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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5524_Библиотеки_им_академика_М_И_Перельмана.pdf
368 E. Gonzalez and E. E. Moore
between the classic description of mutually exclusive extrinsic
(TF, VII) and intrinsic (XII, XI, IX) pathways.
Propagation
Ö As tenase and pro-thrombinase potentiate each other, the so-called
thrombin burst occurs. This amount of thrombin can now cleave
fibrinogen into fibrin (fibrin then integrates activated platelets into
the clot by binding to the GP-IIb-IIIa receptor), activates factor XIII
(which polymerizes fibrin), and generates more Va and VIIIa (which
further potentiates thrombin generation). This amount of thrombin
also further activates platelets, generating a stable and growing clot.
A sub-fraction of red blood cells are also capable of generating throm-
bin through the meizothrombin pathway.
Endogenous anti-coagulant system
Endogenous anti-coagulant proteins ensure microvascular integrity
during hemostasis; protein-C, protein-S, tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), and anti-thrombin (AT) have been
well-characterized.
Heparan sulfate, heparin co-factor II, alpha-2-macroglobuliln, alpha-
1-antitrypsin also enhance endogenous anti-coagulation.
AT directly inhibits thrombin, and most coagulation protein factors.
TFPI inhibits factor Xa and the VIIa/TF complex.
TM, an endothelial trans-membrane protein, binds and inactivates
thrombin.
Ö The thrombin/TM complex activates protein-C that is attached to
the endothelial protein-C receptor (EPCR).
Ö Activated protein-C cleaves Va and VIIIa, preventing their assem-
bly into the pro-thrombinase and tenase complexes, thus hindering
thrombin generation (Fig. 2).
Ö Through TM, thrombin is diverted from its pro-coagulant role to
an anti-coagulant one, the so-called thrombin switch.
Fibrinolysis
Fibrinolysis is clot breakdown executed by plasmin-mediated cleav-
age of fibrin.
Plasmin is generated from tissue plasminogen activator (tPA) or
urokinase plasminogen activator (uPA) cleavage of plasminogen.
Anti-plasmin (plasmin inhibitor), plasminogen activator inhibitor
(PAI-1)(tPA inhibitor), and thrombin-activated fibrinolysis inhibitor
Diagnosis and Management of Coagulopathy 369
(TAFI)(down-regulates fibrinolysis), are endogenous anti-fibrinolytics
that keep fibrinolysis in check (Fig. 3).
Platelet function
Platelet function is conceptualized into adhesion, activation, and
aggregation for its study and understanding.
Ö Adhesion: attachment to sub-endothelial collagen via the platelet
receptors GP-VI, GP-1b-IX-V, and the integrin α2β1.
Ö Activation (secretion): platelet adhesion and thrombin (via PAR-1
and PAR-4) cause platelet activation.
— Thrombin is the most potent platelet activator.
— Activated platelets undergo a cytoskeletal change becoming
more spherical with extended pseudopods, thus spreading over
the exposed sub-endothelium.
— The eicosanoid pathway is activated (via thromboxane-A2)
and the content of platelet granules is released (alpha-granules:
vW factor, factor V, fibrinogen, vitronectin, platelet factor-4,
PAI-1)(dense bodies: ADP, serotonin, calcium).
— Negatively-charged phospholipid micro-particles are trans-
ported to the outer surface (via a calcium dependent mechanism),
which favors enzymatic assembly of coagulation proteins leading to thrombin generation.
Ö Aggregation: activated platelets attach to fibrin via the GP-IIb-IIIa
receptor, which tethers them to other platelets, leading to formation of a stable platelet and fibrin rich clot.
Main Body
• Inherited coagulopathies
The most common inherited bleeding disorder is Von Willebrand disease
(vWD)(1–2% general population)(autosomal dominant).
vW factor is a carrier of circulating factor VIII, and binds platelets to
exposed blood vessel collagen via the GP-1b-IX-V receptor.
Type 1: partial quantitative deficiency, type 2: qualitative deficiency,
type 3: total quantitative deficiency.
Bleeding manifestations are bruising and hemorrhage from mucous
membranes such as menorrhagia, gastrointestinal (GI) bleeding,
epistaxis, and severe post-partum bleeding.
370 E. Gonzalez and E. E. Moore
Diagnosis is by vWF quantification (vWF antigen) and function
(ristocetin co-factor activity).
Treatment should be managed through a hematology consultation.
Urgent empiric treatment during severe hemorrhage in a patient with
known vWD irrespective of type: 50 units/kg of VIII/vWF concentrate
or cryoprecipitate at 1– 2 bags/10 kg of body weight. Desmopressin
(DDAVP) should not be used for an acute hemorrhagic event.
Hemophilia A and B [deficiency of factor VIII and IX(Christmas factor),
respectively](X-linked recessive)(A and B are indistinguishable clinically,
hemophilia A is more common).
Hemarthrosis during childhood is the most common clinical manifestation.
Males with history of severe, unexplained bleeding after surgical or
dental procedures, history of hemarthrosis, spontaneous retroperitoneal hematoma, or with a family history of hemophilia warrant a
diagnostic workup.
Diagnosis is by plasma factor VIII and IX quantitative assays.
Mild hemophilia (residual factor level >5%, diagnosed as young adult
after major surgery or trauma, spontaneous bleeding rare), moderate
hemophilia (residual factor level 1–5%, diagnosed in childhood after
minor trauma or surgery, hemarthrosis common), severe hemophilia
(residual factor level <1%, diagnosed as neonate, severe spontaneous
bleeding).
Treatment should be managed through a hematology consultation.
Emergent treatment during severe hemorrhage in a patient with a
known diagnosis of hemophilia A or B is with 50 units/kg of body
weight of factor VIII or IX respectively (elevates factor concentrations
to >80%). Cryoprecipitate at 1–2 bags/10 kg may be used for hemophilia A but not hemophilia B (does not contain factor IX). Prothrombin
complex concentrate (factors II, VII, IX, and X) can be used for hemophilia B, if factor IX is not available.
Factor concentrations of 30–50% are required for surgical
hemostasis; however higher levels may be desired for major
trauma, intracranial hemorrhage, major surgery, and neurosurgical
procedures.
Factor XII (Hageman factor), prekallikrein, and kininogen deficiencies
significantly prolong the partial thromboplastin time (PTT); however they
are not associated with bleeding, even after surgery or trauma.
Diagnosis and Management of Coagulopathy 371
Prolonged prothrombin time (PT) with normal PTT: factor VII deficiency
(rare). Normal PT with prolonged PTT: hemophilia A and B. Prolonged
PT and PTT: factor V deficiency (rare), factor X deficiency (rare), and
dys- or hypo-fibrinogenemia.
Hereditary disorders of platelet function (rare; 1:1,000,000).
Bernard-Soulier syndrome: GP 1b-IX-V receptor deficiency, autoso-
mal recessive, low platelet counts since childhood, family history of
low platelet counts, platelet size is large on smear, high mean platelet
volume (MPV) on CBC.
Glanzmann thrombasthenia: GP IIb-IIIa receptor deficiency, autoso-
mal recessive, normal platelet count and morphology.
Bleeding manifestations are bruising and hemorrhage from mucous
membranes such as menorrhagia, GI bleeding, epistaxis, and severe
post-partum bleeding.
Treatment of bleeding complications is with platelet transfusion; how-
ever, patients with multiple previous transfusions develop antibodies
against the deficient receptor, limiting their effectiveness. In this scenario, factor VIIa, DDAVP, or PCC can be used as salvage therapy.
• Pathophysiology
Trauma induced coagulopathy (TIC)
The “ bloody vicious cycle” described in 1981 by the Denver
General group (later referred as “lethal triad” by others) was characterized as clinical and experimental research data indicated that
hypothermia and acidosis were conspicuous factors associated with
early mortality in coagulopathic trauma patients. This notion has
been integrated into the contemporary understanding of coagulopathy
described in Fig. 4.
Ö A pH < 7.25 significantly decreases enzymatic coagulation factor
assembly and decreases the yield of thrombin generation.
Ö A core temperature <34°C compromises coagulation factor enzy-
matic activity and platelet function. PT/INR and PTT assays are
done with samples warmed to 37°C, and do not detect these effects.
Ö Acidosis mostly affects enzymatic coagulation, while hypothermia
mostly affects platelet function.
Although decreased concentration of coagulation factors has been
reported after trauma/hemorrhagic shock and with fluid and blood
372 E. Gonzalez and E. E. Moore
administration, recent data demonstrates that clotting is not compromised, as measured by viscoelastic parameters, until resuscitation
with crystalloid fluids achieves 50% hemodilution in vivo.
25% to 35% of trauma patients have been reported to have deranged
coagulation assays upon ED arrival, and prior to fluid and blood
product administration.
Hypothermia, acidosis, hemodilution, and factor consumption are not
primary drivers of coagulopathy but they rather exacerbate an already
endogenously deranged hemostatic system.
Protein-C activity: Brohi, Cohen et al. demonstrated increased
protein-C activity in trauma patients with prolonged PT and PTT upon
ED arrival. It has been proposed that increased protein-C activation
results from tissue hypoperfusion, since patients with no base deficit
had normal PT and PTT without increase in protein-C activation.
Ö In a mouse model of trauma and hemorrhagic shock, prolongation
of PTT was prevented by antibody-mediated inhibition of protein-C,
and synergism of tissue injury and shock were required for prolongation of PTT when protein-C was not inhibited.
The endothelium: elevated circulating syndecan-1, an endothelial
glycocalyx protein that serves as a marker of endothelial injury, has been
associated with a prolonged PTT, increased protein-C activity, increased
circulating catecholamines, and is an independent predictor of mortality.
Ö Syndecan-1 serves as a peptide backbone where heparan sulfate chains
are attached. Circulating heparan sulfate has the potential of causing
heparin-like endogenous anti-coagulant effects by potentiating AT.
Platelet dysfunction is evident upon ED arrival in 45% of trauma patients
by multi-plate impedance aggregometry. Early platelet dysfunction is
characteristic of patients with traumatic brain injury (TBI).
Ö Thrombelastography (TEG) platelet mapping has demonstrated
86% inhibition of adenosine diphosphate (ADP) mediated platelet
aggregation and 44% arachidonic acid (AA) inhibition in trauma
patients. In TBI patients, ADP inhibition correlates strongly with
severity of TBI, and distinguishes between survivors and non-survivors of TBI.
Ö Platelet dysfunction has been attributed to early excessive platelet
activation with subsequent exhaustion, as evidenced by elevated
circulating CD40L (a soluble platelet ligand) early after injury
and/or shock.
Diagnosis and Management of Coagulopathy 373
Ö It remains unclear whether platelet dysfunction after injury and hem-
orrhagic shock is independent of enzymatic coagulation dysfunction.
Fibrinolysis is a conspicuous factor in patients with TIC with the high-
est hemorrhage-related mortality.
Ö Fibrinolysis can be physiologic (protecting the microvasculature
and preventing systemic clot propagation), pathologic (premature
clot breakdown from hyper-fibrinolysis), or shut-down (impaired
fibrinolytic system that favors un-regulated clotting).
— This is evidenced by recent clinical evidence that in trauma
patients, there is a u-shaped distribution of mortality based on
fibrinolysis quantified upon ED arrival; those with hyperfibrinolysis and fibrinolysis shutdown have increased mortality
compared to those with fibrinolysis within a physiologic range.
9 Early mortality is seen in those with hyper-fibrinolysis and
late mortality is seen in those with fibrinolysis shutdown.
Ö Hyper-fibrinolysis is associated with a 52–92% mortality rate.
Ö It has been proposed that excessive tPA derived from endothelial
ischemia may bind all available PAI-1; this tPA/PAI-1 complex is
subsequently cleared by the liver, favoring un-inhibited tPA leading to hyper-fibrinolysis.
Ö Hyper-fibrinolysis has not yet been fully integrated into the currently
proposed mechanisms of TIC, as a mechanistic link is lacking.
Disseminated intravascular coagulation (DIC) is a clinico-pathological
syndrome characterized by generalized generation of fibrin leading to
organ failure due to microvascular occlusion, and in more severe forms,
concomitant consumption of coagulation factors and platelets, and occasionally hyperfibrinolysis, leading to coagulopathic bleeding.
The initiating event for DIC is excessive tissue factor exposure leading to
thrombin generation that overwhelms endogenous anticoagulants.
Conditions with increased activation or expression of tissue factor: sepsis
(TF expressed by cytokine-activated monocytes), meningococcemia, TBI,
tumor emboli, myeloproliferative disorders, fat emboli, certain snake
venoms, placental abruption, fetal demise, and amniotic fluid emboli.
During sepsis, endothelial cells have a dysfunctional anti-coagulant sur -
face glycocalyx, as well as dysfunctional endothelial cell-surface proteins
such as TM which impairs protein-C activation. This favors widespread
un-regulated thrombin generation throughout the microvasculature.
374 E. Gonzalez and E. E. Moore
Most cases of DIC do not manifest hyper-fibrinolysis, however it has
been reported in the most severe cases. The mechanism under which
DIC leads to fibrinolysis remains to be elucidated.
• Coagulation assessment
Optimal management of coagulopathy starts with prompt diagnosis. Time
is the main catalyst of coagulopathy, as the bloody vicious cycle perpetuates itself with every minute untreated.
Patients with coagulopathic bleeding (or with high clinical suspicion of)
should be initially evaluated with a CBC (Hgb/Hct and platelet count) and
a viscoelastic assay such as TEG (or PT/INR, PTT, fibrinogen, and
D-dimer when not available).
Conventional coagulation assays
PT/INR and PTT: initially developed to screen for heritable coagu-
lopathies and later used to monitor anticoagulation therapy.
Ö They are performed on platelet-poor plasma and the end point for
these tests is the time (in seconds) until the earliest formation of
fibrin is detected. They do not assess the evolution of the clot
beyond the formation of the first strands of fibrin.
Ö PT/INR and PTT have shown to correlate poorly with bleeding
risk in elective general and vascular surgeries.
Ö PT/INR and PTT value thresholds used to define coagulopathy:
PT>18 seconds, INR>1.5, PTT>38 seconds, or any of these values
at a threshold of 1.5 times their reference value.
Ö In trauma patients, the prevalence of a prolonged PT is higher, but
prolongation of the PTT is more specific. Adjusted odds ratio for
mortality: 1.35 for PT and 4.26 for PTT prolongation.
Fibrinogen: concentrations >1.5g/L should be maintained in actively
bleeding patients. In patients with TIC, fibrinogen concentrations
decrease much earlier than other coagulation proteins.
Coagulopathic bleeding may exist in patients with normal values of
PT/INR, PTT, fibrinogen, or platelet count.
Ö A study of markers of coagulopathy in 80 trauma patients identi-
fied that increasing injury severity correlated with elevated
markers of endothelial glycocalyx damage, protein C activation,
and clotting factor consumption even when INR and PTT values
were in the normal range.
Diagnosis and Management of Coagulopathy 375
Ö Nevertheless, in an actively bleeding patient, if any of these
parameters are deranged they certainly contribute to hemorrhage
and should be corrected.
Viscoelastic hemostatic assays (VHA) (Fig. 5; Table 1)
TEG provides data on the viscoelastic changes of whole blood as it
clots in a 360 microliter plastic cup in which a rotational pin is suspended; increasing resistance generated by the clot is detected by the
rotating pin and generates a characteristic tracing (Fig. 5).
Ö The amplitude of the tracing (y-axis) represents the mechanical
strength of the forming clot plotted over time (x-axis).
Ö The clot is evaluated in a dynamic way; from the earliest mechan-
ical resistance provided by the first strands of fibrin, to loss of
strength secondary to fibrinolysis.
Blood coagulation in TEG is initiated by contact of whole blood to the
foreign surface of the TEG cup. Addition of coagulation activators
such as kaolin (kaolin-TEG) or tissue factor (rapid-TEG) will expedite
generation of results. Most TEG parameters can be obtained within
ten minutes when using rapid-TEG (Table 1).
The temperature at which VHA are performed can be adjusted to
match that of the patient’s.
Clot formation via TEG is dependent on thrombin, mostly because
clotting initiation is via contact of whole blood with the foreign surface of the cup and because of addition of activators such as kaolin
and TF. Given that thrombin is the most potent platelet activator,
inhibited platelets (e.g., with acetyl-salicylic acid or clopidogrel), may
still generate enough clot strength to yield normal parameters due to
the presence of thrombin. The TEG-platelet mapping assay (see
below) has been developed to increase the sensitivity of TEG to platelet inhibition.
Rotational thromboelastometry (ROTEM) is another viscoelastic
assay that is based on the same principle as TEG, however it is mostly
used in Europe. Its graphical output appears similar to that obtained
with TEG; however, values of parameters are not interchangeable and
separate treatment algorithms must be used.
Limitations of VHA: (1) these assays do not reflect interactions
between the fluid phase of coagulation and the endothelial cell surface;
this dynamic is clearly present in the coagulopathic patient, however it
376 E. Gonzalez and E. E. Moore
remains to be fully understood; (2) pharmacologic platelet inhibition
may not be evident with the standard assays, unless thrombin is inhibited and platelet agonists are utilized in the TEG-platelet mapping
assay; (3) results can be operator dependent and subject to sampling
and/or processing errors, as well as inter-sampling variability.
Platelet assays
Incidence of thrombocytopenia (<150,000/mcl) in ICU patients
ranges from 35% to 70%; it is due to increased consumption, destruction, sequestration, and suppressed bone marrow production.
Platelet counts correlate with shock, trauma, and sepsis severity,
mostly decreasing during the first four days of critical illness.
Thrombocytopenia is an independent predictor of ICU mortality in
multivariate analyses (relative risk: 1.9–4.2); particularly in those
patients who fail to increase platelet counts after the first four days of
illness (stronger predictor of mortality than the APACHE-2 score).
Ö This may not be directly related to coagulopathy as the cause of
mortality.
Ö Platelet counts are not reflective of platelet function, and bleeding
from dysfunctional platelets may occur regardless of platelet
count, particularly in settings of acute physiologic extremis such
as hemorrhagic shock.
Ö 30% of the total platelet volume is pooled in the spleen of normal
individuals. >50% of platelets can be sequestered in patients with
splenomegaly.
Platelet aggregometry (evaluates platelet aggregation by collagen,
ADP, and epinephrine under high shear rates through microscopic
aperture) is the gold standard for assessment of platelet function; however its results are not immediately available, and it has not been
validated clinically during resuscitation.
VHA such as TEG have been modified to evaluate platelet function
(TEG-platelet mapping).
Ö In this assay, heparin is used to eliminate the thrombin contribu-
tion to clot formation and platelet aggregation is then stimulated
with AA or ADP. A separate assay from the same sample is done
using reptilase and factor XIIIa to generate a pure fibrin clot. The
maximum amplitude (MA) from the fibrin clot is then subtracted
from the AA or ADP-generated MA, isolating the platelets’ contribution to clot formation.
Diagnosis and Management of Coagulopathy 377
Ö Effects of endogenous or pharmacological (aspirin, clopi-
dogrel) platelet inhibition can be evaluated with TEG-platelet
mapping. However, it has not been validated clinically during
resuscitation.
Disseminate intravascular coagulation (DIC)
The diagnosis of DIC is one of exclusion and consequently scoring
systems have been developed.
Laboratory parameters in conjunction with clinical suspicion are
employed to establish the diagnosis of DIC (score >5 compatible with
DIC, <5 suggestive of DIC).
Ö Platelet count (>100,000/mcl=0, <100,000/mcl=1, <50,000/mcl=2).
Ö D-dimer (no increase=0, moderate increase=2, strong increase=3).
Ö PT (elevation from normal range)(<3 sec=0 , 3–6 sec=1, >6 sec=2).
Fibrinogen (>1.0g/L=0, <1.0g/L=1).
35% of ICU patients will meet the criteria for DIC.
The cornerstone for management of DIC is correction of the underly-
ing cause (e.g., sepsis).
• Management: all bleeding patients should be initially approached with the
universal A-B-C (airway, breathing, circulation) assessment and management
strategy, regardless of their coagulation status, as efforts to achieve hemostasis will be futile if these principles are not addressed. Particular attention
to treatment of hypothermia while resuscitation is ongoing is imperative.
Crystalloid and colloid administration to coagulopathic patients worsens
their coagulopathy.
In vitro studies have demonstrated increased fibrinolysis with crystal-
loid and colloids.
In particular, hydroxyethyl starch can precipitate coagulopathy, and
has been associated with increased mortality when used in patients at
risk for coagulopathy.
Patients with coagulopathic hemorrhage should be resuscitated with
blood products when available, until bleeding has been controlled or
coagulation parameters corrected.
Blood products (Table 2)
Blood transfusion risks in the U.S.: HIV (1:1,800,000), hepatitis C
(1:1,600,000), hepatitis B (1:220,000), bacterial contamination (platelets, 1:75,000), hemolytic reaction (1:25,000), mis-transfusion
(1:19,000), transfusion-related acute lung injury (TRALI) (1:5,000),
fever/allergic reaction (1:100).