Adv Ther (2014) 31:66–90 DOI 10.1007/s12325-013-0083-7

ORIGINAL RESEARCH

Use of Plasma in the Management of Central Nervous System Bleeding: Evidence-Based Consensus Recommendations Aryeh Shander • Edward A. Michelson • Babak Sarani

•

Matthew L. Flaherty Ira A. Shulman •

To view enhanced content go to www.advancesintherapy.com Received: October 25, 2013 / Published online: December 14, 2013 Ó Springer Healthcare 2013

ABSTRACT

of plasma in many clinical settings, alongside

Introduction: Central nervous system (CNS)

increasing concern about transfusion-associated adverse events. Despite these concerns, plasma

hemorrhage is a potentially life-threatening

is widely used. Moreover, plasma transfusion

condition, especially in patients with acquired coagulopathy. In this setting, treatment of CNS

practice is variable and there is currently no uniform approach to treatment of traumatic,

bleeding includes hemostatic therapy replenish coagulation factors. There

to is

surgical or spontaneous CNS hemorrhage. This study addresses the need for guidance on the

currently a debate over the hemostatic efficacy

indications and potential risks of plasma

Electronic supplementary material The online version of this article (doi:10.1007/s12325-013-0083-7) contains supplementary material, which is available to authorized users. A. Shander Department of Anesthesiology and Critical Care Medicine, Englewood Hospital and Medical Center, Englewood, NJ, USA A. Shander Departments of Anesthesiology, Medicine and Surgery, Mount Sinai School of Medicine, New York, NY, USA

transfusion in these settings. An Expert Consensus Panel was convened to develop recommendations guiding the use of plasma to treat bleeding and/or coagulopathy E. A. Michelson Case Western Reserve University School of Medicine, Cleveland, OH, USA E. A. Michelson University Hospitals Case Medical Center, Cleveland, OH, USA B. Sarani Department of Surgery, Trauma and Acute Care Surgery, George Washington University, Washington, DC, USA M. L. Flaherty Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, OH, USA

Enhanced content for Advances in Therapy articles is available on the journal web site: www.advancesintherapy.com

123

Adv Ther (2014) 31:66–90

67

associated with CNS hemorrhage. The panel did

Keywords: Central nervous system bleeding;

not advise on the best treatment available but rather proposed recommendations to be used in

Cerebral hemorrhage; hemorrhage; Plasma; Warfarin

Intracranial

the formulation of local procedures to support emergency physicians in their decision-making

INTRODUCTION

process. Methods: Evidence was systematically gathered from the literature and rated using

Acquired

methods established by Intercollegiate Guidelines

clinical scenarios and can be spontaneous, surgical or trauma-induced. Central nervous

the Scottish Network. The

coagulopathy

occurs

in

various

graded

system (CNS) bleeding is associated with many

consensus recommendations, which are presented along with the evidence-based

causes, including vitamin K antagonist (VKA)induced anticoagulation, antiplatelet therapy,

rationale for each in this report. Results: Sixty-five articles were

nutritional deficiency and hypertension. CNS bleeding, and intracranial hemorrhage (ICH) in

evidence

covering

was

both

used

to

vitamin

develop

K

identified antagonist-

particular,

is

associated

with

significant

anticoagulation reversal and treatment of bleeding/coagulopathy in non-anticoagulated

morbidity and mortality [1–4]. Recommendations on treatment of ICH

patients. Recommendations were then developed in four clinical scenarios within

typically focus on VKA-associated hemorrhage. In this setting, guidelines recommend therapy

each area, and agreed on unanimously by all members of the panel.

with vitamin K plus vitamin K-dependent

Conclusion: The Panel considered plasma to be

coagulation factors [5–7], though there are inconsistencies between recommendations.

reasonable therapy for CNS hemorrhage requiring urgent correction of coagulopathy,

Different guidelines recommend coagulation factor therapy using fresh-frozen plasma (FFP),

although physicians should be prepared for potential cardiopulmonary complications, and

prothrombin complex concentrate (PCC) or

evidence suggests that alternative therapies

recombinant activated factor VII (rFVIIa) [5]; FFP or PCC [7]; or PCC preferentially, and FFP only if

have superior risk–benefit profiles. Plasma could not be recommended in the absence of

PPC is unavailable [6]. In the US, plasma is the standard of care for factor-replacement therapy

hemorrhage or coagulopathy. Consideration of the absolute risks and benefits of plasma

for VKA-associated bleeds [8] and its effectiveness

therapy before transfusion is imperative.

for this indication remains undefined. The value of plasma therapy for CNS bleeds in non-anticoagulated patients is also uncertain. Guidelines for managing ICH make no recommendations on plasma transfusion in non-

I. A. Shulman (&) Transfusion Medicine Services Group, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]

anticoagulated patients [7], and non-CNS-specific guidelines recommend against plasma transfusion

I. A. Shulman Department of Pathology, University of Southern California Medical Center, Los Angeles, CA, USA

[10–12]. Since 1962, drug approval in the US has

if coagulopathy is absent [9]. In addition, there are concerns about the safety and efficacy of plasma included a statutory requirement for evidence of

123

Adv Ther (2014) 31:66–90

68

effectiveness in two ‘‘adequate and well-controlled

supplementary

trials’’, each convincing in isolation [13]. Plasma

recommendations.

was never subject to this requirement. If plasma was submitted for a new drug application today, it

stakeholders

is uncertain whether adequate evidence exists to support its approval.

bleeding. Additional physicians were invited,

Although the field is currently changing at a

hematology, pathology, and cardiovascular

fast pace with the increased availability of better alternative therapies, plasma is still widely used

anesthesiology, although these individuals did

to treat CNS bleeding and it is important to establish whether this is appropriate, taking

manuscript was submitted to the Society for

into account therapeutic risks and benefits. To

post

address this, a Consensus Panel was convened to develop evidence-based recommendations

systematic literature search was performed

on use of plasma products [FFP, plasma frozen at 24 h (FP24), thawed or cryoreduced plasma]

by the Panel co-chairs. PubMed and Embase/

in clinical scenarios associated with CNS

clinical studies, excluding congress abstracts,

bleeding. The Panel focused on whether plasma is effective and safe in these settings,

addressing the use of plasma in CNS bleeding.

irrespective of whether alternative therapies are available. Transfusion practice is an emotive

Headings were used alongside ‘‘free text’’,

issue [14], so selection and assessment of evidence and development and grading of recommendations were performed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology, ensuring that the grades of any recommendations would solely reflect the weight of supporting evidence. Surrogate outcomes

such

as

time

to

coagulopathy

correction were used to reach a consensus on appropriate use, limitations, and risks of plasma in several scenarios. The Panel’s findings aim to provide guidance on appropriate use of plasma

material)

who

The manage

prepared

these

Panelists

were

or

recommend

treatment of patients with coagulopathic CNS covering specialties including neurosurgery,

not attend. Consequently, a draft of this the Advancement of Blood Management for hoc

independent

expert

review.

A

using a strategy based on keywords identified Embase Alert were interrogated to identify

To

enhance

sensitivity,

Medical

Subject

combining up to 45 distinct phrases for each of the terms: ‘‘plasma’’, ‘‘bleeding’’ and ‘‘CNS’’ (see Supplementary Table S2 in the online electronic supplementary material). All English language articles published up to and including July 2012 were considered. In accordance with SIGN methodology, titles/abstracts of the retrieved articles were manually

screened

by

two

independent

reviewers using defined inclusion/exclusion criteria (see Supplementary Table S3 in the online electronic supplementary material), as

when managing CNS bleeding. More precisely,

directed by the Panel co-chairs. The full text of

the recommendations presented in this report are intended to be used for the development of

any article complying with the inclusion and

local policies and procedures.

Articles

exclusion criteria was analyzed in depth. were

according

to

assigned the

levels

SIGN

of

grading

evidence system

METHODS

(Table 1). Based on the evidence that was

A multidisciplinary panel of seven experts (see

clinical scenarios in which plasma could

Supplementary Table S1 in the online electronic

potentially be administered to control CNS

123

retrieved, the Panel co-chairs devised eight

Adv Ther (2014) 31:66–90

69

Table 1 Scottish Intercollegiate Guidelines Network levels of evidence and grades of recommendation assigned in this study Level of evidence Type of study 1??

RCTs with a very low risk of bias, high-quality meta-analyses or systematic reviews of RCTs

1?

RCTs with a low risk of bias, well-conducted meta-analyses or systematic reviews

1-

RCTs, meta-analyses, or systematic reviews with a high risk of bias

2??

Case–control or cohort studies (or meta-analyses/systematic reviews of such studies) with a very low risk of confounding or bias and a high probability that the relationship is causal

2?

Well-conducted case–control or cohort studies (or meta-analyses/systematic reviews of such studies) with a low risk of bias and a moderate probability that the relationship is causal

2-

Case–control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

3

Retrospective studies with no defined comparison groups or non-analytic studies, e.g., case series, clinical practice surveys

4

Expert opinion

Grade of recommendation

Level of supporting evidence

A

At least one RCT, meta-analysis or systematic review rated 1??, and directly applicable to the target population or A body of evidence, principally studies rated 1?, directly applicable to the target population and demonstrating overall consistency of results

B

A body of evidence including studies rated 2??, directly applicable to the target population and demonstrating overall consistency of results or Extrapolated evidence from studies rated 1?? or 1?

C

A body of evidence including studies rated 2?, directly applicable to the target population and demonstrating overall consistency of results or Extrapolated evidence from studies rated 2??

D

Evidence level 3 or 4 or Extrapolated evidence from studies rated 2?

RCT randomized controlled trial

bleeding. The articles were divided among these scenarios. scenarios.

Some

articles

covered

multiple

In a modified Delphi process [15, 16], Panel members independently reviewed the evidence and after filling out questionnaires

123

Adv Ther (2014) 31:66–90

70

anonymously, devised initial recommendations

The evidence broadly covered two areas:

for each scenario where data were available. Each

reversal of VKA anticoagulation, and treatment

recommendation was graded using the SIGN scheme, where the grade relates to the

of bleeding/coagulopathy in nonanticoagulated patients. Within each area, four

overall level of evidence for the supporting articles (Table 1) rather than the clinical

scenarios traumatic,

importance of the recommendation. Panelists’

prophylaxis. For each clinical scenario, the

recommendations were collated under guidance from the co-chairs and discussed at a face-to-face

recommendations are listed in Table 2 and the evidence is discussed below. Wherever possible,

Panel meeting. Where appropriate, multiple similar recommendations were summarized

we specify the plasma product used, e.g., FFP, and otherwise use the generic term ‘‘plasma’’.

into

Discordant

The consensus group unanimously agreed on

recommendations were vetted during the faceto-face meeting. The Panel voted upon inclusion,

phrasing and grades of all recommendations; there was no dissent to report.

single

statements.

were or

identified: spontaneous, surgical bleeding, and

phrasing and grading of recommendations. Where consensus was reached (C5 out of 7 in

agreement)

the

finalized,

graded

Clinical Scenario 1: Spontaneous Bleeding

recommendations were included in this report. Any differences of opinion were recorded for

with Oral VKA Therapy

presentation herein. Updates to these recommendations will be considered if new

Background

evidence becomes available from randomized controlled trials (RCTs) investigating plasma use.

Spontaneous, non-traumatic CNS bleeding, particularly spontaneous ICH, is a major cause

The study is based on previously conducted

of morbidity and mortality [1–4]. ICH is the most feared complication of oral VKA therapy—

studies and does not involve any new studies of human or animal subjects performed by any of

the incidence of spontaneous ICH is up to ten times greater in warfarin-treated patients than

the authors.

in non-anticoagulated patients [17]—and is associated with early neurological deterioration and a 30-day mortality rate of

RESULTS

approximately 50% [18, 19]. There is currently no uniformly effective standard regimen for

Sixty-five articles were included (Fig. 1). Nine were systematic reviews and/or meta-analyses,

reversing VKA anticoagulation in patients with

generally of high or moderate quality (levels of evidence 1?? or 2??). Fifty-six were original research articles including four high-quality studies (RCTs rated 1?), two moderate-quality observational studies (2??), and ten lowquality observational studies (2?). The remaining evidence was very low quality (2- or 3), mainly uncontrolled observational studies.

123

spontaneous ICH, although plasma is commonly administered for this purpose in the US. Forty articles relating to anticoagulantassociated CNS bleeding were identified; most focused

on

intracranial/intracerebral

hemorrhage. Thirty-three were original research articles, of which one was high quality (1?), eight low quality (2?) and the rest very low quality. Seven systematic reviews/ meta-analyses (mainly 2??) were identified.

Grade of recommendation

C

C C

3. Plasma is a reasonable option for reversal of oral VKA therapy in isolated trauma-related CNS bleeding

4. Clinicians should be prepared to manage cardiopulmonary complications associated with plasma transfusion

123

2. Plasma transfusion is not recommended to treat isolated trauma-related CNS hemorrhage in patients without coagulopathy

B

1. In patients with isolated trauma-related CNS bleeding, with coagulopathy due to factor deficits unrelated to oral VKA therapy, early C diagnosis and early intervention to reverse coagulopathy is recommended when possible

Clinical Scenario 4: isolated trauma-related CNS bleeding in the absence of oral VKA therapy

B

2. Patients with trauma-related CNS bleeding whose INR is elevated due to oral VKA therapy should have VKA withheld, receive therapy to immediately provide vitamin K-dependent factors, and receive intravenous vitamin K

1. In patients with trauma-related CNS bleeding on oral VKA therapy, early diagnosis and rapid intervention to reverse VKA-induced B anticoagulation is recommended

Clinical Scenario 3: isolated trauma-related CNS bleeding with oral VKA therapy

3. Plasma transfusion is not recommended for patients with spontaneous CNS hemorrhage in the absence of any identified coagulopathy C

2. Patients with spontaneous CNS bleeding who have coagulopathy due to factor deficits unrelated to oral VKA therapy should receive C appropriate therapy to reverse the coagulopathy when possible

1. In patients with spontaneous CNS hemorrhage, with coagulopathy due to coagulation factor deficits unrelated to VKA therapy, early C diagnosis and intervention to reverse coagulopathy is recommended

Clinical Scenario 2: spontaneous bleeding in the absence of oral VKA therapy

4. Clinicians should recognize and be prepared to manage complications associated with high volumes of plasma transfusion, and should C also be able to weigh the risk of prolonged time required for plasma infusion versus alternative treatments requiring less volume loads

3. Plasma is a reasonable option for oral VKA reversal in CNS bleeding

2. Patients with CNS hemorrhage whose INR is elevated due to oral VKA-induced anticoagulation should have VKA therapy withheld, B receive therapy to provide vitamin K-dependent factors, and receive intravenous vitamin K

1. In patients with spontaneous CNS hemorrhage on oral VKA therapy, early diagnosis and rapid intervention to initiate anticoagulation B reversal is recommended

Clinical Scenario 1: spontaneous bleeding with oral VKA therapy

Consensus recommendations

Table 2 Consensus recommendations for the use of plasma in the management of central nervous system bleeding for a range of clinical scenarios

Adv Ther (2014) 31:66–90 71

123 Grade of recommendation

B

3. Plasma cannot be recommended in non-bleeding patients not requiring invasive procedures who are on oral VKA therapy with supratherapeutic INR

B

CNS central nervous system, INR international normalized ratio, VKA vitamin K antagonist a Prophylaxis was defined as administration of plasma in non-bleeding patients, either to normalize abnormal coagulation parameters, or as early intervention to reduce the risk of bleeding before invasive procedures or following injury

2. Plasma is not recommended in patients without diagnosed or suspected coagulopathy

1. Patients requiring urgent invasive procedures who have a coagulopathy due to factor deficits unrelated to oral VKA therapy should D receive appropriate therapy to correct the coagulopathy when possible

Clinical Scenario 8: prophylactic transfusion of plasma in patients in the absence of oral VKA therapya

B

2. Plasma cannot be recommended prior to non-urgent, CNS-related, invasive procedures in patients on oral VKA therapy

1. The use of plasma is reasonable prior to urgent, CNS-related, invasive procedures in patients on oral VKA therapy with significantly C elevated INR; plasma should be administered close in time to the invasive procedure

Clinical Scenario 7: prophylactic transfusion of plasma in patients on oral VKA therapya

No recommendation: etiology of the intraoperative bleeding determines therapy, which should be determined locally, making this scenario beyond the scope of the Panel

Clinical Scenario 6: surgical bleeding in the absence of oral VKA therapy

No recommendation: patients receiving oral VKA therapy would have coagulopathy reversed prior to CNS surgery, making this scenario redundant

Clinical Scenario 5: surgical bleeding with oral VKA therapy

Consensus recommendations

Table 2 continued

72 Adv Ther (2014) 31:66–90

Adv Ther (2014) 31:66–90

73

Fig. 1 Summary of the systematic review of the literature to provide the evidence base for review by panelists. CNS central nervous system, FFP fresh-frozen plasma

Recommendations on Use of Plasma 1.

In

patients

with

spontaneous

anticoagulation reversal is recommended CNS

hemorrhage on oral VKA therapy, early diagnosis and rapid intervention to initiate

(Grade B). No high-quality, adequately powered evidence was identified on treatment approaches which

123

Adv Ther (2014) 31:66–90

74

improve clinical outcome in spontaneous VKA-

(AHA/ASA) guidelines strongly recommend

associated ICH. However, indirect evidence was

withdrawal of VKA therapy, administration of

identified linking Normalized Ratio

expedited International (INR) correction with

vitamin K and replacement of appropriate coagulation factors [7]. We identified one

improved outcomes. One RCT in patients with warfarin-related ICH found that treatment

study which demonstrated that infusion with FFP or coagulation factor concentrates

using FFP plus PCC shortens time to INR

increased plasma levels of FII, VII, IX and X

correction and may reduce mortality [20]. Similarly, in a retrospective comparison,

[26], and in the majority of studies, treatment using plasma and/or factor concentrates

treatment which accelerated INR correction coincided with reduced frequency and extent

decreased INR. 3. Plasma is a reasonable option for oral VKA

of hematoma enlargement; uncorrected INR at

reversal in CNS bleeding (Grade C). Two-thirds of studies reported vitamin K co-

2 h was the major predictor of hematoma growth [21]. Non-comparative studies also independently associated early reversal with improved survival: Menzin et al. [22], associated uncorrected INR at 1 day posttreatment with increased 30-day mortality in ICH, and Yasaka et al. [23], reported INR greater than 2 within 24 h of onset as the major predisposing factor for ICH enlargement.

administration (typically intravenous). In comparative studies, plasma corrected INR less rapidly and/or extensively than PCC or rFVIIa, although no studies were powered to detect differences between treatments and few investigated clinical outcomes. Mean reported times for VKA reversal using FFP ranged from 17 to 30 h [27–29] and one study of 48-h survivors

Rapid control of bleeding may be critical for survival as intraventricular extension of

with ICH or other major bleeding, receiving FFP to correct INR greater than or equal to 2,

bleeding

reported 67% of patients remaining uncorrected at 1 day post-transfusion [30].

and

ICH

volume

independently

associate with mortality [24]. Time from ICH diagnosis to FFP administration is a major

Although the evidence was generally very low

determinant of INR correction within 24 h, although the effect on clinical outcomes is

quality, plasma transfusion typically had some corrective effect. Moreover, the questionable

uncertain [25]. Prospective evidence is needed

efficacy of plasma is counterbalanced by the poor prognosis associated with not treating ICH

on whether early INR correction arrests bleeding and improves outcomes. Early

[18].

AHA/ASA

guidelines

for

managing

intervention appears warranted given current evidence and the poor prognosis of VKA-

spontaneous ICH recommend factor replacement with FFP or PCC [7], and

associated ICH. 2. Patients with CNS hemorrhage whose INR is

evidence-based guidelines weakly recommend plasma transfusion for warfarin-associated ICH

VKA-induced

[9]. The British Committee for Standards in

anticoagulation should have VKA therapy withheld, receive therapy to provide

Haematology (BCSH) guidelines also suggest that FFP may be used for warfarin reversal in

vitamin K-dependent factors, and receive intravenous vitamin K (Grade B).

ICH, although only if PCC is unavailable [6]. 4. Clinicians should recognize and be

For managing spontaneous ICH, the American Heart Association/American Stroke Association

prepared to manage complications associated with high volumes of plasma

elevated

123

due

to

oral

Adv Ther (2014) 31:66–90

75

transfusion, and should also be able to

Clinical Scenario 2: Spontaneous Bleeding

weigh the risk of prolonged time required for plasma infusion versus alternative

Without Oral VKA Therapy

treatments requiring less volume loads (Grade C).

Background Although VKA therapy increases the risk of

With high-quality efficacy and safety evidence

spontaneous ICH, anticoagulated patients represent a small fraction of the general

lacking, the potential benefits and harms of plasma need consideration. A systematic

population.

Only

5–20%

of

ICH

is

review of morbidity and mortality reported an increased risk of acute lung injury

anticoagulant-associated [18, 37, 38]; most CNS bleeding occurs in patients with no

following plasma transfusion [10]. Another

obvious coagulopathy. Some evidence suggests that ICH without coagulopathy results in lower

study reported plasma transfusion-related complications: Boulis et al. [20], compared

in-hospital mortality, lower 7-day mortality and

patients with VKA-associated ICH (predominantly non-traumatic, in patients

smaller hematoma volume versus ICH with coagulopathy [27, 39]. Nevertheless, ICH-

with

related mortality remains high and only around 20% of patients regain functional

atrial

fibrillation

and/or

valve

prosthesis) treated with FFP alone versus FFP plus PCC. Patients receiving FFP alone

independence [40]. There is no standardized

received mean volume [standard deviation (SD)] 2,712 (346) mL plasma compared with

role for hemostatic therapy in non-VKAassociated ICH. AHA/ASA guidelines for

399 (271) mL in the PCC group, and 63% showed symptoms of fluid overload. In other

managing spontaneous ICH do not make strong recommendations on hemostatic

studies the volume of FFP administered varied

therapy

from mean (SD) 600 (306) mL [31] to 2,044 (773) mL [32]; from median (interquartile

presumably due to limited evidence [7]. Eight articles were identified reporting CNS bleeding

range) 4 (2–6) units [25] to mean 11.5 units [33]; and from 10 to 15 mL/kg body-weight

in patients without VKA anticoagulation; four systematic reviews/meta-analyses (mainly 2??)

(equivalent to 750–1,125 mL for a 75-kg

and four original research articles (two 2?, one

patient) [34]. Such transfusion volumes, especially in patients whose bleeding is

2- and one 3).

restricted to a confined space, and who are anticoagulated due to underlying cardiac

Recommendations on Use of Plasma 1. In patients with spontaneous

conditions,

carry

risks

of

in

non-anticoagulated

patients,

CNS

hemorrhage, with coagulopathy due to coagulation factor deficits unrelated to

complications

including hypertension, heart failure, pulmonary edema and acute lung injury [10,

VKA

therapy,

early

diagnosis

and

35, 36]. Nevertheless, given the lifethreatening nature of VKA-associated ICH, it

intervention to reverse coagulopathy is recommended (Grade C).

is preferable to administer plasma and prepare

No evidence was retrieved establishing a need for hemostatic intervention in non-VKA-

for side effects than to withhold plasma in the absence of alternative options for emergency VKA reversal.

associated ICH. Similarly, no studies examined the

effects

of

timing

of

diagnosis

123

or

Adv Ther (2014) 31:66–90

76

intervention. However, given the association

(1??) systematic review of RCTs concluded that

between

early

plasma has no therapeutic benefits in most

neurological deterioration in VKA-associated ICH, it seems reasonable that early diagnosis

settings examined [11, 12]. Considering uncertainty over the appropriateness of

and treatment would also benefit nonanticoagulated patients. No studies focused on

therapy, the potential harms of plasma transfusion appear to outweigh the potential

specific

VKA

benefits in non-VKA-associated ICH. Guidelines

therapy, e.g., liver disease, chemotherapy, congenital conditions. 2. Patients with spontaneous CNS bleeding

were identified that argue against plasma transfusion in ICH patients without evidence

hematoma

expansion

coagulopathies

unrelated

and

to

who have coagulopathy due to factor deficits unrelated to oral VKA therapy should receive appropriate therapy to reverse the coagulopathy when possible (Grade C).

of coagulopathy [9]; the supporting evidence was of very low quality but again highlighted the fact that it is not uncommon for plasma to be administered to patients who have no clear need for transfusion.

AHA/ASA guidelines for managing spontaneous

Clinical Scenario 3: Trauma-related

ICH recommend appropriate coagulation factor replacement for patients with severe factor

Bleeding with Oral VKA Therapy

deficiencies [7], although no definition of ‘‘severe’’ was provided. No studies were

Background

retrieved which directly evaluated replacement

Trauma-related CNS bleeding is common, particularly with head injury. Annually, more

therapies in non-VKA-associated spontaneous ICH, although where plasma or factor

than one million US patients are admitted to emergency departments with traumatic brain

concentrates were used, laboratory measures of coagulation improved. Generally however, the

injury [41]. The majority sustain ‘‘mild’’ injuries, without Computed Tomography (CT)-identified

underlying coagulopathy, and therefore the

bleeding, caused by sports, falls or automobile

most appropriate therapy, were not established. Appropriate factor-replacement

crashes. However, in patients on VKA therapy the consequences of head injuries may be

therapy may depend on the availability of tests for rapid diagnosis of specific factor

severe. Oral anticoagulation and age over 65 years (typical of anticoagulated patients)

deficiencies. 3. Plasma transfusion is not recommended for

dramatically increase ICH risk following minor

patients with spontaneous CNS hemorrhage in the absence of any identified coagulopathy (Grade C). One retrospective analysis compared treatment using FFP versus FFP plus rFVIIa in neurosurgical emergencies. FFP was insufficient to correct coagulopathy in anticoagulated

and

non-anticoagulated

patients, although the methodology was low quality (2?) [33]. Furthermore, a high-quality

123

head injury [41–43]. Compared with similarly head-injured non-anticoagulated patients, preinjury warfarin therapy increases mortality fourto fivefold [44]. There is no standardized approach for VKA reversal in trauma patients, nor it is clear whether a standardized approach in injured patients is either valid or feasible. Nevertheless, plasma is routinely administered in this setting and guidance is needed on the potential benefits and risks of this practice. Twenty-two articles were identified reporting

Adv Ther (2014) 31:66–90

77

on VKA reversal and treatment of trauma-

therapy to immediately provide vitamin

related

K-dependent factors, and intravenous vitamin K (Grade B).

CNS

bleeding

in

anticoagulated

patients. Sixteen were original research articles: one high quality (1?), one moderate quality (2??) and the rest low or very low quality. Six systematic reviews/meta-analyses of

receive

Like spontaneous ICH, there is no adequately powered evidence establishing the most effective VKA reversal therapy in traumatic

mainly moderate quality were identified.

ICH. One systematic review recommended withdrawal of VKA therapy, administration of

Recommendations on Use of Plasma

vitamin K and replacement of appropriate coagulation factors (using FFP or PCC) [18],

1.

In patients with trauma-related CNS bleeding on oral VKA therapy, early

though clinical outcome data are lacking. One

diagnosis and rapid intervention to reverse VKA-induced anticoagulation is

article reported that use of FFP or coagulation factor concentrates increases plasma levels of

recommended (Grade B).

FII, VII, IX and X [26]. In almost all studies, factor-replacement therapy reduced INR. Co-

One prospective study was identified that associated a protocol for expedited diagnosis and treatment of traumatic warfarin-associated ICH with improved patient outcomes [45]. Compared with retrospective cohorts without a treatment protocol, and without a treatment or diagnosis protocol, the study group showed shorter time from arrival to FFP transfusion, reduced ICH progression and reduced mortality. Indirect evidence from one RCT also links accelerated INR correction with reduced mortality [20], while retrospective multivariate analysis independently associated uncorrected INR at 1 day post-treatment with increased 30-day mortality [22]. Although RCTs are needed which directly evaluate early diagnosis and VKA reversal in trauma-related ICH, current best evidence suggests this beneficial. Consistent with guidelines

recommend

approach is this, BCSH that

VKA-

anticoagulated patients presenting with head injury have their INR measured immediately and suggest that patients with suspected ICH have their anticoagulation reversed before the diagnosis is confirmed [6]. 2. Patients with trauma-related CNS bleeding whose INR is elevated due to oral VKA therapy should have VKA withheld, receive

administration

of

vitamin

K

(typically

intravenous) was reported in 13 of 15 original research articles. 3. Plasma is a reasonable option for reversal of oral VKA therapy in isolated trauma-related CNS bleeding (Grade C). Evidence-based guidelines weakly recommend plasma transfusion for warfarin-associated ICH [9]. The quality of supporting evidence in this setting is low but is counterbalanced by the risk of not treating [18]. BCSH guidelines suggest that FFP may be used for VKAassociated ICH when PCC is not available [6]. This guideline is supported by two studies [20, 26]: in each, FFP corrected INR but was less effective than factor concentrates, although neither study was powered to assess differences between the treatments. Reported times for VKA reversal using FFP in this setting include mean 17.4 h [29] and median (range) 29 (7–72) hours [27]. Using an expedited diagnosis and treatment protocol, a mean time of 3.4 h from admission to complete anticoagulation reversal has been reported [45]. The investigators minimized delays associated with FFP use by preparing universal donor (AB group) FFP while the

123

Adv Ther (2014) 31:66–90

78

patient underwent CT. If CT diagnosis was

bleeding that is confined to the head in non-

positive,

administered

anticoagulated patients. Fourteen studies were

immediately while type-matched FFP was prepared for subsequent transfusions. 4. Clinicians should be prepared to manage

retrieved for this setting: four systematic reviews/ meta-analyses (rated 1?? to 2?) and ten original

AB

FFP

was

cardiopulmonary complications associated with plasma transfusion (Grade C). In this setting, no trials were retrieved which defined the risk of adverse events related to plasma transfusion, although a systematic

research articles, including one RCT (1?) and one well-conducted observational study (2??). Recommendations on Use of Plasma 1.

In patients with isolated trauma-related

review identified acute lung injury as a

CNS bleeding, with coagulopathy due to factor deficits unrelated to oral VKA

possible consequence [10]. Volume overload is also a concern, especially given that reported

therapy, early diagnosis and early intervention to reverse coagulopathy is

volumes of FFP administered for VKA reversal were mean (SD) 2,712 (346) mL [20] and 4.5–9.0

recommended when possible (Grade C).

units [22, 46, 47]. The poor prognosis of VKA-

No studies were identified addressing the efficacy of early, appropriate factor

associated ICH means that any potential benefit of plasma may outweigh the known risks [18].

replacement in non-VKA-associated traumarelated coagulopathy. Some studies reported

Nevertheless, when administering plasma, physicians should prepare to manage possible

significant

morbidity

and

mortality

in

side effects.

coagulopathic trauma patients not receiving VKA therapy [27, 50], so severe prognosis

Clinical Scenario 4: Trauma-related

remains a major concern in this setting. Given the risks of mortality and functional

Bleeding Without Oral VKA Therapy

impairment observed with spontaneous CNS

Background Among the general population, trauma is a major cause of CNS bleeding. Head injury is particularly common, accounting for a significant proportion of emergency department admissions [48]. Prognosis for nonanticoagulated, non-coagulopathic patients

bleeding, it seems reasonable that similar risks may apply for isolated CNS hemorrhage in trauma and that rapid diagnosis and treatment may improve outcomes. However, the nature of any tissue injury and complications such as hypovolemic shock, acidosis and hypothermia may also impact prognosis. No studies focused

with head injuries may be favorable relative to

on specific coagulopathies unrelated to VKA therapy, e.g., liver disease, chemotherapy,

VKA-anticoagulated patients, but the potential consequences remain severe; failure to

congenital conditions. 2. Plasma transfusion is not recommended to

sufficiently control an initial bleed can lead to subsequent coagulopathy and recurrent

treat isolated trauma-related CNS hemorrhage in patients without

hemorrhage. Due to the broad spectrum of

coagulopathy (Grade B).

traumatic ICH severity, optimal management is often unclear [49]. Plasma is a component of

A systematic review of low-quality studies concluded that plasma may be insufficient as

massive transfusion protocols in trauma but it is not clear if plasma has a role in controlling

sole hemostatic therapy in trauma patients, and highlighted the need for multi-

123

Adv Ther (2014) 31:66–90

79

component therapy [51]. Another systematic

therapy within short time frames, eliminating

review and meta-analysis showed no benefits

indiscriminate

of plasma anticoagulated

transfusion outside of patients [10]; derived

associated treatment delay. Observed mortality rates (24.4%) were below those

recommendations suggest against plasma transfusion in patients without demonstrable

predicted by trauma injury severity scores (33.7%) and revised injury severity

coagulopathy

evidence

classification scores (28.7%), although the

reviewed was one RCT showing that, in patients with closed head injury but no

study’s relevance here is limited as only 13% of the study population experienced head

obvious coagulopathy, FFP transfusion was no more effective than saline in preventing

trauma.

poor

Clinical Scenario 5: Surgical Bleeding with Oral VKA Therapy

clinical

[9].

Among

outcomes

the

[52];

moreover,

patients receiving FFP showed increased DTICH (17% versus 0%) and mortality (63%

FFP

transfusion

and

its

versus 35%). Eliminating the confounding effect of hypotension increased these

It is not unusual for VKA-anticoagulated patients to require surgery or invasive

differences, while hypoxia, ICH frequency

procedures. Minor operations such as routine dental or ophthalmic procedures may proceed

and diffuse injury grading had no observable effect. Also identified was an observational

without VKA reversal in patients with an INR

study in closed head-injury patients, with and without coagulopathy, which concluded that

of 2.0–2.5, which withholding VKA

early empiric FFP transfusion may not benefit non-coagulopathic patients [50]; no effects on

procedures with a high risk of bleeding, VKA should be reversed. Consequently, the

outcomes

panelists unanimously concluded that recommendations on the use of plasma to

were

observed,

despite

administration of a mean (SD) 16.2 (24.4) units of FFP. Another retrospective analysis of

control

may be achieved by therapy [55]. For

VKA-associated

bleeding

during

head-injured patients also reported that early FFP administration (mean 13.9 units, range

surgery were unwarranted, as anticoagulated patients in need of operative intervention

1–24

involving the brain or spine would have VKA-induced coagulopathy reversed

units)

was

not

effective

in

non-

coagulopathic patients [53]. A feature of many studies was the use of

preoperatively (see Clinical Scenario 7).

tests that highlight defective coagulation initiation but do not diagnose specific

Clinical Scenario 6: Surgical Bleeding

coagulation factor deficits or indicate the

Without Oral VKA Therapy

most appropriate therapy. In contrast, one study used a goal-directed approach to trauma management, whereby underlying coagulopathies were rapidly diagnosed using point-of-care

viscoelastic

monitoring

(thromboelastometry) [54]. Patients with thromboelastometry-diagnosed coagulation defects received specific, targeted hemostatic

Surgical procedures, particularly major procedures involving the spine or brain, carry a risk of intraoperative bleeding, even in healthy patients. Management strategies vary dramatically depending on the type and urgency of surgery, underlying health of the patient and etiology of the bleed. Components

123

Adv Ther (2014) 31:66–90

80

of perioperative hemostatic management may

monitor placement. Nine relevant studies were

include plasma transfusion but will also involve

reviewed, including

various other surgical or pharmacological interventions. For elective procedures these

articles with methodological quality from 1? to 3.

components may be pre-planned based on a patient’s individual needs. Given the limited

Recommendations on Use of Plasma

evidence available and the breadth of this

1.

clinical scenario, the panelists unanimously concluded that broad recommendations on plasma transfusion to treat bleeding during CNS surgery would be neither useful nor valid. Recommendations

on

specific

sub-settings

within CNS surgery were considered to be beyond the scope of this report. Clinical Scenario 7: Prophylaxis with Oral

four original research

The use of plasma is reasonable prior to urgent, life-saving, CNS-related, invasive procedures

in

patients

on

oral

VKA

therapy with significantly elevated INR; plasma should be administered close in time to the invasive procedure (Grade C). No studies investigated plasma transfusion for VKA reversal before CNS surgery. One RCT compared FFP against intravenous vitamin K for correction of INR from 4–7 to 2–3 [57]. By

VKA Therapy

6 h post-treatment, 1 unit FFP corrected INR more completely than 1 mg vitamin K. This

Background

time frame appears reasonable for correction

In non-bleeding patients there are two main indications for correction of VKA-induced

before semi-urgent surgery, although patients did not require procedures so it is unknown

anticoagulation: (1) conferring a high

supratherapeutic INR risk of spontaneous

whether the correction observed would have been sufficient for surgery to proceed. Also,

bleeding, and (2) imminent need for surgery or invasive procedure with a high risk of

target INR may depend on the type of

the

procedure. Without robust efficacy data for plasma, the potential benefits and harms of

desired time frame for INR normalization. Withholding or lowering VKA doses can

reversal versus no reversal should be considered. Where delaying surgery may worsen prognosis,

reduce INR to within the therapeutic range. There is a wide variation in the INR values used

and where more rapid reversal options such as

bleeding.

The

approach

depends

on

to trigger prophylactic intervention [56] and active reversal may be performed using vitamin K, plasma and/or coagulation factor concentrates. In the US, warfarin reversal is a major reason for plasma administration, with one-third of transfusions going to non-bleeding patients [8]. However, there is no standardized approach to VKA reversal before invasive CNS

PCC are unavailable, plasma transfusion may be considered for preoperative VKA reversal. 2. Plasma cannot be recommended prior to non-urgent,

CNS-related,

procedures in patients therapy (Grade B).

on

invasive oral

VKA

If VKA reversal is not urgent, the potential benefits of plasma transfusion may be outweighed by known side effects. In a

procedures, even though rapid correction may be required even for percutaneous procedures

systematic review, plasma use in patients undergoing surgery without massive

such as lumbar puncture, infusion of epidural

transfusion was associated with increased risk of acute lung injury [10]. The evidence was low

anesthesia

123

or

intracranial

pressure

(ICP)

Adv Ther (2014) 31:66–90

81

quality, and the same working group could not

prophylaxis before invasive procedures [59,

recommend for or against plasma transfusion

60]. Little is known about clinicians’ decision-

for preoperative correction of coagulopathy [9]. Similarly, BCSH warfarin reversal guidelines do

making in this situation, particularly regarding CNS procedures. In a recent survey, 52% of ICU

not recommend plasma transfusion outside of ICH; PCC is recommended for urgent

clinicians stated that they would never administer prophylactic FFP in the absence of

preoperative reversal and vitamin K if surgery

bleeding; however, when the same group was

can be delayed 6–12 h [6]. 3. Plasma cannot be recommended in nonbleeding patients not requiring invasive

asked specifically about lumbar puncture, ICP monitor placement or epidural placement,

procedures who are on oral VKA therapy with supratherapeutic INR (Grade B). In non-bleeding, non-surgical patients, plasma transfusion can correct supratherapeutic INR. In one RCT, FFP corrected INR more effectively

85–94% said they would use FFP prophylactically [56]. Clearly there is a need for rational, evidence-based appraisal of plasma use in non-anticoagulated, non-bleeding patients. Ten relevant articles were identified, including one

than vitamin K within 6 h post-treatment,

RCT (1?) and six studies of lower quality (one 2?, one 2- and four 3).

although vitamin K did reduce INR substantially within 6 h and both groups had

Recommendations on Use of Plasma

comparable INR after 1 week [57]. Given the higher cost of plasma versus vitamin K,

1.

Patients

requiring

urgent

invasive

combined with risks of transfusion-related

procedures who have a coagulopathy due to factor deficits unrelated to oral VKA

adverse events, it is difficult to justify using plasma over vitamin K in this setting. In an

therapy should receive appropriate therapy to correct the coagulopathy when possible

audit examining warfarin reversal practice in Irish hospitals [58], 74% of more than 2,500

(Grade D).

patients with INR greater than 5 were corrected

An observational study was reviewed in which patients received FFP to ‘‘normalize’’

by omission or reduction of warfarin dose. Only 3% of patients received plasma or PCC; active

coagulation parameters before ICP monitor placement [59]. The majority of patients did

reversal was typically performed using vitamin K. No ICH or fatal hemorrhage was related to

not show normalized coagulation post-FFP

over-anticoagulation during the audit period,

(mean 4.3 units), and transfusion increased mean time from admission to procedure

suggesting that plasma transfusion is not needed to treat asymptomatic,

compared with patients not receiving transfusions (19.2 versus 8.8 h). Overall,

supratherapeutic INR.

however,

the

study

methodology

was

insufficient to draw firm conclusions on the effectiveness of plasma in this setting. Clinical Scenario 8: Prophylaxis Without Oral VKA Therapy Background Non-anticoagulated, non-bleeding, coagulopathic patients are often administered plasma as

Moreover, pre-procedural coagulopathy was defined using prothrombin time (PT), activated partial thromboplastin time, INR and platelet count, of which only platelet count diagnoses a specific coagulation defect or indicates the most appropriate hemostatic

123

Adv Ther (2014) 31:66–90

82

therapy.

No

studies

focused

on

specific

phlebotomy)

represented

only

53.8%

of

coagulopathies unrelated to VKA therapy.

plasma administered in the US [61]. Plasma

Despite the lack of evidence in this scenario, the Panel agreed that plasma remains an option

frozen within 24 h comprised 38.8% of transfused units, and other products such as

to prophylactically correct certain coagulation deficiencies, especially where specific factor

cryopoor plasma comprised the remaining 7.4% [61]. As FFP and FP24 are both commonly used

therapies are unavailable. 2. Plasma is not recommended in patients

and show little difference in coagulation factor

suspected

composition [62], the Panel speculated that recent US-based studies reporting FFP

No evidence of efficacy was found supporting

transfusion potentially administered FFP and/ or FP24 [62]. If so, it is possible that other

without diagnosed coagulopathy (Grade B).

or

plasma transfusion in non-bleeding, noncoagulopathic patients. Compounding this, prophylactic FFP had no beneficial effect [53], or was associated with increased morbidity and mortality

[52],

in

non-bleeding,

non-

coagulopathic head-injured patients. These results are reflected in systematic reviews which identify no prophylactic benefit of plasma transfusion in most settings [11, 12],

variants such as thawed or cryoreduced plasma were also used; both of which have distinct coagulation factor content compared with FFP/ FP24 [62]. For clarity, future studies should specify whether ‘‘FFP’’ transfusion is exclusively FFP based. The Panel was unable to make recommendations regarding dosing of plasma

and argue against plasma transfusion in settings

as reported transfusion practice was highly variable. Volumes of up to 2,712 mL of plasma

where effectiveness data are lacking [9, 10]. Potential benefits of plasma in these settings

were administered to adult ICH patients [20], although such volumes may cause

may be minor compared to the risks of serious transfusion-associated adverse events.

complications [35, 36]. Attempts have been

DISCUSSION

made to devise an algorithm for calculating plasma dose; for example, Holland et al. [63] developed an equation relating change in INR to the number of FFP units transfused, allowing clinicians to calculate the FFP dose required to

Based on a clinical need for more consistent and rational plasma transfusion practice, the Panel developed evidence-based recommendations for using plasma in clinical scenarios associated with CNS bleeding. The quality of available evidence was limited in most areas and mostly relied on surrogate outcomes such as time to coagulopathy correction (i.e., timings to initiation of INR reversal or to target INR). Most studies specified FFP as the plasma used. This is surprising considering the 2009 National Blood Collection and Utilization Survey reported that FFP (frozen within 8 h of

123

achieve a given INR. However, minimal effective dose of plasma is not yet established, and the authors questioned the benefits of plasma use in patients with INR less than 1.7. The lack of data prevented the Panel from making plasma dosing recommendations. For urgent reversal of VKA-induced anticoagulation, the Panel suggested that vitamin K should be co-administered intravenously rather than orally. Each ICH is unique, with differing location, severity of bleed and comorbidities. Evidence is lacking on treatment approaches for ICH sub-

Adv Ther (2014) 31:66–90

83

types. Consequently, the Panel could not make

outweigh the benefits. This is consistent with

specific recommendations on timing or nature

guidelines that plasma may be contraindicated

of interventions related to ICH location or hematoma size; these areas need further

when coagulation factor concentrates are available [6, 64]. A systematic review of RCTs

research. evidence

Nevertheless, from the available it seems clear that timing of

[11], and its recent update [12], examined clinical effectiveness of plasma and found no

diagnosis

and

in

prophylactic or therapeutic benefit. Overall, the

patients with CNS bleeds. The evidence shows that early anticoagulation reversal (by any

evidence on plasma is poor-quality and largely inconclusive; plasma should therefore be

method) can expedite INR correction and may limit hematoma expansion, suggesting the

considered to have unproven efficacy rather than being concluded to be ineffective.

intervention

is

critical

mortality

The questionable efficacy of plasma is

[20, 21, 25, 45]. Use of plasma as first-line therapy can introduce multiple delays; in many

important given that there are established risks associated with its use [65]. Plasma may be best

hospitals, plasma still requires thawing and blood-typing. Depending on transfusion

avoided unless the prognosis associated with not correcting coagulopathic bleeding is worse

practice and dosing, VKA reversal using FFP

than

can take up to 30 h on average [28]. This can be shortened to 3.4 h by combining use of AB

adverse events. Our recommendations state that physicians should be prepared to manage

plasma with coordinated protocols for diagnosis and plasma preparation [45]. Thawed plasma

cardiopulmonary complications following plasma transfusion. Transfusion-associated

can be made rapidly available for transfusion, though thawed plasma contains less FV, FVII

circulatory overload (TACO) and transfusionrelated acute lung injury (TRALI) are two of the

and FVIII compared with frozen plasma [62].

most serious adverse events associated with

There is also uncertainty concerning effectiveness of other plasma products (e.g.,

plasma use and often result in fatality [65]. Circulatory overload is a particular concern in

solvent-detergent treated); evaluating this is complicated by the fact that efficacy and

CNS hemorrhage, as the effects of bleeding within a confined space may be exacerbated by

safety

formally

increasing circulatory volume. Patients on oral

established in most settings. Current ongoing trials essentially aim at either identifying the

anticoagulation due to underlying cardiovascular conditions may be susceptible

best INR trigger (Clinicaltrials.gov

for plasma therapy #NCT01461889) or

to hypertension, and transfusion of large volumes into patients with relatively small

determining if early plasma transfusion is

internal bleeds may increase the likelihood of

beneficial (Clinicaltrials.gov #NCT018438863, #NCT01221389). However, given that FFP

pulmonary edema and acute lung injury [10]. Besides TACO and TRALI there are a host of

represents the standard of care in the US for many indications, the need for research to

other transfusion-related adverse events, which were not reported in the studies identified

define their safety and efficacy cannot be

in our literature searches but which have

overstated. In some scenarios, the Panel concluded the

been widely reported elsewhere [52, 66]. These events vary in frequency and severity and

potential harms of plasma transfusion may

include transfusion-related immunomodulation,

potential

of

to

reduce

FFP

have

ICH-related

not

been

the

potential

for

transfusion-related

123

Adv Ther (2014) 31:66–90

84

anaphylactic reactions and infectious risks.

4–6 h may be more accurate for intravenous

Where possible, new strategies are continually

administration [77–79], raising clinical and

being developed to minimize such risks [65, 67], though this will inevitably add to production

economic questions over plasma use for nonurgent VKA reversal.

costs. Using PCC or rFVIIa alongside FFP decreases

Tests such as PT and INR provide a standardized means of measuring clotting.

time to INR normalization [20, 21, 32–34]. PCC

However, these tests have several limitations:

corrects INR more rapidly than FFP or solvent– detergent-treated plasma when used as sole

they are typically plasma based so are slow to generate results; they provide information only

coagulation factor-replacement therapy (±vitamin K) [31, 68, 69]. A recent editorial,

on initial stages of coagulation; they ignore the contribution of cellular elements; and they do

published after the Panel was convened, clearly

not diagnose specific factor deficiencies or

highlights the differences in timing for the various therapies available for VKA-associated

indicate the most appropriate therapy. Increasingly available viscoelastic tests, such as

bleeding [70]. Indeed, onset of effects is estimated at around 15–30 min with PCC

those performed using TEGÒ (Haemoscope Inc., Niles, IL, USA) or ROTEMÒ (Tem International

compared to an onset equal to the duration of

GmbH, Munich, Germany) devices, make rapid

infusion for FFP (which can take up to 928 min) [71]. PCC and rFVIIa avoid the risk of volume

measurements at the point-of-care using whole blood. These techniques diagnose specific

overload associated with plasma; however, high-quality evidence is lacking. Currently, two

coagulation defects, enabling targeted, goaldirected therapy in various settings [80–82]. A

randomized trials comparing rFVIIa to placebo are recruiting patients (Clinicaltrials.gov

trial investigating the benefits of viscoelastic tests to predict bleeding and thrombosis

#NCT00810888,

Suitably

(isrctn.org #ISRCTN50516147) in a critical care

powered studies are required to define efficacy and safety of PCC and rFVIIa relative to plasma,

#NCT1359202).

setting has recently been registered; such trials are needed to investigate viscoelastic testing in

and to determine their effects on patient outcomes (e.g., control of hemorrhage, survival,

CNS bleeding, particularly where anticoagulation reversal is required.

recovery of functional independence). Other therapies also need consideration. For example, the antifibrinolytic tranexamic acid can reduce

LIMITATIONS

bleeding during spinal surgery [72], following trauma with significant (non-CNS) hemorrhage

There

[73, 74], and trials are underway in head injury (CRASH-3 trialClinicaltrials.gov #NCT01402882) and ICH (Clinicaltrials.gov

are

some

limitations

to

the

recommendations in this manuscript. Plasma is used for a broad range of indications, so by addressing only CNS bleeding other clinical

#NCT01702636). Intravenous vitamin K should be co-administered with coagulation factor

conditions may appear to have been overlooked. Given the breadth of this area,

concentrates for anticoagulation reversal since

focusing upon CNS bleeding, where there is uncertainty over how and when to administer

most factors have short half-lives [75, 76]. Despite the perception that vitamin K-mediated reversal takes around 24 h, studies show that

123

plasma, could also be considered a strength of this study. In addition, the Panel’s

Adv Ther (2014) 31:66–90

85

recommendations cover only the appropriate

evidence-based management of anticoagulant

use of plasma and do not provide guidance on

therapy supplement, recommending the use of

alternative therapy options. This report openly acknowledges that alternatives therapies are

PCC over plasma to treat VKA-associated bleeding [83]. However, plasma is still a local

widely used and may be superior in certain clinical scenarios. However, the aim of these

standard of care in the US; it was introduced before evidence of effectiveness was required for

recommendations is not to address the best

approval, so has not been challenged using the

available treatment option in each scenario. Instead, the Panel seeks to provide guidance for

criteria applied to rFVIIa and PCC. Moreover, based on our review of the literature, there is

physicians who are committed to using plasma and to indicate that the relative risks versus

not sufficient evidence to support de novo approval of plasma for use in CNS bleeding.

benefits of plasma transfusion change in

Given

different scenarios associated with CNS bleeding. The recommendations should be

socioeconomic costs associated with poor outcomes from CNS bleeding, prospective

considered in the context procedures and policies.

studies investigating efficacy and safety of hemostatic therapies are needed in this

of

any

local

the

clinical,

economic

and

setting. Although inherently challenging [61], such studies could be a major step towards developing standardized strategies for

CONCLUSION plasma

managing CNS bleeding. These recommendations should be considered in the

transfusion may be considered reasonable treatment in settings where patients are

context of any local procedures and policies meanwhile, clinicians should balance the

hemorrhaging and/or coagulopathic, although alternative options for both urgent (PCC) and

potential

Overall,

the

Panel

agreed

that

non-urgent (vitamin K) VKA reversal are

risks

and

benefits

transfusion, and consider treatment options.

of

plasma

other

available

the

valuable

potentially more effective and have lower risk of treatment-related adverse events. Furthermore, due to their individually defined content, PCC and vitamin K allow more reliable

ACKNOWLEDGMENTS

and accurate dosing than plasma, whose

We

content is unspecified and varies from unit to unit [62]. Generally, current evidence for all

contributions of Michael Diringer MD and Phillip Bahramipour MD in developing these

reversal options is low quality, under-powered and does not assess clinically important

consensus recommendations, John Peter Gruen MD for his critical review of the manuscript,

outcomes. These limitations must be overcome

and Neil Blumberg MD, Maureane Hoffman

before therapies such as PCC can be approved, due to the statutory requirement for evidence of

MD, Lewis Kaplan MD, Majed Refaai MD and Johnathan Waters MD for their critical review

effectiveness in two well-controlled trials [13]. The field is currently in a transition stage

on behalf of the Society for Advancement of Blood Management. The co-chairs (Ira Shulman

with the release of new guidelines, such as the American College of Chest Physicians

and Aryeh Shander) were responsible for

wish

to

acknowledge

selecting the Consensus Panel and developing

123

Adv Ther (2014) 31:66–90

86

and directing the literature review process. Medical writing support was provided by Timothy J. Tavender, PhD and Sandrine M. Dupre´, PhD, Meridian HealthComms, Plumley,

Principal Investigator of a phase II treatment trial (funded by the National Institute of Neurological Disorders and Stroke) testing recombinant activated factor VII (supplied by

Cheshire, UK. The logistical framework for the Panel meeting was provided by Interactive

Novo Nordisk) for intracerebral haemorrhage and received honoraria payment and expenses

Forums Inc.

reimbursement from CSL Behring for attending the Consensus Panel meeting.

CSL Behring provided funding support for the following: honoraria payments and expenses reimbursement for Consensus Panel members for preparation and participation in the Panel;

Compliance

with ethics guidelines. The

honoraria payment and administrative fee to

study is based on previously conducted studies, and does not involve any new studies

The Society for the Advancement of Blood Management for independent review of

of human or animal subjects performed by any of the authors.

the evidence-based administrative/logistical

recommendations; support for the

Consensus Panel meeting from Interactive Forums Inc.; and medical writing support for literature searches and manuscript preparation from Meridian HealthComms. All work, including the literature review, Panel meeting

REFERENCES 1.

Naidech AM. Intracranial hemorrhage. Am J Respir Crit Care Med. 2011;184:998–1006.

2.

Perel P, Roberts I, Bouamra O, Woodford M, Mooney J, Lecky F. Intracranial bleeding in patients with traumatic brain injury: a prognostic study. BMC Emerg Med. 2009;9:15.

3.

Steiner T, Petersson J, Al-Shahi Salman R, et al. European research priorities for intracerebral haemorrhage. Cerebrovasc Dis. 2011;32:409–19.

4.

van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76.

5.

Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th Edition). Chest. 2008;133:160S–98S.

6.

Keeling D, Baglin T, Tait C, et al. Guidelines on oral anticoagulation with warfarin—fourth edition. Br J Haematol. 2011;154:311–24.

7.

Morgenstern LB, Hemphill JC 3rd, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41:2108–29.

and manuscript development, was performed independently of the sponsor; the sponsor had no authorship or editorial control over the content of the meeting or any subsequent publication. Conflict of interest. A. Shander received honoraria payment reimbursement from

and expenses CSL Behring for

attending the Consensus Panel meeting. E.A. Michelson received honoraria payment and expenses reimbursement from CSL Behring for attending the Consensus Panel meeting. B. Sarani received honoraria payment and expenses reimbursement from CSL Behring for attending the Consensus Panel meeting. I.A. Shulman received honoraria payment and expenses reimbursement from CSL Behring for attending the Consensus Panel meeting. The authors received no subsequent payment for manuscript development. M.L. Flaherty is the

123

Adv Ther (2014) 31:66–90

8.

Ozgonenel B, O’Malley B, Krishen P, Eisenbrey AB. Warfarin reversal emerging as the major indication for fresh frozen plasma use at a tertiary care hospital. Am J Hematol. 2007;82:1091–4.

9.

Roback JD, Caldwell S, Carson J, et al. Evidencebased practice guidelines for plasma transfusion. Transfusion. 2010;50:1227–39.

10. Murad MH, Stubbs JR, Gandhi MJ, et al. The effect of plasma transfusion on morbidity and mortality: a systematic review and meta-analysis. Transfusion. 2010;50:1370–83. 11. Stanworth SJ, Brunskill SJ, Hyde CJ, McClelland DB, Murphy MF. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol. 2004;126:139–52. 12. Yang L, Stanworth S, Hopewell S, Doree C, Murphy M. Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials (CME). Transfusion. 2012;52: 1673–86. 13. U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for industry: providing clinical evidence of effectiveness for human drugs and biological products. http:// www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM078749.pdf. Accessed January, 2013. 14. Kozek-Langenecker S, Sorensen B, Hess J, Spahn DR. Emotional or evidence-based medicine—is there a moral tragedy in haemostatic therapy? Crit Care. 2011;15:462. 15. Dalkey N, Helmer O. An experimental application of the Delphi method to the use of experts. Manage Sci. 1963;9:458–67. 16. Linstone H, Turoff M. The Delphi Method: Techniques and Applications; 2002. http://is.njit. edu/pubs/delphibook. Accessed November 26, 2013. 17. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke. 2006;37:256–62. 18. Bechtel BF, Nunez TC, Lyon JA, Cotton BA, Barrett TW. Treatments for reversing warfarin anticoagulation in patients with acute intracranial hemorrhage: a structured literature review. Int J Emerg Med. 2011;4:40. 19. Broderick Huster G. powerful mortality.

JP, Brott TG, Duldner JE, Tomsick T, Volume of intracerebral hemorrhage. A and easy-to-use predictor of 30-day Stroke. 1993;24:987–93.

87

20. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999;45:1113–9. 21. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke. 2006;37:1465–70. 22. Menzin J, Hoesche J, Friedman M, et al. Failure to correct International Normalized Ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records. J Thromb Haemost. 2012;10:596–605. 23. Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost. 2003;89:278–83. 24. Sjoblom L, Hardemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001;32:2567–74. 25. Goldstein JN, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke. 2006;37:151–5. 26. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost. 1997;77:477–80. 27. Bershad EM, Farhadi S, Suri MF, et al. Coagulopathy and inhospital deaths in patients with acute subdural hematoma. J Neurosurg. 2008;109:664–9. 28. Lee SB, Manno EM, Layton KF, Wijdicks EF. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology. 2006;67:1272–4. 29. Mountain D, Sistenich V, Jacobs IG. Characteristics, management and outcomes of adults with major trauma taking pre-injury warfarin in a Western Australian population from 2000 to 2005: a population-based cohort study. Med J Aust. 2010;193:202–6. 30. Menzin J, White LA, Friedman M, et al. Factors associated with failure to correct the international normalised ratio following fresh frozen plasma administration among patients treated for warfarin-related major bleeding. An analysis of

123

Adv Ther (2014) 31:66–90

88

electronic health 2012;107:662–72.

records.

Thromb

Haemost.

from the standing position. J Trauma. 2009;67: 954–8.

31. Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke. 1992;23:972–7.

44. Mina AA, Knipfer JF, Park DY, Bair HA, Howells GA, Bendick PJ. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. J Trauma. 2002;53:668–72.

32. Brody DL, Aiyagari V, Shackleford AM, Diringer MN. Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage. Neurocrit Care. 2005;2:263–7. 33. Roitberg B, Emechebe-Kennedy O, Amin-Hanjani S, Mucksavage J, Tesoro E. Human recombinant factor VII for emergency reversal of coagulopathy in neurosurgical patients: a retrospective comparative study. Neurosurgery. 2005;57:832–6 (discussion -6). 34. Siddiq F, Jalil A, McDaniel C, et al. Effectiveness of Factor IX complex concentrate in reversing warfarin associated coagulopathy for intracerebral hemorrhage. Neurocrit Care. 2008;8:36–41. 35. Li G, Rachmale S, Kojicic M, et al. Incidence and transfusion risk factors for transfusion-associated circulatory overload among medical intensive care unit patients. Transfusion. 2011;51:338–43. 36. Narick C, Triulzi DJ, Yazer MH. Transfusionassociated circulatory overload after plasma transfusion. Transfusion. 2012;52:160–5. 37. Cervera A, Amaro S, Chamorro A. Oral anticoagulant-associated intracerebral hemorrhage. J Neurol. 2012;259:212–24. 38. Flaherty ML, Adeoye O, Sekar P, et al. The challenge of designing a treatment trial for warfarinassociated intracerebral hemorrhage. Stroke. 2009;40:1738–42. 39. Stead LG, Jain A, Bellolio MF, et al. Effect of anticoagulant and antiplatelet therapy in patients with spontaneous intra-cerebral hemorrhage: does medication use predict worse outcome? Clin Neurol Neurosurg. 2010;112:275–81. 40. Sahni R, Weinberger J. Management of intracerebral hemorrhage. Vasc Health Risk Manag. 2007;3:701–9. 41. Jagoda AS, Bazarian JJ, Bruns JJ Jr, et al. Clinical policy: neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. J Emerg Nurs. 2009;35:e5–40. 42. Karni A, Holtzman R, Bass T, et al. Traumatic head injury in the anticoagulated elderly patient: a lethal combination. Am Surg. 2001;67:1098–100. 43. Sarani B, Temple-Lykens B, Kim P, et al. Factors associated with mortality and brain injury after falls

123

45. Ivascu FA, Howells GA, Junn FS, Bair HA, Bendick PJ, Janczyk RJ. Rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduces hemorrhage progression and mortality. J Trauma. 2005;59: 1131–9. 46. Kalina M, Tinkoff G, Gbadebo A, Veneri P, Fulda G. A protocol for the rapid normalization of INR in trauma patients with intracranial hemorrhage on prescribed warfarin therapy. Am Surg. 2008;74: 858–61. 47. Stein DM, Dutton RP, Kramer ME, Scalea TM. Reversal of coagulopathy in critically ill patients with traumatic brain injury: recombinant factor VIIa is more cost-effective than plasma. J Trauma. 2009;66:63–75. 48. Bethel J. Emergency care of children and adults with head injury. Nurs Stand. 2012;26:49–56 (quiz 8). 49. Francis R, Rowan EN, Gregson BA, Mendelow AD. Traumatic intracerebral hemorrhage—to operate or not? World Neurosurg. 2011;76:484–5. 50. May AK, Young JS, Butler K, Bassam D, Brady W. Coagulopathy in severe closed head injury: is empiric therapy warranted? Am Surg. 1997;63: 233–7. 51. Lier H, Bottiger BW, Hinkelbein J, Krep H, Bernhard M. Coagulation management in multiple trauma: a systematic review. Intensive Care Med. 2011;37: 572–82. 52. Etemadrezaie H, Baharvahdat H, Shariati Z, Lari SM, Shakeri MT, Ganjeifar B. The effect of fresh frozen plasma in severe closed head injury. Clin Neurol Neurosurg. 2007;109:166–71. 53. Winter JP, Plummer D, Bottini A, Rockswold GR, Ray D. Early fresh frozen plasma prophylaxis of abnormal coagulation parameters in the severely head-injured patient is not effective. Ann Emerg Med. 1989;18:553–5. ¨ chl H, Nienaber U, Hofer G, et al. Goal-directed 54. Scho coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14:R55.

Adv Ther (2014) 31:66–90

55. Grobler C, Callum J, McCluskey SA. Reversal of vitamin K antagonists prior to urgent surgery. Can J Anaesth. 2010;57:458–67. 56. Watson DM, Stanworth SJ, Wyncoll D, et al. A national clinical scenario-based survey of clinicians’ attitudes towards fresh frozen plasma transfusion for critically ill patients. Transfus Med. 2011;21:124–9. 57. Yiu KH, Siu CW, Jim MH, et al. Comparison of the efficacy and safety profiles of intravenous vitamin K and fresh frozen plasma as treatment of warfarinrelated over-anticoagulation in patients with mechanical heart valves. Am J Cardiol. 2006;97:409–11. 58. Ouirke W, Cahill M, Perera K, Sargent J, Conway J. Warfarin prevalence, indications for use and haemorrhagic events. Ir Med J. 2007;100:402–4. 59. Davis JW, Davis IC, Bennink LD, et al. Placement of intracranial pressure monitors: are ‘‘normal’’ coagulation parameters necessary? J Trauma. 2004;57:1173–7. 60. Stanworth SJ, Grant-Casey J, Lowe D, et al. The use of fresh-frozen plasma in England: high levels of inappropriate use in adults and children. Transfusion. 2011;51:62–70. 61. U.S. Department of Health and Human Services. National Blood Collection and Utilization Survey Report 2009. http://www.hhs.gov/ash/bloodsafety/ nbcus/index.html. Accessed October, 2012. 62. Benjamin RJ, McLaughlin LS. Plasma components: properties, differences, and uses. Transfusion. 2012;52(Suppl 1):9S–19S. 63. Holland LL, Brooks JP. Toward rational fresh frozen plasma transfusion: the effect of plasma transfusion on coagulation test results. Am J Clin Pathol. 2006;126:133–9. 64. AABB, ARC, ABC, ASBP. Circular of information: for the use of human blood and blood components; 2013; http://www.aabb.org/resources/bct/Documents/ coi0413.pdf. Accessed December, 2013. 65. Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012;52(Suppl 1):65S– 79S. 66. Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI, Gracias VH. Transfusion of fresh frozen plasma in critically ill surgical patients is associated with an increased risk of infection. Crit Care Med. 2008;36:1114–8. 67. Triulzi DJ. AABB contributions to plasma safety. Transfusion. 2012;52(Suppl 1):5S–8S.

89

68. Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg. 2000;14:458–61. 69. Demeyere R, Gillardin S, Arnout J, Strengers PF. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251–60. 70. Quinlan DJ, Eikelboom JW, Weitz JI. Four-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding. Circulation. 2013;128:1179–81. 71. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234–43. 72. Xu C, Wu A, Yue Y. Which is more effective in adolescent idiopathic scoliosis surgery: batroxobin, tranexamic acid or a combination? Arch Orthop Trauma Surg. 2012;132:25–31. 73. Crash-2 collaborators; Roberts I, Shakur H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377:1096–101, 101 e1–2. 74. Roberts I, Perel P, Prieto-Merino D, et al. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ. 2012;345:e5839. 75. Brackmann HH, Effenberger E, Hess L, Schwaab R, Oldenburg J. NovoSeven in immune tolerance therapy. Blood Coagul Fibrinolysis. 2000;11(Suppl 1):S39–44. 76. Ostermann H, Haertel S, Knaub S, Kalina U, Jung K, Pabinger I. Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb Haemost. 2007;98:790–7. 77. Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med. 2003;163:2469–73. 78. Raj G, Kumar R, McKinney WP. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med. 1999;159:2721–4.

123

90

79. Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol. 2001;115:145–9. 80. Gorlinger K. Coagulation management during liver transplantation [in German]. Hamostaseologie. 2006;26:S64–76. ¨ chl H, Maegele M, Solomon C, Gorlinger K, 81. Scho Voelckel W. Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma Resusc Emerg Med. 2012;20:15.

123

Adv Ther (2014) 31:66–90

82. Weber CF, Gorlinger K, Meininger D, et al. Point-ofcare testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology. 2012;117:531–47. 83. Holbrook A, Schulman S, Witt DM, et al. Evidencebased management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e152S–84S.