What is heparin’s mechanism of action? Does it cross the Placenta?
Binds to antithrombin III and activates it. It does not cross the placenta (mostly b/c its charged).
What is antithrombin III (AT III)?
A natural anticoagulant. It inactivates thrombin (factor IIa) as well as factors IX, X, XI, XII
If a patient does not respond to heparin, what should you consider doing?
Consider giving them FFP to replenish AT III.
What is used to evaluate heparin activity?
ACT (activated coagulation time) - mix blood with activation substance and measure how long it takes to clot. ACT is measured 3 min after heparin is given and compared to baseline ACT. Usually want ACT = 2x baseline for vascular procedures.
What is used to prevent DVT/PE/acute MIs?
heparin or lovenox
What are Streptokinase and Alteplase used for? What is their mechanism of action?
They are thrombolytic drugs. They are tissue plasminogen activators. activate plasminogen-> plasmin (destroys clots)
Indications: acute coronary syndrome, stroke
Can be be given into a clogged vascular access device (dyalisis, PICC)
What is the mechanism of aspirin and its effects on coagulation?
Antiplatelet drug. NSAID (COX-1 and COX-2 inhibitor).Irreversible prevention of platelet aggregation
What is aspirin commonly prescribed for?
prevent of stroke, MI, occlusion of coronary stents
What is the mechanism of Clopidogrel (Plavix) and its effects on coagulation?
irreverible inhibition of platelet activation and aggregation
What is the mechanism of Amicar (E-aminocaproic acid) and Tranexamic acid and their effects on coagulation?
they are antifibrinolytic drugs - they protect the clot. prevent plasminogen->plasmin AND inactivate plasminplasmin degrades fibrin (fibrin cross-links stabilize platelets)
What is recombinant factor VIIa?
Directly activates Factor X and initiates thrombin burst without requiring Factors VIII or IX. Requires presence of factors V,X,II, fibrinogen, and at least some platelets
What is DDAVP?
causes release of factor VIII, vWF, and t-PA
used in vWD, mild hemophilia, uremia, ASA/NSAIDS/dextran/plavix
Desmopressin (DDAVP), a vasopressin analog, is indicated for control of hemorrhage in patients with mild-to-moderate hemophilia A and von Willeband’s disease. It’s primary mechanism of action is to increase circulating levels of factor VIII and von Willebrand factor (vWf) leading to secondary improvements in platelet adhesion to endothelial defects. It has also been considered for use in patients with uremia and prolonged bleeding time due to decreased expression of vWF and decreased activity of the vWF-factor VIII complex. Two advantages to DDAVP are its relatively quick onset of action (1 hour), similarity to cryoprecipitate, and lack of transfusion-related side effects. However, the effects of DDAVP do not last more than 24 hours and patients are likely to develop tachyphylaxis after a single dose of DDAVP limiting its utility for repeated dosing.
With the increasing use of anti-platelet agents such as clopidogrel and aspirin, interest has been raised for a potential role of DDAVP in the setting of acute bleeding in these patients. The use of desmopressin in patients with normal renal function who have active hemorrhage and a history of recent (within the past 7 days) of aspirin or clopidogrel (Plavix®) administration is mentioned in a number of review articles with positive outcomes
What are the side effects of heparin?
Hemorrhage and hematoma formation
Thrombocytopenia (low platelet level in blood) - this includes mild thrombocytopenia and HITT
Allergic reaction (its derived from animal tissue)
What is HITT?
Heparin Induced Thrombocytopenia and Thrombosis
What is used to reverse heparin?
Protamine - derived from salmon sperm
In the absence of heparin, protamine has what effect?
anticoagulant effect
What are the side effects of heparin?
hTN, pulmonary HTN, allergic rxn
What drug is characterized by the following: Strong base, Combines w/ negatively charged heparin to form a complex, Derived from salmon sperm
Protamine
What 4 factors are part of the extrinsic pathway?
Factors II, V, VII, X
What are the 4 vitamin K dependent factors?
Factors II, VII, IX, X
Factor IIa is also known as what?
thrombin
Hemophilia A is characterized by what factor deficiency?
VIII
Clotting factors are all inactive pro-enzymes that, with the exception of one factor, are all synthesized where? Which factor is the exception?
All synthesized in the liver except fact VIII
What is vWF deficiency characterized by?
poor platelet adhesion AND clinical hemophilia
What are the 3 Phases of Coagulation?
Activation - Amplification - Propogation
Describe the 3 steps involved with the Activation Phase of Coagulation.
Injury->Tissue Factor-> activates VII, X, V, II (thrombin)
Describe the 3 steps involved with the Amplification Phase of Coagulation.
Amplification (“thrombin burst”) - Platelets activated; Thrombin activates V, VIII, IX; platelets bind to collagen
Describe the Propagation Phase of Coagulation.
Propagation: fibrin cross-links stabilize the platelets
Heparin is given as DVT prophylaxis in what group of people most commonly? what is the typical dose?
Hospitalized pts, esp surgical pts (esp hip replacements)
DVT Prophylaxis= 5,000units SQ q8-12h (7,500 for very obese)
What is the heparin dose for treatment of DVT/PE?What PTT are you aiming for?
80 units/kg bolus + infusion at 18 units/kg/hr
PTT: titrate to 1.5-2.5x normal, q6hr
What is Enoxaparin?
Also called Lovenox. It is a LMWH (low molecular weight heparin)
True or False. Lovenox has more protein binding when compared with unfractionated heparin?
False. Lovenox has less protein binding
T or F. Lovenox has no effect on PT/PTT.
TRUE
What are the routes of administration for heparin? Do any have associated risks?
IV or SC. IM carries risk of hematoma
What are the pharmacokinetics of Heparin (unfractionated)?
Non-linear dose-response relationship, partially du to extensive protein binding. Elimination half-life changes based on dose (usually 1-2 hrs)
Which has more predictable pharmacokinetics, Heparin or Enoxaparin?
Enoxaparin (Lovenox) does. More consistent and predictable pharmacokinetics. Less protein binding than Heparin.
Heparin: Non-linear dose-response relationship, partially due to extensive protein binding. Elimination half-life changes based on dose (usually 1-2 hrs)
Which has a longer elimination half-life, Heparin or Lovenox.
Lovenox = 4-5 hrs
Heparin = 1-2 hrs usually
How long must a surgery be delayed after the last dose of Lovenox?
12 hrs
How often are Heparin and Lovenox dosed?
Lovenox = once daily Heparin = q8-12hrs
T or F. Protamine is more effective reversing Lovenox than Heparin?
False. Lovenox only gets partial reversal with Protamine. (neutralizes ~ 65% of anti-Xa activity)
What is the dose of Protamine for Heparin reversal?
1mg Protamine for every 100 units of heparin believed to be in circulation.
What is the difference b/n mild thrombocytopenia and HITT? What % of pts are effected by each as a side effect of heparin?
Mild: < 100,000 platelets - (30-40% of pts) - DRUG-INDUCED platelet aggregation - can happen even w/trivial exposure to heparin
HITT: (0.5-6% of pts) - IMMUNE-MEDIATED formation of ANTIPLATELET ANTIBODIES
T or F. Warfarin (Coumadin) has no effect on platelet activity.
TRUE
What is the mechanism of action of Warfarin?
inhibits vit K epoxide reductase -> deficiency of vit K-dependent coagulation factors (II,VII,IX,X)
What is the time of Warfarin’s onset of action, peak effect, and duration?
onset = 8-12 hrs peak = 36-72 hrs duration = 2-5 days after stopping therapy
Which of the following cross the placenta and should not be used during pregnancy?
a. Heparin
b. Enoxaparin
c. Warfarin
c
What would happen if a pregnant woman took Coumadin?
It crosses the placenta, so it would cause CNS damage, bleeding and developmental defects
T or F. The effects of Warfarin can be measured with PT/INR?
TRUE
What effects the dose response of Coumadin?
changes in intake and absorption of dietary vit K
What is the target INR for a pt on Coumadin?
Target INR = 2.0-3.0
What can be given in an emergency situation to a pt that is on Coumadin?
1mg vit k and/or FFP (up to 15 mL/kg), can also use recombinant FVIIa or prothrombin complex concentrate
Although Lovenox is safe to use during pregnancy, there are still some risks. Name 2.
spontaneous hematoma formation (esp w/neuroaxial blocks)some risk of HITT
What are the indications for use for Warfarin?
prevent and treat DVT/PE thrombus associated with a-fib and prosthetic heart valves
What is the most common side effect of Warfarin?
bleeding (esp intracranial hemorrhage)
T or F. Regarding drug interactions with Warfarin, few drugs can affect absorption, metabolism, protein binding, and vit K levels.
False. many drugs affect these things
T or F. ACT is used to measure Heparin levels.
False. It is used to measure heparin activity…it is hard to measure heparin levels
T or F. PTT reflects heparin activity and PT reflects Warfarin effects.
TRUE
What is a typical heparin IV bolus and what is the typical ACT goal for vascular surgeries?
Bolus = 5,000 unitsACT = 2x baseline
What is the acceptable ACT (in seconds) and what is a typical heparin bolus dose for CPB?
Acceptable ACT = at least 300-480 seconds
Bolus = 300-350 units/kg = 20,000-30,000 units IV
When should Clopidigrel (Plavix) be stopped for elective surgery?
7 days prior to surgery
T or F. You should try to avoid regional anesthesia in pts on Plavix?
TRUE
In an emergent case, what would you give to a pt on Clopidogrel (Plavix) to restore hemostasis?
consider platelet transfusion
What drug is characterized by the following:Mimics the active binding site of heparin - when bound to AT III it inhibits Factor Xa but not thrombin
Fondaparinux (Arixtra)
T or F. Fondaparinux (Arixtra) has a high risk for HITT?
False. Fondaparinux (Arixtra) has a low risk for HITT
Argatroban, Dabigatran (Pradaxa), and Bivalirudin (Angiomax) are what type of anticoagulant drugs?
Direct Thrombin Inhibitors: Highly Specific thrombin inhibitors - suppress platelet function
What 3 drugs are characterized by the following:
- Can be used as an alternative to heparin in pts w/ HITT
- Can be used for CPB and ECMO
- Used in tx of acute coronary syndrome
Argatroban, Dabigatran (Pradaxa), and Bivalirudin (Angiomax)
Which if the following can be used to titrate the dose of Argatroban, Dabigatran (Pradaxa), and Bivalirudin (Angiomax)?
a. PT
b. PTT
c. ACT
d. none of the above
b. PTT
Describe the steps of fibrinolysis.
Plasminogen -> plasmin -> degrades fibrin
What are the contraindications for Tranexamic acid?
Antifibrinoytics are contraindicated in pts w/
- Hx of seizure or known retinal microcirculatory problems
- pro-thombic conditions - Hx DVT/PE, MI, CABG, coronary stents, CVA)
T or F. Recombinant Factor VIIa has become the hemostatic agent of choice for pts w/ hemophilia A or B.
False. It has become the hemostatic agent of last resort.
When is Recombinant Factor VIIa typically used?
trauma, hepatic failure, GI bleed, OB hemorrhage, ICH, transplantation
T or F. Recombinant Factor VIIa can be used to reverse Warfarin.
TRUE
What are complications associated with Recombinant Factor VIIa?
Thrombotic complications - stroke, MI, PE, clotted devices (LVAD)
Recombinant Factor VIIa must be used with caution in high risk pts. List 3 things that would be considered high risk.
CAD, cerebrovascular disease, and DIC
When is Desmopressin (DDAVP) used?
used in vWD, mild hemophilia, uremia, ASA/NSAIDS/dextran/plavix
T or F. DDAVP works at the V2 recceptors only, causing vasoconstriction and anti-diuresis.
False. no vasoconstriction - only anti-diuresis
What is the cost of Recombinant Factor VIIa and what is the hemophilia dose?
$1/mcg and hemophilia dose = 90mcg/kg
What is the half-life of Recombinant Factor VIIa?
half-life = 2hrs
