Antiplatelet, Anticoagulation and Hemostatic agents Flashcards
Warfarin MOA
○ Molecule is structurally related to Vitamin K
○ Binds Vitamin K Oxide Reductase, inhibiting it
■ Inhibits ability to activate Vitamin K (factors II, VII, IX, X, Protein S, & C)
Warfarin indications
○ VTE (DVT/PE) prophylaxis
○ VTE treatment
○ Stroke prevention with A-Fib
○ Prevention of mechanical heart valve
thrombosis
Warfarin Contraindications
○ Pregnancy (teratogenic and risk of fetal bleeding)
○ Active bleed or high risk for bleed (like Thrombocytopenia)
○ Blood dyscrasia
○ Recent major surgery
○ Eclampsia or Preeclampsia
○ Frequent falls or high risk for falls
○ Dozens of Drug-Drug interactions! (Use Interaction Checker!)
Warfarin Side effects
○ Easy bruising
○ Bleeding gums
○ Nausea/vomiting/diarrhea
○ Fatigue and malaise
○ Headaches
○ Dizziness
○ Taste changes
Warfarin Major adverse reactions
○ Intracranial hemorrhage (often
fatal)
○ Skin necrosis
○ GI hemorrhage
○ GU hemorrhage
Warfarin BBW
○ Major or fatal bleeding may occur. Monitor high risk patients closely.
INR > 4.0 is very high risk for bleed
Warfarin (Coumadin) administration and surgery
If surgery planned, D/C warfarin 5 days before procedure. Restart 12-24 hours after
procedure. Bridge w/ a Heparin in high VTE risk.
Warfarin follow up/monitoring
○ Considered contraindicated in pregnancy unless Pt has mechanical heart valve, then need
to weigh risks/benefits. Probably safe with lactation.
○ Adjust doses based on PT/INR. Target INR is 2-3 for most; Some high-risk patients may
require target INR 2.5-3.5.
○ Local “coumadin clinics” are extremely helpful with monitoring.
Indirect Thrombin Inhibitors - Heparin
○ AKA - Unfractionated Heparin (UFH)
■ Mixture of proteins with a wide range of
molecular weights
Low Molecular Weight Heparins
(LMWHs)
○ Enzymatically or chemically broken down UFH, about 1⁄3 the size of UFH
■ Enoxaparin (Lovenox)**
■ Dalteparin (Fragmin)
■ Fondaparinux (Arixtra)
Indirect Thrombin Inhibitors MOA
○ Antithrombin III inhibits Factor
X and Thrombin
○ Heparin binds to Antithrombin
III and accelerate its rate of action by about 1000 fold
○ UFH: Thrombin ___ Factor X
○ LMWH: Factor X ___ Thrombin
> ; >
Indications (SC, IV) of UFH and LMWH
■ Prevention of thrombosis with Atrial
Fibrillation and PCI
■ VTE Prophylaxis in high risk patients
■ Treatment of acute VTE
■ Treatment of Acute Myocardial Infarction
and unstable angina in combo with
antiplatelet Rx
○ Enoxaparin (Lovenox) is the drug of choice during pregnancy
Indirect Thrombin Inhibitors contraindications
○ Thrombocytopenia
○ Personal history of Heparin-Induced Thrombocytopenia
○ Hemorrhage or active bleed
○ Not to be given as an IM administration
○ Hypersensitivity to Pork or Corn
Indirect Thrombin Inhibitors Minor Side Effects
○ Urticaria
○ Fever
○ Minor elevation in ALT, AST
Indirect Thrombin Inhibitors Major Adverse Reactions
○ Osteoporosis with long-term use
○ Hemorrhage (reversed by Protamine Sulfate)
○ Heparin-Induced Thrombocytopenia
○ Anaphylaxis
○ Hepatotoxicity
BBW Indirect Thrombin Inhibitors
High risk for Epidural/Spinal hematoma from acute hemorrhage during lumbar puncture or spinal injection. Can cause acute spinal cord or spinal nerve compression
Follow up and monitoring - UFH
○ UFH can be given IV or SC
■ Usually IV bolus for immediate anticoagulation, then continued until PO anticoagulant takes over
– Anticoagulant effect within minutes of IV administration
■ Monitor closely using PTT or Heparin Anti-Xa
Monitor platelets daily if on IV UFH, for at least 10 days
Follow Up and Monitoring - LMWHs
■ Peak effect is reached in 2-4 hours
■ Don’t routinely need to be monitored, but if renal insufficiency or
pregnancy, can check Heparin Anti-Xa
If drop in platelet count by more than ___%
from baseline, D/C medication as now
there is concern for HIT
50
Direct Thrombin Inhibitors
● Bivalirudin (Angiomax)
● Argatroban (Acova)
● Dabigatran (Pradaxa)**
Direct Thrombin Inhibitors
○ Just as the name implies, these
work by directly inhibiting Thrombin
○ Inhibitory effects on the Coagulation Cascade
Direct Thrombin Inhibitors Indications (IV, PO)
Bivalirudin and Argatroban are only IV
– Anticoagulation during HIT
– Prevention of thrombosis during PCI (in presence of Heparin
allergy/HIT)
Dabigatran is a PO capsule
● Stroke prevention in Atrial Fibrillation
● DVT/PE prophylaxis in high risk patients
● DVT/PE treatment
Direct Thrombin Inhibitors contraindications
○ Active bleeding
○ History of a bleeding disorder
○ Peptic ulcer disease
○ Mechanical Heart Valve Anticoagulation
Direct Thrombin Inhibitors BBWs
○ Dabigatran has earned 2 BBWs
■ Increased incidence of Thromboembolism if D/C treatment before
recommended duration
■ Large risk for epidural hematoma with spinal injections
Direct Thrombin Inhibitors minor side effects
○ Easy bruising
○ Nausea/vomiting
○ Dabigatran (PO): Gastritis
○ IV use: Hypotension, fever,
headache, IV site pain
Direct Thrombin Inhibitors Major adverse reactions
○ Severe bleeding / hemorrhage
○ Spinal hematoma w/ injection
○ Thrombocytopenia
○ Anaphylaxis
○ Thrombosis with premature D/C
Direct Thrombin Inhibitors Follow Up and Monitoring
○ Argatroban and Bivalirudin – Benefits likely outweigh risks in pregnancy
○ Dabigatran – Avoid use in pregnancy; animal studies show potential harm
○ IV meds should be monitored using PTT
○ Dabigatran does not require monitoring due to large therapeutic window and short
half-life (12-24 hours)
○ Argatroban and Bivalirudin do not have reversal agents, however…
Direct Thrombin Inhibitors Follow Up and Monitoring
○ In late 2015, the FDA announced approval for Idarucizumab (Praxbind), a reversal agent for the anticoagulant Dabigatran (Pradaxa)
○ Given as an IV dose in emergency situations (ie. head bleed)
■ Binds to Dabigatran and its metabolites,
neutralizing the drug in circulation
Direct Factor Xa Inhibitors
● Rivaroxaban (Xarelto)**
● Apixaban (Eliquis)**
● Edoxaban (Savaysa)
● Fondaparinux (Arixtra) – SQ
Direct Factor Xa Inhibitors MOA
○ These work by directly inhibiting
active Factor X, just like the name
implies
○ Fondaparinux also binds to and
accelerates Antithrombin
Direct Factor Xa Inhibitors Indications
○ All four agents
■ DVT/PE prophylaxis in high risk patients (like Ortho surgery)
■ Acute DVT/PE treatment
○ Xarelto, Eliquis, and Savaysa*
■ Thromboembolism/Stroke prevention in Atrial Fibrillation
Direct Factor Xa Inhibitors Contraindications
○ Active bleeding
○ Hepatic or Renal impairment
○ Acute PE with hemodynamic instability or requiring thrombolytics
Direct Factor Xa Inhibitors Side effects
○ Easy bruising
○ Nausea
○ Rash
○ Mild ALT/AST elevation
Direct Factor Xa Inhibitors Adverse effects
○ Severe bleeding/hemorrhage
○ Spinal hematoma with injection
○ Thrombosis with premature D/C
○ Thrombocytopenia
Direct Factor Xa Inhibitors BBWs
○ Large risk for epidural hematoma with spinal injections
○ NOACs – Increased incidence of Thromboembolism if D/C treatment before
recommended duration
○ Edoxaban – Increased risk of A-Fib related stroke if Creatinine Clearance is
greater than 95 mL/min
Direct Factor Xa Inhibitors follow up and monitoring
○ Avoid use during pregnancy and lactation safety unknown
○ Check Creatinine at baseline
■ Remember creatinine clearance BBW of Edoxaban (Savaysa)
○ Consider checking CBC periodically for thrombocytopenia
○ No routine coagulation monitoring needed because of large therapeutic
window and short half life
○ Fondaparinux is given SC and behaves similar to Heparins
If acute hemorrhage and the pt is on a Direct Factor Xa Inhibitor, can also provide ____
Fresh Frozen Plasma (FFP)
The Antiplatelets
○ Aspirin (ASA)**
○ Cilostazol (Pletal)
○ ADP Receptor Inhibitors:
■ Clopidogrel (Plavix)**
■ Ticagrelor (Brilinta)
■ Prasugrel (Effient)
○ Glycoprotein IIb/IIIa Inhibitors:
■ Abciximab (Reopro)
■ Eptifibatide (Integrilin)
■ Tirofiban (Aggrastat)
The Antiplatelets prolong bleeding time without affecting _____
PT and PTT
The Antiplatelets of antiplatelets
○ Prevention of occlusive coronary disease
○ Long term treatment of acute coronary syndrome
○ Maintenance of vascular grafts and arterial patency
Aspirin MOA
○ Thromboxane (TXA2) is a substance Platelets make and secrete which enhance platelet aggregation
○ Aspirin irreversibly inhibits
COX1-mediated TXA2 synthesis
■ This is irreversible, so stays in
effect through the life of that
platelet (7 days)
Aspirin indications
○ Mild pain
○ Fever
○ Acute Coronary Syndrome
○ MI prevention (primary or secondary)
○ TIA/CVA prevention (primary or
secondary)
Aspiring contraindications
○ ASA-induced asthma or urticaria
○ Aspirin triad (nasal polyps, asthma, aspirin intolerance)
■ Can develop rash and/or life threatening asthma attack
○ GI bleeding
○ Coagulation disorder
○ G6PD deficiency
○ Uncontrolled hypertension
○ Febrile illness in children under 2 YOA
Aspirin Side effects
○ Dyspepsia
○ Nausea
○ Dizziness
○ Rash
○ Tinnitus
○ Abdominal pain
○ Constipation
○ Ecchymosis
○ Bleeding
Aspirin Adverse Reactions (Major)
○ Anaphylaxis
○ Angioedema
○ Bronchospasm
○ Bleeding
*○ GI perforation or ulcer
*○ DIC (rarely)
○ Pancytopenia
○ Thrombocytopenia
○ G6PD Deficiency Anemia
○ Aplastic anemia
○ Nephrotoxicity
○ Hepatotoxicity
○ Salicylism
*○ Reye Syndrome
Aspirin follow up
○ May use low dose ASA in pregnancy. Avoid high dose ASA in 3rd Tri as this can trigger premature closure of patent ductus arteriosus
○ Possibly unsafe during lactation
○ Check creatinine at baseline as excreted renally
○ Aspirin can displace coumadin from plasma proteins (as well as other medications like Phenytoin)
■ Run interaction check
Cilostazol (Pletal) MOA
○ Phosphodiesterase III (PDE3) is an enzyme
involved in the intracellular regulation of
platelet factor synthesis
○ Cilostazol inhibits PDE3, leading to a complex reaction that ultimately results in decreased Platelet Aggregation
○ Also causes vasodilation
Cilostazol (Pletal) Indications
○ Intermittent Claudication of Peripheral
Arterial Disease (PAD)
Cilostazol (Pletal) Contraindications
○ Congestive Heart Failure
○ Hemostatic bleeding disorders
○ Active bleeding
○ Caution if chronic renal disease
Cilostazol (Pletal) BBW
Do not use in CHF as it has been shown to decrease survival
Cilostazol (Pletal) Side effects
○ Headache
○ Dizziness
○ Abdominal pain
○ Diarrhea
Cilostazol Major adverse reactions
○ Hemorrhage
○ Angina/Myocardial infarction
○ Agranulocytosis
○ Thrombocytopenia
Follow Up and Monitoring for Cilostazol (Pletal)
○ Caution advised in pregnancy as some animal studies suggest fetal harm. Safety during lactation unknown
○ Check CBC prior to starting and recheck CBC periodically if taking long-term
Antiplatelets – ADP Receptor Inhibitors
● Clopidogrel (Plavix)**
● Ticagrelor (Brilinta)
● Prasugrel (Effient)
ADP Receptor Inhibitors MOA
○ Inhibit the binding of ADP to its
receptor on platelets, which inhibits
GP IIb/IIIa receptor activation,
thereby preventing Platelet
Aggregation
ADP Receptor Inhibitors Indications (PO)
○ Treatment of Acute Coronary Syndrome (all 3 drugs)
■ Along with an indirect thrombin inhibitor (ie. Heparin)
○ Clopidogrel (Plavix) and Ticagrelor (Brilinta)
■ Prevention of thrombotic events in Coronary Artery Disease
○ Clopidogrel (Plavix) only:
■ Prevention of thrombotic events in Peripheral Arterial Disease and
Cerebrovascular Disease (Stroke/TIA)
Contraindications of ADP Receptor Inhibitors
○ Active bleed
○ High risk for ischemic stroke hemorrhaging
ADP Receptor Inhibitors side effects
○ Easy bruising
○ Rash and pruritus
○ Nausea/vomiting/diarrhea
ADP Receptor Inhibitors BBWs
○ Clopidogrel (Plavix): Efficacy is
dependent on conversion to active metabolite by Cyp2C19. Poor Cyp2C19 metabolism results in poor efficacy
○ Ticagrelor and Prasugrel: Severe
bleeding, possibly fatal
○ Ticagrelor: Taking ASA with this
drug may reduce the effectiveness of Ticagrelor for unknown reasons
ADP Receptor Inhibitors Major adverse reactions
○ Severe hemorrhage/bleeding
○ Agranulocytosis
○ In very rare instances, Ticagrelor
(Brilinta) and Prasugrel (Effient) has
been associated with TTP
ADP Receptor Inhibitors Follow up
○ Benefits likely outweigh risks during pregnancy; Risk of fetal harm
not expected based on limited human data.
○ Lactation safety is mostly unknown
○ Despite some potentially life
threatening adverse reactions that can
occur with these medications, there are
no current recommendations for
routine monitoring.
Antiplatelets - Glycoprotein IIb/IIIa Inhibitors
● Abciximab (Reopro)
● Eptifibatide (Integrilin)
● Tirofiban (Aggrastat)
All 3 are IV medications
Glycoprotein IIb/IIIa Inhibitors MOA
Blocks the Glycoprotein IIb/IIIa receptor proteins on the
membranes of activated platelets, preventing Platelet Aggregation
Source: Epocrates
Glycoprotein IIb/IIIa Inhibitors Indications
○ Acute Coronary Syndrome – Adjunct
○ Percutaneous Coronary Intervention – Adjunct
Glycoprotein IIb/IIIa Inhibitors contraindications
– Recent major surgery
– Recent stroke
– Recent GI bleed
– Thrombocytopenia
Glycoprotein IIb/IIIa Inhibitors Minor side effects
○ Easy bruising
○ Dizziness
○ Nausea/vomiting
○ Mild hypotension
Glycoprotein IIb/IIIa Inhibitors Major adverse ractions
○ Significant hemorrhage
○ Severe thrombocytopenia
○ Coronary artery dissection
○ Anaphylaxis
Glycoprotein IIb/IIIa Inhibitors follow up
○ Benefits likely outweigh risks during pregnancy; Risk of fetal harm not
expected based on limited human data
○ Check creatinine at baseline
○ Check CBC, PT, and PTT at baseline; recheck CBC daily if prolonged
treatment (which is not common)
Thrombolytics
○ Alteplase (tPA)**
○ Reteplase (Retavase)
○ Tenecteplase
(TNKase)
Thrombolytics MOA
These bind to fibrin and convert Plasminogen to Plasmin, promoting
Fibrinolysis (clot buster)
Thrombolytics indications
○ Acute ST-Elevation Myocardial Infarction (STEMI)
■ Only if PCI is impossible within 120 minutes of arrival
■ Fibrinolytics ideally within 12 hours of symptom onset
○ Alteplase (tPA) only
■ Massive Pulmonary Embolism with shock
■ Acute Thromboembolic Stroke
Thrombolytics Absolute contraindications
○ History of intracranial hemorrhage
○ Known structural cerebral vascular lesion (such as AVM)
○ Known malignant intracranial neoplasm
○ Ischemic stroke within 3 months (EXCEPT acute ischemic stroke within 3-4 1⁄2
hours)
○ Suspected aortic dissection
○ Active bleeding or unusual susceptibility to bleeding
○ Significant closed head trauma or facial trauma within 3 months
○ Intracranial or intraspinal surgery within 2 months
○ Severe uncontrolled hypertension (unresponsive to emergency therapy)
Thrombolytics relative contraindications
○ Trauma or major surgery within past 3 weeks
○ Recent internal bleeding within past month
○ Pregnancy
○ Active Peptic Ulcer Disease
○ Current use of anticoagulation with an INR > 1.7
Thrombolytics minor side effects
Bleeding at IV sites
Thrombolytics Major adverse reactions
○ Severe bleeding, often fatal
○ Intracranial hemorrhage
○ Stroke
○ Arrhythmias
○ Anaphylaxis
Follow Up and Monitoring
○ Benefits likely outweigh risks during pregnancy; Risk of fetal harm not expected based on limited human data
○ Monitor BP and EKG closely
throughout
○ PT and PTT at baseline and then
frequently
Hemostatic Promoting Agents - plasma derivatives
■ Factor VIII concentrate (Advate)
■ Factor IX concentrate (Rixubis)
Hemostatic Promoting Agents - Hemostasis promoting agents
■ Protamine sulfate
■ Vitamin K (Phytonadione)
■ Idarucizumab (Praxbind)
■ Coagulation Factor Xa (Andexxa)
■ Desmopressin acetate (DDAVP)
■ Thrombin, topical
Plasma Derivatives MOA
○ Specific Coagulation Factor replacement
○ Given via IV infusion
Plasma Derivatives indications
○ Advate – Hemophilia A
○ Rixubis – Hemophilia B
Plasma Derivatives contraindications
Plasma Derivatives
Plasma Derivatives minor side effects
○ Headaches
○ Fever
○ Flushing
○ Nausea/Vomiting
Plasma Derivatives Major adverse reactions
○ Anaphylaxis
○ Thromboembolism Factor IX
(Rixubis)
Plasma Derivatives Follow up
○ Caution advised in pregnancy, limited
data available
○ Safety unknown with lactation
○ No routine tests recommended
Hemostatic Promoting Agents - Protamine sulfate MOA
Binds to Heparin molecule, forming a stable
molecule and rendering Heparin useless,
effectively reversing Heparin
Protamine Sulfate Indications
○ Acute bleed while on Heparin
■ Unfractionated Heparin reversal
■ LMWH reversal
■ Does not work for Fondaparinux
Protamine Sulfate contraindications
Caution in cardiac or pulmonary failure
Protamine Sulfate BBW
Can cause severe hypotension,
cardiovascular collapse,
pulmonary edema, catastrophic
pulmonary constriction, and
pulmonary HTN. Be ready for
ACLS protocol
Protamine Sulfate major adverse reactions
In addition to BBW…
■ Paradoxical hemorrhage
with “Heparin Rebound”
■ Thrombocytopenia
Protamine Sulfate minor side effects
○ Hypotension
○ Bradycardia
○ Flushing
○ Nausea/vomiting
○ Hives
Protamine Sulfate follow up and monitoring
○ Benefits outweigh risks during pregnancy; limited data
○ Safety unknown during lactation
○ Monitor EKG and BP during infusion
Vitamin K (Phytonadione) MOA
Acts as vital cofactor in the hepatic production
of coagulation factors II, VII, IX, and X
Vitamin K (Phytonadione) indications
○ Warfarin stabilization
○ Warfarin reversal in an active bleed situation
○ Vitamin K deficiency
Vitamin K (Phytonadione) Contraindications
○ Heparin anticoagulation
Vitamin K (Phytonadione) BBW
Severe reactions including death have occurred during and
immediately after IV injection. Resembles anaphylactic reaction with shock. Only applicable for IV
Vitamin K (Phytonadione) Major adverse reactions
○ Anaphylaxis
○ Anticoagulant resistance (warfarin mostly)
Vitamin K (Phytonadione) Minor side effects
○ Injection site hematoma
○ Flushing (if IM or IV)
○ Bad taste in mouth (lasts a few days)
Vitamin K (Phytonadione) Follow up
○ May used during pregnancy; risk of fetal harm is
not expected based on limited human data
○ Safe during lactation (based on lots of data)
○ No routine tests recommended for monitoring
Idarucizumab (Praxbind) MOA
A monoclonal antibody that binds
to Dabigatran (Pradaxa) and its metabolites, neutralizing the drug’s anticoagulant effect
Idarucizumab (Praxbind) Indications (IV)
○ Reversal of Dabigatran (Pradaxa)
○ Used to reverse anticoagulant during acute hemorrhages or need for emergent surgery
Idarucizumab (Praxbind) adverse reactions
○ Thrombosis / Thromboembolism
○ Hypersensitivity reaction
Idarucizumab (Praxbind) Follow up
The medication is given as a single IV
push (one time)
The medication is given as a single IV
push (one time) MOA
Binds and sequesters Factor
Xa Inhibitors and restores
thrombin generation
Factor Xa (AndexXa) Indications
Reversal of Apixaban (Eliquis) and
Rivaroxaban (Xarelto)
■ Used to reverse anticoagulant
during acute hemorrhages or
need for emergent surgery
Factor Xa (AndexXa) BBWs
Serious and life-threatening arterial and venous thromboembolic
events (including MI, stroke, cardiac arrest, and sudden death) may
occur with use
Factor Xa (AndexXa) Adverse reactions
○ Thrombosis / Thromboembolism
○ Ischemic stroke, Myocardial infarction
Factor Xa (AndexXa) Follow up
○ The medication is given as an IV push with continued infusion
Desmopressin (DDAVP)
A synthetic version of ADH (Vasopressin)
Desmopressin (DDAVP) MOA
○ At very low doses, activation of V2
receptors on collecting ducts of the
nephron, triggering water reabsorption
(Antidiuretic)
○ At higher doses, can activate V1 receptors
on endovascular epithelium, triggering
release of Coagulation Factor VIII and vWF
Desmopressin (DDAVP) Indications (PO, SL, IN, SC, IV)
○ Surgical preparation for those with Hemophilia A or von Willebrand
disease (give 30 min before surgery)
○ Central Diabetes Insipidus (was discussed in Endo)
○ Nocturnal Enuresis (works for bedwetting)
Desmopressin (DDAVP) contraindications
○ Hemophilia A or vWD patients under 3 months of age
○ Kidney disease with poor creatinine clearance
○ Hyponatremia
○ Psychogenic polydipsia
Desmopressin (DDAVP) adverse reactions
○ Dilutional Hyponatremia
○ Hypotension or Hypertension with IV administration
○ Thrombosis
○ Seizures
Desmopressin (DDAVP) follow up
○ Caution advised during pregnancy. Probably safe with lactation
○ Check Creatinine at baseline; periodically if chronic use
○ Watch serum sodium throughout treatment
○ If administering by IV, watch BP and HR closely
Topical Thrombin MOA
○ Recombinant thrombin applied directly to a
site with mild active bleeding will trigger
Fibrin production as well as ignite the
coagulation cascade and activate platelets.
Topical Thrombin Indications
○ Surgical application
○ Most commonly neurosurgery, liver surgery, and vascular surgery
○ Applied topically when suture ligation or cautery is not a safe
option
