Anticoag, antiplatelet, thrombolytics Flashcards

Question

Heparin PK/PD? indications for use?

Answer 1

VARIABLE * baseline antithrombin activity can influence patient response * *if have a lot of baseline antirhombin III activity, then need less heparin* * *if lower, need more heparin!* * temp dependent (more active at higher body temp) * highly polar and large MW (3000-300000 dlatons, does nto cross biological membrane) * iv/sq only * good choice in pregnancy and breast feeding!! * protein binding * lots of non speicifc binding- variable free drug/unpredictable resposne * metabolism * onset : minutes IV, SQ 1-2 hours * 1/2 life- 1 hours- precise mechanism of clearnace/metabolism is unclrea, hepatic metabolism, renal excretion * indications: * PE, DVT, DVT prevent, acute MI, stroke, dialysis, CPB, DIC

Answer 2

aptt (activated partial thromboplastin time) * typical goal 1.5-2 x normal (30-25 seconds) * activated clotting time (act) used with high dose (CPB) * baseline, 3-5 min after heparin and every 30 min

Answer 3

* hemorrhage * HIT (heparin induced thrombocytopenia) *sometimes occurs after 5-7 days on heparin* * **50% decrease in plt count \<100,000 cells/mm3 with thomrobsis * osteoporosis * hypersensitivity * animal tissue extraction source

Answer 4

Heparin induced thrombocytopenia * potentially fatal immune mediated d/o characterized by reduced plt counts and a paradoxical increase in thrombotic events * underlying cuase is antibodies agonist heparin-plt protein complexes * antibodies activate PLT and promote thombosis and loss of circulating plts * DVT, PE, Coronary thombus, loss of ciruclation to an extremity requiring amputation * 1-3% develop HIT when they receive heparin for \>4 days * monitor plt count q 2-3 days for first 3 weeks of heparin use and then every month * Txmt- d/c heparin and change ot non-heparin anticoag from later slide---\> * Heparin binds to PF4 (platelet factor 4) * This exposes new surface of PF4 --\> antibodies * The antibody binds the PF4/Heparin complex * The Ab binds the Fc receptor on platelets * This activates the platelet → releasing more PF4 * And activating thrombin --\> blood clots! * Tx: antithrombin drugs (but not heparin)

Answer 5

protamine * Alkaline and **positively** charged (heparin acidic and **–** charged) → neutralize heparin * DOA: 2 hours (may need a redose) * 1 mg protamine /per 100 units heparin * Give slowly! (fast = hypotension) * And consider how much heparin has been metabolized at the time of reversal

Answer 6

* Liver or kidney disease * Indwelling epidural catheter- leave in until hep metabolized * Traumatic placement of epidural or spinal anesthetic * Other anti-platelet or anti-coagulation medications (and herbals) * Peri-surgical: eye, brain or spinal cord (comp bleeding bad) * Patients at high risk for bleeding * Ex: Hemophilia, aneurysm, severe HTN, GI bleed risk (i.e. PUD), thrombocytopenia

Answer 7

Spinal Hematomas: * No heparin * Atraumatic – 1.00 (set as control) * **Traumatic** placement w/o heparin- 11.2 * **Aspirin- 2.5 risk than with an atraumatic pt** * Heparin following neuraxial procedure * Atraumatic- 3.16 * Traumatic- 112 (HUGE RISK OF SPINAL HEMATOMA) * If had a traumatic placement → don’t want to give heparin/anticoag after… * Heparin \>1 hr after puncture- 2.18 (WAIT AN HOUR for heparin bolus → LOWERS RISK) * **Heparin \< 1 hr after puncture- 25.2** * **With Aspirin- 26** (d/c w/in 7 days to decrease risk) Takeaway: * DON’T GIVE HEPARIN AFTER TRAUMATIC PLACEMENT * WAIT 1 HR AFTER PUNCTURE TO GIVE HEPARIN

Answer 8

* **Enoxaparin (Lovenox)** * Dalteparin (Fragmin) * Tinzaparin (Innohep) * 1^st line therapy for DVT prophylaxis and tx * Also used in unstable angina/MI/coronary ischemia * **Equal efficacy compared with heparin (even though just blocking Xa)** * Same 5 sugar sequence inactivates Xa * Not as effective in inactivating thrombin * **More predictable pharmacokinetics** * Higher bioavailability * Longer half life (up to 6X that of heparin) * No aPTT monitoring required * No hospitalization required

Answer 9

* **Adverse Effects** * **Bleeding** (lower risk compared with unfractionated heparin) * HIT – if hx (no heparin for rest of life) * **Contraindications/Precautions** * Effect greatly prolonged in renal failure → *use unfractionated heparin instead* * Spinal or epidural anesthesia * Anti-plt or anti-coagulant drugs * Delay surgery 12 hours after last dose

Answer 10

* Exclusively inactivates Xa by enhancing antithrombin III activity (no direct effect on thrombin activity) * Chemically identical to the 5 sugar active site of heparin and LMWH * Much smaller than heparin and LMWH * **Half-life LONG (over 3x as long as LMWH)** * E1/2t = 15 hours * Effect onset 2 hours/effect lasts 2-4 days after last dose * ~ Stop med earlier than unfractionated heparin/LMWH

Answer 11

* **No reversal agent** * HIT does not occur * thrombocytopenia occurs (3%) → not r/t HIT * **Contraindications** (excessive risk of bleeding): * **Severe Renal Impairment** (CrCl \< 30ml/min) * **Weight \< 50kg** undergoing hip fracture/replacement surgery, or knee replacement surgery (too dramatic of effect) * Caution: * Elderly patients * CrCl (30-50ml/min) – borderline * Epidural or spinal anesthesia – long half life → d/c long enough?

Answer 12

* Directly bind thrombin at both the catalytic and fibrinogen binding site. * Bind to circulating thrombin and thrombin already associated in clot * Useful in history of HIT * *all approved fairly recently (2010/2011)* examples: * **Dabigatran (Pradaxa**) – most common recognize this one * **PO** * Desirudin * SQ * Approved for DVT prevention in patients undergoing elective hip replacement * Lepirudin (Refludan) * IV infusion only * Approved for thrombus prevention in patients with HIT * Bilvarudin (Angiomax) * IV infusion only * Used with ASA in coronary angioplasty for thrombus prevention * E 1/2 time is 25 minutes * Argatroban * IV infusion only * Approved for thrombus prevention in patients with HIT

Answer 13

* **Pro-drug:** binds and reversibly inhibits circulating thrombin and clot integrated thrombin * FDA approval: Indicated for Atrial Fibrillation only * Rapid onset; E1/2t = 13 hours * **Effect measured by thrombin times TT (best) or aPTT** * Not significantly metabolized by hepatic enzymes * Primarily cleared by the kidneys (renal fx important!) * Encourage fluid intake * Recommendations to D/C: * Normal renal fx: d/c 48 hours before sx * Abnormal renal fx: d/c 72-96 hours before sx * High risk for bleed during sx: d/c 5 days before

Answer 14

* Adverse Effects * **Bleeding** (17% all types with 3% major bleed) * Risk of life-threatening bleed: Warfarin \> Dabigatran * GI (35%) * Dyspepsia * Gastritis * Drug interactions * **P-glycoprotein inhibitors** will increase drug levels of dabigatran * Ex: Ketoconazole, amiodarone, verapamil, quinidine → can push super therapeutic risk

Answer 15

* **Praxbind^® (idarucizumab)** * humanized monoclonal antibody fragment (Fab) * binds to dabigatran and metabolites with higher affinity than the binding affinity of dabigatran to thrombin → neutralizing their anticoagulant **effect immediately after administration** * FDA has granted full approval in 2018

Answer 16

* Highly selective direct factor Xa inhibitor * **Can inhibit free Factor Xa or bound Xa** (heparins only bind free) * Marketed for use in hip and knee replacement surgery as DVT/PE prophylaxis & approved in Afib * Metabolized by CYP3A4 & Substrate for P-glycoprotein (interactions) * ~35% eliminated unchanged by kidneys

Answer 17

* Adverse effect * **Bleeding (potentially fatal)** * but lower risk compared with warfarin * Contraindicated * Renal, hepatic disease, major bleeding risk, etc.

Answer 18

* **Andexxa** (coagulation factor Xa [recombinant], inactivated-zhzo) for reversal (bind and neutralize drug) * Fast-track status → be aware of unanticipated SE * FDA just approved (2018)

Answer 19

* No blood test reliably estimates effect * **Recommendations preop:** * Preop: Hold 48 hours * High risk for bleed during sx: 5 days

Answer 20

For the new direct oral anticoagulants (direct thrombin/Xa inhibitors): * ASRA guidelines: * Interval of **5 half-lives** of the drug **before** a regional/pain intervention. → then eligible * Resumption of drug after a _neuraxial procedure_ → 6 hours * Resumption of drug after _pain intervention_ → 24 hours

Answer 21

1. **Thromboxane inhibitor** * Aspirin (ASA) 2. **P2Y₁₂ ADP Antagonists** * Ticlopidine (Ticlid) * **Clopidogrel (Plavix)** * Aspirin/dipyridamole (Aggrenox) 3. **GIIb/IIIa Antagonists** **→** **intense drugs** * Abciximab (Reopro) * Tirofiban (Aggrestat) * Eptifibatide (Integrilin)

Answer 22

* Plts have receptors → GPiib./IIIa * GPiib./IIIa – tons of these * Bind fibrinogen (goal of coag cascade is convert fibrinogen → fibrin) * Want GPiib./IIIa receptors to be in optimal shape/confirmation to bind fibrinogen (bc then will convert to fibrin → plt plug) * Several things work to stabilize confirmation: * 1. Thromboxane A2 (TXA2) * 2. ADP (P2Y12 receptor which binds ADP) * Drugs we use INHIBIT these signals * Ex: Aspirin INHIBITS TXA2 * → less GPiib./IIIa receptors in optimal shape (no binding fibrinogen → discourages plt aggregation)

Answer 23

* **COX-1:** Produced by platelets * No nuclei * So once inhibited → platelets cannot produce more COX-1 * Induces platelet aggregation and vasoconstriction _via thromboxane A2_ * **PROCOAGULANT** factors * **COX-2:** Produced by vascular endothelial cells * Have nuclei, can replace inhibited enzyme * Inhibits platelet aggregation and promotes vasodilation _via prostacyclin_ * **ANTICOAGULANT** factors stimulated

Answer 24

**Low doses (75 to 81 mg/day****): lifetime plt inhibition (7-10 days) \<--** *hold prior sx* * Selectively/irreversibly inhibit (COX)-1 → inhibits generation of thromboxane A2 → GPiib./IIIa receptors not in optimal confirmation shape → * **Antithrombotic effect** * less vasoconstriction too (Less TXA2) **Intermediate doses (650 mg to 4 g/day):** * inhibit COX-1 and COX-2 → blocking prostaglandin (PG) production → **_analgesic and antipyretic effects_** * COX 2: don’t want to block (has endogenous anticoag, dilation effect) * *Higher doses* *→* *lose anticoag effects…* **High doses (4 and 8 g/day):** * **_anti-inflammatory effect_** **-** COX-2 dependent PGE2 * Limited by toxicity: tinnitus, hearing loss, and gastric intolerance

Answer 25

* Arachidonic pathway uses cyclooxygenase (COX) to produce thromboxane A2 (TXA2) and prostacyclin I2 (PGI2) * ASA i**rreversibly inhibits** the COX pathway * 7-10 days (hold for this period before surgery unless risk of bleeding\< benefit of continuing) * Effect of cox 1 inhibition- TXA2 inhibition decreases vasoconstriction and decreases degranulation of platelets * Effect of cox 2 inhibition (higher doses of ASA)- PGI2 inhibition reduces vasodilation and promotes platelet degranulation

Answer 26

* Indications * Transient ischemic attack/ischemic stroke * Stable and unstable angina * Prevention and treatment of MI (research varies) * Maintenance of patent coronary stents * Adverse Effects: * GI bleed * Hemorrhagic stroke

Answer 27

P2Y12 Adenosine Diphosphate (ADP) receptor antagonist * Structurally related class of compounds reduce plt aggregation * **Inhibition** of the P2Y12 ADP receptor (P2Y12 receptor which binds ADP) * Blocks stimulated adenylyl-cyclase activity * Prevents GPiib./IIIa receptor optimization * **Prodrugs:** subject to genetic variability * Converted *in vivo* to thiol-containing active metabolites * Metabolism pathways are different for each member of this class.

Answer 28

* **Irreversible blockade for life of plt:** **7-10 days** * **Ticlopidine** – 1^st generation * Use less common * **Clopidogrel** – 2^nd generation * Most commonly used * **Pasugrel** – 3^rd generation * **Black Box Warning** for bleed risk in \>75 year \< 60 kg /TIA/Stroke patients * **Reversible blockade:** * **Ticagrelor**

Answer 29

* Indications: * Inhibits plt aggregation ~50% * Maintenance of coronary stent patency * Prevention of MI/Stroke/vascular occlusion in high risk patients (usually combined with ASA in acute coronary syndromes) * Alternative primary prevention in ASA intolerant patients * Ex: Aspirin increases leukotrienes → asthmatics get bronchodilation

Answer 30

class: ADP receptor antaognists * Pharmacokinetics * Rapid oral absorption * Onset 2 hours (delayed- Prodrug → needs metabolism to active form) * Peak 3-7 days * Once daily dosing regimen considered sufficient * **Pro-drug**: Must undergo metabolism by CYP2C19 to become active * “Poor metabolizers” (variant CYP2C19) may fail therapy * **Black Box Warning\*** * Consider **prasugrel or ticagrelo**r in these patients

Answer 31

* Other medications that increase bleeding * Drugs that inhibit CYP2C19 * Ex: Proton-pump inhibitors- want to put pts on PPI for increase GI bleed risk but actually prevents clotting * Still used together but with caution

Answer 32

* Severe rash * Diarrhea * Bleeding complications * *really these patients will just be bloodies, even if clopidorgrel stopped before surgeyr* * *be smart about ordering blood!* * Thrombocytopenia (rate similar to aspirin) * TTP – usually within the first two weeks of therapy * (Diff mechanism to HIT), r/t genetic condition in ADA enzyme- monitor when first started * **No significant rate of neutropenia** (contrast with ticlopidine)

Answer 33

* **Clopidogrel + aspirin** **vs aspirin alone:** CURE & COMMIT trials - **combination better** * Complimentary mechanisms → _additive effect_ * Effective for patients undergoing PCI and med mgmt. * Combo better but increase risk of bleeding

Answer 34

* P2Y12 ADP receptor antagnoist * A pyrimidopyrimidine derivative with vasodilator and antiplatelet properties * Mechanism of action is not clear * **Increases plasma adenosine levels** * **Half Life:** 10 hours * Requires BID dosing * **Indication:** * Used in combination with warfarin * Indicated for prevention of thrombus following heart valve replacement * ***Aggrenox****:* Combined with aspirin → reduce the risk of _ischemic stroke_ * FDA approved as combination medication for **stroke prevention** * No intrinsic antiplatelet activity or increased bleeding risk noted when used alone (w/o aspirin) * ~ Good to add to aspirin w/o having increased risk of bleeding

Answer 35

* **Adverse Events:** * Headache (most common) - dilation * Hypotension (vasodilator properties) * Bronchospasm/dyspnea * Myocardial ischemia/infarction * Arrhythmias * Nausea/dizziness * Rash/flushing

Answer 36

* **Glycoprotein IIb/IIIa Receptor:** Receptor responsible for binding fibrinogen → which ultimately makes fibrin→ plt plug * **_Antagonists:**_ _**powerful antiplts_** * **Abciximab (IV only)** * Tirofiban (IV only) * Eptifibatide (IV only) **ONLY** used in **Acute** situations (IV only!) * **Mechanism of action**: Reversible blockade of GP-IIb/IIIa receptors -**the final step of plt aggregation** * This prevents platelets from attaching to each other despite TXA2, ADP, thrombin or plt activation factor stimulation. * Most effective form of antiplatelet activity

Answer 37

* **Indications** 1. Unstable angina, acute MI 2. Percutaneous coronary intervention (angioplasty, etc.) * **\*Can develop allergy after 1 dose\*** * **Prototype: Abciximab** 1. Purified Fab fragment of monoclonal antibody that binds near the GPIIb/III receptor occluding the binding of fibrinogen (blocks fibrinogens ability to binds) 2. Adverse effects: * Bleeding risk 2X increase (only use in acute care situations)

Answer 38

* Streptokinase * Urokinase * Tissue plasminogen activator **tPA (alteplase)**

Answer 39

* Fibrinolytic system dissolves intravascular clots * Plasminogen → plasmin (active form) * Plasmin is a nonspecific protease → digests fibrin clots and other proteins in clot * Fibrinolytic drugs are also **non-specific (breakdown any clot in path)** * Both protective thrombi and target thromboemboli are broken down * Potential for **hemorrhage is high**

Answer 40

* A version of tissue plasminogen activator (tPA) produced by recombinant DNA technology * IV infusion * E1/2T = 5 minutes (very short) * Binds plasminogen catalyzing the reaction: plasminogen→plasmin * Plasmin digests fibrin (breaks down thrombi) * Plasmin breaks down fibrinogen and other clotting factors (increasing risk of subsequent hemorrhage * Indicated: * Acute MI * Acute ischemic stroke (after CT scan to r/o hemm stroke) * Symptomatic PE

Answer 41

* Bleeding!!!! **5-30%** * Intracranial hemorrhage (r/o hemorrhagic stroke) - 1.7-8% * Pretherapy CT critical * Healing area with previous clot formation * (wounds, intravenous & arterial lines, invasive procedure) * May need to administer blood products to restore hemostasis * Angioedema → (especially if also on ACE inhibitor)

Answer 42

* **Must administer quickly after symptom onset** * GUSTO-I trial (coronary artery occlusion) * Administered within 2 hours death rate: ~5% * Administered within 2-4 hours death rate ~6.7% * Administered within 4-6 hours death rate ~ 9.4%

Answer 43

* **Absolute** * Intracranial hemorrhage/brain tumor/cerebral vascular lesion * Known source of internal bleeding * Aortic dissection * **Relative** **→** **risk of bleed…** * Severe HTN (\> 180/110 mmHg) * Intracerebral issues not noted in absolute contraindications * Other anti-coagulants/anti-plt drugs (increase bleeding risk) * Known bleeding pathophysiology/non-compressible vascular puncture * History of traumatic injury major surgery, internal bleeding ~ 3 wks * Pregnancy * Peptic ulcer disease

Answer 44

* **Antifibrinolytic Agents** * Lysine analogs * Aprotinin (not currently available in US secondary to safety concerns- see BART trial) * **Recombinant Proteins** - see chapter 29 * Activated Factor VIIa * Factor XIII * Prothrombin Concentrates

Answer 45

Antifibrinolytics: lysine analogs- help people stop hemorrhaging ex- transexamic acid and aminocaproic acid * MOA: competitively inhibits plasminogen activation * (binds to the kringle domain in place of lysine on plasminogen) * _reducing plasmin concentration and fibrinolytic activity_. * TXA will directly inhibit plasmin at high doses. * Opposite of TPA- see inhibition of fibrolytic activity * Basic science is still examining exact MOA * Alternative hypothesis has been suggested: TXA improves survival via reduction of pro-inflammatory plasmin activity * **Blood loss and need for transfusion are reduced in surgical patients- elective and traumatic cases** * **No increase of risk for thromboembolic events based on current evidence** * **No MI, stroke risk**

Answer 46

**\*\*Give** **within 3 hours** **for reduced risk of death due to bleeding in trauma and obstetrical hemorrhage** **CRASH -2:** * Randomized, prospective study of trauma patients * 247 hospitals, 40 countries, n = \>20,000 * All cause mortality decreased by 10% (RR 0.91, 95% CI 0.85-0.97) * Risk of death from bleeding decreased by 15% (RR 0.85, 95% CI 0.76-0.96) * Best outcome if given within 3 hours of injury * ~ After traumatic activity and in OB → increased activity of plasmin (helps offset paradoxical effect) **WOMAN Trial** * Randomized, prospective study of obstetric patients * 191 hospitals, 20 countries, n= \>20,000 * Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients *vs* 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group *vs* 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). * Takeaway: if pt hemorrhaging (elective, trauma, obstetrics) → admin w/in 3 hr → IMPROVES OUTCOMES

Answer 47

* **1 gm in 100cc/NSS given over 10 minutes (loading dose)** **→** **Followed by 1gm in 100cc/NSS over 8 hrs** * Do not administer in the same line as blood products, rFVIIa or Penicillin * Should be stored between 15-30C or 56-86F

Answer 48

* 3% protein bound (does not bind to albumin) * Vd 9-12 liters * 95% excreted unchanged * Reduce dose in renal disease (see below) * Onset 5-15 min; duration 3 hours * E1/2 t= 2- 11 hours

Answer 49

* Seizures * GABA blockade in frontal cortex * Vision changes – particularly color vision * Ureteral obstruction and bleeding * Renal toxicity