Clotting component abnormalities: elevated factor VIII, hyperhomocysteinemia, Factor V Leiden, prothrombin 20210, protein C deficiency, protein S deficiency, antithrombin deficiency, estrogen therapy, pregnancy, malignancy
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
Initial treatment of DVT/PE
Acute Coronary Syndromes (ACS)
Acute ischemic stroke (CVA)
Prophylaxis for DVT, PE, and/or CVA
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
Musculoskeletal: Osteoporosis, With long-term, high-dose administration
Other: Increased risk for bruising and bleeding
Renal function (Serum Creatinine)
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.
LMWH and Anti Factor Xa Levels
Peak @ 4 hours after last injection
Trough just prior to next injection
Enoxaparin (Lovenox): Renal dosing guidelines available
Dalteparin (Fragmin): No specific dosing guidelines for renal impairment.
Tinzaparin (Innohep) : No specific dosing guidelines for renal impairment.
Synthetic LMWH: inhibits FX
Indications: DVT/PE treatment and prophylaxis, Acute Coronary Syndrome
Dosing: weight based, once daily
Elimination: Renal Excretion
LMWH Clinical Pearls
Use caution with impaired renal function
Weight limits apply
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
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
Warfarin (relative) Contraindications
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
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.
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.
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.
Warfarin Drug Interactions
Any drug or herbal preparation has potential to interact with Coumadin
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)
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)
Direct Thrombin Inhibitors
Monitor similar to UFH
May Falsely elevate INR, Chromogenic Factor Xa
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.
HIT/HITT Clinical Pearl
If you are suspicious enough to send the test, stop all heparin and start a DTI.
Vitamin K deficiency
Von Willebrand’s Disease (vWD)
Idiopathic Thrombocytopenia Purpura (ITP)
Thrombotic Thrombocytopenia Purpura (TTP)
Hemolytic-Uremic Syndrome (HUS)
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)
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.
Vitamin K Deficiency
Replacement: Oral Vitamin K, 5-10mg PO daily x 3 days
Chronic: MVI with vitamin K daily
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.
Fresh Frozen Plasma (FFP)
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
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
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
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
Must have stores of X, II, I (common pathway)
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.
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
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
Idiopathic Thrombocytopenic Purpura (ITP)
Auto-immune Antibodies form and alter platelets
Platelet removal by the spleen is increased
Increased bone marrow production, but cannot keep up with destruction
ITP Treatment Rationale
Platelet transfusions are generally not given unless the patient is acutely bleeding.
Therapy is aimed at eliminating the antibodies.
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
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
TTP Treatment Options
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