CONTENTS

getting started

• General considerations
• Pre-procedure coagulation management for common procedures

common reversal situations

• Approach to warfarin reversal
  • Urgent reversal
  • Non-urgent supratherapeutic INR
• Approach to DOAC reversal
  • Dabigatran
  • Factor Xa inhibitors (riveroXABAN, apiXABAN, edoXABAN, fondaparinux)
    • Apixaban level
• Reversal of other agents
  • Thrombolytics (e.g. tPA)
  • Antiplatelet agent reversal
  • Heparin reversal

pharmacology of procoagulant agents

• FFP (Fresh Frozen Plasma)
• PCC (Prothrombin Complex Concentrate)
• Cryoprecipitate
• Fibrinogen concentrate
• DDAVP
• Tranexamic acid & aminocaproic acid
• Protamine for heparin reversal
• Factor IX Complex
• Recombinant activated factor 7 (rFVIIa)

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considerations when approaching anticoagulation reversal

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how coagulopathic is the patient?

• Critically ill patients often have several coagulopathies (e.g., thrombocytopenia plus supratherapeutic INR on warfarin).   Consider all medications and coagulation labs in order to get a global sense of how coagulopathic the patient is.
• For patients with cirrhosis or disseminated intravascular coagulation (DIC), traditional coagulation parameters (e.g., INR) don't necessarily reflect the true coagulation state.  In this situation, thromboelastography (TEG) may be more accurate.

pharmacology specifics

• Review all medications the patient is taking which may affect coagulation (including over-the-counter aspirin or aspirin-containing products).
• Determine what doses of medication the patient is on, and when is the last time a dose was taken.

why was the patient initially anti-coagulated?

• Most patients are anti-coagulated for atrial fibrillation or deep vein thrombosis.   Short-term interruption is generally fine.
• Some patients are anti-coagulated for higher risk conditions (e.g. a mechanical mitral valve, which has a high risk of thrombosis).  This may shift the risk/benefit ratio.

how important is it to reverse the anticoagulation?

• Life-threatening bleeding requires aggressive normalization of coagulation parameters, but minor bleeding may respond to local measures.
• There is little evidence that moderately elevated INR correlates with post-procedural bleeding after many procedures (e.g., ultrasound-guided central line placement or thoracentesis).   Anticoagulation reversal for minor procedures is generally unnecessary.

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pre-procedure coagulation management for common critical care procedures

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pitfalls in pre-procedure coagulation management for common critical care procedures

• (#1) We overestimate the risk of bleeding. Most bedside ICU procedures carry a very low risk of bleeding and don't require aggressive coagulation reversal (with the possible exception of lumbar puncture).
• (#2) We fail to consider the big picture. ICU patients are sometimes on a potpourri of anticoagulant medications, along with various other hemostatic challenges (e.g., uremic platelet dysfunction, thrombocytopenia). Although any single medication or abnormality may not be severe, the overall constellation may be quite problematic.
• (#3) We put excess faith in the INR. This is foolish, because INR interpretation depends on the clinical context. For example, an INR of 2.5 in the context of cirrhosis is likely to reflect rebalanced hemostasis without any increase in hemorrhage risk. Alternatively, an INR of 2.5 in a patient on apixaban suggests a high bleeding risk. Thus, any studies or guidelines based predominantly on INR values is fundamentally flawed.
• (#4) We try to push the INR to 1.0 using FFP. Please note the above discussion about the futility of giving FFP to patients with an INR of ≤1.7.📖 Additionally, in the context of cirrhosis, FFP will improve the INR but it generally doesn't improve clinical hemostasis.

how to avoid these pitfalls

• (#1) Recognize that most of our procedures are low-risk for hemorrhage. Note, for example, the below guidelines by the Society of Interventional Radiology.(31229333) Essentially every bedside procedure in the ICU is listed as a “low risk” procedure.🗞
• (#2) Try to consider the larger picture, including all coagulopathies and anticoagulant medications.
• (#3) Thromboelastography has a proven ability to guide hemostatic replacement in the operating room (including complex surgeries such as liver transplantation). When in doubt about whether factor replacement is needed, ordering thromboelastography may provide a “second opinion.”📖 TEG is especially useful in cirrhosis, where it clearly outperforms traditional coagulation tests such as INR.🌊

low-risk ICU procedures: central line placement, thoracentesis, paracentesis

• There is no evidence that any specific threshold exists for coagulation labs, below which these procedures are unsafe. For example:
  • Varying guidelines recommend different platelet threshold targets prior to central line insertion (including >50, >30, >20 and >10).(31229333) The reality is probably that no threshold exists.
  • The 2019 Society of Interventional Radiology Consensus Guidelines concluded that the risk of bleeding following thoracentesis or paracentesis is so low that “the need for prophylactic blood products before these procedures has been called into question.”(31229333)
• Ultimately, decisions about risk versus benefit of prophylactic blood product administration should be individualized, based on a holistic assessment of the patient's risk of bleeding. There are some situations where prophylactic transfusion may be beneficial, although on the whole it is grossly over-utilized.
• The key to minimizing risk is to avoid arterial injury. Some safety steps which may help in this regards are as follows:
• Central line:
  • The procedure should be done by an expert operator using ultrasound guidance.
  • Do not attempt the procedure if there isn't a favorable ultrasound view (e.g., clear visualization of the vein and separation between vein and artery).
  • Use a shallow angle of approach and try not to backwall the vessel (i.e., avoid going through-and-through the vessel; ideally only the proximal vessel wall should be punctured).
• Thoracentesis:
  • Avoiding thoracentesis near the spine (the intercostal artery position may be more variable there).
  • Staying close to the upper edge of the rib.
  • When possible, ultrasound may be used to visualize the intercostal artery. This allows for pre-procedure identification of aberrant vessels and avoidance of them.
  • As the syringe is advanced, there should be continuous negative suction. If arterial blood appears in the syringe, pull out! Do not advance into the pleura (this may create an arterial-pleural fistula).
• Paracentesis:
  • Use a very small-bore needle (e.g. 24-gauge lumbar puncture needle, with the stylet removed of course).
  • Before performing the procedure, use ultrasound with doppler to make sure that there are no arteries in the vicinity. The inferior epigastric arteries should ideally be identified and avoided, as any trauma to these arteries may cause massive peritoneal hemorrhage.

lumbar puncture: 📖

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warfarin: urgent reversal

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[1/3] assessment of coagulopathy

• INR.
• ⚠️ For intracranial hemorrhage in a patient on warfarin, PCC should be given immediately without waiting for the INR to result. (35579034)

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[2/3] management

urgent reversal of warfarin requires two simultaneous therapies

• [1] 10 mg IV vitamin K over 30 minutes.
• [2] PCC or fresh frozen plasma:
  • PCC is preferred 💉
  • Alternative: four units of fresh frozen plasma. 💉

followup

• May follow a repeat INR.
• For patients with intracranial hemorrhage, follow INR every 3-6 hours to ensure adequate reversal. (33288539)

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[3/3] discussion, physiology, additional comments

intravenous vitamin K

• This is arguably the most important intervention to reverse warfarin.
• 10 mg should be given intravenously, as soon as possible (infused over 30 minutes).
  • FFP or PCC will only work for approximately 8 hours.
  • Vitamin K will take effect after the FFP/PCC wears off. It takes Vitamin K 6-12 hours to start working, so vitamin K must be given simultaneously with FFP or PCC.
• Intravenous vitamin K may theoretically cause an anaphylactoid response if infused rapidly.
  • This is exceedingly rare (~1/30,000 patients), especially with newer formulations of intravenous vitamin K. (22315259, 38926082)
  • This is an anaphylactoid reaction (not anaphylactic), so it can be avoided by infusing the vitamin K slowly (e.g., over 30 minutes).
    • An anaphylactoid reaction is due to a drug's directly stimulating mast cells to release histamine (unlike an anaphylactic reaction, which involves IgE antibodies). Anaphylactoid reactions can present similarly to anaphylactic reactions and may be treated in a similar manner. However, anaphylactoid reactions are generally less severe and can be avoided by infusing a drug slowly.
  • A fear of this reaction should never be a barrier to administering intravenous vitamin K to patients who require it. If you're terrified about this reaction, then infuse the vitamin K incredibly slowly (e.g., over an hour). An anaphylactoid reaction is rate-related, so the likelihood of a severe adverse reaction at this slow rate is close to zero.
• Other routes are inferior for emergent reversal:
  • Subcutaneous administration has erratic absorption.
  • IM administration may cause hematoma formation.
  • PO administration has slower absorption.
• 💡 For the emergent reversal of anticoagulation, there is only one dose and one route of vitamin K that should be used: 10 mg of IV vitamin K infused over 30 minutes.

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warfarin: non-urgent supratherapeutic INR

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Patients with supratherapeutic INR without bleeding are commonly encountered. Below is a general rubric that may help guide management. However, this isn't based on substantial evidence. Most importantly, management should be individualized based on patient-specific factors. 

• INR 3-5 without bleeding:
  • Hold warfarin.
  • Resume at a lower dose when INR is therapeutic.
• INR 5-9 without bleeding:
  • Hold 1-2 doses of warfarin.
  • Vitamin K 1-2.5 mg PO/IV if risk for bleeding.
  • Resume warfarin at a lower dose when INR is therapeutic.
• INR >9 without bleeding:
  • Hold 1-2 doses of warfarin.
  • Vitamin K 2.5-5 mg PO/IV.
  • Repeat vitamin K in 24 hours if INR remains elevated.
  • Resume warfarin at a lower dose when INR is therapeutic. (Bojar 2021)

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Direct thrombin inhibitor: Dabigatran

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[1/3] assessment of coagulopathy

• Crude assay = PTT
  • Normal PTT argues against a clinically significant dabigatran effect, but doesn't exclude this possibility. (39089758)
• Better assay = Thrombin Time (TT)
  • Thrombin time has a good correlation with dabigatran levels, but may be unmeasurably elevated at therapeutic dabigatran concentrations.
  • Normal thrombin time excludes clinically significant dabigatran effect. (31339254, 39029742)
  • Availability may vary; often cannot be run STAT.

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[2/3] management

tx: idarucizumab (PRAXBIND)

• Monoclonal antibody Fab fragment that binds and inactivates dabigatran.
• Possible indications for reversal:
  • Major bleeding or planned high-risk procedure.
  • Last dose taken within <12-24 hours (with normal renal function). For patients with intracranial hemorrhage, reversal may be considered if the previous dose was within <5 half-lives (i.e., within the past 2-4 days. (Albin 2022)
  • Significantly abnormal PTT and/or thrombin time (especially thrombin time >25 seconds).
• Dose:
  • [1] A total of 5 grams is usually sufficient. This is typically provided as two separate 2.5-gram doses no more than 15 minutes apart.
  • [2] For patients with an unusually high level of dabigatran (e.g., new-onset renal failure with drug accumulation), there is a possibility that additional doses might be needed.
• Monitoring
  • Follow PTT (or thrombin time if available) at baseline, 2-4 hours after idarucizumab, and q12 hours.
  • A small proportion of patients may have a rebound of dabigatran levels >12 hours after reversal due to drug redistribution out of adipose tissue, which may be associated with bleeding. Redosing idarucizumab may be considered. (Albin 2022)
• Side effects may include hypokalemia, delirium, pyrexia, and bankruptcy.
• Little high-quality evidence is available regarding this drug.
• If idarucizumab is unavailable, four-factor PCC may be used as an alternative. (33403486)

tx: activated charcoal

• If ingested in <2 hours may consider activated charcoal 50 grams.

tx: hemodialysis

• Due to its low percent protein binding, dabigatran can be removed by dialysis (whereas other DOACs cannot be).
• Dialysis may be considered if idarucizumab is unavailable.

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[3/3] discussion, physiology, additional comments

pharmacology of dabigatran

• Half-life: 12-17 hours (doubles if GFR <30 ml/min).
• Renal excretion: 80%.
• Removal by dialysis: ~65%.

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factor Xa inhibitors (riveroXaBAN, apiXaBAN, edoXaBAN, fondaparinux)

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[1/3] assessment of coagulopathy

• Crude assay = INR.
  • Normal INR argues against a significant drug level but doesn't exclude this entirely. (31317796, 39089758)
• Better assay = Anti-Factor Xa level.
  • Anti-Xa activity correlates well with drug level. 
  • Normal anti-Xa level excludes the presence of clinically relevant Xa inhibitors.
  • The Anti-Xa assay optimized to detect LMWH may be more sensitive. (39089758) However, any anti-Xa assay is probably fine. (30916798)
• Best assay = Apixaban level (discussed in the section below ⚡️).

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[2/3] management

• [1] 4-factor PCC (KCENTRA) 💉
• [2] If ingested within <2 hours, may consider activated charcoal 50g.
• [3] If INR is elevated, consider 10 mg IV vitamin K to exclude vitamin K deficiency.
• (Adnexanet Alfa may be considered if available. However, clinical data is mixed and the price is extremely high.)

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[3/3] discussion, physiology, additional comments

pharmacology

• ApiXaBAN:
  • Half-life ~12 hours (ranging ~9-14 hours).
  • Clearance: ~55% in stool; ~25% renal excretion.
  • Protein binding: ~90% (not dialyzable).
• RiveroXaBAN:
  • Half-life 6-9 hours (11-13 in elderly).
  • Clearance: 70% renal excretion.
  • Protein binding: ~95% (not dialyzable).
• EdoXaBAN:
  • Half-life 10-14 hours.
  • Clearance: 50% renal excretion.
  • Protein binding: ~50% (somewhat dialyzable).

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apixaban level

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Apixaban level is a chromogenic anti-Xa level that is calibrated to evaluate the level of apixaban. The assay's mechanics are identical to an anti-Xa level used to dose-adjust a heparin infusion. As such, an apixaban level will only be a valid measurement of the apixaban level in the absence of any other medications that inhibit factor X. 

potential indications for checking an apixaban level

• [1] Active hemorrhage.
• [2] Need for an emergent/urgent procedure.
• [3] Expected abnormal pharmacokinetics, e.g.:
  • Extremes of weight.
  • Elderly.
  • Renal impairment.
  • Drug-drug interactions are expected to affect apixaban levels.
• [4] Clinical failure with breakthrough thrombosis.
• [5] Evaluation of medication adherence.

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test limitations

• Other medications that will elevate the measured apixaban level:
  • Heparins (unfractionated or LMWH).
  • Fondaparinux.
  • Any other Xa inhibitors (e.g., rivaroxaban, edoxaban).
• Falsely low anti-Xa/apixaban levels may occur with: (35080509)
  • [1] Hemolysis (plasma-free hemoglobin >50 mg/dL). ⚡️
  • [2] Hypertriglyceridemia (triglycerides >360-500 mg/dL). (36703184)
  • [3] Bilirubin >6 mg/dL.

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interpretation of levels

normative levels during treatment of AF

• Peak level (2-4 hours after dose); median (5th-95th percentile)
  • 2.5 mg (twice daily): 123 (69-221) ng/mL.
  • 5 mg (twice daily): 171 (91-321) ng/mL.
• Trough level (10-12 hours after dose); median (5th-95th percentile)
  • 2.5 mg (twice daily): 79 (34-162) ng/mL
  • 5 mg (twice daily): 103 (41-230) ng/mL.

normative levels during treatment of DVT/PE

• Peak level (2-4 hours after dose); median (5th-95th percentile)
  • 2.5 mg (twice daily): 67 (30-153) ng/mL.
  • 5 mg (twice daily): 132 (59-302) ng/mL.
  • 10 mg (twice daily): 251 (111-572) ng/mL.
• Trough level (10-12 hours after dose); median (5th-95th percentile)
  • 2.5 mg (twice daily): 32 (11-90) ng/mL.
  • 5 mg (twice daily): 63 (22-177) ng/mL.
  • 10 mg (twice daily): 120 (41-335) ng/mL.

very rough cutoff values 

• >50 ng/mL: roughly correlates with a therapeutic level. 
  • In major bleeding, a level >50 ng/mL indicates that the DOAC should be reversed (e.g., with PCC). (26637710) 
  • In acute ischemic stroke, a level <50 ng/mL is often regarded as a benchmark below which it may be safe to administer thrombolysis. (31484174)
• 30-50 ng/mL: roughly correlates with some significant drug activity. (39089758)
  • If an invasive procedure with high bleeding risk is immediately required, DOAC should be reversed before the procedure. (26637710) 
  • In life-threatening bleeding, reversal can be considered at levels of 30-50 ng/mL. (39029742)
• <30 ng/mL: no significant drug activity
  • Lumbar puncture may be safe with an apixaban level <30 ng/mL. (31396920)

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thrombolytics (e.g. tPA)

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[1/3] assessment of coagulopathy

• Order INR, PTT, and fibrinogen levels. (32224752)
• (But don't wait for the lab result before giving reversal for an actively bleeding patient.)

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[2/3] management

essential interventions

• [1] Tranexamic acid or aminocaproic acid:
  • Tranexamic acid: ⚡️ 1 gram IV loading dose, followed by 1 gram infused over the next hour.
  • Aminocaproic acid: ⚡️ 4-5 gram IV loading dose, followed by 1 gram/hour infusion.
  • Either is fine, choose whichever agent will be faster to obtain.
• [2] Cryoprecipitate: ⚡️ Administer 10 units initially (or two 5-unit “pools”). (36333037)

optional interventions

• Fresh frozen plasma, for example, ~2 units (may help manage fibrinogen degradation product coagulopathy).
• Platelet transfusion may be considered, especially in ongoing or life-threatening bleeding with borderline thrombocytopenia or receipt of antiplatelet agents.

followup care

• Repeat coagulation studies (complete blood count, INR, PTT, fibrinogen, and ideally TEG).  Provide additional products as needed to address deficiencies. In particular:
  • Targeting a fibrinogen level >150-200 mg/dL is essential (for intracranial hemorrhage, >200 mg/dL may be desirable).(33952393)  Each 10 units of cryoprecipitate will increase fibrinogen by ~50 mg/dL.(36333037)  
  • If the TEG shows ongoing hyperfibrinolysis, then administration of additional tranexamic acid or aminocaproic acid should be strongly considered.
  • If INR >1.6, fresh frozen plasma should be considered. (36333037)
  • Thrombocytopenia should be treated appropriately.

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[3/3] discussion, physiology, additional comments

pharmacology of alteplase

• Alteplase has a very short half-life, so it is gone from the blood within minutes.
• Even after alteplase has left the bloodstream, levels of many clotting factors (especially fibrinogen) are profoundly reduced. Therefore, the effects of alteplase last much longer than the tPA molecules themselves.
• tPA has profound effects on numerous components of coagulation.(discussed further here) Reconstructing coagulation takes more work than might initially be expected.

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anti-platelet agent reversal

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[1/3] assessment of coagulopathy

• Platelet assays generally have poor availability and/or prolonged turnaround time. The most useful assays for emergent use might be the following:
  • [1] Platelet Functional Assay (PFA) – more widely available, useful to evaluate aspirin effect.📖
  • [2] Thromboelastography with platelet mapping is superior for P2Y12 inhibitors. 📖
• In practice, decisions about reversal agents are often based on the clinical history of when the medication was last ingested:
  • Reversible inhibition: platelet function restored after 3-5 half-lives.
  • Irreversible inhibition: platelet function is restored after new platelets are generated (about a week). (35918220)

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[2/3] management

Rx #1/4: Desmopressin (DDAVP) improves platelet function

• Desmopressin (DDAVP) 0.3-0.4 ug/kg, infuse over 20-30 minutes.
• More on this below. 💉

Rx #2/4: Consider a higher fibrinogen target

• Platelets cooperate with fibrinogen to form a clot. To a certain extent, increased activity of either platelets or fibrinogen may compensate for a deficiency of the other.
• Evidence regarding the use of fibrinogen to counteract the effects of antiplatelet agents is nearly nonexistent. However, a study investigating this confirmed that increasing the fibrinogen level may enhance clot firmness in blood treated with antiplatelet agents, as measured by thromboelastography. (28159767)
• The optimal fibrinogen target in a bleeding patient is controversial, as different guidelines recommend values ranging from approximately 150 to 200 mg/dL. For a patient on antiplatelet agents who is hemorrhaging, it might be sensible to target a slightly higher fibrinogen target than usual.

Rx #3/4: Generally avoid: Platelet transfusion

• Platelet transfusion is generally inadvisable (if the platelet count is otherwise adequate). Reasons to avoid platelet transfusion are explored in further detail in the section below.
• Platelet transfusion could be considered if the following conditions are present:
  • [1] Patient was taking an antiplatelet agent which causes permanent platelet inhibition (e.g., aspirin, clopidogrel, or prasugrel).
    • Theoretically, transfusion would be most effective for aspirin. Aspirin causes permanent inhibition of platelet function and has a short half-life.
    • Theoretically, transfusion would have intermediate efficacy for clopidogrel.  Clopidogrel causes permanent inhibition of platelet function, but it has a moderate half-life of 6 hours. Thus, if the patient took a dose of clopidogrel within the past 6-12 hours, residual drug could interfere with transfused platelets.
    • Theoretically, transfusion would have minimal effect for ticagrelor. Ticagrelor is a reversible platelet inhibitor, so platelet inhibition is a reflection of the real-time serum drug levels of ticagrelor. Transfused platelets will be inhibited by ticagrelor along with native platelets – adding little benefit. (30395148)
  • [2] The last dose of medication should ideally be >3 half-lives prior. Otherwise, residual drug may inhibit transfused platelets.
  • [3] There is some laboratory evidence that the patient's platelets are inhibited (if platelet function labs are available and time permits evaluation).
  • [4] There is significant ongoing hemostatic stress (e.g., active bleeding or planned procedures).
  • [5] Platelet count is low (e.g., <150,000).
• Normalizing platelet function may require a substantial amount of platelets (e.g., ~2-3 apheresis platelet units). (36872002)

Rx #4/4: If desperate: Tranexamic acid (TXA) 💉

• Tranexamic acid inhibits the conversion of plasminogen into plasmin. Tranexamic acid is generally conceptualized as an inhibitor of fibrinolysis, but it's a lot more than that. For example, plasmin also degrades the glycoprotein Ib receptors on the surface of platelets, impairing their ability to interact with von Willebrand Factor. (30474416) By preventing this interaction, tranexamic acid could potentially improve platelet function.
• Several studies suggest that tranexamic acid could improve platelet function, particularly in the context of antiplatelet agents:
  • Two studies involving patients undergoing CABG found that tranexamic acid improved in vitro platelet function among those who had received antiplatelet therapy. (20962655, 27388281)
  • Three prospective RCTs involving CABG patients demonstrated that tranexamic acid can reduce operative blood loss among patients taking antiplatelet medications. (31363394, 22033349, 23426385)

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[3/3] discussion: why platelet transfusion usually doesn't help

clinical evidence: PATCH trial

• This is a multi-center RCT regarding the use of platelet transfusion in patients with spontaneous intracranial hemorrhage who were taking antiplatelet agents. Approximately 90% of patients were taking aspirin, with a relatively small number using P2Y12 inhibitors. In short, this is precisely the situation where we would expect platelet transfusion to be beneficial.
• The study found no benefit from platelet transfusion. Patients receiving platelets had worse neurologic outcomes and a trend towards more bleeding.
• This is an enormously important trial, which reminds us that we cannot assume platelet transfusion will reverse the effects of antiplatelet drugs.
• Patients undergoing neurosurgery were excluded from the trial, so this is one potential limitation.

understanding the PATCH trial: why doesn't platelet transfusion improve clinical outcomes in patients prescribed anti-platelet drugs

• The PATCH trial was a bit surprising, but in retrospect, perhaps it shouldn't have been. There are numerous signals in the literature that platelet transfusion isn't great for the reversal of antiplatelet drugs. The following are some reasons that platelet transfusion may fail to work clinically.
• [1] Many patients who are prescribed antiplatelet agents don't experience clinical platelet inhibition:
  • Some patients are non-adherent and simply aren't taking the medications.
  • Some patients may have altered drug metabolism, causing the antiplatelet agent to be ineffective (particularly in the case of clopidogrel).
• [2] Among patients whose platelets are truly inhibited, platelet transfusion often does not cause a substantial improvement in platelet function. Several studies have found this result. (30814031, 27653814, 26553698, 24256671) This might be explained as follows:
  • Especially with newer antiplatelet drugs, longer half-life may lead to the persistence of drug in the body. Residual antiplatelet medication may cause dysfunction of transfused platelets.
  • Transfused platelets may not be as effective as normal platelets, due to changes that occur during storage.
  • It's conceivable that even if functional platelets are transfused into the patient, the dysfunctional platelets still get in the way and impair coagulation.
• [3] Platelet function is only one of many determinants of clinical outcome. Other factors may be more critical (e.g., fibrinogen levels, blood pressure, features of the anatomic lesion which is bleeding).
• [4] Platelet transfusion carries several risks, including transfusion reactions, TRALI, cytokine release, infection, and suppression of native platelet production. These may serve to counterbalance any potential benefit.

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fresh frozen plasma (FFP)

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contraindications, drug interactions, side effects 👎

• The main side-effect is volume overload.
• TRALI may also occur.

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indications, advantages 👍

• Warfarin reversal:
  • PCC is generally preferred over FFP.
  • FFP may be used for less acute bleeding or if PCC is unavailable.
  • ⚠️ It is not beneficial to give FFP to a patient with an INR of 1.7 or lower. (16753596)
  • (Note that a patient with an INR of 1.7 can receive thrombolysis for stroke). (32455460)
• Massive transfusion protocol (replacement of numerous factors and blood).
• Antithrombin deficiency.

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dosing of FFP (1 U = 250 ml)

general dosing

• 2-4 Units is often used as a dose of FFP.
  • 4 units will increase clotting factors by ~10%, which is considered necessary to improve coagulation. (Bojar 2021)
• Intracranial hemorrhage with unknown INR: 10-15 ml/kg may be utilized. (27858808, Erstad 2022) This equates to roughly a liter of FFP, or four units (12.5 ml/kg x 80 kg).

dosing for warfarin reversal based on INR

• INR 2-3.9: 10 ml/kg
• INR 4-6: 12-15 ml/kg
• INR >6: 15-20 ml/kg.
• Follow the INR and consider additional FFP as needed.

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additional comments

what is in FFP?

• FFP contains clotting factors at their normal concentration in the plasma (it doesn't contain concentrated levels of clotting factors). This makes it impossible to restore the patient's INR to a 1.0 (this would require an infinite amount of FFP). In practice, it's impossible to achieve an INR below ~1.7. 🌊
• When cryoprecipitate is obtained from the same unit of blood, FFP will have low levels of factors I, VIII, XIII, von Willebrand factor, and fibronectin. (Bojar 2021)

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prothrombin complex concentrate (PCC)

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contraindications, drug interactions, side effects 👎

• Contraindication: Heparin-induced thrombocytopenia (contains small amounts of heparin). In this situation, may consider either: fresh frozen plasma 💉 or Factor IX complex concentrates 💉.

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indications, advantages 👍

• Involves less volume administration.
• Faster to administer than FFP.

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dosing

dosing PCC for warfarin reversal

• Traditional dosing (might be preferable for intracranial hemorrhage):
  • INR 1.5-2: 15 units/kg (max 1500 units). (35579034) AHA/ASA guidelines suggest reversal if the INR is 1.3 or higher, but the benefit of reversing an INR of 1.3-1.4 is dubious.
  • INR 2-4: 25 units/kg (max 2,500 units).
  • INR 4-6: 35 units/kg (max 3,500 units).
  • INR >6: 50 units/kg (max 5,000 units).
• Fixed dose PCC
  • Uses include:
    • (1) May reduce cost for patients with non-CNS bleeding that isn't immediately life-threatening.
    • (2) May be applied immediately in situations where the INR is unknown.
  • Initial dose:
    • If weight >95 kg or INR is known to be >7.5: 2,000 units.
    • Otherwise: 1,500 units.
  • Repeat INR STAT after 30 minutes. If the INR is >1.4, give additional PCC.

dosing PCC for anti-Xa (XABAN) reversal

• Many algorithms recommend 50 units/kg (max 5,000 units). (27894493, 33403486) This may be ideal for CNS bleeding.
• An alternative dosing strategy is to give 25 units/kg absolute body weight (max 2,500 units), and then follow clinically and repeat INR. This dose may be repeated if hemostasis is not achieved.
• Fixed dosing with 2,000 units may be used. This strategy has the advantage that it is simple and also has the best evidentiary support. (30916798) Additionally, fixed-base dosing may be ordered immediately rather than awaiting laboratory tests.

dosing: other coagulopathies

• The usual dose is often 20-40 IU/kg, depending on coagulation tests.
• Cardiac surgery: 20 IU/kg IBW may be used. (33251719)

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additional discussion

pharmacokinetics, rebound, & monitoring of PCC

• PCC works immediately.
• The duration of effect is ~6-8 hours.
  • Some DOACs will persist beyond this effect, leading to rebound bleeding.
  • Warfarin reversal requires IV vitamin K plus PCC to avoid rebound bleeding when PCC wears off.
• The effect is generally monitored in terms of INR.
  • For anti-Xa reversal, follow the INR after administering PCC and subsequently every 6 hours. Rebounding INR might indicate the waning effectiveness of PCC, but this remains unclear.

basics of four-factor prothrombin complex concentrate (PCC) – specifically KCentra 💊

• Contains a lot of stuff:
  • Clotting factors (II, IX, X, and VII).
  • Endogenous anticoagulants (Protein C, Protein S, and antithrombin-III)
  • Very small amount of heparin.
• The inclusion of endogenous anticoagulants reduces the risk of thrombosis. This may explain studies that found no increase in thrombosis risk with PCC when compared to fresh frozen plasma. (33403486)
• PCC includes all the vitamin K-dependent coagulation factors, ideally suited to reverse warfarin. PCC is the preferred agent for warfarin reversal in major bleeding. (22315259) Advantages include:
  • Lower volume, which reduces the risk of volume overload.
  • Faster reversal (low volume of PCC allows for complete reversal in <30 minutes).
  • More consistent reversal than fresh frozen plasma.
  • There is no need to be thawed and cross-matched before administration.
  • No risk of transfusion-related acute lung injury (TRALI).

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cryoprecipitate

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contraindications, drug interactions, side effects 👎

• None.

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indications, advantages 👍

• Hypofibrinogenemia.
• von Willebrand disease.
• Factor XIII deficiency with hemorrhage.
• Uremic patients with hemorrhage refractory to other interventions.

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dosing

• Cryo is often provided in 5-unit “pools.”
• Two 5-unit pools will raise the fibrinogen level by ~70-100 mg/dL. (Flynn 2020)
• The number of units of cryoprecipitate required may be estimated as follows: (Bojar 2021)

# Units = (Desired increase in fibrinogen in mg/dL)(Weight in kg)/500

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additional discussion

factors contained within a unit of cryoprecipitate (from 1 donor unit of plasma)

• Factor VIII (80–150 units).
• von Willebrand factor (100–150 units).
• Factor XIII (50–75 units).
• Fibrinogen (150–250 mg). (Dabbagh 2018)

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fibrinogen concentrate

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contraindications, drug interactions, side effects 👎

• No contraindications.
• Drawbacks compared to cryoprecipitate:
  • Fibrinogen concentrate doesn't deliver von Willebrand factor (which can be problematic among patients on ECMO or status post cardiopulmonary bypass who have acquired von Willebrand syndrome).

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indications, advantages 👍

• Benefits compared to cryoprecipitate:
  • Doesn't require ABO blood matching.
  • Doesn't require thawing.
  • Reduced risk of pathogen transmission.
  • Contains a known amount of fibrinogen.
  • Lower amount of volume administration.

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dosing

• 30-60 mg/kg.
• As a general rule of thumb, for a 70-kg patient, administering 3-4 grams of fibrinogen will increase the plasma fibrinogen level by approximately 100 mg/dL. (Dabbagh 2018, Flynn 2020)

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DDAVP

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contraindications, drug interactions, side effects 👎

side effects

• Hyponatremia: DDAVP blocks renal excretion of free water, which may lead to hyponatremia. This can be avoided by limiting the administration of water while administering desmopressin.
• Hypotension does seem to occur – this has been demonstrated in a meta-analysis. (27893176) In a critical care setting, this is manageable; the main problem may be incorrectly attributing the hypotension to hemorrhage (e.g., using it as a trigger to initiate a massive transfusion). Hypotension might be prevented or mitigated by slower administration.
• Thrombosis is a theoretical risk. However, the most recent meta-analysis detected no increase in thrombotic events. (27893176)

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indications, advantages 👍

• Uremic platelet dysfunction. (25933676)
• Reversal of antiplatelet agents:
  • DDAVP is arguably the front-line agent to improve platelet function. Evidence shows platelet function improvement among patients on antiplatelet medications, including P2Y12 inhibitors. (18068065, 1434725, 8330156)
  • Among patients with intracranial hemorrhage on antiplatelet therapy, a retrospective study found that DDAVP use correlated with lower rates of hemorrhage expansion. (31567345) Neurocritical care guidelines suggest consideration of a single dose of DDAVP for patients with intracranial hemorrhage on antiplatelet agents. (26714677) 2022 AHA-ASA guidelines suggest that DDAVP may be utilized (with a level 2B recommendation). (35579034)
• Von Willebrand Disease:
  • Congenital (Type I).
  • Acquired:
    • Chronic aortic stenosis.
    • ECMO.
    • Post-CT surgery patients with cardiopulmonary bypass time >140 minutes. (Dabbagh 2018)
• Hemophilia A.
• Patients with inherited platelet disorders. (Dabbagh 2018)
• Management of hyponatremia (“DDAVP clamp”).

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dosing

dosing of DDAVP for procoagulant effect

• 0.3-0.4 micrograms/kg IV infused over 15-30 minutes to avoid vasodilation:
  • 0.3 mcg/kg may be used for Hemophilia, Von Willebrand Disease, or antiplatelet reversal. (35579034)
  • 0.4 mcg/kg may be used for uremic platelet dysfunction.
• In practice, DDAVP is usually given only as a one-time dose. DDAVP may be repeated q12hr for up to 6 doses, but this is usually not utilized for a few reasons:
  • [1] DDAVP stimulates vWF release but doesn't increase its synthesis. Consequently, vWF stores are depleted, leading to tachyphylaxis.
  • [2] Hyponatremia may become increasingly problematic over time.

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pharmacology, mechanism of action

• Bioavailability & Administration:
  • Oral bioavailability is erratic.
  • Nasal
• Distribution: Volume of distribution is ~30 liters.
• Metabolism: Unknown.
• Clearance: 50% excreted in the urine.
• Half-life: Duration of action is 6-14 hours.
• Mechanism of action:
  • DDAVP stimulates the release of von Willebrand Factor and factor VIII from the endothelium. Von Willebrand factor binds the GPIIb-IIIa receptor on platelets, causing platelet aggregation.
  • This improves platelet function in a nonspecific fashion. However, DDAVP may be especially effective in patients with a deficiency of von Willebrand Factor or factor VIII.

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tranexamic acid & aminocaproic acid

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contraindications, drug interactions, side effects 👎

cautions & relative contraindications

• Seizure history (may reduce seizure threshold). Seizure seems to be less common with aminocaproic acid than with tranexamic acid. (35747005)
• End-stage renal disease.
• Risk of thrombosis:
  • Patient at high risk of venous thromboembolic disease.
  • DIC (disseminated intravascular coagulation): Aminocaproic acid and tranexamic acid are indicated for hyperfibrinolysis but are contraindicated in disseminated intravascular coagulation. Further discussion of sorting out DIC vs. hyperfibrinolysis is here: 📖
  • Active hematuria from the upper urinary tract (may promote clot formation within the kidney or ureter).

drug-drug interactions

• Minimal pharmacokinetic drug-drug interactions.

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indications, advantages 👍

indications for TXA or aminocaproic acid

• Trauma (CRASH-2 trial).
• Postpartum hemorrhage (WOMAN trial).
• Perioperative bleeding (especially cardiothoracic and orthopedic surgery).
• Laboratory evidence of hyperfibrinolysis.
• Accelerated Intravascular Coagulation and Fibrinolysis (AICF) in cirrhosis.📖
• Bleeding after receiving fibrinolytic therapy (e.g., alteplase).📖
• Massive transfusion protocol. 📖
• Possibly: Reversal of antiplatelet agents. 📖

choice of tranexamic acid vs. aminocaproic acid

• Overall, tranexamic acid and aminocaproic acid are very similar agents. Realistically, the selection of one agent may relate to factors such as availability and cost.

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dosing

dosing of IV tranexamic acid

• Loading dose:
  • Loading dose is typically one gram as a slow IV push over 10 minutes, but it may range over 10-30 mg/kg. (Dabbagh 2018)
  • The CRASH trials utilized one gram infused over 10 minutes.
  • IV tranexamic acid must be infused slowly over 10-20 minutes (to avoid hypotension).
• Maintenance infusion:
  • Maintenance infusion is typically 125 mg/hour (often formulated as one gram infused over 8 hours, repeatedly).

dosing of aminocaproic acid

• Intravenous administration:
  • Loading dose of 4-5 grams IV during the first hour.
  • Maintenance infusion of 1 gram/hour.
  • In severe renal failure, the maintenance infusion should be reduced (but no published dosing scheme is available).
• For ongoing hyperfibrinolysis, IV aminocaproic acid may be transitioned to oral aminocaproic acid (e.g., 3 grams PO q6hrs). (30986390) Given the possibility of rhabdomyolysis with extended use, the lowest possible dose that suppresses hyperfibrinolysis should be utilized. A dose of 1 gram PO four times daily may be effective for outpatients. (16393288, 16819496)

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monitoring

• Serial coagulation studies should be monitored. The efficacy of aminocaproic acid in suppressing excessive fibrinolysis may be supported if the fibrinogen rises or stabilizes (stops dropping) during therapy. (26907195)
• Rhabdomyolysis may occur with extended use of aminocaproic acid, so following creatinine kinase may be advisable.

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pharmacology, mechanism of action

basics

• Both agents have the same mechanism of action: fibrinolysis inhibition due to competitive binding to plasminogen.
• Tranexamic acid is ten times more potent than aminocaproic acid. (Dabbagh 2018)

tranexamic acid pharmacology

• Bioavailability & Administration:
  • Oral bioavailability is ~30-50%.
  • Often utilized intravenously in critical illness.
• Distribution:
  • Low volume of distribution (0.2-0.4 L/kg).
  • Minimal protein binding (3%).
• Metabolism: Doesn't appear to be metabolized.
• Elimination:
  • Excreted unchanged in the urine.
  • Half-life of ~2 hours.

aminocaproic acid pharmacology

• Bioavailability & Administration:
  • Oral bioavailability is 100%, with absorption within 1-2 hours.
• Distribution:
  • Low volume of distribution (0.3-0.4 L/kg).
  • Minimal protein binding (<5%).
• Metabolism:
  • Minimal metabolism (~10% metabolized into adipic acid).
• Elimination:
  • Clearance is predominantly renal.
  • Half-life of ~2 hours and a duration of action of ~3-4 hours.

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protamine for reversal of heparin & LMWH

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when to use protamine & side-effects

general approach to heparin reversal

• Protamine may cause anaphylaxis or pulmonary hypertension.
• In most cases of bleeding caused by a heparin infusion, discontinuing the infusion alone is sufficient.
• Protamine may be considered for severe bleeding (e.g., heparin-associated intracranial hemorrhage).
• ⚠️ Excessive protamine may cause coagulopathy.

protamine reactions

• A range of adverse reactions can occur, including:
  • Pulmonary vasoconstriction.
  • Anaphylactoid reactions, including bronchospasm.
  • Acute hypotension.
  • Bradycardia. (36872002)
  • Noncardiogenic pulmonary edema.
• Risk factors:
  • History of fish allergy or nonprotamine medication allergy.
  • Prior exposure to protamine.
  • Rapid protamine administration.
• Protamine reactions generally occur within minutes of administration.
• Treatment varies depending on the clinical manifestation and severity.

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dosing

general guidance

• 🔑 Usually, avoid giving more than 50 mg at once. Higher doses may cause a paradoxical increase in anticoagulation. (38926082)
• 🔑 Give slowly over 15 minutes (rapid administration may cause hypotension, bradycardia, and anaphylactoid reaction).
• 🔑 Protamine lasts for about two hours so that multiple doses may be required (especially for low molecular weight heparin).

reversal of unfractionated heparin

• If given as a bolus:
  • Heparin given within <30 minutes: 1 mg protamine per 100 units heparin (max 50 mg).
  • Heparin given 30-60 minutes ago: 0.5-0.75 mg protamine per 100 units heparin.
  • Heparin given 60-120 minutes ago: 0.375-0.5 mg protamine per 100 units heparin.
  • Heparin given 2-6 hours ago: 0.25-0.375 mg protamine per 100 units heparin.
• If given as an infusion:
  • Determine the amount of heparin infused over the last two hours (usually calculated by multiplying the infusion rate by two).
  • Give 1 mg protamine per 100 units of heparin that the patient has received over the last two hours.
• Post-cardiac surgery heparin rebound: May start with 25-50 mg protamine.
• Monitoring: monitor PTT 10 min after protamine is given, then again in 2 hours.

reversal of enoxaparin

• Enoxaparin within <8 hours: 1 mg protamine per 1 mg enoxaparin (max 50 mg). If bleeding continues, may give an additional 0.5 mg protamine per mg enoxaparin.
• Enoxaparin given 8-12 hours previously: 0.5 mg protamine per 1 mg enoxaparin.
• Enoxaparin given >12 hours previously: Protamine less likely to be beneficial.
• Monitoring:
  • Follow Xa level after giving protamine and then q2hr. Protamine neutralizes at most ~60-75% of enoxaparin, so don't expect normalization of anti-Xa level.(Albin 2022) May consider re-dosing at 0.5 mg protamine per mg enoxaparin if bleeding persists or anti-Xa level is rising (max 25 mg).
  • Note that protamine will reverse enoxaparin only by ~50%.

reversal of dalteparin or tinzaparin

• Dalteparin or tinzaparin given within <4 hours: 1 mg protamine per 100 units of dalteparin or tinzaparin. May repeat half this dose four hours later.
• Given 4-8 hours previously: 0.5 mg protamine per 100 units dalteparin or tinzaparin.

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pharmacology, mechanism of action

• Distribution:
  • Vd is low (~10 liters), indicating distribution to the vascular compartment.
  • Does not have significant protein binding.
• Metabolism: Some metabolism may occur from peptidases, but this doesn't seem to be substantial.
• Elimination: Rapidly cleared by the kidneys with a half-life of 5-7 minutes.

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Factor IX complex

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basics of Factor IX complex – specifically Profilnine SD 💊

• Contains factors II, IX, X, and a small amount of VII.
• ⚠️ Unlike KCentra, does not include any endogenous anticoagulants. This gives Factor IX complex a greater tendency to promote thrombosis.
• Factor IX concentrate be used as an alternative to KCentra in patients with a history of heparin-induced thrombocytopenia. However, it is probably riskier and is supported by less evidence, when compared to KCentra.

pharmacokinetics

• Onset is essentially immediate.
• Duration of action is 12-24 hours.

dosing

• Emergent warfarin reversal in patients with a history of heparin-induced thrombocytopenia (HIT):
  • 25 units/kg absolute body weight (max 2,500 units) combined with one unit of fresh frozen plasma.
  • Maximal daily dose is 5,000 units.

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recombinant activated factor seven (rFVIIa)

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• Treatment of last resort for ongoing bleeding.
• The standard dose is 90 ug/kg, with a second dose considered after two hours.
• A lower dose (40 ug/kg) may be effective without exposing patients to an increased risk of adverse events. (33251719)
• There is a high risk of thrombotic events as compared to other blood products.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• A common error is trying to reverse warfarin with PCC or FFP alone. If either of these is given without simultaneous vitamin K, it will wear off over several hours.
• For serious bleeding, vitamin K should be given intravenously (NOT im, sq, or orally).
• Vitamin K should never be given subcutaneously (erratic absorption) or intramuscularly (risk of hematoma).
• Beware of patients on NOACs who develop renal failure, but keep on taking their NOACs. They may accumulate drug and become severely supratherapeutic, without any screamingly abnormal lab values (unlike, for example, the patient on warfarin with an INR of 9 – who is quite obviously supratherapeutic).
• Aggressive reversal of anticoagulation prior to minor procedures (e.g. ultrasound-guided central line placement in a patient with a gigantic, superficial internal jugular vein).
• Don't try to correct the pre-procedure INR to <1.7 using FFP – this is impossible and dangerous.

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• 🗞 = Link to PDF of an open-access journal article.
• = Link to supplemental media.