventually results in pernicious anemia 

  • These patients do not benefit from any form of oral vitamin B12

• Patients with severe deficiency or pernicious anemia = injectable B12 (IM injection)

  • At the start of therapy, (injections are given daily for 5-10 days (1,000 mcg = 1 g) for severe deficiency 

  • Thereafter, maintenance doses are given once a month 

    • Sometimes bridged to 1 injection weekly for one month, then switching to 1 injection monthly 

• Vitamin B12 cannot be overdosed on, just creates expensive pee… it isn’t dangerous 

Growth Factors 

• Colony-stimulating factors (CSFs), erythropoietin, and others stimulate differentiation and maturation of bone marrow progenitor cells 

Poietin Drugs 

• Dosed SQ injection for patients with renal failure or malignancy and RBC are low but there are no other deficiencies

• Epoetin (Epogen, Procrit) 

  • Dosed 3 per week 

• Darbipoetin has a longer duration of activity and may reduce the need for multiple injections every week  

• These drugs must have all the needed factors and cofactors present

  • Correct any underlying deficiencies prior to treatment 

• Black box warning: 

  • Can make blood to thick = lead to CVA, stroke, MI

  • Increased risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access and tumor progression