Term
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Definition
Thrombosis: arterial/venous vessel clot
• Arterial->acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke
- Arterial circulation: oxygen rich, high shear stress due to rapid flow
• Venous->deep vein thrombosis (DVT), pulmonary embolism (PE)
- Venous circulation: capacitance system, oxygen poor, low shear stress
• All blood clots can cause major morbidity and mortality
-Therapy selection depends on acuity, clot composition/location |
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Definition
• Associated with atherosclerotic plaque rupture
• Exposed vessel collagen à platelet cascade
• Rich in platelets because of high shear in
arteries
- “White” clots |
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Definition
• Associated with surgery, critical illness, hemostasis
• Rarely form at site of vascular injury
• Rich in fibrin cross-linkages, trapped red blood cells
- “Red” clots |
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Definition
Again, with this image here on the left, side A, we can see that the lipid-rich clot forms, and an atherosclerosic plaque ruptures over time. This is the arterial circulation-- for instance, like a coronary artery. Over time, this lipid-plaque builds up and may rupture, and exposes some epithelium underneath, forming a platelet-rich clot, like we described previously.
In contrast, in slide B, we can see that there is no such lipid-rich plaque in the capacitance system. This is low, slow flow, which enables time for the entire coagulation cascade to form a fibrin-rich clot. Given the different composition between each of these thrombus-formation pathways, different therapies are needed to clot bust in either scenario. |
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Definition
| So we'll review the coagulation cascade in order to get a better idea of what we're treating and where our molecular targets are going to be. At the site of vessel injury, clotting-factor VII forms a tissue factor in order to initiate the entire platelet cascade, as well as the anticoagulation cascade. The main players here are going to be factor X, antithrombin III, and thrombin, or factor II. Now these are the end products that form a thrombus, at the end of the day, that's usually rich in composition of fibrin, or red clot. |
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Definition
| Heparin, Argatroban, Bivalirudin |
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Definition
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Definition
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| (PTpatient / PTcontrol)ISI |
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Definition
• Time in seconds for fibrin clot to form
• Measures extrinsic/common pathway
• Varies depending on lab reagents
• INR accounts for variability |
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Definition
| Heparin is one of the most commonly used anticoagulants inside the hospital. It is a multi-chained polysaccharide that acts at the point of antithrombin III inside the coagulation cascade. Antithrombin III is a negative regulator of the coagulation cascade. It down regulates the production of both thrombin and Xa. And heparin, in its pentasaccharide form, targets both of the Xa and the thrombin section after activating antithrombin III's endogenous activity. |
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Definition
So as I mentioned, heparin is a rather large molecule. It's a pentasaccharide that actually is formed from porcine heparin analogs. In a given intravenous or subcutaneous form, it attacks that antithrombin III and activates it, making it more active inside the body where antithrombin III normally in humans will actually down regulate factor X and thrombin.
In the presence of heparin, antithrombin III acts about twice or 10 times as much to down regulate the production of Xa and thrombin, meaning that a fibrin-rich clot, which would normally form in the presence of vessel injury or after hemostasis, won't get the chance to form. And in fact, 1.5 to 2 times as much time will have to go past before a normal clot would be able to form in the presence of heparin. And that's generally considered the range of therapeutic anticoagulation. |
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Term
| Unfractionated heparin (UFH) |
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Definition
• Mixture of molecules of different weights and activity
• Binds antithrombin III to inhibit factors IIa, IXa and Xa
• Dose
• Prophylaxis 5,000–7,500 units SubQ Q8H
• Treatment 10–20 units/kg/hr IV to goal PTT/anti-Xa
• Adverse effects: bleeding, rare thrombocytopenia, alopecia, hepatotoxicity, hypersensitivity reactions
• Monitoring: PTT, anti-Xa, CBC, platelets, potassium
• Antidote: protamine 1 mg per 100 units heparin, maximum 50 mg |
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Term
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Definition
Heparin-induced thrombocytopenia (HIT)
• Heparin binds platelet factor 4 (PF4)
• Complex acts as antigen
• Causes immune-mediated HIT
• 1–4% of heparinized patients
• LMWH risk <1%
• Up to 50% thrombosis risk |
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Definition
[image]
High Score (6–8): HIT is likely Intermediate Score (4–5): HIT is possible Low Score (0–3): HIT is unlikely |
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Term
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Definition
• Discontinue all heparin products
• Send HIT antibody, serotonin release assay (SRA) performed if antibody positive to confirm
• Initiate therapeutic anticoagulation with a direct thrombin inhibitor (argatroban, bivalirudin)
• Fondaparinux preferred if CrCl>30mL/min
• Once platelets recover, initiate warfarin
- Emerging literature in support of DOACs
• Document heparin allergy
- Can rechallenge after 180 days |
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Definition
| Now, low molecular weight heparins are very similar to the unfractionated heparins, except they only represent about 1/5 of the size of a heparin molecule. Enoxaparin and dalteparin are the most commonly prescribed in the hospital. They are much, much smaller and therefore carry a much lower risk of HIT. But they're also used for the same indications that heparin are, such as VT prevention and thrombosis prevention or active treatment. |
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Definition
• Shortchainheparinmolecules
• PrimarilyaffectfactorXa
• Morepredictablepharmacokinetics,less interpatient variability than heparin
• Adverseeffects:bleeding,rare thrombocytopenia, skin necrosis, skin hypersensitivity reactions
• Monitoring:potassium,CBC,platelets,serum creatinine, anti-Xa units for selected patients
• Antidote:protamine1mg/1mgenoxaparin |
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Definition
• Spinal or epidural hematomas, including subsequent paralysis, may occur with recent or anticipated neuraxial anesthesia (epidural or spinal) or spinal puncture in patients anticoagulated with LMWH or heparinoids.
• Hold LMWH before and after the spina lprocedure.
• Patient should be observed closely for bleeding and signs and symptoms of neurological impairment if therapy is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia. |
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Definition
| Enoxaparin (Lovenox)- Reduce dose in renal impairment, Dalteparin (Fragmin)- Increase dose for high BMI, Fondaparinu x (Arixtra)- Only available as injection; reduce dose/avoid in renal impairment and weight <50kg |
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Definition
Warfarin was one of the first oral anti-coagulants that was ever discovered and one of the most commonly prescribed oral anti-coagulants for atrial fibrillation and venous drama anabolism in the entire country. Warfarin is also, however, one of the more promiscuous anti-coagulants, as it targets multiple clotting factors all along the coagulation cascade. It's part of the medication class vitamin K antagonists, because it disrupts the formation of all vitamin K-dependent clotting factors, II, VII, IX, and X, as well as our endogenous anti-coagulant proteins C and S.
Now, this disruption in the clotting cascade prevents the formation of these clotting factors from being formed. So at the moment we take warfarin, we aren't therapeutically anti-coagulated. But it takes time, based on the half life of these clotting factors, for them to be depleted enough such that our blood will be thin to the point where we're therapeutically or prophylactically anti-coagulated against blood clots. |
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Definition
| So warfarin inhibits the oxygen transfer from the active form of vitamin K, epoxide reductase, which then goes on to activate the clotting factors dependent on vitamin K. It disrupts this enzyme from that critical step that then there goes to make factors II, VII, IX, and X, as well as proteins C and S. The half-life becomes critically important, as I mentioned, because the longer half-life clotting factors, such as thrombin or factor II, tends to hang around the longest and protect the patient against forming blood clots. |
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Definition
| However, shorter proteins C and S, which have half-lives of 10 and 60 hours, are endogenous protectants against blood clots, as well. So the depletion of proteins C and S may actually make us pro-thrombotic during the initial time that we're taking warfarin. Whereas, it's dependent on the 60-hour half life of thrombin or factor II to be depleted, in order for us to actually be anti-coagulated. So this is why, when patients have an acute venous thromboembolism event, and we prescribe warfarin to treat this condition, we may need to bridge or overlap anti-coagulation therapy for up to three or five days, while we wait for the half-life of all the other anti-coagulant clotting factors to be depleted-- so basically offering patients parenteral acute anti-coagulation while we wait for factor II to be dissipated. |
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Term
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Definition
• Vitamin K antagonist decreases formation of clotting factors II, VII, IX, X; as well as endogenous anticoagulants proteins C and S
• Dosing:5mg PO daily, titrate with caution, effect of a given dose seen in ~72 hours, may take five days for full anticoagulant effect
• Many drug interactions(CYP2C19,1A2,2C9, 3A4 substrate) and diet interactions (Vitamin K)
-Consistency is critical
• Monitoring: INR(goal 2–3 for most patients), CBC |
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Term
| has ADE: bleeding, teratogenic, rare hypersensitivity reactions |
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Definition
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Definition
• Four-Factor Prothrombin Complex Concentrate (Kcentra)
• Phytonadione (Vitamin K) 1–10mg PO/IV
- Large doses can result in warfarin resistance for up to a week
- ACCP 2012 guidelines recommend against vitamin K for
INR <10 without bleeding |
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Term
| Warfarin diet interactions |
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Definition
- High vitamin K
• Kale
• Spinach
• Turnip greens
• Collard greens
• Swiss chard
• Parsley
• Mustard greens
- Moderate
• Brussel sprouts
• Broccoli
• Romaine lettuce |
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Term
| warfarin drug interactions |
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Definition
INR elevation: amiodarone, ciprofloxacin, TMP/SMX, Metronidazole
INR depression: rifampin, secobarbital, carbamazepine, phenytoin, phenobarbital, primidone, st john's wort, cigarette smoking, charbroiled food |
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Term
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Definition
• Initial hypercoagulable state due to depletion of proteins C and S relative to clotting factors
• Overlap or“bridge”therapy with an immediate acting, injectable anticoagulant provides coverage while warfarin takes effect
• Overlap warfarin until INR is within therapeutic range for two consecutive draws
- Minimum five days overlap
- VTE-6 Core Measure (often not needed for AFib) |
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Term
| lower initial warfarin dose for: |
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Definition
• Advanced age
• Low weight
• Poor nutritional status
• Hepatic impairment
• Congestive heart failure
• Coadministration with agent that decreases warfarin clearance |
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| higher initial warfarin dose for: |
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Definition
• Young age
• Overweight
• Coadministration with agent that increases warfarin clearance |
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Definition
| Adjust dose by 10–15% based on weekly warfarin dose |
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'SJ is a 75 y/o gentleman with atrial fibrillation and a prior stroke who is currently on warfarin. You check his INR and find that it is elevated at 6.4 (goal 2–3). You evaluate SJ and identify no signs or symptoms of active bleeding.
What is your plan? |
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Definition
| Hold dose, then restart at lower weekly dose. |
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AL is a 48-year-old woman with recurrent deep vein thromboses who is currently on warfarin. You check her INR and find that it is 2.4 (goal 2–3). She is hypotensive, tachycardic, and reports coffee-ground emesis and a feeling of lightheadedness.
What is your plan? |
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Definition
Reverse with 10 mg IV vitamin K and/or 4-factor PCC.
It is appropriate to reverse regardless of INR if the patient is symptomatic with a significant bleed. |
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Term
Current dose: 5 mg Monday and Thursday, 7.5 mg all other days of the week (47.5 mg total per week)
INR 3.5 (goal 2–3), no signs or symptoms of bleeding
What dose adjustment would you make?
When would you recheck the INR? |
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Definition
In order to reduce weekly dose by approximately 10–15% and keep the same tablet strength, could change to regimen such as the one below:
Warfarin 7.5 mg Monday, Wednesday, Friday, 5 mg all other days of the week (42.5 mg total per week).
Recheck at least 2 to 3 days to see changes, up to 5 to 7 days to see result of small changes. |
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FS is a 56 y/o female on Coumadin (warfarin) who also has C. difficile associated diarrhea and is treated with metronidazole, which inhibits warfarin clearance.
You enter the medications into a drug interaction database and find that the hypoprothrombinemic effects of the s-isomer of warfarin are enhanced by 100% and the half-life is prolonged.
What is your plan? |
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Definition
A good initial plan of action would probably be to share that there's lots of literature about this interaction with the team. And you may actually notice that C. diff has lots of medications that are actually used to treat it as an infection. Using oral vancomycin, which does not inhibit any cytochrome enzymes and does not compete with any of the binding sites of warfarin, may be a good idea to treat the infection and not interact with the medication.
But if, for instance, the patient has an intolerability to oral vancomycin or doesn't like the taste given the liquid does tend to carry a poor taste, metronidazole maybe the only option available. And if that's the case, you should empirically reduce the dose of warfarin and expect that the INR is going to be exaggerated with any little bit of warfarin that's given.
So checking the INR at least once a day while having the dose of warfarin empirically before giving a dose of metronidazole will probably lend you the best chance at getting a therapeutic range without overshooting and getting a super therapeutic INR given that metronidazole exaggerates the effect of warfarin and can increase the risk for patients' level of bleeding. |
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Term
| Direct Oral Anticoagulants MOA |
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Definition
| Direct oral anticoagulants, also known as the DOACs, are the newest class of blood thinners to enter the anticoagulation arena. They act at various sites in the entire coagulation cascade, but namely at factor X or factor II, also known as thrombin. |
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Term
| Direct thrombin inhibitor agent (DOAC) |
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Definition
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Term
| Factor Xa Inhibitors (DOAC) |
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Definition
• ApiXaban (Eliquis®)
• BetriXaban (Bevyxxa®)
• EdoXaban (Savaysa®)
• RivaroXaban (Xarelto®) |
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Term
| Factor Xa Inhibitors MOA, AE, monitoring, antidose |
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Definition
• Inhibit factor Xa
• CYP3A4, p-glycoprotein substrate
• Adverse effects: bleeding
• Monitoring: none routine, CBC, serum creatinine
• Antidote: andexanet alfa |
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Term
• Cannot remove from original packaging
• Dyspepsia and gastritis very common side effects (35%)
• Greater GI bleed risk than warfarin and other DOACs
• 75mgBIDdosenot studied in RE-LY trial |
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Definition
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Term
| Do not crush, drug interactions w: PPI’s, potent CYP3A4 inducers and P-gp Inhibitors |
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Definition
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Term
• Once daily dosing convenience
• Take with meals
• Safe in patients status
post-gastric bypass
surgery
• Preferred DOAC in
obese and underweight
patients
• Recent label update for
hemodialysis patients |
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Definition
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Term
drug interactions w: Potent CYP3A4 inducers and
P-gp inhibitors |
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Definition
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Term
| drug interactions w P-gp inhibitors |
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Definition
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Term
• 5 mg BID superior to warfarin for NVAF
• All-cause mortality benefit compared to warfarin in NVAF
• Lowest bleeding risk of all DOACs, warfarin, and even aspirin
• May be preferred DOAC in hemodialysis, but dosing controversial
• Avoid intentional under- dosing |
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Definition
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Term
• Once daily dosing convenience
• 60 mg dose superior to warfarin for NVAF
• Contraindicated in CrCl <15 mL/min or >95 mL/min
• Not covered by many insurance plans
• May be preferred DOAC in cancer associated thrombosi |
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Definition
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Term
| Direct Thrombin Inhibitors |
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Definition
• Inhibit thrombin which prevents thrombin-induced conversion of fibrinogen to fibrin
• Pradaxa (dabigatran) approved for non-valvular atrial fibrillation (contraindicated with mechanical heart valves)
• Angiomax (bivalirudin) and argatroban used for procedural anticoagulation or anticoagulation in setting of HIT
• Adverse effects: bleeding, hypotension, gastritis-like symptoms (dabigatran)
• Monitoring: PTT, INR (argatroban), CBC
• Antidote: idarucizumab (Praxbind) for dabigatran |
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Term
Co-formulated with acid to enhance absorption → dyspepsia
Reduce dose or avoid in renal impairment
Capsule cannot be opened/crushed Antidote available |
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Definition
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Term
| Reduce dose in renal impairment (Direct Thrombin Inhibitors) |
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Definition
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Term
| Avoid in hepatic insufficiency (Direct Thrombin Inhibitors) |
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Definition
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Definition
• No need for routine lab monitoring
• Fewer drug interactions
• Onset within hours (no need for IV anticoagulant bridge at initiation)
• Recommended over warfarin in patients without cancer who have a lower extremity DVT or PE in 2016 Chest Guidelines
• Less fatal and intracranial hemorrhage
• Generallymoreexpensive
• LimiteddatainESRD/hemodialysis
• Noestablishedtherapeuticrange/monitoring
• Antidoteavailableinlimitedsupply
• Offset within hours
-Rapid loss of efficacy with missed doses, use caution in non-adherent patients
- Consider anticoagulant bridge if temporarily held for any reason other than significant bleeding
• Meta-analysisofover40,000patientsonnovel anticoagulants and nearly 30,000 on Coumadin (warfarin)
• Compared to warfarin, DOACs:
- Reduced risk of stroke and systemic embolism by 19%
- Reduced mortality by 10%
- Reduced risk of hemorrhagic stroke by 51%
- Increased the rate of gastrointestinal bleeding by 25% |
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Term
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Definition
As we've discussed previously, there are black box warnings for all blood thinners of any kind. And this includes patients who are going to get neuraxial analgesia, have their dorsal spinal cord punctured, a lumbar puncture of any kind. Anticoagulants should not be given at the same time or within several days of patients who have had this procedure done, as bleeding into these closed spaces can potentially be fatal.
So depending on a patient's renal function, stopping the DOAC prior to the procedure and waiting to reinitiate the DOAC until after the procedure when a safe time has been determined becomes of critical importance. This is, again, a black box warning-- do not use these at the same time as this procedure. And use the patient's renal function to determine whether or not you should continue and hold for two to three days, or perhaps even longer. |
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Term
| Compare and contrast warfarin and DOACs. |
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Definition
-Reduced risk of stroke and systemic embolism, hemorrhagic stroke and mortality
-Increased the rate of gastrointestinal bleeding
-Do not require routine lab monitoring
-More expensive
-Shorter acting
-Fewer drug interactions |
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