CONTENTS

• General considerations
• Approach to warfarin reversal
  • Urgent reversal
  • Non-urgent supratherapeutic INR
• Approach to DOAC reversal
  • Dabigatran
  • Factor Xa inhibitors (riveroXABAN, apiXABAN, edoXABAN, fondaparinux)
• Reversal of other agents
  • Thrombolytics (e.g. tPA)
  • Heparin reversal
  • Antiplatelet agent reversal
• Pharmacology of broad-spectrum reversal agents
  • Fresh Frozen Plasma (FFP)
  • Prothrombin Complex Concentrate (PCC)
  • Factor IX Complex
  • DDAVP
  • Tranexamic acid
  • Aminocaproic acid
• Pre-procedure coagulation management for common procedures
• Podcast
• Questions & discussion
• Pitfalls

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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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warfarin: urgent reversal

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rapid reference for warfarin reversal

• Investigation:
  • INR
  • ⚠️ For intracranial hemorrhage in a patient on warfarin, PCC should be given immediately without waiting for the INR to result.(35579034)
• Reversal
  • (1) 10 mg IV vitamin K over 30 minutes *plus* PCC or FFP.
  • (2) PCC or fresh frozen plasma:
    • PCC is preferred 💉
    • Alternative: four units fresh frozen plasma.💉

assessment & target

• Assessed by measuring INR.
• For patients with intracranial hemorrhage, follow INR every 3-6 hours to ensure adequate reversal.(33288539)

intravenous vitamin K

• Probably the most important intervention to reverse warfarin is vitamin K.
• 10 mg should be given intravenously, as soon as possible (infused over 30 minutes).
  • FFP or PCC will work only for ~8 hours.
  • Vitamin K will do the job 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).(22315259)
  • 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 similarly. However, anaphylactoid reactions are generally less severe and can be avoided by infusing a drug slowly.
  • Fear of this reaction should never be a barrier to giving intravenous vitamin K to patients who need it.
    • If you're absolutely 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 of a rate is really 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 emergent reversal of anticoagulation, there is only one dose & one route of vitamin K that should be used: 10 mg IV vitamin K.

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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 which may help guide management. However, this isn't based on strong evidence. Most importantly, management should be individualized based on patient-specific factors (e.g., risk factors for bleeding/clotting etc.).

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Direct thrombin inhibitor: Dabigatran

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rapid reference for dabigatran reversal

• Investigation:
  • PTT and thrombin time (if available).
• Reversal:
  • Idarucizumab 5 g.
  • If ingested in <2 hours may consider activated charcoal 50 grams.

lab assessment of drug levels

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

pharmacology

tx: idarucizumab (PRAXBIND) 💊

• Monoclonal antibody binds and inactivates dabigatran.
• Possible indications for reversal:
  • (1) Major bleeding or planned high-risk procedure.
  • (2) Last dose taken within <12-24 hours (with normal renal function). For patients with intracranial hemorrhage, reversal may be considered if the last dose was within <5 half-lives (i.e., within the past 2-4 days.(Albin 2022)
  • (3) Significantly abnormal PTT and/or thrombin time (especially thrombin time >25 seconds).
• Dose
  • 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.
  • However, for patients with an unusually high level 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 12-24 hours later.
  • 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 associate 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, second-line treatment.(33403486)

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

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rapid reference for Xa-inhibitor reversal

• Investigation:
  • Usually INR (Ideally = anti-Xa level)
• Reversal:
  • 4-factor PCC (KCENTRA) 💉
  • If ingested in <2 hours may consider activated charcoal 50g.
  • If INR elevated, consider 10 mg IV vitamin K to exclude vitamin K deficiency.

lab assessment of drug levels

• Crude assay = INR
  • Rough assay
  • Normal INR argues against a significant drug level, but doesn't exclude this entirely.(31317796)
• Better assay = Anti-Factor Xa level
  • Anti-Xa activity correlates well with drug level, but not necessarily with anticoagulant effect. (31339254)
  • Normal anti-Xa level excludes the presence of clinically relevant Xa-inhibitors (but not dabigatran). Any anti-Xa assay may be used (e.g. assays designed for use with unfractionated heparin or low molecular-weight heparin) – the key issue is whether there is any detectable anti-Xa activity.(30916798)
  • With anti-Xa levels increasingly being used to titrate heparin infusions, the availability and turn-around time of this laboratory are improving.

pharmacology

tx: four-factor PCC – see below 💉

tx: Andexanet Alfa ??

• Specifically designed as a reversal agent for Xa-inhibitors.
• Clinical data is limited, and this agent is insanely expensive.
• Many hospitals have chosen not to include this agent in their formularies.

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thrombolytics (e.g. tPA)

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thrombolytic reversal: immediate management

• Order INR, PTT, and fibrinogen levels (but don't wait for the lab result before giving reversal for an actively bleeding patient).(32224752)
• Essential interventions:
  • Tranexamic acid: 1 gram IV loading dose, followed by 1 gram infused over the next hour.  (An alternative therapy is aminocaproic acid 💉.)
  • Cryoprecipitate: Start by giving 10 units.(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.

thrombolytic reversal: 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 (with a platelet target depending on the location and severity of hemorrhage).

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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protamine for reversal of heparin & LMWH

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general approach

• Protamine may cause anaphylaxis or pulmonary hypertension.
• In most cases of bleeding due to a heparin infusion, discontinuing the infusion alone is adequate.
• Protamine may be considered for severe bleeding (e.g. heparin-associated intracranial hemorrhage).

protamine dose 💊

• General rules
  • Usually avoid giving more than 50 mg at once.
  • Give slowly over 15 minutes (rapid administration may cause hypotension, bradycardia, and anaphylactoid reaction).
• Reversal of heparin given via bolus:
  • Heparin given within <30 minutes: 1 mg protamine per 100 units heparin
  • 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
• Reversal of heparin infusion:
  • Determine amount of heparin infused over the last two hours (usually the infusion rate multiplied by two).
  • Give 1 mg protamine per 100 units of heparin which the patient has received over the last two hours.
• Dose required to reverse enoxaparin
  • Enoxaparin within <8 hours: 1 mg protamine per 1 mg enoxaparin. If bleeding continues, may give 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.
• Dose required to reverse 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.
• Monitoring
  • Protamine lasts for ~2 hours, so multiple doses may be required (especially for low molecular-weight heparin).
  • Reversal of unfractionated heparin: monitor PTT 10 min after protamine is given, then again in 2-8 hours.
  • Reversal of enoxaparin:
    • 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%.

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anti-platelet agent reversal

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rapid reference for antiplatelet reversal

• Investigation: Platelet function assays (if available).
• Reversal
  • Desmopressin (DDAVP) 0.3-0.4 ug/kg, infuse over 20-30 minutes.
  • Consider targeting a higher fibrinogen level than usual.
  • (If desperate: Might consider addition of tranexamic acid.)
  • (Platelet transfusion is generally not supported by evidence.)

overview of approaching antiplatelet agents

• Medications seem to be the safest, fastest, and most effective strategy:
  • (2) Tranexamic acid may improve platelet function as well. Evidence is of fair quality, albeit not robust. However, tranexamic acid is inexpensive, generally safe, and widely available.
• Fibrinogen or cryoprecipitate – Targeting a slightly higher level than usual might be helpful, but evidence on this is scant.

assessment of anti-platelet medication effects

• This is impossible to do with most assays. Specifically, platelet agents will not affect conventional coagulation tests or standard thromboelastography (TEG).
• Numerous assays exist to evaluate platelet function, but most have poor availability or prolonged turn-around 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 – may be superior for P2Y12 inhibitors.📖
• In practice, decisions about reversal agents often need to be made in the absence of any laboratory data regarding platelet function. Thus, the best approach to assessment may be a clinical history of whether the patient is adherent with antiplatelet agents and when the last dose was taken.

Rx #1: Desmopressin (DDAVP) improves platelet function

• More on this below. 💉

Rx #2: Target a slightly higher fibrinogen level ??

• Platelets cooperate together with fibrinogen to form a clot. Thus, 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 reverse anti-platelet agents is nearly nonexistent. However, one study which investigated this confirmed that increasing the fibrinogen level may increase clot firmness in blood treated with antiplatelet agents, as measured by thromboelastography. (28159767)
• The optimal fibrinogen target in a bleeding patient is controversial (different guidelines recommend values ranging between ~150-200 mg/dL). For a patient on antiplatelet agents who is hemorrhaging, it might be sensible to target a slightly higher fibrinogen target than usual (if you're on the fence about whether to give fibrinogen).

Rx #3: 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 actually a lot more than that. For example, plasmin is involved in bradykinin generation, so tranexamic acid may have a role in the treatment of bradykinin-mediated angioedema.🌊 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 anti-platelet agents:
  • Two studies involving CABG patients found that tranexamic acid improved in vitro platelet function among patients who had received antiplatelet therapy.(20962655, 27388281)
  • Three prospective RCTs involving CABG patients have demonstrated that tranexamic acid can reduce operative blood loss among patients on antiplatelet medications. (31363394, 22033349, 23426385)
• Tranexamic acid isn't widely recommended to reverse antiplatelet medications. However, it is widely available, relatively inexpensive, safe, and overall has a favorable track record for use in a variety of types of bleeding. The risk/benefit ratio is probably more favorable for tranexamic acid than for platelet transfusion (more discussion on both of these therapies below).

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platelet transfusion & why it's generally not a wise idea

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when might we expect exogenous platelets to help reverse antiplatelet agents?

• From a pharmacological standpoint, platelet transfusion would make the most sense if the following conditions were met:
  • (#1) The anti-platelet drug should cause permanent inhibition of platelet function (drugs which do this include aspirin, clopidogrel, and prasugrel).
  • (#2) The anti-platelet drug itself should already be cleared from the body (otherwise, residual drug may cause inhibition of the new platelets).
  • (#3) Immediate hemostasis is essential (e.g. for an intracranial hemorrhage).
• Based on these principles, we can theoretically stratify the predicted effectiveness of platelet transfusion for common antiplatelet agents as follows:
  • #1 = Most effective for aspirin. This drug causes permanent inhibition of platelet function and has a short half-life.
  • #2 = Intermediate effect for clopidogrel. This drug 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.
  • #3 = 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)

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. ~90% of the patients were taking aspirin, with relatively few patients 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 – in fact, 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 that platelet transfusion will reverse anti-platelet drugs.
  • More platelets doesn't equate with a better outcome.
• 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 reversal of anti-platelet drugs. The following are some reasons that platelet transfusion may fail to work clinically.
• (1) Many patients who are prescribed anti-platelet agents don't experience clinical platelet inhibition:
  • (a) Some patients are non-adherent and simply aren't taking the medications.
  • (b) Some patients may have altered drug metabolism, causing the anti-platelet agent to be ineffective (particularly in the case of clopidogrel).
• (2) Among patients whose platelets are truly inhibited, platelet transfusion often doesn't cause a substantial improvement in platelet function! This result has been found by several studies. (30814031, 27653814, 26553698, 24256671) This might be explained as follows:
  • (a) Especially with newer antiplatelet drugs, longer half-life may lead to the persistence of drug in the body. Residual anti-platelet medication may cause dysfunction of transfused platelets.
  • (b) Transfused platelets may not be as effective as normal platelets, due to changes which occur during storage.
  • (c) 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 important (e.g. fibrinogen levels, blood pressure, features of the anatomic lesion which is bleeding).
• (4) Platelet transfusion has several risks (e.g. transfusion reaction, TRALI, cytokine release, infection, suppression of native platelet synthesis). These may serve to counterbalance any potential benefit.

possible prerequisites for platelet transfusion

• The final word remains to be written regarding the use of platelet transfusion to reverse anti-platelet medications. Routine use of platelet transfusion certainly seems misguided. However, there may be situations where platelet transfusion is reasonable (e.g. a surgeon or interventional consultant strongly feels that platelets are needed).
• Four prerequisites are suggested which could define patients who might potentially benefit from a platelet transfusion:
• (1) Patient is taking an antiplatelet agent which causes permanent platelet inhibition (e.g., aspirin, clopidogrel, or prasugrel).
• (2) The last dose of medication should ideally be >3 half-lives previously. Otherwise, residual drug may inhibit transfused platelets (this is discussed further above).
• (3) There is some laboratory evidence that the patient's platelets are inhibited (if platelet function labs are available and time permits this evaluation).
• (4) There is significant ongoing hemostatic stress (e.g. active bleeding or planned procedures).

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fresh frozen plasma (FFP)

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use

• Warfarin reversal:
  • PCC is generally preferred over FFP.
  • FFP may be used for less acute bleeding, or if PCC is unavailable.
• Massive transfusion protocol (replacement of numerous factors and blood).
• 🛑 Plasma should not be used in an attempt to reverse NOACs.(33403486)

dosing FFP for warfarin reversal

• Initial dose:
  • INR 2-3.9: 10 cc/kg
  • INR 4-6: 12-15 cc/kg
  • INR >6: 15-20 cc/kg.
• One unit of FFP is 250-300 ml, so 10-20 cc/kg equates to roughly ~3-6 units of FFP.
• Follow the INR and consider additional FFP as needed.
• 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.🌊
  • It's non-beneficial to give FFP to a patient whose INR is 1.7 or lower.(16753596)
  • (Note that a patient with an INR of 1.7 can receive thrombolysis for stroke).(32455460)

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prothrombin complex concentrate (PCC)

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contraindications to PCC

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

dosing: 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, give 2,000 units.
    • Otherwise give 1,500 units.
  • Repeat INR STAT after 30 minutes. If the INR is >1.4, give additional PCC.

dosing: 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.

pharmacokinetics, rebound, & monitoring of PCC

• PCC works immediately.
• The duration of effect is ~6-8 hours.
  • Some DOACs will outlast this effect, causing 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 INR after giving PCC and then subsequently q6hr. Rebounding INR might be an indication of 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.
• 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, so this is ideally suited to reverse warfarin. PCC is the preferred agent for warfarin reversal in major bleeding.(22315259) Advantages includes:
  • Lower volume, which reduces risk of volume overload.
  • Faster reversal (low volume of PCC allows for complete reversal in <30 minutes).
  • More consistent reversal than fresh frozen plasma.
  • No need to be thawed and cross-matched prior to administration.
  • No risk of transfusion related acute lung injury (TRALI).
• PCC is generally the mainstay of reversal for anti-Xa NOACs (XABANs). This is supported by in vitro evidence and clinical data.

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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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DDAVP

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mechanism of action

• DDAVP increases the release of von Willebrand Factor and factor VIII from the endothelium. on Willebrand factor binds the GPIIb-IIIa receptor on platelets, causing platelet aggregation.
• Among most patients, this serves to improve platelet function in a nonspecific fashion.
• DDAVP may be especially effective in patients with a deficiency of von Willebrand Factor or factor VIII.

general indications 💊

• Alleviation of uremic platelet dysfunction.(25933676)
• Reversal of antiplatelet therapy:
  • DDAVP is arguably the front-line agent to improve platelet function. Evidence shows benefit in platelet function 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)
• Hemophilia A.
• Von Willebrand Disease (Type 1).

dose

• 0.3-0.4 micrograms/kg IV infused over 20-30 minutes:
  • 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.
• DDAVP may be repeated q12hr for up to 6 doses, but complications may increase in likelihood over time (especially hyponatremia). In practice, DDAVP is usually given only as a one-time dose.

side effects

• DDAVP blocks renal excretion of free water, which may lead to hyponatremia. This can be avoided by limiting administration of water while giving 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 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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tranexamic acid

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Emerging evidence suggests that tranexamic acid may be useful for bleeding from a variety of causes (e.g. trauma, postpartum hemorrhage, orthopedic surgery).(28432428) Numerous large RCTs and meta-analyses show it to be safe and potentially beneficial. Below is a general discussion of tranexamic acid, which will not apply perfectly to every application.

potential indications for IV tranexamic acid

• Trauma (CRASH-2).
• Postpartum hemorrhage (WOMAN).
• 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.📖

pharmacology

• Excreted unchanged in the urine.
• Half-life of ~3 hours.
• IV tranexamic acid must be infused slowly over 10-20 minutes (to avoid hypotension).

cautions & relative contraindications

• Seizure history (may reduce seizure threshold).
• Patient at high risk of venous thromboembolic disease.
• End-stage renal disease.
• Aminocaproic acid and tranexamic acid are indicated for hyperfibrinolysis, but contraindicated in disseminated intravascular coagulation. Further discussion of sorting out DIC vs. hyperfibrinolysis is here: 📖

dosing

• Generally:
  • (i) Loading dose = 1 gram as a slow IV push over 10 minutes
  • (ii) Maintenance dose(s) = 1 gram IV as a gradual infusion over 8 hours. This should be started immediately following the loading dose. This maintenance dose is often repeated three times to create a continuous infusion over 24 hours.
• In renal failure: Increase time interval between dosing (95% excreted in urine).

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aminocaproic acid

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general indications 💊

• Indications are similar to the indications for tranexamic acid above.(31321578)
• Overall, tranexamic acid and aminocaproic acid are very similar agents. Realistically, selection of one agent may relate to factors such as availability and cost.

pharmacology

• Clearance is predominantly renal, with a half-life of ~2 hours and a duration of action of ~3-4 hours.
• Oral bioavailability is 100%, with absorption within 1-2 hours.

cautions & relative contraindications

• Contraindications:
  • Aminocaproic acid and tranexamic acid are indicated for hyperfibrinolysis, but contraindicated in disseminated intravascular coagulation. Further discussion of sorting out DIC vs. hyperfibrinolysis is here: 📖
  • Contraindicated in active hematuria from the upper urinary tract (may promote clot formation within the kidney or ureter).
• Cautions:
  • Seizure is a potential side effect, but this seems to be less common as compared to tranexamic acid.(35747005)
  • Thrombosis is a theoretical concern. However, meta-analysis of patients undergoing knee or hip surgery didn't find an increased risk of venous thrombotic events due to aminocaproic acid.(29471157)

monitoring

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

dosing

• 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 patients with 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. For outpatients, a dose of 1 gram PO four times daily may be effective.(16393288, 16819496)

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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

• This is perhaps the most worrisome procedure commonly performed in an ICU, since an epidural hematoma might potentially compress the spinal cord and thereby cause permanent neurological damage.
• A platelet count >50 is generally recommended prior to lumbar puncture.(31229333)
• Some series suggest that lumbar puncture is safe among patients on single or dual antiplatelet therapy.(29573815, 31378231)

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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.