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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
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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
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UFH Indications
- Initial treatment of DVT/PE
- Acute Coronary Syndromes (ACS)
- Acute ischemic stroke (CVA)
- Prophylaxis for DVT, PE, and/or CVA
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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
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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
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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)
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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
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Management of UFH AEs
- Time
- Protamine (antidote)
- Fresh Frozen Plasma (FFP)
- Recombinate Factor VIIa (rFVIIa), $$$ !
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UFH Clinical Pearls
- Quick onset and elimination
- BIG people require BIG doses (weight based)
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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
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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)
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LMWH Kinetics
- Absorption: Time to [peak] : 2-4h
- Metabolism: Renal excretion
- Dialyzable: No
- Elimination Half Life: 5-7h
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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
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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
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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.
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LMWH and Anti Factor Xa Levels
- Peak @ 4 hours after last injection
- Trough just prior to next injection
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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.
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Fondaparinux (Arixtra)
- Synthetic LMWH: inhibits FX
- Indications: DVT/PE treatment and prophylaxis, Acute Coronary Syndrome
- Dosing: weight based, once daily
- Elimination: Renal Excretion
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LMWH Clinical Pearls
- Use caution with impaired renal function
- Weight limits apply
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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
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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
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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
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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.
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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.
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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.
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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
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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
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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.
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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
- WARFARIN CAUSES BIRTH DEFECTS (teratogenic)
- Patients should use adequate contraception—condoms not considered sufficient
- Patients should be transitioned to LMWH prior to ATTEMPTING pregnancy
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Warfarin Prophylaxis Options
- SCD’s (mechanical sequential compression device)
- Low Molecular Weight Heparin (SC)
- Fondaparinux (SC)
- Unfractionated Heparin (SC)
- Retrievable IVC filter
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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
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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.
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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)
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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
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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
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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.)
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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)
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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)
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Direct Thrombin Inhibitors
- Monitor similar to UFH
- aPTT
- Hemoglobin/Hematocrit/Bleeding
- Platelet count
- May Falsely elevate INR, Chromogenic Factor Xa
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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.
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HIT/HITT Clinical Pearl
If you are suspicious enough to send the test, stop all heparin and start a DTI.
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Hemostasis Disorders
- Vitamin K deficiency
- Von Willebrand’s Disease (vWD)
- Idiopathic Thrombocytopenia Purpura (ITP)
- Thrombotic Thrombocytopenia Purpura (TTP)
- Hemolytic-Uremic Syndrome (HUS)
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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)
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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.
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Vitamin K Deficiency
- Replacement: Oral Vitamin K, 5-10mg PO daily x 3 days
- Chronic: MVI with vitamin K daily
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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.
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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
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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
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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
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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)
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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.
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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
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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
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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
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ITP Treatment Rationale
- Platelet transfusions are generally not given unless the patient is acutely bleeding.
- Therapy is aimed at eliminating the antibodies.
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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
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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
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TTP Treatment Options
- Plasmapheresis
- Steroids
- Rituximab
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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
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HUS Treatment
- Symptomatic & Supportive
- Pressors
- Antibiotics
- Dialysis/Transplant
- Plasmapheresis
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