2.

Coagulopathy (definition, signs and symptoms, epidemiology,

general mechanisms of coagulopathy, differential diagnosis,
general principles of management of these patients).
Coagulopathy:
Coagulation disorders are a very common finding in critically ill patients.
They include abnormalities in platelets, coagulation factors and the fibrinolytic
system, and in general they are due to three mechanisms: impaired production
or synthesis, peripheral destruction, consumption, sequestration or accelerated
loss, and dysfunction. This chapter will review the epidemiology of coagulation
abnormalities in the ICU, the general mechanisms of coagulopathy, the
differential diagnosis of specific abnormalities, and the general principles of
management of these patients (1).

1. Definition(2):
An impairment in the blood’s ability to clot, leading to prolonged or
excessive bleeding. Some coagulopathies are primary medical conditions,
but they can also be a complication of other health conditions.
2. Signs and symptoms(2):

 excessive bleeding that can occur spontaneously or following an injury, surgery,

or other trauma
 difficulty stopping bleeding or bleeding that takes a long time to improve
 symptoms of bleeding into the joints, such as:

o swelling, pain, or heat in the joints

o involvement of the knees, elbows, or ankles
o reduced range of motion, pain, or stiffness when moving
 hematoma or bleeding into the skin
 bleeding in the mouth or gums
 bleeding after receiving an injection
 nosebleeds that may be frequent or difficult to stop
 low iron levels or treatment for anemia
 symptoms of a bleeding condition and at least one family member with a
bleeding disorder diagnosis

3. epidemiology of coagulation abnormalities in critically ill patients

(1):
Abnormalities in platelet count:
1. Thrombocytopenia
(defined as a platelet count <150000 × 10 9/L) is present in
one-third to one-half of all patients admitted to an ICU for a
medical condition.
2. Platelet counts <100000 × 109/L can be found in up to one
quarter of patients, whereas counts <50000 × 10 9/L are
present in about 15% of patients.
3. The incidence of thrombocytopenia is higher in surgical and
trauma patients: about 40% of them have platelet counts
<100000 × 109/L.
4. Platelet counts <50 000 × 109/L are associated with a four- to
fivefold higher bleeding risk and about 90% of critically ill
patients with intracranial bleeding have a platelet count
<100000 × 109/L.
5. Thrombocytopenia has been found to be an independent
predictor of mortality in numerous studies.
6. Persistent thrombocytopenia for more than 4 days or a drop
in the platelet count >50% during an ICU stay is related to a
four- to six fold increase in mortality.
 Abnormalities in global coagulation assays:

1. Global coagulation assays (prothrombin time, PT, or

activated partial thromboplastin time, aPTT) are found to be
prolonged in 14–28% of ICU patients.
2. Prolongation of coagulation assays as reflected by a PT or
aPTT ratio greater than 1.5(i.e. the ratio of the patient’s
coagulation time compared to a control) predicts excessive
bleeding.
3. Prolonged PT or aPTT are independent predictors of
mortality in trauma patients.

Other coagulation abnormalities:

1. Elevated D-dimer and fibrin degradation products (FDPs)

can be found in intensive care patients (42%), trauma
patients (80%) and patients with sepsis (99%).
2. Low fibrinogen levels are frequently found in ICU patients
and are related to increased mortality.
3. Low levels of the natural anticoagulants antithrombin and
protein C are found in approximately half of trauma patients
and up to 90% of patients with sepsis.
4. Evidence of hyper fibrinolysis can be found in 57% of
trauma patients and is also a predictor of mortality.
4. Mechanisms of coagulopathy (3):
The coagulation system is a highly phylogenetically preserved system
and has a fundamen tal role for survival. In addition to its pivotal function
of maintaining the integrity of the vascular bed it has a number of
additional functions that are increasingly recognized. These
nonhemostatic functions explain the frequent and profound disruption of
the coagulation system observed in critically ill patients.
I. Coagulation system and inflammation (4):
1. Natural anticoagulant pathways, in particular the protein C
system, play a central role in the regulation of inflammation.
2. Deficiency in the protein C system is associated with a
general dysregulation of the coagulation system in sepsis.
3. Binding of activated protein C to the endothelial protein C
receptor (EPCR) potentiates its anticoagulant and anti-
inflammatory effects.
4. In sepsis, the presence of proteolytic enzymes such as
neutrophil elastase results in degradation of the inactive
protein C with a subsequent deficiency.
5. Additionally, EPCR is downregulated in sepsis, which may
negatively affect the protein C system.
6. Pro-inflammatory cytokines such as TNF-α and IL-1
downregulate the expression of thrombomodulin, the
endothelial target of thrombin, resulting in a lower activation
of inactive protein C.
7. Additionally, a relative protein S (the cofactor of protein C)
deficiency can result from an increase in the complement
component C4bBP from acute phase reaction, because
C4bBP forms a complex with protein S.
8. All of these alterations result in a prothrombotic state.
II. Coagulation system and immunity
 In the presence of a thrombus (either arterial or venous)
monocytes and neutrophils are swiftly recruited to the vessel
wall and the nascent clot.
Platelets interact with neutrophils in response to bacterial
products and trigger the release of neutrophil extracellular traps
or NETs, which are constituted by neutrophil intracellular
components and have important antibacterial functions, but are
also potent activators of the coagulation system.
Coagulation factors such as thrombin and activated factor X, as
well as platelets, are capable of regulating the effector functions
of immune cells.
Under normal circumstances the activation of coagulation by
immune cells serves a role in the response to pathogens by
exerting direct antimicrobial effects and limiting bacterial
spreading.
However, the concurrent activation of coagulation and
inflammation might induce a vicious loop resulting in excessive
activation of immune cells and pathological thrombus formation.
III. Coagulation system and vascular homeostasis (5):
The coagulation system interacts with the renin–angiotensin
system at multiple levels. These interactions could result in
bidirectional alterations of both systems, potentially leading to a
prothrombotic state or altering the vessel tone. Examples where
these interactions might be relevant are sepsis and hypertensive
emergencies.
The Prekallikrein–Kallikrein–high-molecular-weight kininogen
(PK-K-HMWK) system, also known as the contact pathway, can
 stimulate the coagulation system through activation of
coagulation factor XII.
Angiotensinase C (PRCP) converts PK to K. This reaction also
generates bradykinin (a vasodilator peptide) from kininogen.
Under conditions of sepsis or exposure to artificial surfaces (e.g.
extracorporeal circuits) factor-XII-dependent coagulation
activation can be observed.
PRCP also degrades angiotensin II to angiotensin, resulting in
vasodilatation.
The angiotensin-converting enzyme (ACE) degrades bradykinin
and converts angiotensin I to angiotensin II, resulting in
enhanced vasoconstriction and inhibition of the fibrinolytic
system.
Bradykinin (1–5) – a degradation product of bradykinin –
inhibits thrombin-induced platelet aggregation.
Stimulation of AT2 receptors enhances bradykinin formation.
Angiotensins I, II and III induce expression of tissue factor by
stimulating the AT1 receptor. This overexpression of tissue
factor results in a thrombogenic endothelium.
IV. Coagulation system and tissue remodelling
The fibrinolytic system has been found to play an important role
in tissue and vascular remodeling, mainly through activation of
matrix metalloproteinases and their regulators. These enzymes
are involved in the degradation of extracellular matrix
components and are crucial in many processes, including
angiogenesis and wound healing.
Plasmin and plasminogen activators can regulate the activation
of growth factors and are involved in tissue proliferation.
 Plasminogen activator inhibitor-type1 (PAI-1), the main
regulator of plasmin generation, is involved in cell adhesion and
migration and has an active role in carcinogenesis.
Alterations in the fibrinolytic system have been associated with
venous, but mainly arterial, thrombosis and atherogenesis.

5. Differential diagnosis of coagulation abnormalities in critically ill

patient:
Identifying the coagulation abnormalities developing in critical
patients might be not straightforward. Characteristics to be considered in
the differential approach include timing, severity, underlying disorders,
drug exposure and other clinical or laboratory findings. These might help
to determine the mechanism of coagulopathy. A simplified diagnostic
algorithm is shown in figure 1 (1).
Figure 1 (Diagnostic algorithm for coagulation abnormalities in critically ill patients. (Adapted and
modified from [2]). Abbreviations: aPTT activated partial thromboplastin time; DAT direct antiglobulin
test; DIC disseminated intravascular coagulation; FDPs fibrin(open) degradation products; HIT heparin-
induced thrombocytopenia; HUS hemolytic uremic syndrome; PT prothrombin time; TTP thrombotic
thrombocytopenic purpura)

I. Thrombocytopenia (6):

In critically ill patients thrombocytopenia is usually

multifactorial and related to illness severity. Its magnitude
correlates with the length of ICU stays and also with mortality. It
is important to recognize the underlying cause in order to establish
an effective management plan.
 The major mechanisms of thrombocytopenia include
hemodilution, increased consumption, increased destruction,
decreased production and sequestration.

 The major causes of thrombocytopenia and their relative

incidences include sepsis (52%), disseminated intravascular
coagulation (25%), massive blood loss (8%), thrombotic
microangiopathy (1%), heparin-induced thrombocytopenia
(1%), immune thrombocytopenia (1%) and drug-induced
thrombocytopenia (10%).

Diagnostic approach to thrombocytopenia in critically ill

patients:

When evaluating a patient with thrombocytopenia in the ICU,

clinicians must consider the time of onset of the
thrombocytopenia, the nadir platelet count and the dynamic course
of the platelet count. In general, after an initial drop in the platelet
count (for example, after cardiac surgery) an increase follows,
usually around 3 or 4 days later, frequently reaching higher levels
than baseline. This response indicates that physiologic
compensation mechanisms remain intact. However, the differential
diagnosis is not straightforward in many cases (6).

 A gradual decline in platelet count is generally caused by

consumptive coagulopathy or bone marrow failure.

 A sudden drop in platelet count, especially if it develops

after an initial increase, is usually due to immunologic
causes.
 Pseudothrombocytopenia, an in vitro phenomenon due to
platelet clumping when blood is exposed to EDTA
anticoagulant in test tubes, should always be ruled out.

 In all cases, the underlying medical or surgical conditions

must be considered. In patients admitted to the ICU with
thrombocytopenia after surgery, trauma or bleeding, the
drop in the count is almost always due to consumption.

 In medical patients, the most common cause of

thrombocytopenia is sepsis, and the thrombocytopenia is
usually moderate (50–100 × 109 /L). When the platelet
count is less than 50 × 109 /L, disseminated intravascular
coagulation (DIC) must be considered. Other, much less
common causes include autoimmune thrombocytopenia,
thrombotic microangiopathies and drugs. In patients living
or traveling to endemic areas, malaria should be considered.

 If thrombocytopenia is associated with a thrombotic

complication, the diagnostic considerations must include
antiphospholipid antibodies syndrome and heparin-induced
thrombocytopenia in patients with recent heparin exposure.

 Heparin-induced thrombocytopenia (HIT) should be

considered in patients with recent exposure to heparin, if the
thrombocytopenia develops between days 5 and 10–14 after
an initial heparin exposure, is associated with a thrombotic
complication or skin necrosis, the nadir is between 20 and
100 × 109 /L, and there is no alternative explanation .
  In patients with severe thrombocytopenia (a (<20 × 109/L)
the most common cause is sepsis, but marrow infiltrative
conditions such as acute leukemia, myelodysplastic
syndromes or myelopthisis should be considered, in
particular if other cell lines are affected.

 A gradual decrease in platelet count may indicate

multiorgan failure and the development of consumptive
coagulopathy – DIC.

 DIC frequently presents with other coagulation

abnormalities in addition to the thrombocytopenia, such as
prolonged coagulation times, decreased levels of
coagulation factors, and increased FDPs (3, 6)

II. Prolonged coagulation times:

Critically ill patients frequently develop prolongation of global

coagulation times (PT and aPTT). Although these tests are a
practical way of measuring one or multiple coagulation factors,
they might not reflect the hemostatic function in vivo.

 In general, PT or aPTT will be prolonged if coagulation

factors drop below 50% of normal. However, there is great
variation depending on reagents or instruments used.

 The International Normalized Ratio (INR) is a ratio of the

PT in a patient compared to a control that is normalized in
reference to an international standard. Although it has
greatly increased its use to evaluate global coagulation in an
attempt to allow better standardization, it has only been
 validated for monitoring anticoagulant therapy with vitamin
K antagonists such as warfarin or acenocoumarol.

 Deficiencies in coagulation factors are usually due to

consumption, impaired synthesis or massive loss. A less
common cause is the presence of inhibitors (acquired
hemophilia, acquired von Willebrand’s disease, lupus
anticoagulants)

Diagnostic approach to prolonged coagulation times in

critically ill patients:

 Causes of isolated PT (or INR) prolongation include

factor VII deficiency, mild vitamin K deficiency, mild
liver insufficiency and use of vitamin K antagonists.

 Causes of isolated aPTT prolongation include factors

VIII, IX or XI deficiency, use of unfractionated heparin
(or low-molecular-weight heparin overdose), acquired
inhibitors (most frequently against factor VIII), factor
XII or PK deficiencies and hemophilia A (factor VIII
deficiency) or B (factor IX deficiency).

 Causes of concurrent prolongation of PT and aPTT

include factors X, V, II or fibrinogen deficiencies, severe
vitamin K deficiency, use of vitamin K antagonists, liver
failure, massive loss and consumption (DIC) (3).

III. Disseminated intravascular coagulation (DIC)

This is a frequent complication in critically ill patients caused by

systemic intravascular activation of the hemostatic system
resulting in the formation of microvascular thrombi, which can in
turn contribute to worsening organ dysfunction.

 Proinflammatory cytokines released by mononuclear and

endothelial cells during a severe inflammatory response
result in thrombin generation mediated by the tissue factor–
factor VIIa pathway. This activation concurrently with a
decrease in the function of the anticoagulant antithrombin
and protein C systems, and an inhibition of the fibrinolytic
system mediated by high levels of PAI-1, result in
progressive activation and consumption of platelets and
coagulation factors, leading to intravascular fibrin
deposition and microvascular thrombi. In serious cases the
thrombocytopenia and the depletion of coagulation factors
might lead to major bleeding.

 DIC frequently presents with several coagulation

abnormalities including thrombocytopenia, and prolonged
coagulation times as a result of a decrease in coagulation
factors. It also results in increased FDPs.

 A diagnosis of DIC depends on the presence of a

combination of coagulation abnormalities in the appropriate
setting; however, some scoring systems have been
developed with high diagnostic sensitivity and specificity.

 The International Society on Thrombosis and Haemostasis

scoring system includes risk assessment, major laboratory
criteria (platelet count, PT, FDPs) and specific criteria
(thrombin, protein C, thrombin–antithrombin complexes).
  The Japanese Association for Acute Medicine DIC score
includes platelet count, PT, FDPs and evidence of systemic
inflammatory response.

 DIC score is an independent predictor of mortality (7).

IV. Other coagulation abnormalities:

Routine coagulation tests such as PT, aPTT and platelet count

do not account for all possible defects potentially leading to
bleeding complications. Special tests are needed to confirm such
conditions and involvement of the hematology service is necessary
in the assessment and management of these abnormalities.

1. Platelet function defects:

 Platelet function defects are frequently present in

critically ill patients.

 Platelet function can be abnormal as a result of systemic

conditions, in particular uremia and severe liver failure.

 Several drugs can affect platelet function and lead to

hemorrhagic complications, including aspirin,
thienopyridines, nonsteroidal anti-inflammatory drugs,
hirudins (e.g lepirudin and bivalirudin) and abciximab.

 In cardiac patients, exposure of blood to extracorporeal

circuits can induce severe platelet dysfunction.

 No routine laboratory tests can identify platelet

dysfunction. The use of bleeding time has been
abandoned due to its notorious unreliability. Other tests
 such as platelet aggregometry and closure time (PFA100
analyzer) can help to better identify these defects, but
they are not widely available and their interpretation is
not straightforward (8).

2. Hyperfibrinolysis (primary)

 This condition is manifested by a marked activation of

the fibrinolytic system and it can lead to serious
hemorrhagic problems.

 It is relatively rare and it can be observed typically in

patients with acute promyelocytic leukemia and prostate
cancer.

 Patients exposed to extracorporeal circuits can also

present this condition as a result of plasminogen release
from the endothelium.

 Treatment with thrombolytic agents, typically for

ischemic cardiac or cerebral events, results in an induced
hyperfibrinolytic state.

 Patients present with high levels of D-dimer or FDPs and

low levels of fibrinogen, plasminogen, or α-2
antiplasmin or FDPs, Other tests such as euglobulin lysis
time can help to identify this condition (8).

6. Principles of management of patients with coagulation abnormalities:

 The cornerstone of the management of critically ill patients with
coagulation abnormalities is the proper and timely management of the
underlying condition. However, supportive measures are frequently
needed. Adequate transfusional support with packed red blood cells is
important. Recent evidence confirms that erythrocytes play an active role
in supporting thrombin generation (9). Improvement of hematocrit has
been shown to improve hemostasis in vitro (10) and some studies suggest
it might also decrease mortality in some groups of patients (11).
Correction of metabolic abnormalities such as acidosis, hypothermia and
hypocalcemia should also be pursued, since all of these will have a
negative impact on the hemostatic function (12). Maintaining adequate
tissue perfusion is also fundamental, and consideration should be given to
the use of permissive hypotension, which has been found to reduce
coagulopathy in trauma patients
1. Platelet abnormalities:
 In general, patients with a platelet count of less than 10 × 10 9 /L
should be managed with prophylactic platelet transfusions
which have been shown to decrease, albeit not eliminate, major
bleeding events (13).
 Patients with higher platelet counts (20–50 × 10 9 /L) should also
receive platelet transfusions in the presence of bleeding. In
patients with platelet dysfunction and major bleeding, platelet
transfusions can be indicated, even in the case of normal platelet
counts.
 Platelet transfusions are more effective in cases of
thrombocytopenia due to increased consumption or impaired
production. In cases of conditions leading to increased platelet
destruction (such as immune thrombocytopenia) they are
usually not helpful and are reserved only for cases of critical
 bleeding. In such cases other treatments, such as intravenous
immunoglobulin, steroids, immunosuppressive agents or
thrombopoietin mimetics might be necessary.
 In cases of suspected or confirmed heparin-induced
thrombocytopenia, cessation of heparin and use of alternative
anticoagulants such as lepirudin, argatroban or fondaparinux
should be instituted. Platelet transfusions are usually
contraindicated since they might aggravate the condition and
should be reserved for cases with critical bleeding. Warfarin
initiation should be postponed until normalization of platelet
count (14).
2. Coagulation factor deficiencies
 In cases of coagulation factor deficiencies, they can be
replenished by using fresh frozen plasma, or coagulation factor
concentrates. Plasma is usually reserved for patients with
bleeding events; however, a risk of volume overload exists if
large amounts are required.
 Use of coagulation factor concentrates can be considered in
cases of single factor deficiencies.
 Prothrombin complex concentrates are indicated for the rapid
reversal of warfarin
 Associated coagulopathy. Their use outside this context (e.g. for
replenishing a global coagulation factor deficiency) should be
considered off-label and it cannot be routinely recommended.
Consideration should be given only in extreme cases.
Additionally, these agents do not replenish all coagulation
factors and hemostatic defects might persist.
 Use of fibrinogen concentrates or cryoprecipitates should be
considered in patients with critically low levels of fibrinogen, in
particular in patients with active bleeding or at high risk, such
as patients with acute promyelocytic leukemia.
 Recombinant activated factor VII (rFVIIa) is approved for the
treatment of bleeding in hemophiliac patients with inhibitors. A
great deal of anecdotal evidence exists suggesting improved
hemostatic function in bleeding patients after using this agent.
A meta-analysis suggested that the use of rFVIIa reduces blood
transfusion and it may reduce mortality, but increases the risk of
arterial thrombosis (15). However, a well-designed randomized,
controlled trial failed to show improvement in mortality or
relevant clinical outcomes in patients with intracranial
hemorrhage, in spite of a reduction of hematoma growth (16).
Therefore, the use of this agent is not recommended routinely
and it should only be considered in cases of life-threatening
events as a last resource.
 1-Deamino-8-D-arginine vasopressin (DDAVP) induces release
of von Willebrand factor from endothelial cells, resulting in a
significant increase of this factor and its associated factor VIII,
with a subsequent hemostatic response. Its main use is in the
treatment of patients with certain types of von Willebrand’s
disease and mild hemophilia A, but it has been used with
success to treat patients with platelet dysfunction secondary to
uremia.
 Antifibrinolytic agents such as ε-aminocaproic acid or
tranexamic acid can be used to reduce blood loss and
transfusion requirements. The use of tranexamic acid has been
 shown to reduce mortality in bleeding trauma patients and it
seems to be safe (17).
3. Vitamin K supplement
it is a medication used to manage and treat bleeding due to the
coagulation disorder caused by warfarin and vitamin K
deficiency.

Vitamin K
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