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review article
T
he definition of coagulopathy is a condition in which the From Kings College London and Guys
bloods ability to clot is impaired. However, for some clinicians, the term and St. Thomas Trust both in London.
Address reprint requests to Dr. Hunt at
also covers thrombotic states, and because of the complexity of the hemo- the Thrombosis and Haemophilia Centre,
static pathways, the two conditions can exist simultaneously. Some practitioners St Thomas Hospital, Westminster Bridge
would consider that mildly abnormal results on coagulation screening without Rd., London SE1 7EH, United Kingdom,
or at beverley.hunt@gstt.nhs.uk.
bleeding can also indicate a coagulopathy. This review is confined to the original
definition of coagulopathy as given above. Such states are common in patients in N Engl J Med 2014;370:847-59.
DOI: 10.1056/NEJMra1208626
the intensive care unit (ICU) and require a clinicopathological approach to ensure Copyright 2014 Massachusetts Medical Society.
that the correct diagnosis is made and the appropriate treatment administered. The
lack of evidence for managing coagulopathies in critical care is striking. This re-
view will highlight selected areas in which there is high-quality evidence and at the
same time point out areas for which there is poor evidence. In the latter case, there
is little consensus on management.
Differ en t i a l Di agnosis
A medical history taking and physical examination are vital, since many different
conditions can produce similar laboratory abnormalities. For example, end-stage
liver failure and disseminated intravascular coagulation produce thrombocytopenia
and similar changes in standard tests of coagulation, and yet the management of
and prognosis for these conditions are very different. A peripheral-blood smear is
a vital investigation tool in most cases to confirm a low platelet count and the pres-
ence or absence of other diagnostic features, such as red-cell fragmentation, plate-
let morphologic abnormalities, or evidence of dysplasia or hematinic deficiency.
Table 1 and Figure 1 highlight the relationship between laboratory findings and
various coagulopathies.
Once it has been determined that the underlying cause is not a response to
therapeutic agents meant to modify the coagulation response (e.g., treatment with
vitamin K antagonists, heparinoids, or direct factor Xa or IIa inhibitors), practitioners
need to evaluate the pattern of bleeding, which may include widespread petechiae
and mucosal bleeding in platelet disorders, generalized oozing from de-epithelialized
surfaces, and fast bleeding from damaged major vessels.
Major Bleeding
The lack of good-quality evidence is most marked in the use of blood components to
manage major bleeding. When blood components were introduced into critical care
practice decades ago, their benefit was never assessed in randomized clinical trials.
Table 1. Laboratory Findings in Various Platelet and Coagulation Disorders in the ICU.
Later, concern about transfusion-transmitted infec- an increase by a factor of 6 in the multiple organ
tions (human immunodeficiency virus infection, dysfunction syndrome.5
hepatitis, and a new variant of CreutzfeldtJakob The critical transfusion ratio of fresh-frozen
disease) and limitations in the blood supply led to plasma to red cells in the management of major
a more restrictive use of blood components. bleeding is not known. This question is being
In the absence of randomized, controlled trials, evaluated in the North American Pragmatic, Ran-
retrospective studies of military casualties1 and, domized Optimal Platelets and Plasma Ratios
later, similar studies of civilian casualties2 show- study (ClinicalTrials.gov number, NCT01545232).
ing improved survival with transfusion of 1 U of This multicenter, randomized trial is comparing
fresh-frozen plasma for each unit of red cells the effect of various ratios of blood products
have resulted in earlier administration of an in- administered to trauma patients who are pre-
creased number of units of fresh-frozen plasma. dicted to require massive transfusion (>10 U of
However, these studies have been criticized, packed red cells within the next 24 hours) on
particularly for methodologic flaws that include rates of death at 24 hours and 30 days. In the
survival bias (i.e., patients who did not survive interim, a North AmericanEuropean divide in
were not transfused with fresh-frozen plasma) the practice of using blood components to sup-
and heterogeneity between studies.3 port hemostasis has emerged. Although in North
Despite the lack of evidence that bleeding America there has been increased use of fresh-
after surgery and gastrointestinal or obstetric frozen plasma in patients with major hemor-
hemorrhage are associated with hemostatic rhage, some European practitioners have aban-
changes similar to those in acute traumatic co- doned the use of fresh-frozen plasma, relying on
agulopathy, the early use of a transfusion ratio the exclusive use of factor concentrates on the
of fresh-frozen plasma to red cells of 1:1 or 1:2 basis of rotational-elastometryguided interven-
has become widespread. This increased use of tion with prothrombin complex concentrate,
plasma is not risk-free, since the incidence of factor XIII, and fibrinogen.6 In contrast, other
transfusion-related acute lung injury is increased,4 practitioners believe that the treatment of major
as may be the risk of the acute respiratory dis- hemorrhage should begin with fibrinogen sup-
tress syndrome (ARDS). In one study involving plementation with tranexamic acid, a synthetic
trauma patients requiring a nonmassive transfu- derivative of the amino acid lysine that acts as an
sion (<10 U of packed red cells within 12 hours antifibrinolytic agent by competitively inhibiting
after admission), the administration of more than plasminogen, with red cells and intravenous fluid
6 units of fresh-frozen plasma, as compared used on an as-needed basis.7
with no transfusion, was associated with an in- Fibrinogen is a critical molecule in coagula-
crease by a factor of 12 in the rate of ARDS and tion. It is the protein that ultimately forms fibrin,
the ligand for platelet aggregation, and in pa- outcomes in patients with major bleeding. Future
tients with major bleeding, it is required to a randomized, controlled trials should assess the
larger extent than any other hemostatic protein.8 overall benefit and safety, including the rate of
In such patients, this requirement reflects in- hospital-acquired venous thromboembolism.10,11
creased consumption, loss, dilution, and fibrin- Similarly, the use of recombinant factor VIIa,
ogenolysis. On the basis of these multiple roles, which has been shown to reduce the use of red
even in the absence of evidence from random- cells in bleeding but not to reduce mortality,
ized, controlled trials, guidelines for the man- needs further evaluation. Data from placebo-
agement of traumatic bleeding now indicate that controlled trials have shown that the off-label
the trigger level for supplementing fibrinogen use of recombinant factor VIIa significantly in-
should be 1.5 to 2.0 g per liter rather than 1.0 g creased the risk of arterial thrombosis.12,13
per liter.9 It is unknown whether early fibrino- Tranexamic acid should be administered to
gen supplementation and the use of prothrom- all patients with major bleeding after trauma. This
bin complex concentrate, as compared with the recommendation is supported by a large, random-
use of fresh-frozen plasma, improves clinical ized, controlled trial, the Clinical Randomization
Low platelet count with normal Low platelet count and Normal platelet count with Low platelet count with
results on coagulation screening fragmented red coagulation deficiencies coagulation deficiencies
cells (microangiopathic
hemolytic anemia)
Disseminated
Reduced
intravascular
survival
Failed production of coagulation
coagulation factors
Thrombocytopenia
and coagulation factor Microvascular
deficiency thrombotic obstruction
Release of
platelets
Megakaryocyte Bleeding
Organ failure
Sepsis
Microparticles
Monocyte
Insufficient
Impairment of removal
anticoagulant
mechanisms
Plasminogen
activator inhibitor 1
Endothelial cell Activation of
endothelial cells
* Data are adapted from Toh and Hoots21 on the basis of the scoring system developed by the International Society on Thrombosis and Hemostasis.
factor pathway inhibitor appeared to be benefi- activated protein C,25 antithrombin,26 and tissue
cial in a study of endotoxemia in animals. These factor pathway inhibitor27 in patients with sepsis.
promising studies led to major randomized, con- However, the studies showed no reductions in the
trolled trials of the supplementation of physio- rates of death and increased bleeding episodes.
logic anticoagulants with pharmacologic doses of The consumption of the coagulation proteins
arteries. Thus, an active diagnosis of this disor- However, in parallel with the reduction in
der or failure to rule it out should lead to urgent coagulation factors, there is a similar reduction
plasmapheresis. in the production of physiologic anticoagulants.
Thus, patients with chronic liver disease and a
L i v er Dise a se prolonged prothrombin time are no longer con-
sidered to have a deficiency of coagulation fac-
Thrombopoietin and most hemostatic proteins tors, since their coagulation is rebalanced and
are synthesized in the liver. Thus, reduced he- thrombin generation is usually normal.35 In
patic synthetic function results in prolongation such cases, there is no need to treat prolonged
of the screening tests of coagulation (particularly coagulation times in the absence of bleeding. If
the prothrombin time) and reduced platelet counts, bleeding does occur in liver disease, then con-
although levels of factor VIII and von Willebrand sensus guidelines, which are largely based on
factor are increased.35 Acute alcohol intake in- consensus expert opinion, recommend blood-
hibits platelet aggregation. In chronic liver dis- component management as determined by the
ease, there is also increased fibrinolytic potential results of testing of the platelet count, prothrom-
due to the failure of the liver to metabolize tissue bin time, activated partial-thromboplastin time,
plasminogen activator. In cholestatic liver dis- thrombin time, and fibrinogen. In a recent ran-
ease, there is reduced absorption of lipid-soluble domized, controlled trial, investigators com-
vitamins, so reduced amounts of the vitamin K pared a liberal red-cell transfusion strategy
dependent coagulation factors II, VII, IX, and X (hemoglobin level, <9 g per deciliter) and a re-
are produced. Furthermore, in liver disease, the strictive strategy (hemoglobin level, <7 g per
failure of the normal enzymatic removal of si- deciliter) in patients with acute upper gastro-
alic acid from fibrinogen results in dysfibrino- intestinal bleeding. Patients who were treated
genemia36 (Fig. 3A). with the restrictive strategy had longer survival
A Hepatic failure
Acute alcohol
Liver failure and drug intake
2-Antiplasmin
Hemostatic balance preserved
Impaired polymerization of fibrin
Plasminogen Plasmin
B Renal disease
Uremic toxins
Diseased produced
kidney Erythropoiesis
Normal axial red-cell flow, Anemia, resulting in loss of axial Platelet dysfunction due to
hematocrit 30% red-cell flow, hematocrit <30% platelet adhesion and granule release
Subendothelial matrix von Willebrand
factor
Glycoprotein Ib Adhesion
Platelet
Fibrinogen
Aggregation
Glycoprotein
IIb/IIIa
Granule release
Draft 5 2/11/14
Author Hunt
Fig # 3b
Title Bleeding and Coagulotherapies
(6 weeks) and a lower rate of rebleeding than R ena l Dise a se ME
in Critical Care
In the past, the bleeding time was considered proliferative disorders,44 or the breakdown of high-
to be the most useful clinical test of coagulation molecular-weight von Willebrand factor multimers
in patients with renal disease, but much of the owing to high intravascular or extracorporeal cir-
evidence supporting testing and treatment was cuit shear stresses, may also occur in patients in
derived from poor-quality studies performed more the ICU. This disorder can also be caused by
than 30 years ago. We now know that dialysis, shear stresses on blood flow in extracorporeal
especially peritoneal dialysis, improves platelet circuits, such as those caused by extracorporeal
function. Erythropoietin, cryoprecipitate, conju- membrane oxygenation44 and left ventricular assist
gated estrogens, desmopressin, and tranexamic devices. Intravascular shear stress from aortic-
acid have all independently been shown to reduce valve stenosis can cause acquired von Willebrands
bleeding time.38,39 In the past decade, citrate has disease, leading to gastrointestinal bleeding
risen in popularity as a replacement anticoagulant (Heydes syndrome).45
in continuous renal-replacement therapy, with a Acquired von Willebrands disease is treated
reduction in bleeding, although data on its safety with the use of either desmopressin, which stimu-
in patients with liver failure are lacking.40 lates the release of residual stores of von Wille-
brand factor by endothelial cells, or von Willebrand
Fibr inoly t ic Bl eeding factor concentrates, with the latter considered to be
the more effective therapy.46 The use of antifibri-
Excessive fibrinolysis that threatens clot integrity nolytic agents may be considered to alleviate muco
is known as hyperfibrinolysis.41 Abnormal fibri- cutaneous bleeding. Acquired von Willebrands
nolytic activity may be overlooked as a cause of disease due to high shear stresses requires the
bleeding, particularly in liver disease, and the removal of the cause of the condition whenever
condition is difficult to diagnose because of the possible.
absence of a specific routine assay. Clinical sus-
picion should be high in cases in which bleeding Bl eeding A sso ci ated w i th
continues despite hemostatic replacement therapy, A n t i thrombo t ic Ther a py
platelet levels are relatively conserved but fibrino-
gen levels are disproportionately low, and d-dimer Table 4 summarizes the current antithrombotic
levels are disproportionately high for disseminat- drugs, their mechanisms of action, and reversibil-
ed intravascular coagulation. Thromboelastogra- ity.47,48 It is difficult to treat a bleeding patient
phy, which may help differentiate fibrinolytic ac- who is receiving an oral anticoagulant such as
tivation from coagulation factor deficiency, is a dabigatran and rivaroxaban, since there is no
crude tool, since it detects only the most marked specific antidote. Studies that have evaluated the
changes.42 Fibrinolytic bleeding should be con- reversal of the new oral anticoagulants have been
sidered particularly in patients with liver disease limited to reversal of drug effect with the use of
and disseminated cancers. The use of tranexamic recombinant activated factor VII and prothrom-
acid, either by infusion or orally (depending on bin complex concentrate. Current evidence sug-
the severity of the problem and the state of the gests that prothrombin complex concentrate may
patient), is beneficial in controlling bleeding. be the best option and that it reverses the effects
of rivaroxaban better than the effects of dabiga-
Von W il l ebr a nds Dise a se tran.49,50 General measures such as stopping the
antithrombotic medication, documenting the time
If unexplained bleeding occurs, consideration and amount of the last drug dose, and noting the
should be given to the late presentation of an presence of renal and hepatic impairment are
inherited bleeding disorder. A personal and fam- suggested. Management may be aided by obtain-
ily history of easy bruising and bleeding should ing a full blood count and hemostatic screening,
be sought. Occasionally, a condition such as mild along with a specific laboratory test to measure
von Willebrands disease may present with per- the antithrombotic effect of the drug, if avail-
sistent oozing after an injury or surgery.43 able. If the medication has been recently ingested
Acquired von Willebrands disease, which can and there is no specific antidote, oral activated
be caused by several potential mechanisms due charcoal may be given to absorb any residual
to autoantibodies, myeloproliferative and lympho drug in the stomach.
Procedure for
Agent Mechanism of Action Site of Clearance Half-Life Immediate Reversal
Aspirin Irreversible cyclooxygenase 20 min but effect will persist Platelet transfusion; consider use of desmopressin
inhibitor for 5 days
Clopidogrel, prasugrel, P2Y12 antagonists Hepatic 6 to 15 hr Platelet transfusion
ticagrelor
Unfractionated heparin Indirect anti-Xa and anti-IIa Cellular and (at higher doses) 4590 min Protamine (at a dose of 1 mg) neutralizes 80100 U
effect; increases the action renal unfractionated heparin
of antithrombin by factor
of 10,000
Low-molecular-weight Same as for unfractionated Renal Approximately 4 hr, with vari- Protamine reverses 60% of effect; consider the use of
heparin heparin but mainly anti- ability among products recombinant activated factor VII if there is continued
Xa effect life-threatening bleeding and the time frame suggests
there is residual effect
Danaparoid A heparinoid with ratio of Renal 24 hr No specific antidote; plasmapheresis may be considered
anti-Xa to anti-IIa of >20 for critical bleeding
Fondaparinux Synthetic pentasaccharide Renal 1720 hr No specific antidote; use of recombinant activated factor
with indirect anti-Xa VII should be considered for critical bleeding
effect
Bivalirudin Direct antithrombin effect Proteolysis by thrombin (80%) 25 min; 1 hr in renal failure No specific antidote; hemodialysis, hemofiltration, or
with 20% renal excretion plasmapheresis may be considered for critical bleeding
critical care medicine
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857
The n e w e ng l a n d j o u r na l of m e dic i n e
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