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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5524_Библиотеки_им_академика_М_И_Перельмана.pdf
378 E. Gonzalez and E. E. Moore
Red blood cells
Ö As a general consensus, it is recommended that a hemoglobin level
above 10 g/dl (Hct >30%) be maintained in patients with active
hemorrhage.
Hemostatic blood products (plasma, cryoprecipitate, and platelets)
should be transfused as indicated by a massive transfusion protocol
(MTP) or by a VHA, and in their absence based on the individual
parameters described below.
Plasma
Ö Hemostasis can be achieved when the coagulation factor activity
is at least 30% of normal; this can be achieved with administration
of a 15 mL/kg dose of plasma. Repeated or higher doses may be
needed in patients with ongoing hemorrhage.
Ö By traditional tests and practice, and in the absence of VHA, in a
patient with active hemorrhage, plasma is transfused to maintain
an INR<1.5 and PTT<45 seconds.
Ö Plasma transfusion is more effective in correcting significant INR
elevations (>2.0) and less effective with moderate elevation; the
INR of donor plasma ranges between 1.0 and 1.3.
Ö Available data do not support the efficacy of FFP as prophylaxis
for invasive procedures or surgery in patients with an INR < 1.9.
Intracranial, spinal, and ophthalmologic surgery or procedures are excep-
tions in which correction of coagulation parameters to a normal level may
be warranted.
Ö Plasma transfusions in patients with severe liver failure are only
effective for several hours because of the short half-life of factor
VII (4–6h).
Ö Half-life (hours) of coagulation factors in plasma after transfusion:
Fibrinogen (96h), II (60h), V (24h), VII (4-6h), VIII (10h), IX
(22h), X (35h), XI (60h), XIII (144h), vWF (10h). All factors are
stable in vitro except V and VIII, which are labile.
Cryoprecipitate
Ö A fibrinogen level >150 mg/dL (>1.5g/L) should be maintained
during active hemorrhage.
Platelets (transfusion thresholds)
Ö <100,000/mcl: active hemorrhage, severe or multi-system trauma, TBI,
intracranial hemorrhage, major surgery, or neurosurgical procedures.
Diagnosis and Management of Coagulopathy 379
Ö <50,000/mcl: minor surgery or interventional procedures.
Ö <10,000/mcl: non- bleeding patients (spontaneous bleeding rarely
occurs with platelets >10,000/mcl).
Massive transfusion protocols (MTP) (Fig. 6)
MTP allow for immediate processing of blood products by the blood
bank and their systematic delivery to the patient’s bedside. They create uniform treatment strategies to be easily followed by all medical
providers across all disciplines.
MTP’s are either based on fixed plasma:RBC, cryoprecipitate:RBC,
and/or PLT:RBC ratios agreed upon an institution, or goal directed by
traditional coagulation assays or VHA.
MTP activation criteria, their method of coagulation assessment (tra-
ditional coagulation tests vs. VHA), and their blood product ratio vary
widely between institutions.
Studies have demonstrated a survival benefit with a RBC:FFP ratio
between 1:1 and 1:2. However, it remains unclear at which specific
ratio within this range does administration of higher plasma ratios
become no longer beneficial.
Ö These studies have been criticized, particularly for methodological
flaws that include survival bias (e.g., patients who did not survive
were not transfused with plasma, and hence survivors had a higher
plasma to RBC ratio) and heterogeneity between studies.
While the optimal ratio remains a matter of debate, and randomized
clinical trials are in progress, the majority of the data supports a 1:2
ratio.
Ö Achieving this ratio requires early transfusion of plasma.
Ö It appears that the benefit from a 1:2 or 1:1 ratio is not necessarily
the ratio of blood products given per-se, but the fact that plasma is
being transfused earlier.
This increased use of plasma is not risk-free, since the incidence of
transfusion-related acute lung injury is increased, as may be the risk
of the acute respiratory distress syndrome and transfusion related
circulatory overload (TACO).
Liberal criteria for activation of MTP, or lack of re-assessment of
these patients’ hemodynamic and hemostatic status, may lead to indiscriminate administration of blood products.
For trauma patients, the Denver Health Medical Center MTP (Fig. 6) is
initiated based on field and ED vital sign criteria established by the
380 E. Gonzalez and E. E. Moore
Research Outcomes Consortium (ROC), with the addition of high-risk
injury patterns such as penetrating torso wounds, unstable pelvic fracture, or abdominal ultrasound with evidence of bleeding in more than
one region. It is a goal-directed, TEG-guided protocol.
Pediatric patients <40kg of actual body weight meeting criteria
for MTP activation, are managed according to the pediatric MTP
algorithm in Fig. 7.
Factor component replacement and hemostatic medications
Current evidence supports the use of factor replacement and hemo-
static medications only as adjunct therapy to blood products (with
very specific indications), and not as a substitute of them.
Factor VIIa
Ö Its use is mostly limited to promptly reverse coagulopathy of
therapeutically anti-coagulated patients with severe hemorrhage or
intracranial hemorrhage, or as salvage therapy when blood products are being delivered and hemostasis needs to be achieved more
rapidly.
Ö When used, it is important to correct acidosis, hypothermia,
thrombocytopenia, and hypofibrinogenemia, in order for it to be
effective.
Ö Dose: 60–90 mcg/kg i.v., can be repeated in two hours if needed.
Prothrombin concentrate complex (PCC)
Ö Concentrate of factors II, VII, IX, and X.
Ö Its use is mostly limited to promptly reverse coagulopathy of
therapeutically anti-coagulated patients with severe hemorrhage or
intracranial hemorrhage, or as salvage therapy when blood products are being delivered and hemostasis needs to be achieved more
rapidly.
Ö Preparations vary worldwide; with the U.S. receiving FDA
approval for “3-factor” PCC (II, IX, X) whereas many clinical
studies conducted outside the U.S. used “4-factor” PCC, which
includes activated factor VII.
Ö When using a 3-factor PCC, supplementation with a plasma trans-
fusion or factor VIIa (20 mcg/kg) has been recommended.
Ö Median time for correction of INR to normal levels is 30 min.
Ö Dose: INR 2.0–3.9 = 25 units/kg i.v. (max. dose: 2500 units), INR
4.0–5.9 = 35 units/kg i.v. (max. dose: 3500 units), INR >6.0 = 50
units/kg i.v. (max. dose: 5000 units).
Diagnosis and Management of Coagulopathy 381
Factor VIIa and PCC administration should be administered with
extreme caution and at the clinician’s discretion, given their cost and
possibility of associated thromboembolic complications.
DDAVP
Ö Causes release of endothelial Weibel-Palade bodies, which contain
vW factor, thus improving platelet adhesion.
Ö Used in the treatment of type 1 von Willebrand disease, and uremic
bleeding in renal failure patients.
Ö In the absence of these conditions, there is no data to support its
use; however it has been used as salvage therapy during coagulopathic hemorrhage.
Ö Preliminary animal studies show that desmopressin improves
hypothermia and acidosis-induced platelet dysfunction, but clinical
validation is lacking.
Ö Dose: 0.3 mcg/kg i.v., can be repeated in four hours.
Anti-fibrinolytics
Tranexamic acid (TXA) is a lysine analogue that prevents fibrinolysis
by binding to plasminogen, preventing its interaction with fibrin, and
activation by tPA into plasmin.
TXA should only be used in patients with coagulopathic hemorrhage
and documented hyper-fibrinolysis (TEG-LY30 >3.0%).
Ö Empiric use of TXA when a TEG is not available or has not been
resulted should be restricted to two conditions: patients at high risk
of hyper-fibrinolysis (severe injury with SBP <75 mmHg), and
patients in hemorrhagic shock not achieving adequate hemostasis
despite appropriate blood product resuscitation.
Administration of TXA >3h from injury is harmful as it results in
increased mortality.
TXA should be administered with extreme caution given the possibility
of associated thromboembolic complications and other potential nonthrombotic complications.
Dose: 1000 mg i.v. If fibrinolysis persists despite initial dose (rare), a
continuous infusion of 1000 mg i.v. over eight hours can be used.
Hemorrhage in anticoagulated patients [Table 3 in Chapter 9-(iii) describes
pharmacokinetics of anticoagulation agents].
Major spontaneous bleeding is most commonly gastrointestinal, geni-
tourinary or intracranial, otherwise bleeding in anticoagulated patients
occurs after trauma or surgery.
382 E. Gonzalez and E. E. Moore
Identification of anticoagulation should be performed with a specific
assay according to the pharmacologic agent used or suspected:
Ö Unfractionated heparin: PTT, LMWH: anti-Xa activity levels, fon-
daparinux: anti-Xa activity levels, rivaroxaban and apixaban: anti-Xa
activity levels, dabigatran: ecarin clotting time or thrombin time
(a normal PTT may exclude anticoagulation with dabigatran), bivalirudin and argatroban: PTT, warfarin: INR.
Ö TEG-ACT (rapid-TEG) or TEG R-time (kaolin-TEG) can be used
to identify anticoagulation with most anticoagulant agents.
Ö Platelet inhibition with aspirin, clopidogrel, ticlopidine, prasugrel,
ticagrelor, abciximab, eptifabatide, or tirofiban can be quantified
with TEG-platelet mapping or platelet aggregometry (not available in most clinical settings).
Hemorrhage with unfractionated heparin anticoagulation
Ö Life-threatening or intracranial hemorrhage: protamine dose
estimated based on UFH half-life (50 mg max-dose).
Time elapsed Protamine to neutralize 100 units of heparin
Immediate 1.0 mg
30–60 min 0.5 mg
>2 h 0.25 mg
Ö When heparin is given as a continuous i.v. infusion, only heparin
given in the preceding several hours should be considered (e.g., a
patient receiving heparin at 1250 units/hour will require ~20 mg of
protamine for reversal of heparin given in the last 2–2.5h).
Ö Rapid infusion of protamine may result in hypotension and a
systemic inflammatory state.
Hemorrhage with LMWH anticoagulation
Ö Life-threatening or intracranial hemorrhage: enoxaparin adminis-
tered in ≤8 hours: 1 mg of protamine neutralizes 1 mg of enoxaparin
(e.g., dose of protamine should equal the last dose of enoxaparin
administered). Administered in > 8 hours: 0.5 mg of protamine for
every 1 mg of enoxaparin.
Ö Protamine completely reverses factor II inhibition by LMWH,
however only 75% of Xa inhibition is reversed by protamine.
Diagnosis and Management of Coagulopathy 383
Hemorrhage with warfarin anticoagulation
Ö Life-threatening or intracranial hemorrhage: 10 mg vitamin K
(phytonadione) i.v. and PCC or factor VIIa (if no PCC or factor
VIIa available transfuse a 20 mL/kg dose of plasma).
9 Not administering vitamin K may result in a rebound
coagulopathy.
Ö For mild or moderate bleeding oral vitamin K administration along
with local bleeding control and supportive measures is adequate.
Ö Treatment with high doses of vitamin K may make it difficult to
resume effective anticoagulation with warfarin for days to weeks
after the bleeding episode has been controlled.
Hemorrhage with direct thrombin inhibitor (argatroban, dabigatran,
bivalirudin) anticoagulation
Ö There is no reversal agent for direct thrombin inhibitors.
Ö Life-threatening or intracranial hemorrhage: PCC and factor VIIa
have been proposed as salvage therapy.
Ö Argatroban and bivalirudin have short half-lives (<1h); however
can be increased to 4h with liver failure (argatroban) and renal
failure (bivalirudin).
Ö Dabigatran has a 16h half-life and clearance can be prolonged with
renal dysfunction. This drug can be cleared by emergent hemodialysis in cases associated with hemorrhage.
Hemorrhage with fondaparinux anticoagulation
Ö There is no reversal agent for fondaparinux.
Ö Life-threatening or intracranial hemorrhage: PCC and factor VIIa
have been proposed as salvage therapy.
Hemorrhage with rivaroxaban and apixaban anticoagulation
Ö There is no reversal agent for apixaban or rivaroxaban.
Ö Life-threatening or intracranial hemorrhage: PCC and factor VIIa
have been proposed as salvage therapy.
Hemorrhage with pharmacologic platelet inhibition (aspirin, clopidogrel,
ticlopidine, prasugrel, ticagrelor, abciximab, eptifabatide, tirofiban).
Ö There is no reversal agent for platelet inhibitors.
Ö It is important to remember that the platelet inhibitory half-life of
aspirin and clopidogrel exceeds their pharmacokinetic half-life.
384 E. Gonzalez and E. E. Moore
Ö Life-threatening or intracranial hemorrhage: platelet transfusion.
DDAVP and vW factor administration have been proposed as
salvage therapy.
• Immune thrombocytopenic purpura (ITP)
Abrupt onset of thrombocytopenia, no explained by medications, illness,
or other causes.
Petechiae, bruising, mucosal bleeding.
Most commonly chronic and relapsing in adults, acute in children.
Autoimmune etiology; antibodies against platelet membrane glycoproteins.
Clinical diagnosis by exclusion.
Acute treatment is with corticosteroids: prednisone (1 mg/kg per day
orally) or dexamethasone (40 mg/day orally for four days, repeated every
14 to 28 days as needed).
Patients with life-threatening hemorrhage and ITP-induced thrombocyto-
penia require platelet transfusion.
Splenectomy should be only considered for those patients who do not
respond to corticosteroid treatment. Rituximab (thrombopoiesis-stimulating agent) can be used in patients who are not candidates for splenectomy.
• Thrombotic thrombocytopenic purpura (TTP) with hemolytic uremic syndrome (HUS)
Suspect in patients with microangiopathic hemolytic anemia and throm-
bocytopenia without an apparent alternative etiology.
Pentad of signs (only present in 25% of patients): thrombocytopenia,
microangiopatic hemolytic anemia, fever, neurologic signs or symptoms,
and renal dysfunction.
Caused by deficiency of the vW factor cleaving enzyme (ADAMTS-13),
resulting in persistence of large multimeric vWF leading to increased
platelet adhesion and consumption.
Can be congenital from decreased ADAMTS-13 synthesis or acquired
from autoantibodies against ADAMTS-13.
Platelet thrombi in the microvasculature lead to organ dysfunction (e.g.,
stroke, renal dysfunction) and intravascular hemolysis.
Diagnosis is clinical and supported by laboratory findings of schis-
tocytes on peripheral blood smear, elevated LDH, and indirect
hyperbilirubinemia.
Diagnosis may be confirmed by ADAMTS-13 level, however not neces-
sary to initiate treatment.
>90% mortality rate without treatment.
Diagnosis and Management of Coagulopathy 385
Managed with emergent plasma exchange upon diagnosis, replacement
fluid must be plasma, continue daily until LDH and platelet count have
normalized for two days.
Transfuse plasma (4–6 units in adults) if plasmapheresis is delayed.
Practical Algorithm(s)/Diagrams
Fig. 1. Cell-based model of hemostasis.
TF: tissue factor, PAR-1: protease activated receptor 1.
386 E. Gonzalez and E. E. Moore
Fig. 2. Protein-C activation system.
EPCR: endothelial protein-C receptor, IIa: thrombin, aPC: activated protein-C.
Diagnosis and Management of Coagulopathy 387
Fig. 3. Fibrinolysis system.
PAI-1: plasminogen activator inhibitor, tPA: tissue plasminogen activator, AP: anti- plasmin, II:
thrombin, TAFI: thrombin activated fibrinolysis inhibitor, FDP’s: fibrin degradation products.