Fisiologi dan Manajemen Transfusi Masif

Perdarahan akibat pendarahan yang tidak terkontrol adalah masalah klinis

yang biasa dihadapi oleh dokter yang menangani cedera traumatis,
pasien bedah, dan pasien obstetri. Ada banyak istilah yang digunakan
untuk menggambarkan masalah yang mengancam jiwa ini, termasuk
koagulopati transfusi masif atau koagulopati yang diinduksi oleh trauma.
Koagulopati kompleks yang terjadi dalam situasi ini lebih lanjut
mengkompromikan kemanjuran pengobatan hemostatik selanjutnya.
Cedera jaringan akibat trauma, intervensi bedah, setelah melahirkan
pada pasien kebidanan, atau terkait dengan sirkulasi ekstrakorporeal
selama bypass kardiopulmoner atau oksigenasi membran ekstrakorporeal
juga dapat berkontribusi pada keadaan koagulopati.
Hemostasis adalah respons fisiologis terhadap cedera vaskular dan
gangguan endotelium vaskular dan telah dijelaskan pada bab-bab
sebelumnya. Setelah pembedahan atau trauma di mana ada cedera
jaringan yang luas, selain kehilangan banyak darah, integritas endotel
terganggu; koagulopati yang mengikuti cedera jaringan dan kehilangan
darah menghasilkan perubahan kompleks pada pembuluh darah yang
sering digambarkan sebagai endotelialopati. Kehilangan aspek kritis
regulasi vaskular juga dapat bermanifestasi sebagai koagulasi
intravaskular diseminata (DIC), suatu gangguan keseimbangan antara
efek antikoagulan dan prokoagulan.
Manajemen hemostasis setelah cedera traumatis dan perdarahan yang
mengancam jiwa telah berubah secara signifikan selama bertahun-tahun
dari resusitasi awal dengan kristaloid / koloid dan sel darah merah (sel
darah merah) ke pemberian rutin plasma / fresh frozen plasma (FFP) dan
trombosit di samping sel merah. Pengalaman yang dipelajari dari medan
perang dan studi sipil sangat penting untuk mengembangkan beberapa
pendekatan terapi yang telah digabungkan dalam protokol transfusi masif
yang rasional. Studi retrospektif telah melaporkan peningkatan
kelangsungan hidup dengan penggunaan awal plasma dan trombosit
sebagai bagian dari protokol ini. Bab ini akan mengulas fisiologi transfusi
masif dan pendekatan terapi modern.

Patofisiologi Kelainan Hemostatik Terkait dengan Trauma

Perdarahan adalah penyebab utama kematian setelah cedera traumatis
dan bertanggung jawab atas sekitar 50% kematian dalam 24 jam cedera
dan sekitar 80% kematian akibat trauma intraoperatif.1 Evolusi resusitasi
cairan awalnya termasuk kristaloid, diikuti oleh transfusi RBC, dan
penambahan FFP / plasma, trombosit, dan cryoprecipitate baik secara
empiris atau sebagai dipandu oleh pengujian laboratorium tambahan.
Terapi di masa lalu didasarkan pada pengobatan koagulopati setelah
resusitasi awal dan stabilisasi pasien. Pengamatan yang lebih baru pada
korban trauma dan di medan perang menemukan bahwa pemberian
plasma dini menghasilkan peningkatan lebih awal, sedangkan beberapa
penelitian melaporkan bahwa penggunaan volume kristaloid yang besar
dikaitkan dengan peningkatan perdarahan dan kelangsungan hidup yang
lebih rendah.
2 P a rt V • B lo o d a n d H e m o s ta s is

Disfungsi Trauma dan Endotel

Efek syok hemoragik pada fungsi endotel telah dijelaskan dan istilah
endotelium trauma telah diusulkan untuk menggambarkan cedera dan
disfungsi endotel sistemik yang berkontribusi terhadap koagulopati,
peradangan, permeabilitas pembuluh darah, edema jaringan, dan
disfungsi sistem multiorgan. disfungsi endotel adalah sekunder dari
cedera vaskular dan faktor-faktor lain yang dihasilkan dari syok, cedera
iskemik, dan pelepasan mediator inflamasi. Replesi plasma dianggap
memiliki fungsi restoratif pada persimpangan ketat endotelial untuk
memodulasi integritas vaskular yang lebih baik dibandingkan dengan
kristaloid yang mempelajari model in vitro. Plasma mengandung
beberapa serine protease inhibitor yang mungkin memiliki efek
antiinflamasi. Endotelium menjadi permeabel dengan syok hemoragik dan
cairan ekstravaskuler dimobilisasi secara intravaskular. Plasma
mengandung protein untuk pemeliharaan osmotik tetapi ada juga
beberapa serine protease inhibitor yang meliputi antitrombin (juga
disebut antitrombin III), penghambat esterase C1, penghambat jalur
faktor jaringan (TFPI), penghambat aktivator plasminogen-1 (PAI-1), 2-
antiplasmin, dan inhibitor lain yang mungkin penting untuk respons
antiinflamasi. Kristaloid tidak memiliki faktor-faktor ini dan dianggap
meningkatkan edema interstitial, meningkatkan cedera paru-paru, dan
meningkatkan disfungsi sistem multiorgan.
Aktivasi inflamasi setelah cedera jaringan berkontribusi pada
disfungsi endotel seperti halnya peran penting fibrinolisis. Dengan cedera
jaringan, sistem fibrinolitik diaktifkan mengubah plasminogen menjadi
plasmin, enzim kritis yang membelah fibrin. Plasmin dan generasinya
dihambat oleh PAI-1, oleh inhibitor fibrinolisis yang diaktifkan trombin
(TAFI), dan oleh 2-antiplasmin. Oleh karena itu, fibrinolisis diatur oleh
beberapa inhibitor protease serin yang bersirkulasi dalam kondisi
fisiologis yang dapat dihabiskan dengan perdarahan masif. Sebagai hasil
dari aktivasi patologis ini, terapi antifibrinolitik adalah komponen penting
dari pendekatan ultimodal, yang keberhasilannya telah dilaporkan pada
beberapa populasi pasien yang menjalani operasi. Selain berkontribusi
pada diatesis perdarahan, generasi plasmin menyebabkan banyak efek
lain, termasuk pensinyalan sel, respons proinflamasi, dan aktivasi kaskade
komplemen.

Transfusi Besar-besaran
Transfusi masif didefinisikan sebagai lebih besar dari 10 unit sel
darah merah dalam waktu 24 jam setelah memulai pengobatan dan
terjadi pada sekitar 10% dari trauma militer dan sekitar 5% dari pasien
trauma sipil.1,2 Pasien yang berdarah akut dan menerima lebih dari 10 u
nits sel darah merah dalam waktu 6 jam dari trauma memiliki angka
kematian yang lebih tinggi. Namun, transfusi masif itu sendiri
kemungkinan merupakan penanda untuk cedera yang lebih parah
daripada efek langsung dari transfusi. Pengembangan strategi transfusi
masif dan penggunaan protokol spesifik meningkatkan kelangsungan
hidup dan telah menjadi evolusi penting dalam pengelolaan pasien
trauma, cedera masa perang, dan bahkan perdarahan besar di rumah
 C h a p te r 3 1 • P h y s io lo g y a n d M a n a g e m e n t o f M a s s iv e Tra n s fu s io n 3

sakit yang terjadi setelah pendarahan postpartum atau perdarahan bedah

masif.

Pendekatan Terapi untuk Transfusi Masif dan Koagulopati

Layanan transfusi, bankir darah, dokter, dan rumah sakit telah
mengembangkan dan menerapkan protokol untuk secara cepat
menyediakan produk darah bagi pasien yang menderita perdarahan akut
dan masif. Studi pengamatan dan analisis retrospektif dari trauma militer
dan sipil awalnya melaporkan hasil yang lebih baik dengan pemberian
seluruh darah atau setara darah lengkap dengan transfusi masif yang
mencakup rasio transfusi 1: 1: 1 atau RBC, plasma, dan trombosit. , ada
juga data yang saling bertentangan yang menunjukkan peningkatan
morbiditas dan mortalitas terkait dengan transfusi produk plasma. Studi
baru-baru ini mengevaluasi rasio plasma kritis dalam trauma dan akan
dibahas secara lebih rinci di bab ini.5

Dampak Buruk Transfusi

Semua transfusi memiliki risiko dan kekhawatiran tertentu tentang
plasma adalah penting. Risiko utama yang mengancam jiwa dari
pemberian plasma termasuk cedera paru akut terkait transfusi,
kelebihan sirkulasi yang berhubungan dengan transfusi, reaksi transfusi
hemolitik, dan anafilaksis (fenomena ini telah dibahas dalam bab
sebelumnya, Bab 28, Produk Darah dan Komponen Darah. Menguraikan
penyebab hasil yang merugikan setelah transfusi dapat menjadi sulit
karena pasien yang lebih kritis yang memiliki hasil yang lebih buruk juga
akan memerlukan lebih banyak transfusi, dan alasan yang mendasari
perlunya transfusi akan selalu mengaburkan setiap interpretasi dari hasil
klinis.

Perubahan Hemostatik Terkait dengan Koagulopati Transfusi

Masif
Abnormalitas hemostatik setelah transfusi masif dan / atau trauma
dapat terjadi sebagai akibat dari beberapa faktor yang tidak secara
langsung berhubungan dengan pemberian darah. Seiring dengan
koagulopati, hipotermia dan asidosis melengkapi triad yang
menghasilkan kematian yang lebih tinggi dalam pengelolaan trauma
akut. Faktor-faktor ini dapat memainkan peran dalam penipisan lokal
atau penurunan fungsi faktor hemostatik melalui kehilangan darah,
cedera jaringan, dan / atau konsumsi faktor. Volume resusitasi dengan
kristaloid, koloid, dan sel darah merah atau penggunaan sistem
penyelamatan sel setelah kehilangan darah dapat menyebabkan
koagulopati dilusional. Keseimbangan hemostatik antara aktivitas
antikoagulan dan prokoagulan dapat hilang karena cedera jaringan
setelah trauma (termasuk trauma kepala), hipoksia / asidosis jaringan,
luka bakar / sepsis, atau kejadian fisik lainnya terutama dalam keadaan
intraoperatif dari pengisapan dan pemasukan kembali serpihan.
Hipotermia bisa menjadi faktor penting yang mengendapkan atau
memperburuk koagulopati, karena kaskade enzimatik terganggu;
4 P a rt V • B lo o d a n d H e m o s ta s is

gangguan ini dapat muncul mulai bahkan pada penurunan kecil pada
suhu tubuh inti, bahkan setinggi 35 ° C. Fungsi trombosit juga dapat
terganggu dengan hipotermia, dan disfungsi trombosit juga dapat terjadi
karena peningkatan produk degradasi fibrinogen (FDP) dan kadar D-
dimer. Pertimbangan penting lainnya termasuk faktor yang berhubungan
dengan anemia, yaitu penurunan RBC adenosine difosfat dan penurunan
difusivitas trombosit; dan efek asidemia, yang mungkin termasuk
hipokalsemia dengan transfusi masif.

Perubahan Hemostatik Perioperatif

Trauma dan pasien bedah memiliki berbagai tingkat cedera vaskular dan
exsanguination. Kehilangan darah hingga 30% dari total volume darah
umumnya dapat ditoleransi dengan baik dengan resusitasi cairan saja.
Faktor-faktor koagulasi secara progresif terdilusi menjadi 30% dari normal
setelah kehilangan satu volume darah, dan turun hingga 15% setelah
kehilangan dua volume darah. Dengan hemodilusi berat, pembentukan
trombin, langkah penting dalam pembentukan bekuan terganggu oleh
reduksi. di tingkat prokoagulan. Generasi trombin juga terganggu oleh
trombositopenia. Selain itu, fibrinogen dan faktor XIII, substrat kritis untuk
pembentukan bekuan darah juga berkurang tanpa penggantian faktor
yang tepat selama resusitasi volume. Meskipun gumpalan dapat
terbentuk, kadar fibrinogen dan / atau faktor XIII yang rendah akan
mengakibatkan berkurangnya kekuatan gumpalan, sebuah temuan yang
sering dipantau dengan pemantauan darah viskoelastik menggunakan
tromboelastografi atau tromboelastometri. Kadar protein pembekuan
yang rendah memengaruhi kemampuan fibrin untuk berpolimerisasi

Koagulopati Transfusi Masif

Because standard laboratory tests oft en take too long to obtain, and with
severe hemorrhage, several blood volumes may be replaced by the time
the results are available, laboratory testing plays an uncertain role in
decision making in many settings where massive transfusion is necessary.
Thus, transfusion protocols have been developed where fi ed doses of FFP
and platelets are administered after a specific number of RBC units have
been given, often in a 1:1:1 ratio. 6 Whether these fi ed ratios prevent the
development of coagulopathy or improve bleeding is not well established
in cardiac surgery, but in trauma patients and in noncardiac surgical
battlefield conditions, there is growing data that fi ed ratios improve
survival.7,8
With life-threatening hemorrhage, as seen in trauma patients, transfusion
of fi ed ratios of RBCs, FFP, and platelets should be administered. 6
Transfusion with fi ed plasma/FFP:platelet:RBC ratios report a survival
benefit. As a result, the Army Surgeon General established a clinical policy
of 1:1:1 (plasma/FFP:platelets:RBCs) for combat casualties expected to
receive massive transfusion. One large study of civilian massive
transfusion patients demonstrated improved survival with increased use
of platelets.8 Th e current U.S. military resuscitation practice is to use a
balanced approach, using 1:1:1 as the primary resuscitation fluid for the
most seriously injured casualties (http://
www.cs.amedd.army.mil/borden/book/ccc/UCLAchp4 .pdf). Current studies
 C h a p te r 3 1 • P h y s io lo g y a n d M a n a g e m e n t o f M a s s iv e Tra n s fu s io n 5

are underway to determine what the optimal ratios should be in a variety

of clinical settings.

R o le o f R e d B lo o d C e lls a n d A n e m ia
Anemia may also contribute to bleeding as reported in nonsurgical
patients due to multiple mechanisms that include nitric oxide scavenging,
margination of platelets, and contributions to the hemostatic processes,
although the ideal hematocrit to minimize this risk is not clear. RBC
transfusions are administered for multiple reasons and they are
increasingly recognized for their critical role in hemostasis. RBCs can
release adenosine diphosphate, an important activator of platelets.
Platelets also contribute a s urface for clot initiation by facilitating
thrombin generation.6 Studies suggest that the FXIII activation and fibrin
cross-linking may play an important an important role in mediating RBC
retention within clots.

C a u s e s o f B le e d in g in t h e S e t t in g o f M a s s iv e Tra n s f u s io n C o a g u lo p a t
hy
Risk factors for developing massive transfusion coagulopathy are oft en
related to the surgical or traumatic injury that causes the hemorrhage.
Patients should be evaluated for use of additional medications that can
affect coagulation, including antiplatelet agents (clopidogrel, prasugrel,
ticagrelor), anticoagulation agents (dabigatran, rivaroxaban, apixaban,
warfarin), or parenteral agents such as lowmolecular-weight heparin. 9
Monitoring these agents has been reviewed in other chapters. Many of the
standard coagulation tests used for evaluating hemorrhage cannot
adequately determine the effects of antiplatelet agents (e.g., aspirin,
clopidogrel, prasugrel, or ticagrelor) as the complex platelet function tests
used clinically are usually ineffective with significant bleeding.

Hypothermia, Acidosis, and C o a g u lo p a t h y

Hypothermia has multiple effects because coagulation is an enzymatic
process. As patient temperature decreases, the enzymatic processes that
function maximally at normal body temperature are impaired.
Hypothermia can produce multiple hemostatic defects that include
reversible platelet dysfunction and increased fibrinolysis. 10 In addition,
prothrombin time (PT) and activated partial thromboplastin time (aPTT)
are prolonged at temperatures of 34°C or less when compared with
measurements at 37°C.10 When blood is sampled from a hypothermic
patient, the test is actually conducted at 37°C, so the influence of
hypothermia on coagulopathy and bleeding may not be readily
appreciated by clinicians. Overall, hypothermia is an important
contributing factor to the bleeding defect in coagulopathy in trauma
patients and is part of the lethal triad defined as hypothermia, acidosis,
and coagulopathy. Hypothermia and acidosis can also prevent thrombin
generation, a critical component of clot formation. Hypothermia is thought
to inhibit the initiation phase, whereas acidosis severely inhibits the
propagation phase of thrombin generation. 11 Maintenance of
normothermia is important as part of a multimodal therapeutic plan for
minimizing blood loss with significant hemorrhage in trauma, surgery, or
coagulopathy of any cause. In a perioperative setting, blood warmers and
other warming devices should be used to prevent and treat hypothermia.
6 P a rt V • B lo o d a n d H e m o s ta s is

D ilu t io n a l C o a g u lo p a t h y
Before the development of massive transfusion protocols, dilutional
coagulopathy was a common cause of bleeding in the actively
hemorrhaging patient. Bleeding and coagulopathy associated with
massive transfusions in 21 acutely traumatized soldiers that occurred aft
er transfusion of 20 to 25 units of stored whole blood was described. 12 In
this report, dilutional thrombocytopenia was a primary cause of the
bleeding and was thought to be due to decreased platelet levels in stored
blood. Transfusion of approximately 15 to 20 units caused significant
dilution of blood volumes, and critical decreases in platelet count to
approximately 20,000 to 30,000/mm3, far below the recommended
platelet target goals in actively bleeding patients.12

F ib r in o ly s is
Fibrinolysis is a cr itical component of preventing excessive clot formation
and balances for hemostasis but excessive fibrinolysis as occurs
commonly in trauma patients can cause bleeding. Fibrinolysis is initiated
by mechanisms that include stimulating tissue plasminogen activator
(tPA) release in response to vascular endothelial damage, stress
responses, and other mechanisms.4 Plasmin degrades fibrinogen and von
Willebrand’s factor (vWF), cleaves receptors from platelets (glycoprotein
Ib), and creates degradation products that bind glycoprotein IIb/IIIa
receptors, thus interfering with platelet function. Contact activation
associated with tissue injury and hemostatic activation also activates
kallikrein that initiates plasmin generation but also is involved in other
proinflammatory steps including neutrophil chemotaxis and
chemokinesis.4 Contact activation leads to the cleaving of glycoprotein Ib
receptors from platelets, and generation of FDP resulted in the creation of
multimers that bind with glycoprotein IIb/IIIa receptors to prevent
platelet– fibrinogen cross-linking, similar to the effects of the glycoprotein
IIb/IIIa receptor inhibitor, abciximab.13 Th se alterations in fibrinolysis
adversely affect platelet function.

H y p o fi b r in o g e n e m ia
Fibrinogen is a critical component in clot formation and an acute-phase
reactant protein. Fibrinogen circulates in the highest concentration of all
of the coagulation factors, and normal values for plasma levels are
approximately 200 to 400 mg/dL but increase in pregnancy and as a
nonspecific anabolic postoperative response following tissue injury. 14 In
the late stages of pregnancy, the normal physiologic response is
hypercoagulability to reduce the risk of bleeding complications during
birth. Although benign dilutional thrombocytopenia oft en develops, with a
platelet count of 80,000 to 150,000/mm3, fibrinogen levels increase to
approximately 400 to 600 mg/dL. During delivery, a systemic hemostatic
state develops with consumption of platelets and coagulation factors
(including fibrinogen) to allow clotting to occur; hemostasis then
normalizes within 4 to 6 weeks postpartum.14
If fibrinogen levels fall to approximately 80 to 100 mg/ dL, standard clot-
based coagulation tests including PT and partial thromboplastin time
 C h a p te r 3 1 • P h y s io lo g y a n d M a n a g e m e n t o f M a s s iv e Tra n s fu s io n 7

(PTT) can be affected. Th ese changes may not be corrected by

transfusion of FFP/plasma; however, cryoprecipitate is used or fibrinogen
concentrates in countries that do not have cryoprecipitate (see earlier
chapters on blood and hemostasis). Older transfusion algorithms only
recommend initiating treatment when fibrinogen levels are less than 100
mg/ dL and it may be difficult to reverse the effects of such low levels of
this vital component of hemostatic function. European guidelines have
focused on the role of normal fibrinogen levels in the bleeding patient,
and recent studies also support the potential blood-sparing effects of
fibrinogen concentrates .14

M o n it o r in g H e m o s t a s is d u r in g M a s s iv e Tra n s f u s
io n
PT and aPTT are oft en used for monitoring coagulopathy during massive
transfusion. Th e PT is considered proportional to coagulation factor loss
and/or hemodilution but other factors may also be responsible. Th ese
standard coagulation tests have limitations for evaluating bleeding
because of the multiple coagulation defects that occur. Standard plasma-
based coagulation tests also do not provide information about platelet
function or interactions with coagulation factors and can be prolonged
even with normal clotting factor levels due to protein C deficiency. As a
result, other coagulation tests are being used more and more for
managing massive transfusions.
Whole blood viscoelastic measurements continue to expand for
management of trauma, perioperative bleeding, and massive transfusion
coagulopathy and include either thromboelastography (TEG; Hemonetics
Corporation, Braintree, MA) or thromboelastometry (ROTEM; TEM
International, Cary, NC). Some of the advantages of using these systems
include the ability to rapidly have information for the diagnosis and
management of coagulopathy and also provide methods for algorithm-
and goaldirected management. Th romboelastometry provides
information about clot formation and fibrin polymerization and its use
has been reported for evaluating abnormal trauma-induced
coagulopathy.6 Th e clot strength as determined by maximal amplitude
on TEG and maximal clot firmness on ROTEM is influenced by fibrinogen
levels but also by platelet contributions to the clot. In addition, using the
ROTEM FIBTEM assay, systemic fibrinogen levels can be rapidly
determined. Th e role of these advanced tests during massive
transfusion continues to evolve as therapeutic strategies for transfusion
and treatment algorithms are developed. In European countries where
cryoprecipitate may not be available, these assays are used as
therapeutic guides f or both fi brinogen concentrate and prothrombin
complex concentrate administration.6

Tre a t m e n t o f C o a g u lo p a t h y d u r in g M a s s iv e Tra n
s f u s io n
A fl w chart and example for the activation and institution of a m assive
transfusion protocol are shown in Figures 31-1 a nd 31-2. S pecific
considerations for the management have been discussed and are also
8 P a rt V • B lo o d a n d H e m o s ta s is

included in the following perspectives regarding individual component

therapy.

P la s m a /F re s h F ro z e n P la s m a
Overall, developing massive transfusion protocols has been an important
therapeutic tool for eff ectively managing life-threatening hemorrhage aft
er trauma.15 Plasma/ FFP contains multiple factors for hemostasis and has
increasingly been considered a cr itical component. Most of the analyses
reporting benefic al eff ects of high plasma ratios are retrospective and
include plasma/FFP transfusion:RBC ratios of 1:1 or more from trauma. Th
e optimal ratio of plasma/FFP:RBCs is not known, but prospective studies
including a current investigation from the North American Pragmatic,
Randomized Optimal Platelets and Plasma Ratios study (ClinicalTrials.gov
number, NCT01545232) will provide new information. Th s randomized
trial from 12 diff erent medical centers will evaluate outcomes from
trauma patients who will require massive transfusions as defi ed by the
administration of more than 10 units of RBCs within 24 hours and will
assess overall mortality. Th ere are major diff erences in the management
of severe hemorrhage between the United States and Europe. Based on
currently published European guidelines, clinicians are now using factor
concentrates based on thromboelastometry (ROTEM) guidance, with
prothrombin complex concentrates, fi brinogen, and factor XIII. Fibrinogen
and other factor concentrates have been used for many years in Europe,
as cryoprecipitate is not available in all countries. However, therapy is
multimodal
Massive transfusion protocol (MTP) template
The information below, developed by consensus, broadly covers areas that should be
included in a local MTP. This template can be used to develop an MTP to meet the needs
of the local institution's patient population and resources

Senior clinician determines that patient meets criteria for MTP activation OPTIMIZE:

•• cardiac output oxygenation

Baseline: • tissue perfusion • metabolic state

Full blood count, coagulation screen (PT, INR, APTT, fibrinogen),
biochemistry, arterial blood gases

MONITOR
Notify transfusion laboratory (insert contact no.) to: ( every 30–60 mins):
‘Activate MTP’ • full blood count

• coagulation screen • ionized calcium

• arterial blood gases

Laboratory staff Senior clinician • Request:a

• Notify hematologist/transfusion specialist o 4 units RBC AIM FOR:

 C h a p te r 3 1 • P h y s io lo g y a n d M a n a g e m e n t o f M a s s iv e Tra n s fu s io n 9

• Prepare and issue blood components o 2 units FFP • temperature > 350C as requested •

Consider:a • pH > 7.2

• Anticipate repeat testing and o 1 adult therapeutic dose platelets

blood component requirements o tranexamic acid in trauma patients • base excess < –6
• Minimize test turnaround times • Include:a • lactate < 4 mmol/L

• Consider staff resources a Or locally agreed configuration o cryoprecipitate if fibrinogen < 1 g/L • Ca
• platelets > 50 2+ > 1.1 mmol/L × 109/L

Hematologist/transfusion
specialist • PT/APTT < 1.5 × normal

• Liaise regularly with laboratory • INR ≤ 1.5 • fibrinogen > 1.0 g/L and clinical
team Bleeding controlled?

• Assist in interpretation of results, and

advise on blood component support YES NO

Notify transfusion laboratory to:
‘Cease MTP’

FIGURE 31-1 Massive transfusion protocol (MTP) template. (From

http://www.blood.gov.au/pubs/pbm/module1/transfusion .html, with permission. Accessed S eptember 12,
2014.

Suggested criteria for activation of MTP

• Actual or anticipated 4 units RBC in < 4 hrs, + hemodynamically unstable, +/– anticipated ongoing
bleeding
• Severe thoracic, abdominal, pelvic or multiple long bone trauma

• Major obstetric, gastrointestinal or surgical bleeding

Initial management of bleeding Resuscitation

• Identify cause • Avoid • Avoid excessive crystalloid hypothermia, institute active warming •

Initial measures: • Tolerate permissive hypotension (BP 80–100 mmHg systolic)

- compression

- tourniquet • Do until active bleeding controlled not use hemoglobin alone as a transfusion
trigger

- packing
• Surgical assessment:
- early surgery or angiography to stop bleeding
10 P a rt V • B lo o d a n d H e m o s ta s is

Special clinical situations

Specific surgical considerations • Warfarin: • add vitamin K, prothrombin

complex concentrates/FFP • If significant physiological derangement, consider • Obstetric

hemorrhage:

damage control surgery or angiography • early DIC often present; consider cryoprecipitate

• Head injury:

Cell salvage • aim for platelet • permissive hypotension contraindicated count > 100 × 109/L

• Consider use of cell salvage where appropriate

Dosage Considerations for use of rFVIIab

The routine use of rFVIIa in trauma patients is not recommended due to
Platelet count < 50 x 109/L 1 adult therapeutic dose its lack of effect on mortality (Grade B) and variable
effect on morbidity
INR > 1.5 FFP 15 mL/kga (Grade C). Institutions may choose to develop a process for the use of
rFVIIa where there is:
Fibrinogen < 1.0 g/L cryoprecipitate 3–4 ga • uncontrolled • failed surgical or radiological measures
to control bleeding, hemorrhage in salvageable patient, and and

Tranexamic acid loading dose 1 g over 10 • adequate blood component replacement, 0 and
min, then infusion of 1 g over 8 hrs • pH > 7.2, temperature > 34 C.
Discuss dose with hematologist/transfusion specialist a Local transfusion laboratory to advise on number of
units needed to provide this dose b rFVIIa is not licensed for use in this situation; all use must be part of practice review.
ABG arterial blood gas FF fresh frozen APTT activated partial
INR international normalised ratio P plasma blood MTP thromboplastin time
BP pressure massive transfusion
protocol
DIC disseminated intravascular PT prothrombin time FBC full blood count
coagulation
RBC red blood cell rFVlla activated recombinant factor
VII

FIGURE 31-2 S uggested criteria for activation of massive transfusion protocol (MTP) template. (From
http://www.blood.gov.au/ pubs/pbm/module1/transfusion.html, with permission. Accessed S eptember 12,
2014.

and requires hemodynamic and hemostatic support as well as eff orts to

address the underlying bleeding source. An example of a massive
transfusion protocol is shown in Figure 31-1.6

P la t e le t A d m in is t ra t io n
Following traumatic injury or signifi ant postoperative bleeding, the critical
platelet count for transfusion is oft en based on consensus therapy rather
than true objective data. Although a count of 50,000 or more is
recommended, the threshold for administration of platelets, especially in
cases of dilutional coagulopathy, remains unclear as do the ideal ratio of
platelets to other blood components. Most protocols attempt to develop a
strategy that mimics whole blood replacement with RBC:plasma/FFP:
platelets at a 1:1:1 ratio with massive bleeding.13,14
 C h a p te r 3 1 • P h y s io lo g y a n d M a n a g e m e n t o f M a s s iv e Tra n s fu s io n
11

However, assessing platelet function in the bleeding patient is not

possible; therefore, empiric platelet administration is oft en undertaken. If
patients have received antiplatelet agents recently, then even the
existing platelets and platelet counts may not be helpful. Th erefore, if
patients have received antiplatelet agents or are bleeding aft er
separation from cardiopulmonary bypass, then platelet dysfunction should
be suspected and platelet concentrates considered. However, there are
signifi ant potential adverse events associated with platelet
administration.6

A n t ifi b r in o ly t ic A g e n t s
Because of the critical role of fi brinolysis with severe bleeding and
trauma, the antifi brinolytic agent tranexamic acid is increasingly used
as a t herapeutic strategy. Inhibiting fi brinolysis during acute bleeding
has many benefic al effects including preserving initial clot formation at
a bleeding site that may otherwise be broken down, similar to the clot
destruction seen in hemophilia.6 Th e Clinical Randomization of an Antifi
brinolytic in S ignifi ant Hemorrhage (CRASH 2) study focused on
tranexamic acid as a therapeutic agent in traumatic injury in a p
rospective randomized placebo-controlled trial of 1-g loading followed by
1 g over 8 hours in 20,211 trauma patients. Overall mortality was
reduced from 14.5% to 16.0% (relative risk, 0.91; P 5 0.0035), as were
deaths due to bleeding (4.9% vs. 5.7%; relative risk,
0.85; P 5 0.0077). Tranexamic acid is also approved in the United States
for excessive menstrual bleeding at a dose of 1.3 g three times a day (  4
g total dose), without significant reported safety issues. Despite the
efficacy and safety of tranexamic acid, clinicians oft en substitute epsilon-
aminocaproic acid, another lysine analog, although this agent has not
been studied as well as tranexamic acid and is not available in some
European countries.

P ro c o a g u la n t s
Multiple other agents have been used or studied in trauma and massive
transfusion coagulopathy, including recombinant activated factor VII and
prothrombin complex concentrates. Th e off- abel use of many of these
agents to increase clot formation following major surgery and or traumatic
injury is a reasonable but empiric approach for treating life-threatening
bleeding and oft en used as a “last-ditch effort” in patients with ongoing
bleeding and at risk for death or other adverse events. When clinicians
are presented with a patient who continues to bleed despite standard
therapeutic interventions, they have two choices. Th ey can either
continue to give their standard interventions (that have already failed to
work) or administer a procoagulant such as recombinant activated factor
VII and prothrombin complex concentrates. Clinicians are justified in
choosing a procoagulant plan of action for several reasons. 16 First, it is
clinically evident that patients with massive refractory bleeding will have
adverse outcomes unless the blood loss is controlled in a timely manner.
Second, persisting with standard interventions will likely not achieve this
goal and will unnecessarily expose patients to the risks of excessive blood
product administration. Th rd, the efficacy and safety data from most
randomized trials are not applicable to these situations because patients
with refractory bleeding were not studied. Fourth, even if the safety data
12 P a rt V • B lo o d a n d H e m o s ta s is

from randomized trials do apply, which all suggest that procoagulants by

virtue of their effects increase the risk of thromboembolic complications,
this risk is relative to that of allowing bleeding and exsanguination to
occur. Fift h, observational data from Europe and some randomized trial
data in bleeding patients suggests that use of procoagulant therapy and
concentrates is effective for refractory blood loss using factor concentrate
driven algorithms. Finally, given the ethical implications and impracticality
of such trials, it is unlikely that additional applicable data from placebo-
controlled randomized trials to evaluate life-threatening hemorrhage will
ever be performed.

PostpartumHemorrhage

Postpartum hemorrhage is an important cause of lifethreatening

hemorrhage and continues to be a m ajor cause of maternal mortality. 17 A
recent published report from an international expert panel in obstetrics,
gynecology, anesthesiology, hematology, and transfusion medicine
performed a c omprehensive literature review to identify patients at high
risk of adverse outcomes.17 Th ey defi ed severe persistent postpartum
hemorrhage as
“active bleeding greater than 1,000 mL w ithin the 24 hours following
birth that continues despite the use of initial measures including fi st-line
uterotonic agents and uterine massage.” As in all life-threatening
bleeding, a treatment algorithm that includes a massive transfusion
protocol is important. Th e group suggested coagulation testing should be
performed to guide therapy. If initial therapy fails to stop bleeding and
uterine atony persists, second- and third-line interventions, including
mechanical or surgical maneuvers, that is, intrauterine balloon
tamponade or hemostatic brace sutures with hysterectomy are the final
surgical option for uncontrollable bleeding. 17 Pharmacologic options
include hemostatic agents, including tranexamic acid along with a
massive transfusion protocol for blood product administration are also
critical to minimize blood loss and optimize clinical outcomes in
management of women with severe, persistent postpartum hemorrhage.17

M u lt im o d a l R e s u s c it a t io n :
D a m a g e C o n t ro l R e s u s c it a t io n
Managing life-threatening and uncontrolled bleeding is a clinical problem
that can occur following traumatic injury, during major surgical
procedures, and following delivery. From information learned from combat
and battlefield casualties, a m ultimodal and multispecialty approach has
evolved that includes perspectives from surgeons, anesthesiologists,
emergency medicine physicians, and transfusion medicine specialists for
the optimal resuscitative approach to hemorrhagic shock. 1,10,18 Clinicians
and investigators from multiple specialties have coined the term damage
control resuscitation, a multimodal strategy.19 Th is concept calls for
(a) early and increased use of plasma, platelets, and RBCs while
 C h a p te r 3 1 • P h y s io lo g y a n d M a n a g e m e n t o f M a s s iv e Tra n s fu s io n
13

minimizing crystalloid use; (b) hypotensive resuscitation strategies; (c)

avoiding hypothermia and acidosis that may compound coagulopathy; (d)
use of adjuncts such as calcium, THAM (trishydroxymethyl
aminomethane, an alternate alkalizing agent to sodium bicarbonate), and
tranexamic acid and off- abel uses of procoagulation agents; and (d) early
definitive hemorrhage control.19

Summary

Coagulopathy associated with massive transfusion is a complex,

multifactorial clinical problem. When evaluating the causes of
coagulopathy in this setting, preexisting pharmacotherapy including prior
use of anticoagulants must be considered. Th e role of hypothermia,
dilutional coagulopathy, platelet dysfunction and fibrinolysis should also
be considered. Evaluating fibrinogen levels represents a critical aspect of
all transfusion algorithms, especially for patients with massive transfusion
and life-threatening hemorrhage. Transfusion algorithms are a cr itical and
relatively new aspect of perioperative management; they attempt to
provide adequate factor and hemostatic replacement, although the ideal
ratio of various blood components and factor concentrates are still being
determined. Significant changes in management have become important
in resuscitation strategies and crystalloids are no longer a primary means
of resuscitation; the primary strategy now is replacing acute blood loss
with plasma and platelet-containing products instead of early and large
amounts of crystalloids and RBCs.1 Templates for a massive transfusion
protocol and activation of a massive transfusion protocol are included in
Figures 31-1 and 31-2. Several excellent reviews are available for
additional reading on this subject.1,2,6,18