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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3865_Библиотеки_им_академика_М_И_Перельмана
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170 Anticoagulation Therapy
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TABLE 8-5: Adverse Effects Observed with Parenteral Vitamin K
• Changes in taste
•
Cyanosis
•
Dizziness
•
Dyspnea
Flushing sensations
•
•
Hyper bilirubin (newborns)
•
Hypersensitivity reactions, including anaphylaxis
Hypotension
•
•
Pain/swelling/tenderness at injection site
Profuse sweating
•
•
Rapid and weak pulse
On repeated injections: Erythematous, indurated, and pruritic plaques have occurred,
•
rarely progressing to scleroderma-like lesions; most dermatological effects have occurred
following intramuscular injections.
Vitamin K Dispensing
•
Dispense IV doses in a piggyback bag to ensure slower infusion rates.
•
Use caution with availability of 10-mg vials outside the pharmacy (i.e., available
in the automated dispensing cabinets). If the pharmacy is able to prepare and
dispense a dose (noting that the onset of effect is several hours and that more
rapid-acting agents can be used if necessary), consider the benefits of pharmacy
assessment of the dose and route along with the need for other interventions
to minimize the potential for over- or under-reversal and delay in the use of
other adjuncts (FFP, PCC, or rFVIIa). When pharmacy services are not available,
consider procedures that address safety and dosing concerns.
6
Fresh Frozen Plasma
•
Fluid portion of 1 unit of blood centrifuged, separated, and frozen at –18°C
within 6 hours of collection.
•
The general dose for FFP is 10–20 mL/kg.
•
A unit typically equals about 250–300 mL of FFP.
•
In 1 mL of FFP, there is about 1 unit of each coagulation factor. The INR of FFP is 1.
•
The expected response depends on patient’s predose level of coagulation
factors.
•
Limitations: Thawing (generally 30 minutes), storage, and donor dependence.
•
Primary uses:
For temporary reversal. Partial reversal of warfarin therapy (in
1,7
emergency or high risk for bleeding scenarios where anticoagulation must be resolved by replacing vitamin K-dependent factors)
includes risk of rebound anticoagulation occurring 4–6 hours after
dose. It is most commonly administered with adjunctive therapy
such as IV vitamin K and potentially the short-acting concentrated
clotting factors (rFVIIa), especially for subtherapeutic INR reversal
ANTICOAGULATION REVERSAL: PART I 171
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goals and critical bleeding. It may not be necessary, however, if a
PCC is given because the PCC products have a rapid onset and
prolonged duration of effect.
For emergency or high risk for bleeding scenarios. Used where
anticoagulation must be reversed, but where target is still goal
range INR (2–3.5) and not complete reversal.
•
Volume associated with FFP may cause volume-related complications (fluid
overload, cardiogenic shock) and limit its utility in a life-threatening bleeding
situation (due to slow rate of administration).
•
Volume is benefit in hemorrhagic shock, providing volume in addition to factor
replacement often along with platelets and/or red blood cells.
•
Risk of transfusion reaction (see Appendix F) for transfusion-related reactions)
should be monitored.
•
Transmission of blood-borne pathogens is very low risk.
Prothrombin Complex Concentrate
•
Dosed on factor IX units but take caution that the order for PCC does not confuse
PCC with factor IX, which is a single factor product.
•
PCC or factor IX complex contains factors II, VII, IX, and X, and some also include
7,8
8
proteins C and S. Some are low in factor VII (PCC 3), and others have relatively
equal amounts of all four (PCC 4).
PCC3: Contains therapeutic concentrations of factors II, IX, and X;
9
may contain other factors such as protein C, S, and factor VII to
lesser concentrations.
PCC4: Contains therapeutic concentrations of factors II, VII, IX,
and X; may contain other factors such as Protein C or Protein S to
lesser concentrations.
Activated PCC (i.e., FEIBA
(mainly factor VII) in the activated form.
®
) provides selected clotting factors
1
The proposed advantage of
using activated PCC is that it can work below anti-factor Xa activity
and II in the common pathway of the clotting cascade (thus, after
the sites of activity of the anticoagulants in coagulation cascade).
Heparin and antithrombin have been added to some PCC products
to minimize accumulation of factor II and X effects, which may last
longer and cause thromboembolism. (KCentra has heparin.)
•
Factor components are 25 x more concentrated than that of the plasma concentration.
•
Vials contain variable amounts of coagulation factors.
•
No refrigeration (except Bebulin VH) or thawing is required, but reconstitution
is necessary. Is convenient to store in dispensing cabinets outside of pharmacy.
•
Fluid effects and transfusion reactions are potential adverse reactions, but the
most concerning is thrombosis.
•
Rapid administration relative to FFP makes administration simple. See Table
8-6 for maximum infusion rate.
10
172 Anticoagulation Therapy
anticoagulant(s)-
suggest removing
Stored prior to mixing
Special dissolution
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20-25
RT
®
NovoSeven
Novo Nordisk
(rFVIIa)
NF
®
Baxter
(aPCC)
FEIBA
SD
®
Profilnine
Grifols
(PCC3)
Factor VII activated
(recombinant)
Non-activated II, IX, and X,
and activated VII
FVIII C:Ag
1, 2, 5, 8 mg
Variable doses
500, 1,000, 2,500 units
FVIII inhibitor bypass
Non-activated FII,F IX, and
FX, with small amount FVII
(35 FVII units/100 FIX units)
Variable doses
500, 1,000, 1,500 units FIX
Lyophilized powder for
solution
histidine diluent
provided
Freeze-dried powder
activity units
Lyophilized
Lyophilized
powder
Room temperature
(NTE 77 °F, 25 °C)
Refrigerator-PI says room
temperature (NTE 77 °F,
temperature (NTE 77 °F,
(continued)
Add diluent against vial
wall, NOT onto powder,
gentle swirling
25 °C)
Warm to room
temperature prior to
mixing; use of transfer
set and gentle swirling;
withdrawal with syringe
25 °C)
Warm to room temperature
prior to mixing; use of
transfer set and gentle
swirling; withdrawal with
syringe
VH
®
Baxter
(PCC3)
Bebulin
®
CSL Behring
(PCC4)
Product KCentra
TABLE 8-6: U.S. Coagulation Factor Products: Admixing and Administration
Non-activated FII,F IX,
and FX
Low amounts of FVII
XI, FX
Protein C and S
Warfarin; DTIs Warfarin; DTIs Warfarin; DTIs Dabigatran Warfarin; DTIs
Type Non-activated FII, FVII,F
Reversal of
Variable amounts of FIX
~500-unit vials.(480–760
500 unit-(400–620 units)
Dose per vial Variable amounts FIX in
Lyophilized
powder
Refrigerator Refrigerator or room
units/20 mL vial)
and 1,000 unit-(800–1,240
units) vials
powder
Diluent to add 20- or 40-mL SWFI 20-mL SWFI 5- or 10- mL SWFI 20- or 50- mL SWFI 1-, 2-, 5-, or 8-mL
Formulation Lyophilized
Refrigerator or room
Warm to room
temperature prior to
temperature
(NTE 77 °F, 25 °C)
Warm to room
temperature prior to
mixing; use of transfer
set and gentle swirling;
withdrawal with syringe
mixing; use of transfer
set and gentle swirling;
withdrawal with syringe
RT
Final concentration
Other ingredients
Stability after mixed
Administration
aPCC: activated prothrombin complex concentrate, °C: degree Celsius, DTI: direct thrombin inhibitor,°F: degrees Fahrenheit, FII: factor II, FIX: factor IX, FVII: factor VII,
FVIII C Ag: factor VIII coagulant antigen, FX: factor X, hr: hours, min: minutes, NA: not applicable, NS: normal saline, NTE: not to exceed, PCC: prothrombin complex
concentrate, PCC3: 3-factor prothrombin complex concentrate, PCC4: 4-factor prothrombin complex concentrate, PI: prescribing information, rFVIIa: recombinant factor VII
(activated), SWFI: sterile water for infusion, units: International Units
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®
NovoSeven
Novo Nordisk
(rFVIIa)
NF
®
Baxter
(aPCC)
FEIBA
SD
®
1,000 mcg/mL
NA
500 IU vial≈25 IU/mL
1,000-unit and 2,500-unit
vials ≈50 units/mL
ANTICOAGULATION REVERSAL: PART I 173
2–5 min bolus
NTE 2 units/kg/min
Flush with NS only;
remove from vial
with syringe for
administration
Separate line, not with
other medication products;
flush with NS; plastic Luer
lock syringe (not glass)
Profilnine
VH
®
Bebulin
®
Product KCentra
TABLE 8-6: (Continued)
NA
Grifols
(PCC3)
Baxter
(PCC3)
NA
FIX ~25 units/mL (20–31
CSL Behring
(PCC4)
500- and 1,000-unit vial 100
FIX units/mL
1,500-unit vial 150 FIX units/
mL
10–60 FIX units/mL
units/mL); varies based
on actual FIX content in
each vial
Heparin NA NA NA
Human ATIII
Heparin
NTE 2 mL/min NTE 10 mL/min 10 mL/min
Albumin
0.12 mL/kg/min (~3 units/
Infusion rate Max 8.4 mL/min infusion
Not infused with other
medication products; flush
with NS; do not refrigerate
after mixing
Not infused with other
medication products;
flush with NS; do not
refrigerate after mixing
kg/min), up to a maximum
rate of 8.4 mL/min (~210
units/min)
4 hr 3 hr 3 hr 3 hr 3 hr
Separate line, not with
other medication products
information
174 Anticoagulation Therapy
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•
Onset of effects is generally complete reversal of warfarin-induced, elevated
INR within 10–30 minutes.
•
Adverse effects:
Allergic reactions.
Transfusion-related reactions (see Appendix F).
Thromboembolism (potentially increased when repeat or high
11-14
doses are used).
PCC3 and PCC4 seem similar in rates of thromboembolic events
(both more likely at higher doses).
•
HIT (in theory for those products containing heparin—know your formulary
product).
Specific Dosing Considerations for PCC
Warfarin
•
See Tables 9-17 and 9-18 regarding warfarin-induced elevation, combinations
of phytonadione, and other products.
•
Dosing varies by specific product and studies using the product. In most studies,
25–50 units (factor IX equivalent) per kg or 500 International Units was used.
Be familiar with institution-specific products and be aware of the evidence and
dosing for those agents prior to use.
•
Dose based on degree of INR; weight adjusted in combination appears more
effective than standard dosing (e.g., 500 International Units).
15
Combined with Other Reversal Agents
•
Rebound INR increase can occur in 12–24 hours, especially if used without IV
vitamin K. The addition of vitamin K should be considered (generally 10 mg IV) in
life-threatening, nonsurgically repairable bleeds or with the need for prolonged
complete reversal such as intracranial hemorrhage.
•
Phytonadione should be considered in life-threatening or emergent bleeding
situations when using PCC.
•
Intravenous phytonadione is predominately used in emergent situations with
PCC and FFP compared to oral phytonadione.
•
FFP with PCC, if using a PCC3, has been suggested to augment factor VII levels.
•
Generally, administration of PCC in the high INR situation can result in low normal
goal range or subtherapeutic anticoagulation (<2).
•
The risk for thromboembolic complications may be higher when using PCC and
rFVIIa, either together or in addition to other agents such as aminocaproic acid.
•
Understand your options and products available, including dosing and/or available evidence. Each is different.
•
Several approaches to individualize the PCC dose have been explored.
approach used should consider the agents available, personal experiences with
their use, and published experiences. Multiple approaches have been explored,
and examples are provided below. Dose is based on factor level.
International Units requested = kg weight X (target factor level–
current factor level)
16
8
18
19
17
The
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•
Dose based on the observed INR
Recommended dose of PCC4 (KCentra
25 International Units/kg for INR of 2–3.9, max 2,500 International
®
) for initial INR
20
Units
35 International Units/kg for INR 4–6, max 3,500 International Units
50 International Units/kg for INR >6, max 5,000 International Units
Note: Prescribing and randomized trials did not explore use when the INR
is <2; however, in the setting of a severe/urgent bleed or higher risk procedure, a lower INR may be desired and doses of 10–25 units/kg considered.
• In urgent bleeding situations, mixing several
vials of the PCC in the pharmacy for the total
dose after waiting for the INR to be reported may
delay the onset of therapy. Consider drawing the
INR, and then give the first 1,000 units up front.
Additional PCC can be given depending on the
reported INR and assessment of the patient’s
response to the first 1,000 units.
• PCCs can contain heparin and may not be
preferred in the setting of heparin-induced
thrombocytopenia.
LMWH/Fondaparinux
•
PCC may have a role in reversal.
FEIBA
Note: PCC products contain clotting factors. FEIBA
®
: The ability of FEIBA to work downstream of anti-factor Xa
activity in the common pathway in the coagulation cascade has
been postulated with limited evidence (in vitro) as an advantage
in reversing anticoagulation when in the presence of an anti-factor
Xa activity inhibitor (in this case, fondaparinux was analyzed in the
referenced publication). Dose of FEIBA
Units to 50 units/kg.
10
®
ranges 500 International
®
differs
from other PCCs in that factor VII is in an activated form. The
activated factors may produce immediate thrombin generation
in the presence of an anti-factor Xa activity inhibitor, such as
fondaparinux.
10
176 Anticoagulation Therapy
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• KCentra® is labeled by the U.S. Food and Drug
Administration (FDA) for warfarin reversal in the
United States.
• Several PCC products are currently available.
Be familiar with the products available for use.
Differences between products do exist. Some
are PCC3, where an additional transfusion of
other blood products may be considered. Some
products contain additional substances including
heparin, which may be of concern for patients
with a history of HIT. The duration of effect and
potential for inducing thrombosis may be related
to the dose given. Generally, rFVIIa should be
avoided in individuals receiving a PCC.
Recombinant Activated Factor VII
•
Available in vials that contain 1 mg, 2 mg, 5 mg, or 8 mg of coagulation factor
VIIa (recombinant), or rFVIIa.
•
A recombinant product is not derived from blood; thus, it can be an option in
patients refusing blood products.
•
Common approaches used for hemostasis in presence of an anticoagulant: 10–40
mcg/kg IV, but doses as high as 90 mcg/kg have been used.
Dose may depend on the risk of bleeding complications (higher)
and thrombosis (lower).
No dose ranging trials in this setting are available.
Lower doses (e.g., 1 mg) have recently been explored out of concern
for thromboembolic concerns with the rFVIIa.
•
Hemostatic effects observed within 5–15 minutes (allows potential titration to
effects by starting with lower doses if time permits).
•
Rebound in the INR for warfarin patients can occur in 6–12 hours when rFVIIa
is used alone. Prolonged reduction in the INR can be accomplished by adding
vitamin K. FFP and IV vitamin K may be a consideration to provide continued
reversal until the full onset of vitamin K effects (see Figure 8-1).
•
Observations from a small registry suggest a potential benefit when used with
other antidotes to reestablish hemostasis during LMWH and UFH therapy.
•
No direct comparisons in outcomes evidence to PCC are available.
•
Adverse effects with use in non-hemophiliacs list are list in Table 8-7.
1,26
27
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TABLE 8-7: Adverse Events Associated with the Use of rFVIIa
Outside Hemophiliacs
Thromboembolism The reported incidence of thromboembolism may be higher than
Hypersensitivity • Including anaphylaxis.
rFVIIa: recombinant factor VII (activated)
observed in the hemophiliac population due to increased embolic risks
for embolism.
Black box warnings with off label use:
•
Arterial and venous thrombotic and thromboembolic events
following administration of rFVIIa have been reported during
postmarketing surveillance.
• Clinical studies have shown an increased risk of arterial
thromboembolic adverse events with rFVIIa when administered
outside the current approved indications.
• Discuss the risks and explain the signs and symptoms of thrombotic
and thromboembolic events to patients who will receive rFVIIa.
Fatal and nonfatal thrombotic events have been reported.
•
•
Monitor for signs or symptoms of activation of the coagulation
system and for thrombosis.
Administer only if clearly needed in patients with known
•
hypersensitivity to rFVIIa or any of its components, or mouse,
hamster, or bovine proteins.
24
DOAC REVERSAL AGENTS
Direct Thrombin Inhibitor Antidote
Idarucizumab (Praxbind)
•
Is FDA-approved humanized antibody fragment directed at dabigatran (350 x
greater affinity than thrombin).
•
Binds free and thrombin-bound dabigatran.
•
Is structurally similar to thrombin with no procoagulant activities.
•
Dose: 5 gm as two 2.5-gm 50 mL bolus injections administered as consecutive
infusions no more than 15 minutes apart (neutralizes approximately 800–1,000
ng/mL; see Chapter 9).
•
Administer within 1 hour of removal from the vial.
•
Onset: Completely reverses ecarin clotting time (ECT) and aPTT within
10 minutes of administration.
•
Duration: Some patients showed rebound increases in ECT and aPTT within
12 to 24 hours of administration.
•
Thrombin time (TT) can be used as a surrogate marker to determine if any
dabigatran effects remain present.
•
Hypersensitivity reactions are a concern.
•
Sorbitol as an excipient poses risk for serious adverse reaction in those with
hereditary fructose intolerance.
28
178 Anticoagulation Therapy
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•
Adverse effects reported include pyrexia, bronchospasm, hyperventilation, rash,
and pruritus.
•
Storage: Store vials in the refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not
freeze. Do not shake.
Prior to use, the unopened vial may be kept at room temperature
25°C (77°F) for up to 48 hours, if stored in the original package to
protect from light, or up to 6 hours when exposed to light.
Anti-factor Xa Inhibitor Antidotes
Andexanet Alfa
•
FDA approved modified recombinant factor Xa decoy protein binds factor Xa
inhibitors but lacks pharmacologic anticoagulant activity.
•
Neutralizes direct and indirect factor Xa inhibitors (FDA-approved for rivaroxaban
or apixaban reversal).
•
Onset: 10 minutes.
•
Duration: Approximately 1–2 hours (reversal effects diminish 1 hour after bolus
and 2–3 hours after bolus + infusion).
•
Dose (see Tables 8-8 and 8-9 below)
29
TABLE 8-8: ANDEXXA Dosing Regimens
Dose Initial IV Bolus Follow-Up IV Infusion
Low dose 400 mg at a target rate of 30 mg/min 4 mg/min for up to 120 minutes
High dose 800 mg at a target rate of 30 mg/min 8 mg/min for up to 120 minutes
*The safety and efficacy of more than one dose have not been evaluated.
•
The extent of reversal may depend on the initial serum concentration (how long
post the last dose) and presence of factors that may reduce elimination. In such
situations, full reversal may not be achieved.
•
Infusions may need to be extended during surgical procedures incurring bleeding risks lasting more than 2 hours.
•
Several vials will be required for a dose. Consider developing a process in
pharmacy to limit any delays in the preparation process.
•
After stopping the infusion, consider that a rebound in anticoagulation effect
may occur.
29
ANTICOAGULATION REVERSAL: PART I 179
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TABLE 8-9: Andexanet Dose Based on Rivaroxaban and
Apixaban Dose
FXa Inhibitor FXa Inhibitor Last Dose Timing of FXa Inhibitor Dose Before
Rivaroxaban ≤10 mg Low dose Low dose
Apixaban ≤5 mg Low dose
•
Undergoing clinical trials in patients with major bleeding events receiving a
factor Xa inhibitors (NCT:02329327).
•
Unopened vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). DO
NOT FREEZE.
•
Reconstituted ANDEXXA in vials is stable at room temperature for up to 8 hours,
or may be stored for up to 24 hours at 2°C to 8°C.
•
Reconstituted ANDEXXA in IV bags is stable at room temperature for up to 8
hours, or may be stored for up to 16 hours at 2°C to 8°C.
29
ANDEXXA Initiation
Less Than or Equal to
8 hr or Unknown
>10 mg or unknown High dose
>5 mg or unknown High dose
Onset of hemostasis may take several hours.
In trials, initiation of therapy after recognition, consent, random-
ization, and administration of agent took several hours, creating a
potential limitation on outcomes.
30
Greater Than 8 hr
Broad Spectrum Reversal Product
Aripazine, Ciraparantag (PER977) (Investigational)
•
Synthetic, small, water-soluble cationic molecule with broad binding activity
against UFH, LMWH, fondaparinux, factor Xa inhibitors, and direct thrombin
inhibitors.
•
Dose: Single IV dose of 100–300 mg has been studied.
•
Onset: 10 minutes.
•
Duration of effect: 24 hours.
See Chapter 9 on considerations for using antidotes when devices or surgical procedures requiring parenteral anticoagulation prior to the effects of
the antidote wear off.
31
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