Pharmacolocy Thrombosis Hemostasis

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Pharmacolocy Thrombosis Hemostasis
2010-10-23 13:59:26
DPAP2012 Pharmacology Thrombosis Hemostasis

Pharmacology Thrombosis Hemostasis
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  1. Virchow’s Triad
    • Blood flow abnormalities: AFib, L ventricular dysfunction, bed rest, venous obstruction
    • Contact surface abnormalities: atherosclerosis, vascular injury/trauma, abnormal or mechanical heart valve, indwelling vascular catheter
    • Clotting component abnormalities: elevated factor VIII, hyperhomocysteinemia, Factor V Leiden, prothrombin 20210, protein C deficiency, protein S deficiency, antithrombin deficiency, estrogen therapy, pregnancy, malignancy
  2. UF HEPARIN (UFH): Mechanism of Action
    • Complex glycosaminoglycan purified from animal tissues (bovine, porcine)
    • Binds with Antithrombin III (heparin cofactor), and accelerates its activity by blocking thrombosis via inactivation of Factor Xa and Factor IIa
    • Inhibits clot formation by blocking: prothrombin → thrombin and fibrinogen → fibrin
  3. UFH Indications
    • Initial treatment of DVT/PE
    • Acute Coronary Syndromes (ACS)
    • Acute ischemic stroke (CVA)
    • Prophylaxis for DVT, PE, and/or CVA
  4. UFH Dosing
    • Prophylaxis: 5000 units q12 or q8h
    • General Treatment: weight based dosing, Bolus 50-80 units/Kg followed by 15-18 units/Kg/hr continuous infusion
  5. UFH Monitoring
    • Partial Thromboplastin Time (aPTT)
    • Goal: 1.5-2.5 times normal
    • Normal aPTT ~ 30 sec, therefore Therapeutic aPTT = 50-80 seconds
    • Hemoglobin/Hematocrit
    • Platelet count (UF can cause thrombocytopenia)
    • Signs/symptoms of bleeding
  6. UFH Kinetics:
    • Absorption: time to peak concentration 2 to 4 hr
    • Metabolism: Hepatic and reticuloendothelial system
    • Dialyzable: No
    • Elimination Half Life 1.5 hr (anticoagulation effect half-life)
  7. UFH Adverse Effects (AEs)
    • Dermatologic: Erythema, Injection site ulcer, Local irritation (primarily with SC injections)
    • Hematologic: Hematoma, Heparin-induced thrombocytopenia,
    • Musculoskeletal: Osteoporosis, with long-term, high-dose administration
    • Other: Increased risk for bruising and bleeding
  8. Management of UFH AEs
    • Time
    • Protamine (antidote)
    • Fresh Frozen Plasma (FFP)
    • Recombinate Factor VIIa (rFVIIa), $$$ !
  9. UFH Clinical Pearls
    • Quick onset and elimination
    • BIG people require BIG doses (weight based)
  10. LMWH Mechanism of Action
    • Fragment of unfractionated heparin
    • Inhibits Factor X > Factor II (thrombin)
    • More predictable response
    • Equally as effective
    • May be used in the outpatient setting
    • Given subcutaneously
  11. LMWH Indications
    • Prophylaxis: medical and postoperative (restricted mobility from acute illness, abdominal or orthopedic surgery)
    • Treatment: DVT/PE
    • Acute Coronary Syndromes: Non-Q wave MI, Acute STEMI, Unstable angina
    • Contraindication: Heparin Induced Thrombocytopenia (HIT)
  12. LMWH Kinetics
    • Absorption: Time to [peak] : 2-4h
    • Metabolism: Renal excretion
    • Dialyzable: No
    • Elimination Half Life: 5-7h
  13. LMWH dosing
    • Prophylactic: set dose, 30mg SC q12h or 40mg SC once daily
    • Therapeutic/Treatment: Wt. based, Maximum weight / dose limits apply, Adjust dose with renal insufficiency
  14. LMWH Adverse Effects
    • Dermatologic: Erythema, Injection site ulcer, Local irritation
    • Hematologic: Hematoma, Heparin-induced thrombocytopenia,
    • Musculoskeletal: Osteoporosis, With long-term, high-dose administration
    • Other: Increased risk for bruising and bleeding
  15. LMWH Monitoring
    • Renal function (Serum Creatinine)
    • Platelet count
    • Hemoglobin/Hematocrit
    • Signs/Symptoms of bleeding
    • Anti-Factor Xa (measure in pts with cancer, pregnant women, renal function problems)
    • Protamine for Adverse Effects?
    • Has not been studied in peds, obese, or underweight pts.
  16. LMWH and Anti Factor Xa Levels
    • Peak @ 4 hours after last injection
    • Trough just prior to next injection
  17. Available LMWHs
    • Enoxaparin (Lovenox): Renal dosing guidelines available
    • Dalteparin (Fragmin): No specific dosing guidelines for renal impairment.
    • Tinzaparin (Innohep) : No specific dosing guidelines for renal impairment.
  18. Fondaparinux (Arixtra)
    • Synthetic LMWH: inhibits FX
    • Indications: DVT/PE treatment and prophylaxis, Acute Coronary Syndrome
    • Dosing: weight based, once daily
    • Elimination: Renal Excretion
  19. LMWH Clinical Pearls
    • Use caution with impaired renal function
    • Weight limits apply
  20. Warfarin (Coumadin): Wisconsin Alumni Research Foundation
    • Vitamin K Antagonist
    • Antagonizes the vitamin K-dependent γ-carboxylation of factors II, VII, IX, and X (as well as protein C and protein S
  21. Warfarin Indications
    • Treatment of DVT and PE
    • Atrial fibrillation (CHADS2>2), prevention of left atrial thrombus, stroke prevention
    • Mechanical heart valve —stroke prevention
    • Severe left heart failure – prevention of left ventricular thrombus, stroke prevention
    • Myocardial RE-infarction
  22. Warfarin (relative) Contraindications
    • Active cancer
    • ACCP guidelines recommend 3-6 months of LMWH before transitioning to oral anticoagulation
    • Patients in whom vitamin K intake not stable (NPO or otherwise)
    • Unable or unwilling to return to clinic for monitoring
  23. Warfarin Dosing
    • Achieve therapeutic anticoagulation with UFH or LMWH prior to initiating warfarin
    • Begin warfarin at 5mg daily, NO BOLUS
    • Adjust per INR
    • Bridge or treat [an active thrombosis] with UFH or LMWH + warfarin x at least 5 days or until INR therapeutic (whichever is longer).
    • With acute thrombus, never begin Warfarin until thrombin inhibition is achieved with a heparin. Continue heparin until the ProTime/INR has been therapeutic for 2 days.
    • Protein C is a Vit K dependent anticoagulant factor with a very short plasma half life, and Warfarin will decrease protein C earlier than the procoagulant proteins, and initially increase clot formation.
  24. Initiating Warfarin
    • Check INR twice weekly until therapeutic.
    • Once INR is therapeutic and stable, may decrease frequency of monitoring
    • At a minimum, monitor INR every 4-6 weeks.
  25. Warfarin Genetic Testing
    • Recommended in package insert
    • 3-5 day turnaround time
    • Results: more/less/or average doses of warfarin, not very useful at this time.
  26. Warfarin Drug Interactions
    • Any drug or herbal preparation has potential to interact with Coumadin
    • Check INR 3-5 days after beginning new drug
    • Antibiotics, Antifungals: Septra, Cipro, Metronidazole, Fluconazole, Rifampin
    • Amiodarone: decrease warfarin dose by 1/2
    • Anticonvulsants: Phenytoin
    • NSAIDS: Ibuprofen, Naproxen
  27. Warfarin Monitoring
    • Prothrombin Time and International Normalized Ratio (PT/INR)
    • Monitor 2x/wk until on a stable dose, then q4-6 weeks.
    • S/S bleeding: stool, urine
    • Sx of new clot: swelling, erythema
    • Changes in: Diet, Dose, Disease, Drinks, Drugs
  28. Warfarin Adverse Effects
    • Supratherapeutic: Increased bleeding risk, Treat with Vitamin K, FFP
    • Subtherapeutic: Risk of recurrent DVT/PE or CVA, Bridge back to therapeutic if extremely subtherapeutic with a recent event.
  29. Warfarin Patient Education
    • Verbal and written information provided
    • Dietary restrictions concerning vitamin K
    • Signs and symptoms of hemorrhagic/thromboembolic complications
    • Drug interactions (alcohol, prescription drugs, OTCs)
    • Recommend Med-Alert bracelet/necklace
    • Monitoring Contract?
    • Warfarin Clinical Pearls
    • Patients should use adequate contraception—condoms not considered sufficient
    • Patients should be transitioned to LMWH prior to ATTEMPTING pregnancy
  30. Warfarin Prophylaxis Options
    • SCD’s (mechanical sequential compression device)
    • Low Molecular Weight Heparin (SC)
    • Fondaparinux (SC)
    • Unfractionated Heparin (SC)
    • Retrievable IVC filter
  31. Management of Acute DVT
    • Acute extremity DVT can be given LMWH and managed without hospitalization (Recommended)
    • Unstable patients or patients unable to afford or administer LMWH may need hospitalization for IV heparin or SC LMWH
    • Draw baseline PT, ABC and SCr
  32. Acute DVT
    • Initiate SC LMWH or IV unfractionated heparin
    • Continue UFH/LMWH while transitioning to warfarin. Overlap x at least 5 days, and 24h after therapeutic INR.
    • Monitor CBC, PTT (if using heparin), and INR.
  33. Problem: Treatment Duration
    • Transient risk factors (birth control, pic line, long flight): 3 mo
    • Isolated calf vein thrombosis: 3 mo
    • Unprovoked thrombosis: 3-2 mo (2nd consider indefinite)
    • Significant underlying thrombophilia: 12mo (consider indefinite)
    • Recurrent VTE: Indefinite
    • Cancer-related VTE : Indefinite until cancer is resolved (LMWH recommended first 3-6mo)
  34. Bridge Therapy
    • Initiation of warfarin in patients with a new thrombosis
    • Patients on chronic oral anticoagulation need normal coagulation for surgery/procedures
    • As INR falls, LMWH is begun keeping the number of days with subtheraputic anticoagulation to a minimum
  35. Bridging with LMWH
    • Last dose of warfarin 5 days prior to surgery
    • Therapeutic LMWH begun 4 days prior to surgery
    • Last dose of LMWH 24 hours prior to surgery
    • Post op LMWH and warfarin restarted when hemodynamically stable
    • LMWH stopped when ProTime/INR is therapeutic
  36. Heparin Induced Thrombocytopenia (HIT) Clinical Diagnosis
    • Thrombocytopenia: Platelet drop of 50%
    • Timing: Platelet count nadir of 30-50K after ~ 5-10 days of heparin
    • Thrombosis: High risk of arterial and venous thrombosis
    • Other: other causes of thrombocytopenia (sepsis, chemo, etc.)
  37. Heparin Induced Thrombocytopenia (HIT) Laboratory Diagnosis
    • IF high clinical suspicion, send both functional assay (high specificity, low sensitivity)
    • (Platelet aggregation, C-Serotonin Release, Heparin-Induced Platelet Activation, or Flow cytometry) and serological (ELISA, Gel Particle) assays (low specificity, high sensitivity)
  38. HIT / HITT Treatment
    • STOP ALL HEPARIN: including line flushes
    • Reverse Coumadin/warfarin if already initiated
    • Begin a Direct Thrombin (FII) Inhibitor (DTI): Lepirudin (Refludan or Hirudin), Argatroban, Bivalirudin (Angiomax), Fondaparinux (Arixtra)
  39. Direct Thrombin Inhibitors
    • Monitor similar to UFH
    • aPTT
    • Hemoglobin/Hematocrit/Bleeding
    • Platelet count
    • May Falsely elevate INR, Chromogenic Factor Xa
  40. HIT/HITT Treatment Duration
    • Once platelet count normalizes, transition to Coumadin/warfarin
    • Uncomplicated HIT: anticoagulate for 4-6 weeks.
    • HIT with a thrombosis (HITT): anticoagulate for 3-6 months.
  41. HIT/HITT Clinical Pearl
    If you are suspicious enough to send the test, stop all heparin and start a DTI.
  42. Hemostasis Disorders
    • Vitamin K deficiency
    • Von Willebrand’s Disease (vWD)
    • Idiopathic Thrombocytopenia Purpura (ITP)
    • Thrombotic Thrombocytopenia Purpura (TTP)
    • Hemolytic-Uremic Syndrome (HUS)
  43. Management of Bleeding Complications
    • Minor bleeding: hold warfarin, PO vitamin K if INR reversal required.
    • Serious bleeding: Hold warfarin, IV vitamin K, supplement with FFP, factor VIIa, or prothrombin complex concentrates depending on clinical picture
    • Life-threatening bleeding: Reverse prolonged INR with IV vitamin K and with factor VIIa or Prothrombin Complex Concentrates (PCC’s)
  44. Vitamin K Dose and Administration
    • INR 3.5-5.0 with no significant bleeding: lower dose or omit dose; monitor and resume at lower dose when INR therapeutic.
    • INR 5.0-9.0 with no significant bleeding: Omit 1-2 doses, monitor, resume at lower dose when INR in therapeutic range. Alternatively, give vitamin K 1-2.5mg po. If more rapid reversal is needed (urgent surgery), vitamin K 5mg po.
    • INR 9.0 with no significant bleeding: hold Warfarin, vitamin K 2.5-5mg po. Monitor and use additional vitamin K if necessary. Resume at lower dose when INR is therapeutic.
    • Serious bleeding at any elevation of INR: Hold warfarin therapy and give vitamin K 10mg by slow IV infusion, supplemented with FFP, PCC, or rVIIa, depending on the urgency; vitamin K can be repeated q12h.
    • Life threatening bleeding: hold warfarin therapy and give FFP, PCC, or rVIIa supplemented with vitamin K 10mg by slow IV infusion. Repeat if necessary on INR.
  45. Vitamin K Deficiency
    • Replacement: Oral Vitamin K, 5-10mg PO daily x 3 days
    • Chronic: MVI with vitamin K daily
  46. Vitamin K Clinical Pearls
    • For mildly elevated INR without bleeding, VK isn’t always indicated.
    • If indicated, a little bit is usually enough
    • Minor bleeding: oral Vitamin K,
    • Major bleeding: give IV vitamin K.
    • Try to avoid SC/IM administration.
  47. Fresh Frozen Plasma (FFP)
    • Liver disease
    • Vitamin K deficiency
    • Disseminated Intravascular Coagulation (DIC)
    • Immediate short-term reversal of over-anticoagulation with Coumadin
    • Half-life of 3-5 hours, factor VII is difficult to replace with FFP without volume overload. Thus, vitamin K and FFP are indicated in patients who have a high INR and are bleeding.
    • FFP is not indicated unless the PT or PTT is >1.5 x the mean of the normal range. FFP should not be used as a volume expander, or to correct a mildly prolonged PT or PTT
  48. Cryoprecipitate (CRYO)
    • Factor 1 replacement
    • Acquired deficiencies, either due to DIC or thrombolytic therapy, or for congenital hypofibrinogenemia or dysfibrinogenemia.
    • CRYO is the only source of concentrated fibrinogen available
    • On the Horizon: RiaSTAT
  49. Prothrombin Complex Concentrates
    • Profilnine: non-activated Factor IX, II, X and low level of Factor VII
    • FEIBA: non activated Factors II, IX, and X, and activated Factor VII
  50. NovoSeven (rFVIIa)
    • Alternative for patients who do not respond to other replacement methods
    • May be useful in patients with major bleeding associated with Warfarin overdose or hepatic failure who require fast hemostasis
    • $ Expensive
    • Must have stores of X, II, I (common pathway)
  51. Von Willebrand Disease
    • Defect of Primary Hemostasis (Platelets)
    • Qualitative and/or quantitative deficiency of von Willebrand factor.
    • Frequency of mild vWD ~1 in 200 individuals.
    • Clinical symptoms vary according to severity of the deficiency.
  52. What is von Willebrand Factor?
    • A bridge between platelets and subendothelium
    • A bridge between platelets
    • Carrier protein for factor VIII
    • Defects may be quantitative (Type 1,3) or Qualitative (Type2).
    • All defects result in decreased platelet aggregation and adhesion
  53. von Willebrand Disease Therapeutic Management
    • Desmopressin (DDAVP): Increases circulating vWF from endothelial cell stores. Most useful for minor bleeding in Type 1 vWD
    • Factor VIII preparations: Intermediate-purity factor VIII preparations contain vWF (recombinant and monoclonal-purified do not); Humate P, Alphanate, Willate; Use for major bleeding and patients with Types 2 and 3 vWD
    • Therapeutic Management: All products will have both FVIII units/vial and Ristocetin cofactor activity/vial.
    • Dosing: Von Willebrand Disease is dosed on RISTOCETIN COFACTOR activity
  54. Idiopathic Thrombocytopenic Purpura (ITP)
    • Auto-immune Antibodies form and alter platelets
    • Platelet removal by the spleen is increased
    • Unknown cause
    • Increased bone marrow production, but cannot keep up with destruction
  55. ITP Treatment Rationale
    • Platelet transfusions are generally not given unless the patient is acutely bleeding.
    • Therapy is aimed at eliminating the antibodies.
  56. ITP treatment options
    • Glucocorticoids (Prednisone): About 60% will respond, however, 60% of those patients will relapse when tapered.
    • IV Immune globulin (IVIg): more immediate effect for severe thrombocytopenia and/or bleeding. 75% will respond, but responses are generally transient
    • Splenectomy
  57. Thrombotic Thrombocytopenic Purpura (TTP)
    • Result of the lack of an enzyme (ADAMSTS13) responsible for cleaving Von Willebrand factor.
    • Causes formation of many small blood clots
    • Abnormally high number of platelets consumed resulting in decreased platelet count
    • Schistocytes on blood film
  58. TTP Treatment Options
    • Plasmapheresis
    • Steroids
    • Rituximab
  59. Hemolytic Uremic Syndrome (HUS)
    • Related to TTP
    • Caused by E. coli infections
    • Hemolysis, micro thrombi to brain and kidneys
    • Most common in infants, young children, and pregnant women
  60. HUS Treatment
    • Symptomatic & Supportive
    • Pressors
    • Antibiotics
    • Dialysis/Transplant
    • Plasmapheresis