Exam 5 Flashcards
What is the MOA for indirect thrombin inhibitors (heparin, LMW heparins)?
Heparin binds to antithrombin, which changes the conformation of the protein, allowing for an increase in the interaction between AT and its target factors. AT inactivates factors Xa, IXa, XIa, XIIa, IIa, and VIIa.
Low molecular weight heparins are too small to bind to AT, so their target is mostly just Xa.
What is the MOA for direct thrombin inhibitors (hirudin, bivalirudin, argatroban, dabigatran)?
Hirudin - direct inhibitor of thrombin, irreversibly binds to active site and exosite I. This is a leach protein, so it can produce hypersensitivity reactions. This does not act on AT.
Bivalirudin - Synthetic peptide that binds to the catalytic site and exosite I of thrombin. This is reversible and has a short duration. No risk of hypersensitivity.
Argatroban - Reversibly binds to the active site of thrombin.
Dabigatran - A prodrug that directly binds to thrombin active site.
- with DTIs, there is a more predictable anticoagulant effect due to these not needing a cofactor. Also has antiplatelet effects due to inhibiting thrombin. These can inhibit both soluble and fibrin-bound thrombin.
What is the MOA for Xa inhibitors (fondaparinux, rivaroxaban, apixaban)?
Fondaparinux - indirectly inhibits factor Xa by selectively binding AT
Rivaroxaban, apixaban - Directly bind to the active site on factor Xa to inhibit the activity of the enzyme
What is the MOA for warfarin?
Warfarin inhibits the synthesis of clotting factors II, VII, IX, and X. Warfarin has 2 enantiomers, R and S. The S-enantiomer is the most active. Warfarin inhibits Vit. K epoxide reductase, which blocks oxidized vit K from getting reduced (active). This reduced vit K is needed to have g-glutamyl carboxylase modify non-functional prozymogens into functional zymogens (clotting factors).
What is the role of plasminogen/plasmin in the process of blood clotting?
Plasmin plays into the fribrinolytic pathway to dissolve the blood clot after the blood vessel defect has healed. Plasmin is a proteolytic enzyme that digests fibrin and fibrinogen, thus breaking up the clot.
What is the mechanism for the conversion of plasminogen to active plasmin?
t-PA (tissue plasminogen activator, a serine protease) or u-PA converts plasminogen to active plasmin by cleaving the arg-val bond.
What are the names of the drugs that are thrombolytics (5) and what is their MOA?
Thrombolytics - used for acute problems (ex. acute MI, acute stroke, PE)
Alteplase (tissue-type plasminogen activator, tPA)
Reteplase (recombinant plasminogen activator, rPA
Tenecteplase (TNK-tPA)
- MOA: Binds to fibrin and activates bound plasminogen 100x more rapidly than when in circulation. This causes active plasmin to break down fibrin.
Streptokinase
Urokinase
- MOA: Forms 1:1 activator complex with plasminogen to increase amount of active plasmin.
What is the difference between alteplase and streptokinase in terms of source, structure, and activity?
Alteplase: has a protease domain and a fibrin binding site that includes the finger and kringle 1/2. It’s a large protein with a short duration of action of 5-10mins.
- The most common complication is bleeding (surface and internal)
Streptokinase: comes from b-hemolytic streptococci (not used commonly in US for this reason). It’s non-enzymatic so it doesn’t have direct effects on the clot. It forms a 1:1 complex with plasminogen that produces an enzyme complex that converts plasminogen to plasmin.
- Common complications include bleeding and allergic reactions
What are the names of the drugs that are anti-fibrinolytic agents (2) and what is their MOA?
Anti-fibrinolytic agents: Used to stop the bleeding that could be caused by thrombolytics. Prevents plasmin binding to fibrin by acting as a lysine analog to block plasmin blocking. Normally, there are lysine residues on fibrin that bind to plasmin and its activator. By being lysine analogs, the drug binds in that site of the plasma, preventing fibrin from binding.
- Aminocaproic acid (EACA)
- Tranexamic acid
- Biggest complication is risk of intravascular thrombosis from preventing dissolution of the clot.
What is the pathophysiology of VTE, including the role of the coagulation cascade?
Stasis blood (lack of blood flow) promotes the formation of a thrombus due to decreased clotting factor clearance. These thrombi are made of RBCs, fibrin, and platelets.
Coagulation cascade:
- Epithelial injury exposes vessel wall to tissue factor, which produces a trace amount of thrombin. Thrombin promotes amplification of clotting factors, then more thrombin is made. Fibrin is produced in the propagation phase which develops the clot. As this clot grows, it could cause a DVT that could break off into a PE.
What are the contributing factors to the development of VTE?
Virchow’s Triad:
1. Abnormalities of clotting components (hypercoagulable state).
- Ex. pregnancy, cancer
2. Abnormality of surfaces in contact with blood flow (endothelial injury)
- Ex. injury of blood vessels from surgery or injury
3. Abnormalities in blood flow (circulatory stasis)
- Ex. long periods of immobility
What does the clinical presentation of a VTE look like? (DVT & PE)
Symptoms result when the flow is obstructed, vascular tissue wall becomes inflamed, a thrombus occurs and affects venous blood flow, or when emboli occur and enter pulmonary circulation. Some blood clots are asymptomatic.
DVT: Pain, swelling, redness in lower extremity
PE: Shortness of breath, chest pain, coughing, coughing up blood, rapid heart rate, dizziness or fainting
What is postthrombotic syndrome and what are the consequences of this condition?
Postthrombotic syndrome is a long-term complication of DVT caused by damage to venous valves.
Consequences of this condition include chronic venous obstruction, chronic pain and swelling, stasis ulcers, and the development of an infection.
- Make sure to rule out recurrent thrombosis before diagnosing a pt with postthrombotic syndrome.
What are the risk factors for development of a VTE?
- Age over 40 years old
- Family history of DVT
- Heart failure
- Immobilization of over 10 days
- Malignancy (extremely high risk)
- Orthopedic injury (extremely high risk)
- Obesity
- MI
- Pregnancy
- Oral contraceptive/estrogen
- Paralysis
What are the methods of diagnosis that are appropriate for DVT and/or PE?
If pt has symptoms of a DVT, could do a d-dimer test (would be increased if pt has a clot) or a ultrasonography to get imaging.
For a PE, we could do a CT scan for pulmonary angiography.
What are the goals of therapy for a VTE?
- Prevent the formation of a PE
- Stabilize the clot
- Reducing recurrence
- Preventing postthrombotic syndrome
What are the non-pharmacological treatment options for a VTE?
- Baseline monitoring
DVT:
- Bed rest
- Elevation of feet
- Pain management
- Compression stockings
PE:
- Oxygen
- Mechanical ventilation
- Compression stockings
Unfractionated heparin - What is the MOA? When would we use it in therapy? What are the appropriate monitoring we need to go for therapeutic and adverse effects?
MOA - Increases activation of AT and inactivates various clotting factors, which results in decreased clotting
Use - Acute DVT
Monitoring -
- aPTT monitoring (activated partial thromboplastic time); Goal is 1.5-2.5 x control; Check 6 hours after dose/dose change for the first 24 hours, then check daily
- Monitor platelet levels for HAT/HIT
Unfractionated heparin - What is the dosing regimen, route of administration, and duration of therapy for this drug? What are the adverse effects? How would we manage bleeding from heparin?
Dosing - Weight based dosing, dependent on how many times larger the aPTT is compared to control.
Route of administration - Parenteral (IV)
Duration - Use until ready to start other therapy
Adverse effects - Bleeding, thrombocytopenia
Bleeding? - Protamine sulfate for targeted reversal
Low molecular weight heparin - What is the MOA? When would we use it in therapy? What are the appropriate monitoring we need to go for therapeutic and adverse effects?
MOA - Binds to factor Xa to decrease clotting.
Use - Prophylaxis or treatment of acute DVT, maintenance therapy for treatment of DVT/PE; Better than heparin due to more predictable dose response, able to do SQ dosing and less incidence of HIT
Monitoring - None needed
- Consider monitoring anti Xa levels for children, pts with severe kidney failure, obesity, long courses of treatment, and pregnancy; Goal is 0.6-1 for BID, 0.1-0.3 for daily dosing
LMW heparin - What is the dosing regimen, route of administration, and duration of therapy for this drug? What are the adverse effects? How would we manage bleeding from LMW heparin?
Dosing - Once or twice daily dosing
- Enoxaparin (Lovenox): prophylaxis -> 30mg q12h if surgical, 40mg daily if acutely ill; treatment -> 1mg/kg q12h OR 1.5mg/kg daily; renal dysfunction -> 30mg daily for prophylaxis, 1mg/kg daily for treatment
Route of administration - Parenteral (SQ)
Duration - 3 months for treatment, 5-10 days if bridging to warfarin
Adverse effects - bleeding, injection site redness
Bleeding? - Protamine sulfate for targeted reversal
What are the differences between HAT and HIT? (pathophysiology & diagnostics)
HAT - Heparin associated thrombocytopenia (AKA HIT type 1)
- Not immune mediated, so this occurs earlier on (around 48-72 hours after heparin administration)
- See a mild decrease in platelets, but we don’t need to stop heparin
HIT - Heparin induced thrombocytopenia
- Immune mediated, so it takes longer (around 7-14 days) to present
- Causes thrombotic complications and it can occur up to 9 days after stopping therapy
** See a 50% drop in platelets from baseline OR < 100,000/mm^3 platelets **
How do we manage HIT?
- Stop all heparin products and give an alternative anticoagulant (ex. lepirudin, argatroban, bivalirudin, or fondaparinux).
- Don’t give platelet infusions
- Don’t give any warfarin until the platelet count is back up to > 150,000
- Evaluate for thrombosis since this is a prothrombic complication
Injectable factor Xa inhibitors (FXa) - MOA? Use in therapy? Monitoring for therapeutic and adverse effects?
MOA - Activates AT to inhibit factor Xa, thus reducing clotting.
Use - Prophylaxis following THA, TKA, hip replacement, abdominal surgery; Treatment of DVT or PE (can be first line), HIT
Monitoring - None needed
- Consider monitoring anti-Xa levels if renal dysfunction, pediatric, pregnant, or long course of therapy, obesity
Injectable factor Xa inhibitors (FXa) - Dosing, route of administration, duration of therapy, adverse effects, management of bleeding?
Dosing - Fondaparinux 2.5mg daily for prophylaxis with the hip, knee, or abdominal surgery. Weight based dosing for treatment.
Route of administration - Parenteral, SQ
Duration - Unclear how long prophylaxis should go for.
Adverse effects - Bleeding, injection site redness
Bleeding? - Nothing for targeted reversal
IV Direct Thrombin Inhibitors (DTI) - MOA? Use in therapy? Monitoring for therapeutic and adverse effects?
MOA - Binds to thrombin to inhibit clotting
Use - IV DTIs used for HIT (lepirudin, bivalirudin, argatroban)
Monitoring - For lepirudin, monitor aPTT; goal is 1.5-2.5 x control
IV Direct Thrombin Inhibitors (DTI) - Dosing, route of administration, duration of therapy, adverse effects, management of bleeding?
Dosing - Weight based dosing, argatroban requires dose adjustment for hepatic impairment
Route of administration - Parenteral (IV)
Duration - Until resolution of aPTT?
Adverse effects - bleeding
Bleeding? - Nothing for targeted reversal
NOAC/DOAC - MOA? Use in therapy? Monitoring for therapeutic and adverse effects?
MOA - Dabigatran is a prodrug that is an oral direct thrombin inhibitor; Rivaroxaban, apixaban, edoxaban, betrixaban are oral direct factor Xa inhibitors
Use - Postoperative prophylaxis for knee or hip replacement surgery, non-valvular atrial fibrillation for prevention of stroke or embolism, DVT or PE treatment, secondary prevention of DVT or PE, inpatient VTE prophylaxis
Monitoring -
NOAC/DOAC - Dosing, route of administration, duration of therapy, adverse effects, management of bleeding?
Dosing - Dosing various for indication and drug
Route of administration - Oral
Duration - Depends on indication
Adverse effects - Bleeding
Bleeding? -
- Idarucizumab for dabigatran (direct binder to dabigatran)
- Hemodialysis for dabigatran only
- Andexanet alfa for rovaroxaban and apixaban (binds and sequesters); dosing depends on what and when last dose was
What indications are the NOACs approved for (Dabigatran, Rivaroxaban, Apixaban, Edoxaban, Betrixaban): postoperative prophylaxis, non-valvular atrial fibrillation, DVT/PE treatment, secondary prevention of DVT/PE, VTE prophylaxis
Postoperative prophylaxis: Dabigatran (hip only), rivaroxaban, apixaban
Non-valvular atrial fibrillation: Dabigatran, rivaroxaban, apixaban, edoxaban
DVT/PE treatment: Dabigatran, rivaroxaban, apixaban, edoxaban
Secondary prevention of DVT/PE: Rivaroxaban, apixaban
VTE prophylaxis: Rivaroxaban, betrixaban
What are the appropriate INR ranges for these specific indications: Prophylaxis of VTE, treatment of VTE/PE, prevent systemic embolism, antiphospholipid antibody syndrome, mechanical aortic heart valve, mechanical heart valve (not atrial)
2.0-3.0 is the goal for prophylaxis of VTE, treatment of VTE/PE, prevent systemic embolism, antiphospholipid antibody syndrome, mechanical aortic heart valve
2.5-3.5 is the goal for non aortic mechanical heart valve (ex. mitral, caged ball, high risk)
How do we make warfarin dose adjustments?
- Check at least one INR within the first week (ex. days 3-5). If INR is within goal, check INR in one week and proceed weekly for the first month. If INR wasn’t in range, adjust the weekly dose
For INR of 2.0-3.0:
- INR below 2.0 -> increase dose by 5-10%
- INR 3.1-3.5 -> decrease by 5-15%
- INR 3.5-4.0 -> hold 0-1 dose and/or decrease by 10-15%
- INR over 4.0 -> hold 0-2 doses and/or decrease by 10-15%
For INR of 2.5-3.5:
- INR below 2.5 -> increase dose by 5-10%
- INR 3.6-4.0 -> decrease dose by 5-15%
- INR 4.1-4.5 -> hold 0-1 dose and/or decrease by 10-15%
- INR over 4.5 -> hold 1-2 doses, decrease by 10-15%
- Don’t give more than 1 strength of warfarin at a time
- Don’t have only 1 day that they take a different dose
- Don’t stack different doses
Order of switching doses:
1. Mon + Fri
2. MWF
3. T, Th, Sat, Sun
What are the common gene mutations associated with warfarin metabolism?
CYP2C9 - Normal is CYP2C91
- 2C92 and 3 require a decrease in dose. 3/3 requires most decrease in dose (2/3 very common in white patients)
- 2C95, *6, *11 are more common with asians and african americans. These pts need a lower dose requirement as well
VKORC1 -
- -1639A causes increased warfarin sensitivity, requiring a decrease in dose. (-1639AA most sensitive)
- -1639G causes increased warfarin resistance, requiring an increase in dose (-1639GG most resistant)
*only test if patient is warfarin naive, genetic test results are available before the 6th dose, AND the patient is at high risk of bleeding if INR is elevated (on meds that increase bleeding)
What are the common drug interactions we are concerned with with warfarin?
Increase INR (more bleeding):
- Metronidazole
- Amiodarone
- Fluconazole
- Ciprofloxacin
- Bactrim
- actue EtOH (or w/ liver damage)
Decrease INR (more clotting):
- Rifampin
- chronic EtOH
**vit K reverses warfarin activity
What are some important counseling points for someone starting warfarin?
- Need to start with at least 5 days of UFH/LMWH/Xa AND get into therapeutic INR range
- Ask about the 5 Ds everytime (drugs, diseases, doses, diet, drinks)
- Ask about bleeding/bruising
