Module 9 Haematology Flashcards
What are the features of iron deficiency anaemia?
Early: Normocytic, normochromic
•Late: Blood smear shows microcytic, hypochromic cells with central pallor
•MCV 55-74 fL, MCHC 25-30 gm/dL
•Serum iron
What are the features of clinical presentation of iron deficiency anaemia?
- Weakness
- Irritability
- Fatigue
- Headache
- Exercise intolerance
- Tachycardia
- Shortness of breath
- Restless Leg Syndrome
- Pica - craving for non nutritive items
Decreased Iron Absorption - these medications can decrease iron absorption.
To avoid decreased absorption - separate the administration of iron and acid-reducing medications by as much time as possible (e.g., for antacids).
Antacids (containing Al3+, Mg2+ & Ca2+)
H2 receptor antagonists
Proton pump inhibitors
Cholestyramine
Iron Decreases Absorption or Serum Concentration of these medications.
Thus, administration should be at least 2 hours before or 4 hours after the administration of the iron therapy.
Levodopa Levothyroxine Penicillamine Quinolone antibiotics Tetracycline derivatives Bisphosphonates For bisphosphonates, iron should be administered at least 30 minutes after alendronate and risedronate and at least 60 minutes after ibandronate.
Replacement for Iron Deficiency Anaemia
•Oral Iron Preparations:
–Ferrous sulfate 325mg 1 to 3 times daily
–Side effects include constipation, cramping, diarrhea, nausea
–Manage side effects by giving with meals or substituting ferrous gluconate, or ferrous fumarate, polysaccharide-iron complex
–Bioavailability can be increased by administering with Vitamin C or orange juice
–Different forms contain different amounts of elemental iron (see next slide)
•Parenteral Iron
•Blood Transfusion (Hg
Enteric coated preparations of iron
Enteric coated preparations should not be used in achlorhydric patients. Achlorhydria is when there is low or no gastric acid in the stomach.
What should happen to patients with very high iron requirements
Poor absorption (gastrectomy patients), or intolerance of oral preparations should receive parenteral iron.
IV iron dextran precautions and warnings
IV iron dextran has a black box warning. A 0.5 mL test drug dose should be administered before therapy is started. Patients should be observed for one hour after therapy for reactions. Epinephrine and emergency resuscitation equipment should always be readily available when using IV iron dextran. Patients have experienced delayed arthralgias, myalgias for one to two weeks after the infusion. Patients with a history of allergies, asthma or inflammatory diseases are at higher risk of reactions.
Sodium ferric gluconate and iron sucrose
Alternate parenteral iron products without the black box warning. Iron sucrose has a low incidence of hypersensitivity reaction and patients receiving it should be closely monitored for at least 30 minutes.
Monitoring of oral iron
A reticulocytosis should occur in 5-7 days with an increase in Hb of 2-4 g/dL every 3 weeks until normalized. Iron therapy needs to continue until iron stores are restored. Usually 3-6 months of therapy is needed. Serum ferritin should be normal before iron is discontinued.
Anemia of Chronic Disease (ACD)
–Laboratory findings: •No definitive test confirms the diagnosis •Early: Normocytic, normochromic •Long-standing disease: microcytic, hypochromic •Peripheral smear normal, with possible microcytes •Serum Fe, TIBC - both decreased •Transferrin saturation decreased •Serum ferritin normal to increased –Clinical Presentation: •Pallor •Tachycardia •Asymptomatic
Treatment of Anemia of Chronic Disease (ACD)
–Treatment of underlying disease
–Elimination of nutritional deficiencies, marrow-suppressive drugs
–Not responsive to common deficiency therapies (iron, B12, folic acid)
–Erythropoietic agents (EPAs) or erythropoietic stimulating agents (ESAs) – not FDA-approved for ACD, but may be for underlying causes when low erythropoietin levels are observed
Erythropoietic Stimulating Agents (ESAs) Epoetin Alfa (Epogen®)
Anemia in CKD, HIV, cancer, and some surgeries
Three times weekly; weight and indication based dosing
Adverse reactions:
Hypertension, fever, headache, pruritus, rash, nausea, vomiting, injection site reaction, arthralgia, cough
Monitoring:
Transferrin saturation and serum ferritin, Hb (weekly until goal and after dose changes), blood pressure, seizures
Erythropoietic Stimulating Agents (ESAs) Darbepoetin Alfa (Aranesp®)
Anemia in CKD and cancer
Once weekly to every 2-3 weeks; weight and indication based dosing
Adverse reactions:
Hypertension, peripheral edema, edema, abdominal pain, dyspnea, cough
Monitoring:
Hb (weekly until goal and after dose changes), transferrin saturation and serum ferritin, serum chemistry, blood pressure, fluid balance, seizures
Macrocytic anemias types
Classified by larger than normal red blood cells (RBCs), typically reticulocytes, or immature red blood cells. They are divided into megaloblastic (abnormal DNA metabolism as a result of B12 or folic acid deficiency that result in abnormal cell growth) and nonmegaloblastic (resulting from other causes).
Vitamin B12 Deficiency
Neurologic complications •Bilateral paraesthesia •Ataxia •Dementia-like symptoms •Psychotic symptoms •Unexplained neuropathies
Folic acid anaemia
- Loss of appetite
- Weight loss
- Weakness
- Irritability
- Heart palpitations
B12 Deficiency Causes
- Inadequate intake
- Malabsorption
- Inadequate utilization
Folic Acid Deficiency Causes
- Inadequate intake
- Malabsorption
- Increased folate requirements
Laboratory Diagnosis – Vitamin B12
Serum B12 deficiency
•Serum B12 levels: normal 170-820 pg/mL
•Mild leukopenia and thrombocytopenia
•Methylmalonic acid (MMA) and homocysteine may be elevated
–MMA is more specific to Vitamin B12 deficiency
–Homocysteine can be elevated in both Vitamin B12 deficiency and folic acid deficiency
•Rule in/out Pernicious Anemia
Laboratory Diagnosis – Folic Acid
Folic Acid deficiency
•B12 level normal (170-820 pg/mL)
•RBC folate levels decreased (normal =165-760 ng/mL)
•Serum homocysteine levels usually increased
•MCV, serum lactate dehydrogenase (LDH), indirect bilirubin all may be elevated
•Peripheral smear may show anisocytosis, poikilocytosis, macrocytes, hypersegmented polymorphonuclear leukocytes
•Low reticulocyte count (normal = 33-137 x103/mcL)
Causes of folic acid and Vitamin B12 deficiency
•Hydroxyurea (folic acid) •Zidovudine (folic acid) •Methotrexate (folic acid) •5-fluorouracil (folic acid) •Phenytoin (folic acid) •Trimethoprim (folic acid) •Pentamidine (folic acid) •Pyrimethamine (folic acid) •Metformin (folic acid and B12) •Cytarabine, Cladrabine •Azathioprine •6-mercaptopurine •Alcohol •Barbiturates •Triamterene •Nitrofurantoin •Primidone •Thiopental •Sulfasalazine Many have less well understood mechanisms and are therefore not classified by the deficiency they cause
Vitamin B12 Deficiency Anemia Treatment
Various dosing regimens based on disease severity and other patient factors
Cyanocobalamin (Vitamin B12) 1000 mcg IM or SQ once a week for 4-6 weeks until stores are replenished and hemoglobin and hematocrit are normalized. For an oral therapy option, Vitamin B12 1000 mcg by mouth daily for one month can be used.
•Monitor vitamin B12 and CBC at 1-2 months and then continue every 3-6 months.
Pernicious Anemia treatment
Lifelong IM Vitamin B12 supplementation
A dose of 100-1000 mcg a day for one week, then on alternating days for 2 weeks, then every 3-4 days for 2-3 weeks. Parenteral therapy is typically needed in order to by pass the lack of intrinsic factor. Maintenance therapy is typically 100-1000 mcg once a month. Oral therapy (1000 mcg by mouth once daily) may be used for maintenance in patients who are unwilling to receive injections
Folate Deficiency Anemia treatment
Folic Acid 1 mg PO daily until corrected (4 months)
Sideroblastic Anemia - Causes
- Toxins: lead, copper, and zinc poisoning
- Drug-induced: ethanol, isoniazid, chloramphenicol, cycloserine, linezolid, and oral contraceptives
- Nutritional: pyridoxine (vitamin B6) or copper deficiency
- Diseases: rheumatoid arthritis or multiple myeloma
Sideroblastic Anemia
Diagnosis:
- Reticulocyte count is low
- MCV may be low, normal or high
- Serum iron, transferrin, saturation, ferritin levels high
- Peripheral smear shows marked anisocytosis, poikilocytosis
Sideroblastic Anemia Treatment
- If drug induced, the offending agent should be stopped.
- Pyridoxine 200mg daily
- If unresponsive, treat symptomatically
Hemolytic Anemia - Intrinsic (intracorpuscular, usually membrane defect inherited)
•Spherocytosis and elliptocytosis •Hb defect –Sickle cell anemia –Thalassemia •Metabolic defect –Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hemolytic Anemia -
Extrinsic (extracorpuscular, acquired)
•Membrane defect
–Autoimmune hemolytic anemia
•Oxidants
Hemolytic Anemia: Laboratory
- Normocytic normochromic
- Increased reticulocyte count
- Elevated LDH
- Elevated indirect bilirubin
- Positive Coombs test (autoimmune) - conclusive for autoimmune hemolytic anemia, the most common type among the elderly
microangiopathic hemolytic anemia - causes
penicillin, quinidine, alpha-methyldopa, and cephalosporins - Rx remove offending agent
Glucocorticoids also sometimes used.
Anemia - Summary
WHO definition: Hb
Petechiae and Ecchymoses
Possible Etiology:
Possible Etiology: •Thrombocytopenia •Platelet dysfunction •Autoimmune disorder •Myelodysplastic syndrome •Acute leukemia •Chronic lymphocytic leukemia •Infection •HIV •Medications
Thrombocytopenia - diagnosis
•Decreased platelet count (
Drug-induced Thrombocytopenia - causes
Direct Marrow Suppression: chemotherapy
Hapten-mediated immune: quinine, quinidine, gold salts, sulfonamide antibiotics, rifampin, glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonists, and heparin
Drug-dependent antibodies: quinine, anticonvulsants, and NSAIDs
Treatment: Stop the offending agent!
Abnormal Bruising and Bleeding
High Risk Medications: •Aspirin •Clopidogrel •Heparin •Non-steroidal anti-inflammatory drugs (NSAIDs) •Warfarin •Dabigatran •Rivaroxaban •Apixaban
Abnormal Bruising and Bleeding
Low Risk Medications: •Ginkgo biloba •Gold •Interferon •Penicillins •Selective serotonin reuptake inhibitors (SSRIs) •Propylthiouracil •Testosterone •Tricyclic antidepressants
Abnormal Bruising and Bleeding
Important Diagnostic Tests:
- PT
- aPTT
- CBC with platelet count
Immune (or idiopathic) Thrombocytopenic Purpura (ITP) lab testing and symptoms
- Thrombopoietin (TPO)
- Complete blood count
- Peripheral blood smear
- Petechiae
- Purpura
- Ecchymoses
ITP Treatment
- 1st line: Glucocorticoids
- Severe ITP & high risk for bleeding: Rituximab
- For relapse: Splenectomy
- For relapse after splenectomy: Thrombopoietin receptor agonists
- Life threatening bleeding/surgery: Immune globulin, intravenous immunoglobulin (IVIG), Rho(D) Immune globulin (IGIV) (WinRho®) (anti-Rho(D) antibody to red cell antigen Rho(D)
- Refractory: Immunosuppressants
ITP Treatment - Glucocorticoids
For profound thrombocytopenia with signs of bleeding, very high dose steroids, in the form of methylprednisolone 1 g/d for 3 days is used. High dose dexamethasone 40mg (po or IV) for 4-8 days in cycles has also been used. For less acute cases, prednisone 1 mg/kg daily will be started.
ITP Treatment - Glucocorticoids
MOA: •Immune suppressants •Reduce formation of immune mediators •Inhibit the cell migration to area of injury •Reduce production of inflammatory mediators Side Effects: •Glucose intolerance •Psychosis •Immunosuppression •Osteoporosis
ITP Treatment – Rituximab
MOA:
•Monoclonal antibody that destroys b-cells via the CD20 antigen. It is an antibody against CD20, a cell marker on the B lymphocyte.
Side Effects:
•Fever
•Chills
•Hypotension (infusion-related)
Doses used are 375 mg /m2 IV once weekly x4
black box warning for fatal infusion reactions within 24 hours of infusion, tumor lysis syndrome, severe mucocutaneous reactions, cardiac arrest, and progressive multifocal leukoencephalopathy (PML)
ITP Treatment - Splenectomy
MOA:
•Splenectomy reduces platelet removal from circulation
Side Effects:
•Risk from surgery
•Risk of infection
•Increased risk of clot formation due to thrombocytosis
•Chronic neutrophilia
ITP Treatment – IVIG (IV immunoglobulin)
MOA: •Decreased Fc receptor sensitivity •Decreased antibody production •Activates inhibitory receptor Fc so platelet clearance is impaired Side Effects: •Rigors •Fever •Chills •Hypotension •Renal failure
ITP Treatment – Rho(D) IV immunoglobulin IVIG
MOA: •Fc receptor blockade Patient selection: •Spleen intact •Rh + •Hb > 8 g/dl Side Effects: •Hemolysis •Renal failure •Fever, chills
ITP Treatment - Immunosuppressants
- Vincristine
- Mycophenolate
- Cyclophosphamide
- Azathioprine
- Danazol - Liver dysfunction and thromboembolism are the more serious side effects seen with danazol.
Von Willebrand Disease
Genetic defect of Chromosome 12 leading to a deficiency of a protein called Von Willebrand factor (VWF)
Signs & Symptoms:
•Mucocutaneous bleeding (nose, vaginal, dental, GI)
•Prolonged bleeding time.
•Bruising
•Postoperative bleeding
Von Willebrand Disease treatment
•DDAVP (desmopressin), synthetic analog of the antidiuretic hormone - vasopressin
–IV: 0.3 mcg/kg IV in 50mL NS over 15-30 minutes
–Intranasal: 300 mcg intranasally every 12 hours
•Cryoprecipitate in emergency
•Humate P® (factor VIII and VWF)
–40-80 Units/kg IV every 8-12 hours for acute bleeding episodes
•Alphanate ® (antihemophilic factor and Von Willebrand factor)
•Koate® (Von Willebrand factor)
Acquired Factor VIII Deficiency (Hemophilia A)
- Unexplained prolonged aPTT with normal PT
* Spontaneous bleeding (muscle hematoma, soft tissue ecchymoses, mucosal bleeding, GI bleeding)
Acquired Hemophilia - Treatment
- Antihemophilic Factor (Human; Humate-P®)
- Antihemophilic Factor (recombinant; Helixate FS®)
- Activated Prothrombin Complex Concentrates (APCC)
- FEIBA and Autoplex (human derived plasma products)
- Factor VIIa (NovoSeven®)
- Immunosuppressive therapy (corticosteroids with or without cyclophosphamide, vincristine, cyclosporine, interferon alfa)
Vitamin K Deficiency
Etiology:
•Decreased GI synthesis secondary to antibiotics
Signs & Symptoms:
• Delayed coagulation, prolonged bleeding
Treatment:
•Phytonadione (Vitamin K1 ) oral, subcutaneous, or IV (10 mg in 100 ml saline, over 30 min.) x 3 days
Warfarin Bleeding - Adverse Effects
Most Common Bleeding Sites: •Nose •Oral pharynx •Soft tissue •GI •Urinary tract
Risk Factors for Bleeding:
•Higher frequency in first three months of therapy
•Intensity of anticoagulation
•History of GI bleeding
•Serious comorbid disease (decompensated heart failure, active malignancy)
•Concurrent ASA or NSAID, other anticoagulants, and antiplatelet medications
Elevated INR and Warfarin Bleeding - Management
INR above therapeutic range but
Elevated INR and Warfarin Bleeding - Management
INR ≥10, no significant bleeding AND/OR low-moderate risk of bleeding
•Hold warfarin therapy
•Give Vitamin K1 (2.5-5 mg PO)
Serious bleeding at any elevated INR AND/OR high risk of bleeding
•Hold warfarin therapy
•Prothrombin Complex Concentrate (PCC) recommended over Fresh Frozen Plasma (FFP)
•Vitamin K1 5-10 mg by slow infusion suggested
Disseminated Intravascular Coagulation (DIC)
Clinical Manifestations and causes
Clinical Manifestations: •Asymptomatic •Petechiae and purpura •Bleeding •Thrombosis •Aneurysms
Causes: myocardial infarction, prosthetic devices, infections, heat stroke, chronic inflammatory diseases and pulmonary embolism, prostate cancer, aneurysm.
DIC – Lab Values
Lab values: •D-dimer: increased •Platelets: decreased •Fibrinogen: decreased •PT: prolonged •aPTT: prolonged •Antithrombin: decreased
DIC - Treatment
•Base on predominant symptoms (bleeding or clotting)
•Fresh frozen plasma, platelets to replace clotting factors
•Low dose heparin to control excess thrombin activity
Cryoprecipitate
Antithrombin concentrate
Liver Disease and Coagulopathy
Treatment Prior to an Invasive Procedure
•10mg Vitamin K1 for one to two days
•Fresh frozen plasma and platelets
•Prothrombin plasma concentrate, 10 units cryoprecipitate
Recombinant factor VIIa or (NovoSeven®)
Hemorrhage
Possible Etiology
- Generalized – thrombocytopenia, platelet disorder, DIC
- Localized – anatomical defect (e.g. peptic ulcer, tumor, surgery, laceration, trauma)
- Surgery
Systemic Biologic Hemostatic Agents
•Blood Products
–Cryoprecipitate (concentrated fibrinogen, Factor VIII, von Willebrand Factor)
–Fresh frozen plasma (active bleeding, elevated PT and aPTT)
–Platelets (platelets
Thromboembolic Disorders
Venous thromboembolism (VTE): • Deep vein thrombosis (DVT) • Pulmonary embolus (PE) Arterial thromboembolic disease: •Acute myocardial infarction •Peripheral artery disease •Coronary artery disease •Atrial fibrillation or valvular heart disease •Stroke Microvascular thrombosis: •Disseminated intravascular coagulation (DIC)
High Risk of VTE
Fracture of hip or leg Major trauma Hip/knee replacement Major general surgery Immobility Spinal cord injury Age ≥ 75 years History of VTE
Moderate Risk of VTE
Arthroscopic knee surgery Paralytic CVA Thrombophilia Hormone Replacement Therapy CHF History PE, DVT Respiratory failure Malignancy Antiphospholipid Antibody Antithrombin Deficiency Central Venous Catheter Protein C or S deficiency Chemotherapy Activated protein C deficiency
Low Risk of VTE
Obesity
Varicose veins
Laparoscopic Surgery
Drug therapy – estrogens and megestrol
Treatment of VTE
Heparins: •Unfractionated Heparin (UFH) •Low Molecular Weight Heparin (LMWH) Direct Thrombin Inhibitors Indirect Acting Factor Xa inhibitor Vitamin K Antagonist – Warfarin
Treatment of VTE - Heparins (UFH)
UFH
–Heparin – IV or SQ
•Prevention: 5000 units SQ q8-12hours 10-14 days following hip and knee surgeries
•Treatment:
–IV: 80 units/kg (or 5000 units) IV push followed by continuous IV infusion of 18 units/kg/hr (or 1000 units/hr)
–SQ: 333 units/kg then 250 units/kg every 12 hours
Treatment of VTE - Heparins (LMWH)
LMWH
–Enoxaparin (Lovenox®)
•Prevention: 30 mg SQ q12 OR 40 mg SQ QD
•Treatment: 1mg/kg q12 hours or 1.5mg/kg QD
–Dalteparin (Fragmin®)
•Prevention: initial: 2500 units SQ ≥12 hours before OR after surgery; maintenance: 5000 units SQ QD
•Treatment: 200 units/kg once daily
–Tinzaparin (Innohep®) – note: 1mg tinzaparin = 70-120 units of anti-Xa activity
•Prevention: 75 anti-Xa units/kg SQ QD OR 3500 anti-Xa units SQ QD
•Treatment: 175 anti-Xa units/kg SQ QD
MOA of unfractionated heparin, low molecular weight heparin, and fondaparinux
- Pentasaccharide group on each medication
- Binds to antithrombin
- Structural change occurs
- Inactivates factor Xa and inhibits prothrombins conversion to thrombin
- Prevents clot formation
Pharmacology of UFH
•Large size
•Acts as cofactor to antithrombin III and facilitates antithrombin III mediated inactivation of Factors IIa, Xa, IXa and XIIa
- Heparin binds to both clotting factor II, and to antithrombin
•aPTT: not required for prophylactic doses except in small frail elderly (
Pharmacology of LMWH
•Preferentially inhibits Factor Xa
•aPTT: not needed or useful for monitoring
•Absorption: improved availability; providing a more predictable anticoagulant response
•ADR: HIT & osteopenia (lower incidence) since they don’t bind platelets as well as UFH
Anti-factor Xa level monitoring may be needed in patients with renal impairment, weight less that 50kg, obese (>150kg) or those who require therapy longer than 14 days.
LMW - binding is no longer the predominant method of clearance. Renal clearance becomes a notable route of elimination. Use UFH if CrCl
Heparin-Induced Thrombocytopenia
HIT should be suspected if patients are receiving or have received heparin within the last two weeks and the platelet count falls by ≥50% and/or a thrombotic event occurs between day 5-14 of heparin.
HIT: Treatment
- Discontinue heparin
- Give Direct Thrombin Inhibitors (DTI)
- Start NON-heparin anticoagulants (including LMWH)
Direct Thrombin Inhibitors (DTI) - Lepirudin
Lepirudin is a recombinant protein modified and derived from hirudin.
- Irreversible direct thrombin inhibitor with the longest half life of all direct thrombin inhibitors.
Requires dosage reduction in patients with renal insufficiency (CrCl
Direct Thrombin Inhibitors (DTI) - Argatroban
Argatroban is a synthetic reversible direct thrombin inhibitor derived from L-arginine.
Rapid onset of action, lack of antigenicity, short half life, and predictable pharmacokinetic response.
Prevents further thrombotic events, and reduces extension of existing thromboses
Direct Thrombin Inhibitors (DTI) - Bivalirudin
Bivalirudin is a semi-synthetic analogue of hirudin. Advantages include: direct elimination and a short half life.
FDA approved for anticoagulation in patients with or at risk for HIT thrombosis syndrome undergoing PCI, with concomitant aspirin use.
Fondaparinux
- FDA approval for treating and preventing VTE after major orthopedic surgery, hip fracture surgery or abdominal surgery.
- Not approved for patients with HIT. It is also used for non-stress test (NST) and acute coronary syndrome (ACS) in patients at high risk for bleeding.
- Does not affect thrombin, a platelet activator. It selectively inhibits factor Xa.
- fast onset of action, can be given once a daily subcutaneously and routine monitoring is not required.
- contraindicated with CrCl
Rivaroxaban
- factor Xa inhibitor.
- FDA-approved for treating and preventing VTE after major orthopedic surgery.
- Rivaroxaban should be given with food. Rivaroxaban has a black box warning of increased risk of stroke and thrombotic events in patients following abrupt discontinuation.
- Dosage reduction is recommended in patients with CrCl 30-50 mL/min and rivaroxaban should be avoided in patients with CrCl
Warfarin
•Vitamin K antagonist
•Doses of 5 mg are typically started and then titrated to patient-specific INR goals
–Goal is typically 2-3
–Monitor the INR daily initially then weekly
Acute Coronary Syndrome (ACS)
- ST Segment Elevation Myocardial Infarction (STEMI)
- Non ST Segment Elevation Myocardial Infarction (NSTEMI)
- Unstable Angina (UA)
- Acute Myocardial Infarction (AMI)
ACS: Treatment
•Thrombolytic agents –Streptokinase –Alteplase –Reteplase –Tenecteplase
Coronary artery occlusion treatment
STEMI patients presenting to a PCI capable hospital should be treated within 90 minutes.
For those hospitals without PCI capability that can’t be transferred, fibrinolytic (thrombolytic) therapy should be used with 30 minutes unless contraindicated.
Early treatment emphasis with reperfusion therapy is strong.
Rescue PCI is to be used if the 90 minute electrocardiogram shows clinical evidence for unsuccessful fibrinolytic therapy.
Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy for a minimum of 48 hours and preferably for the duration of the hospitalization up to eight days. Established regimens include UFH, enoxaparin and fondaparinux.
Older adults should be treated as aggressively as other age groups.
Aspirin
–MOA: Blocks the enzyme cyclooxygenase by permanently acetylating the enzyme in the platelet
–Warnings: should not be used in inherited bleeding disorders such as factor VII and factor IX deficiency, history of GI bleeding
–Monitoring/adverse effects: GI bleed, worsening of asthma, GI upset
–Dosing: 81 mg QD (once daily) indefinitely for most cardiac conditions (primary and secondary prevention)
•PCI: initially 325 mg once, then 81 mg indefinitely
•ACS: CHEW 162-325 mg on presentation
•CVA/TIA: initial 325 mg once, then 81 mg indefinitely
Clopidogrel (Plavix®)
–MOA: Selective, irreversible inhibition of adenosine diphosphate (ADP)-induced platelet aggregation
–Monitoring/adverse effects: GI bleeding, increased bleeding risk
–Dosing (renal/hepatic): 300 mg loading dose; 75 mg maintenance dose
Dual antiplatelet therapy with clopidogrel 75mg and aspirin is used in unstable angina, non-STEMI and STEMI.
Combination Antiplatelet Therapy
•Aspirin + clopidogrel
–ACS +/- stent placement: 1 year (ideally)
–Drug Eluding Stents: may continue combination for greater than one year
•Aspirin + clopidogrel + warfarin
–ACS PLUS a. fib or prosthetic valve
Glycoprotein IIb-IIIa Receptor Blockers
eptifibatide, tirofiban, abciximab
–MOA: Receptor site on the platelet surface for von Willebrand’s factor, fibrinogen and other platelet aggregation modulators is blocked, preventing aggregation
–eptifibatide (Integrilin®), tirofiban (Aggrastat®), abciximab (ReoPro®)
–Contraindication: recent major bleeds (CVA), severe HTN, major surgery within 6 weeks, hemodyalisis
–Monitoring: PT/aPTT and ACT, s/sxs of bleeding, Hb/Hct, platelet count, SCr
–Route: intravenous
–Dosing: ACS and PCI: initial weight based bolus (180 mcg/kg) followed by continuous infusion (2 mcg/kg/hr) for 18-24 hours
•2nd bolus dose recommended 10 minutes after first with PCI
•Concurrent aspirin and heparin recommended
•CrCl
Pharmacologic Treatment Stroke
Acute
–Early reperfusion with t-PA (100,000/mm3
–Absence of conditions that would increase bleeding
–No heparin within 48 hours with elevated APTT
–No oral anticoagulants or an INR
Secondary Prevention Goals for Coronary and Atheroschlerotic Disease
•Consider ACE inhibitor for all patients
–With or without thiazide diuretic
•Consider ARB in patients intolerant of ACE inhibitors
•Combination of ACE and ARB not recommended in most patients
•Statin therapy for hypercholesterolemia
Secondary Prevention Goals for Coronary and Atheroschlerotic Disease Antiplatelet Therapy
- Aspirin 50-325mg daily - 81 mg
- Clopidogrel 75mg daily
- Aspirin 25mg and dipyridamole extended release 200mg BID
Secondary Prevention Goals for Coronary and Atheroschlerotic Disease - Anticoagulation Therapy
- Warfarin (Coumadin®)
- Dabigatran (Pradaxa®)
- Rivaroxaban (Xarelto®)
- Apixaban (Eliquis®)
Stroke Risk - CHADS2
C – Congestive Heart Failure
H – Hypertension (BP > 140/90 or on medication)
A – Age ≥ 75 years
D – Diabetes Mellitus
S – Prior Stroke or TIA or Thromboembolism
A score of 0 is low risk and no therapy or aspirin alone is recommended. Each item is worth one point except for the “S” which is worth 2. A score of 1 is moderate risk and aspirin therapy or warfarin (or a newer agent) is recommended. A score of 2 or more warrants therapy with warfarin or a newer agent.
Bleeding Risk – “HAS BLED”
H – Hypertension (systolic >160)
A – Abnormal renal function
– Abnormal liver function
S – Previous history of stroke
B – Major bleeding history (anemia or predisposition to bleeding)
L – Labile INRs
E – Elderly (≥ 60 years old)
D – Drug therapy
– Alcohol use
•Abnormal renal function is defined as: the presence of chronic dialysis or renal transplantation or serum creatinine >~2.3 mg/dL. Abnormal liver function is defined as: chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement (e.g. bilirubin >2x upper limit of normal, in association with AST/ALT/ALP >3x upper limit normal).
•Labile INRs indicate the patient has unstable/high INRs and is in the therapeutic range for
Decreased Warfarin Effect (lower INR)
Drugs •Amobarbital •Butabarbital •Carbamazepine •Cholestyramine •Dicloxacillin •Griseofulvin •Mercaptopurine •Mesalamine •Nafcillin •Phenobarbital •Phenytoin •Primidone •Ribavirin •Rifabutin •Rifampin •Secobarbital •Sucralfate •Vitamin K Herbals •Coenzyme Q1 •Ginseng •St. John’s wort •Green tea
Increased Warfarin Effect (elevated INR)
Acetaminophen Alcohol (binge) Allopurinol Amiodarone Argatroban Aspirin Azithromycin Bactrim Chloral hydrate Chloramphenicol Cimetidine Ciprofloxacin Citalopram Clarithromycin Clofibrate Danazol Diltiazem Disopyramide Disulfiram Doxycycline Entacapone Erythromycin Felbamate Fenofibrate Fluconazole Fluorouracil Fluvoxamine Gemfibrozil Influenza vaccine Isoniazid Itraconazole Levofloxacin Metronidazole Miconazole Moxalactam Neomycin Norfloxacin Ofloxacin Omeprazole Phenylbutazone Piroxicam Propafenone Propranolol Quinidine Ritonavir Sertraline Simvastatin Sulfamethoxazole Sulfinpyrazone Tamoxifen Testosterone Tetracycline Vitamin E Voriconazole Zafirlukas
Increased Warfarin Effect (elevated INR) - HERBALS
Anise Asafoetida Chamomile Clove Danshen Devil’s claw Dong quai Fenugreek Feverfew Fish oil Garlic Ginger Ginkgo Grapefruit Horse chestnut Licorice root Mango Meadowsweet Onion Papain Quassia Red clover Rue Sweet clover Tumeric Willow bark Vitamin E
Drug – Food Interactions- warfarin
•Vitamin K:
–Dietary consistency is the key
–Foods high in Vitamin K (green leafy vegetables: broccoli, Brussels sprouts, turnip greens, kale, spinach, beet greens), cauliflower, legumes, mayonnaise, canola and soybean oils
•Alcohol intake greater than 3 drinks/day can increase INR
–Acute binges can raise INR
–Chronic alcohol intake can decrease INR
•Herbal supplements can affect bleeding time
–Herbal medications should either be avoided or used consistently while on warfarin therapy
Herbal preparations and warfarin interactions
Coenzyme Q10 is an herbal supplement whose chemical structure is similar to Vitamin K, so it has the potential to affect bleeding time. Herbal teas: green tea, buckeye, horsechestnut, tonka, bean, meliot, and woodruff. Other examples include: feverfew, garlic, and ginseng. Herbal medications should either be avoided or used consistently while on warfarin therapy.
Increased Bleeding Risk and warfarin
- Aspirin
- Clopidogrel
- Danaparoid
- Dipyridamole
- LMWHs
- NSAIDs
- Ticlopidine
- Unfractionated heparin
Dabigatran Etexilate
•MOA: oral direct thrombin inhibitor
For treatment of thrombosis: dabigatran is recommended preferentially over warfarin
For thromboprophylaxis with total knee arthroplasty/total hip arthroplasty (TKA/THA), it is listed as a possible agent
•Black Box Warning: serious postmarketing bleeding adverse events
•Extreme caution is recommended it patients 80 years old
•Greater risk of bleeding has been observed in patients >65 years old
Dabigatran Etexilate - dosing
•Dosing:
–Afib: 150 mg BID
–CrCl 30-50 mL/min PLUS dronedarone or oral ketoconazole: 75 mg BID
–CrCl 15-30 mL/min PLUS dronedarone or oral ketoconazole: avoid use
–Per ACCP, contraindicated in patients with CrCl ≤30 mL/min
•Adverse reactions: dyspepsia, bleeding (GI most common)
Rivaroxaban
- Oral factor Xa inhibitor
- Recommended for thromboprophylaxis and non-valvular atrial fibrillation (to prevent stroke and embolism)
- Black Box Warning: increased risk of stroke and thrombotic events with abrupt discontinuation
Rivaroxaban - dosing
•Dosing:
–DVT/PE: 15 mg BID x3 weeks, then 20 mg QD (duration variable)
–Afib: 20 mg QD
–Post operative recommendations: 10 mg QD
–CrCl
Apixaban
Oral direct factor Xa inhibitor
•Alternative option to aspirin or warfarin per AHA guidelines for stroke prevention
•Black Box Warning: increased risk of stroke upon abrupt discontinuation
Apixaban - dose
•Dose: 5mg twice daily –2.5mg twice daily if 2 of the following: •Age ≥80 years •Body weight ≤60 kg •SCr ≥1.5 mg/dL –CrCl
Peripheral Arterial Disease (PAD) - management
Antiplatelet medications, specifically aspirin, have the most evidence to support use. A dosing range of 81 – 325 mg is recommended. Clopidogrel is another option in patients. The dose for clopidogrel would be 75 mg once daily.
Peripheral Artery Embolism and Thrombosis
Therapeutic options for chronic arterial obstruction are limited to the use of heparin to limit thrombus extension and thrombolytic agents to restore patency.
