This patient presented with hypotension, gastrointestinal bleeding, and coagulopathy. She has multiple conditions contributing to her condition including liver disease, immunosuppression, and sepsis. Her coagulopathy is being treated with plasma transfusion and she had an endoscopy which revealed a bleeding varix. After initial treatment, she developed new pulmonary embolisms. Thrombosis is a risk for critically ill patients, and she has several risk factors for developing clots including inflammation, immobility, and previous vasopressor use.

1. 299© Springer Nature Switzerland AG 2019
J.A. LaRosa (ed.), Adult Critical Care Medicine,
https://doi.org/10.1007/978-3-319-94424-1_16
Part A: Case Presentation
A 34-year-old woman with ulcerative colitis has been receiv-
ing treatment with infliximab for 2 years. Her bowel symp-
toms have been under reasonable control, but a year ago
she developed evidence of advanced sclerosing cholangitis.
She presents now with cough, rigors, and pleuritic chest
pain, and a chest X-ray shows right lower lobe pneumonia.
She is admitted to the ICU with hypotension. She remains
hypotensive after 2 liters of Ringer’s lactate and is started on a
Chapter 16
Bleeding and Thrombosis
in the ICU
Donald S. Houston and Ryan Zarychanski
D. S. Houston
Department of Internal Medicine, Section of Medical Oncology
and Haematology, University of Manitoba,Winnipeg, MB, Canada
R. Zarychanski (*)
Department of Internal Medicine, Section of Medical Oncology
and Haematology, University of Manitoba,Winnipeg, MB, Canada
Department of Internal Medicine, Section of Critical Care,
University of Manitoba,Winnipeg, MB, Canada
e-mail: rzarychanski@cancercare.mb.ca

2. 300
norepinephrine infusion. Shortly after the ICU admission,
she vomits a basin full of bright red blood.
On exam she has findings of consolidation in the right lung
base, her extremities are warm, she is jaundiced, and she has
tense ascites and spider nevi. Lactate is 4.3 mmol/L; venous
oxygen saturation is 73%.
Her complete blood count shows white blood cells 2.2 ×
109
/L, hemoglobin 81 g/L, mean corpuscular volume (MCV)
99 fL, platelets 106 × 109
/L, international normalized ratio
(INR) 2.2, activated partial thromboplastic time (aPTT) 44 s,
and fibrinogen 0.9 g/L.
Differential Diagnosis and Assessment
This is a complex patient with multiple factors that may be
contributing to her abnormal blood counts and coagulopathy.
She has a pertinent background of liver disease, a back-
ground of immunosuppression and presents with both sepsis
and bleeding.We would consider the differential diagnosis of
each of her major issues.
Shock: She appears to have vasopressor-dependent shock.
Hypovolemic shock due to her gastrointestinal bleed should
be excluded; however, following fluid resuscitation, should
her blood pressure remain low, septic shock becomes a strong
consideration. She has no cardiac history, is young and well
perfused, and has a normal venous oxygen saturation; cardiac
or obstructive shock are unlikely. Management of septic
shock is beyond the scope of this review.
Prolonged INR: She has multiple possible causes for
coagulopathy (see Box 16.1):
• Vitamin K deficiency due to malabsorption related to her
biliary tract disease, possibly exacerbated by antibiotics or
poor diet if she has been avoiding green vegetables
because of her colitis
• Hemodilution
• Synthetic failure due to liver disease
• Disseminated intravascular coagulopathy (DIC) due to
sepsis
D. S. Houston and R. Zarychanski

3. 301
Her fibrinogen is low, which shows that the coagulopathy is
not solely due to vitamin K deficiency, and moreover it is lower
than could readily be entirely explained by hemodilution at this
point. The fibrinogen level does not distinguish between the
other possibilities, liver failure and DIC. The INR greater than
2.0 with a fibrinogen of 0.9 g/L suggests that multiple coagulation
factor deficiencies exist,which can only be corrected with plasma.
With sepsis as a predisposing factor, the findings of throm-
bocytopenia, a prolonged prothrombin time, and a reduced
fibrinogen suggest DIC [1]. A factor VIII level can be useful
to distinguish liver disease from DIC, as the FVIII will be
elevated in the former and consumed in the latter. Note that
the FVIII level is raised in both inflammatory liver disease
and in infection, so in this patient even a value in the lower
normal range will indicate consumption.
Thrombocytopenia: Multiple factors may contribute to
thrombocytopenia in this case:
• Sequestration due to portal hypertension and congestive
splenomegaly, consequent to her liver disease
• Deficiency of thrombopoietin due to liver synthetic failure
• Hemodilution
• Sepsis
• DIC
While there are many other potential causes of thrombo-
cytopenia (e.g., immune thrombocytopenia, drug-immune
Box 16.1. Differential Diagnosis of Coagulopathy in
Critical Care
• DIC
• Liver failure
• Hemodilution (during massive transfusion)
• Vitamin K deficiency
• Anticoagulants
• Artifactual: heparin contamination of sample, lupus
anticoagulant, etc.
Chapter 16. Bleeding and Thrombosis in the ICU

4. 302
reactions, thrombotic thrombocytopenic purpura (TTP) (see
Box 16.2)), Occam’s razor suggests they are unlikely to be
factors here. If the platelet count deviates strikingly from the
clinical trajectory, however, one must be prepared to recon-
sider a broader differential diagnosis [2].
Box 16.2: Differential Diagnosis of Thrombocytopenia
in Critical Care
Common causes
• Sepsis
• Disseminated intravascular coagulation
• Consumption (in major trauma)
• Dilution (with massive transfusion)
• Myelosuppressive chemotherapy
• Mechanical circulatory support devices (e.g., intra-
aortic balloon pump, extracorporeal membrane
oxygenation)
Less common but important causes of thrombocyto-
penia that should not be missed:
• Heparin-induced thrombocytopenia
• Hemophagocytic syndrome
Uncommon causes of thrombocytopenia that
develop during ICU admission:
• Drug-induced thrombocytopenia (other than hepa-
rin or cytotoxic chemotherapy)
• Leukemia, myelodysplasia, aplastic anemia, etc.
(unless abnormalities were already present before
ICU admission)
• Thrombotic thrombocytopenic purpura
• Immune/idiopathic thrombocytopenia
• Posttransfusion purpura
D. S. Houston and R. Zarychanski

5. 303
To the extent that the thrombocytopenia is due to hyper-
splenism, little can be done; recovery of transfused platelets
will be poor because they too will be sequestered (Fig. 16.1).
Thrombocytopenia is highly prevalent in septic shock.
Multiple pathophysiological processes may contribute (see
Fig. 16.2) [2]. Consideration of these mechanisms suggests
hypotheses about treatments that would plausibly be benefi-
cial, but to date no specific treatments are known to improve
the thrombocytopenia of sepsis. A recent analysis of the time
course of thrombocytopenia in sepsis has illustrated that we
cannot expect the platelet count to recover while the patient
remains on vasopressors, and indeed the platelet count does
not typically start to recover for approximately 2 days after
vasopressor infusions stop (see Fig. 16.3) [3].
Tissue
factor
Coagulation
cascade
Thrombin
Fibrinogen
Fibrin
Fibrin
tPA
Plasminogen Plasmin
FDPs
Bleeding
Platelets
Microvascular
thrombosis
+
Figure 16.1 Pathophysiology of disseminated intravascular coagu-
lation: DIC is a clinical/pathological syndrome of uncontrolled and
delocalized thrombin generation followed by uncontrolled plasmin
activation, leading both to microvascular (and sometimes macro-
vascular) thrombosis and to diffuse bleeding
Chapter 16. Bleeding and Thrombosis in the ICU

6. 304
Management of Bleeding
She is actively bleeding, so the coagulopathy must be cor-
rected. Initial management will be similar regardless of the
results of these investigations. Because there may be a com-
ponent of vitamin K deficiency, empiric replacement with
10 mg of intravenous vitamin K is appropriate, but this should
not delay plasma replacement. One liter of plasma should
raise her fibrinogen by approximately 1 g/L, will replenish all
other coagulation factors, and is expected to decrease her
INR, though it will not correct fully. Further replacement
should be guided by laboratory testing. Prompt turnaround of
conventional hematologic and coagulation tests (platelets,
INR, aPTT, fibrinogen) can adequately inform blood product
administration. Point-of-care tests (e.g., thromboelastography
Thrombin
/ DIC
Complement
activation
Histone
release
ADAMTS13
depletion
Hemophagocytosis
Figure 16.2 Mechanisms of thrombocytopenia in sepsis. Multiple
mechanisms have been proposed to contribute to the thrombocy-
topenia of sepsis. The relative contribution of each potential
mechanism may vary among patients and within a given patient
over time. DIC, disseminated intravascular coagulation
D. S. Houston and R. Zarychanski

7. 305
(TEG) or rotation thromboelastometry (ROTEM)) can also
be used to guide blood product transfusion, but have mostly
been studied in operative settings or in the management of
trauma [4], and have not been conclusively demonstrated to
improve clinical outcomes in patients admitted to an ICU. If
she has DIC, she will require ongoing replacement until the
underlying driver of the DIC (in this case, sepsis) is corrected.
A diagnosis of DIC increases her risk of mortality approxi-
mately twofold [5]. If the coagulopathy is due to liver failure,
the correction achieved with plasma replacement will be
transitory. Repeated dosing may be needed, until bleeding is
controlled.
While coagulopathy and thrombocytopenia should be cor-
rected (to the extent possible) in a bleeding patient, this
should not distract from the need to identify the site of bleed-
ing and achieve local hemostatic control. In this woman,
urgent upper endoscopy is required to distinguish whether
400
360
320
280
240
200
160
120
80
40
0
−15
3# at time
Point eligible
8 35 131 89 47 30
−10 −5
Days before or after discontinutation of vasopressors
Plateletcount(x109/L)
0 5 10 15
Figure 16.3 Time course of thrombocytopenia in septic shock.
Mean platelet count (and 95% confidence interval) in patients with
septic shock who developed thrombocytopenia after ICU admis-
sion.Time axis is anchored to the day that vasopressors were discon-
tinued (day 0). Only data for survivors are included
Chapter 16. Bleeding and Thrombosis in the ICU

8. 306
the bleeding is due to esophageal varices or portal gas-
tropathy or to peptic ulceration, superficial erosions, telangi-
ectasias, or other causes. It is worth commenting that
hemostatic function probably plays relatively little role in the
cessation of bleeding from varices, which is largely deter-
mined by hemodynamic forces.
If severe bleeding continues and repeated red cell transfu-
sions are required, there is evidence that outcomes are better
if the hospital deploys a massive transfusion protocol, to
ensure that supply keeps up with demand, that appropriate
monitoring occurs, and that red blood cells, plasma, and plate-
lets are given in an appropriate ratio to avoid dilutional
coagulopathy and thrombocytopenia [6].
Factor VIIa is not recommended. Other than in hemo-
philia, when studied in randomized trials, it has failed to
improve outcomes in coagulopathic bleeding and increases
the risk of thrombosis [7]. Prothrombin complex concentrates
do not contain all the missing factors (especially Factor V)
and, except in the context of warfarin reversal, should not be
used. Fibrinogen concentrates may have a role, especially if
the patient has volume overload, but we prefer plasma as it is
the only product containing all the factors.
Use of tranexamic acid is controversial. The fundamental
pathophysiology of DIC is overwhelming activation of coag-
ulation, usually due to delocalized expression tissue factor,
and exhaustion of regulatory mechanisms, including tissue
factor pathway inhibitor, protein C, and antithrombin (see
Fig. 16.1). This leads to widespread thrombin generation
and fibrin deposition throughout the microvasculature.
Delocalized and excessive plasminogen activation is driven
by the excess of fibrin, which then results in fibrinolysis,
consumption of clotting factors, and bleeding [1]. Tranexamic
acid effectively inhibits plasmin generation and fibrinolysis,
and should be effective in reducing bleeding, but since
thrombin generation is then unopposed, it risks converting
the DIC to a thrombotic phenotype.
In critically ill patients with thrombocytopenia, when
platelets should be given is also a matter of clinical judgment,
D. S. Houston and R. Zarychanski

9. 307
informed by a paucity of high-quality trial data. Although
considerable practice variability exists, by extrapolation
from practice in the care of hematological malignancies,
prophylactic transfusion when the platelet count falls below
10 × 109
/L is recommended [8, 9]. This extrapolation, how-
ever, may not be valid; in patients admitted to medical-­
surgical ICUs, thrombocytopenia is frequently multifactorial,
and may be accompanied by acquired platelet dysfunction,
but also increased platelet turnover. For bleeding patients
with severe thrombocytopenia, there is consensus that
platelet transfusion should be given but little consensus of
what the target platelet count should be. Most authorities’
suggestions fall in a range between 50 and 100 × 109
/L,
depending on the severity or location of bleeding. In practice
it is often hard to maintain levels that high with transfusion
in such patients. We have provided some suggested target
platelet counts previously [2].
For our patient, plasma transfusion certainly takes prior-
ity over platelet transfusion unless her platelets fall much
more.
Part B: Case Presentation, Continued
The patient described in Part A is treated with broad-­
spectrum antibiotics to cover respiratory pathogens; the
regimen is subsequently tailored when blood and sputum
cultures grow Streptococcus pneumoniae. Mechanical venti-
lation is provided because of hypoxia and metabolic acido-
sis. The patient’s coagulopathy improves with plasma.
Upper GI endoscopy reveals a bleeding varix that is suc-
cessfully clipped. She has no further bleeding. Vasopressors
are weaned off after 4 days and the patient is extubated on
day 5.
On day 6 she develops worsening hypoxemia and tachy-
cardia. A portable chest X-ray shows improvement of her
pneumonia. A CT pulmonary angiogram demonstrates bilat-
eral segmental pulmonary emboli.
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10. 308
The patient’s hemoglobin is stable at 78 g/L. Platelets are
60 × 109
/L. They had fallen progressively over the first
4 days after admission but have been stable for the past
2 days. INR is 1.3, and the aPTT is 32 s.
Differential Diagnosis and Assessment
Although the patient is improving, she has a new, life-­
threatening, thrombotic event. Despite thromboprophylaxis,
venous thromboembolism (VTE) has been shown to occur in
approximately 6% of patients admitted to general medical-
surgical ICUs [10]. Risk factors associated with thrombosis in
critically ill patients include [11, 12]:
• Inflammation.
• Immobility.
• Use of vasopressors.
• Presence of central venous catheters.
• Increased body mass index.
• Platelet transfusion.
• Heparin-induced thrombocytopenia (HIT) is not com-
mon, occurring in approximately 0.3–0.6% of general
medical-­surgical ICU patients [10]. The onset of the fall in
platelet count due to HIT is characteristically 5–12 days
after exposure to heparin and can be associated with
venous and sometimes arterial thrombosis due to platelet
activation [13].
In this case presented, additional prothrombotic consider-
ations may be present:
• Inflammatory bowel disease has been shown to be an
independent risk for thrombosis in epidemiological
studies.
• While reduced synthesis of coagulation factor is expected
with hepatic dysfunction, the production of endogenous
anticoagulant proteins is also reduced. Therefore,
patients cannot be assumed to be protected from throm-
bosis despite elevation in the INR.
D. S. Houston and R. Zarychanski

11. 309
Other risk factors for thrombosis in critically ill patients
could include [11]:
• Antiphospholipid antibody syndrome
• A personal or family history of venous thromboembolism
• End-stage renal disease
• Mechanical circulatory support
• Microangiopathic hemolytic anemia (e.g., thrombotic
thrombocytopenia purpura, DIC)
• Malignancy
• Trauma and major surgery
Our patient has several risk factors for thrombosis, but
inflammation, immobility, the presence of a central venous
catheter, and recent use of vasopressors are likely the major
contributors. Hemorrhage itself adds further risk. The DIC
appears to have resolved with treatment of her sepsis.The con-
tribution of inflammatory bowel disease or hepatic dysfunc-
tion to her thrombotic propensity is possible. Given the early
onset of the fall in platelet count, a fall of less than 50% from
baseline, and the presence of an alternate cause of thrombocy-
topenia (i.e., sepsis), HIT is not suspected [14].As we’ve shown
above, in sepsis, recovery from thrombocytopenia typically lags
behind clinical recovery. Using a 4 T score would help confirm
the low pretest risk probability of HIT in this patient.
Management of Thrombosis
A new diagnosis of segmental or main pulmonary artery
embolus, or proximal deep venous thrombosis, requires
urgent therapeutic anticoagulation. For this patient, we favor
the use of intravenous unfractionated heparin, for several
reasons:
• It has a short half-life, so it can be interrupted briefly if
needed for procedures.
• An antidote (protamine) is available if she has bleeding,
for which she remains at elevated risk.
• Its clearance is not altered by renal dysfunction.
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12. 310
The conventional dosing for unfractionated heparin is
an 80 units/kg bolus followed by an infusion at 18 units/
kg/h to achieve an aPTT of 1.5–2.5× that of the normal
baseline. For this patient, we would adhere to this dosing,
but given the presence of thrombocytopenia, we would
empirically consider reducing the bolus dose by 25%. Prior
to the use of therapeutic unfractionated heparin, a base-
line aPTT should be obtained. If the baseline aPTT is pro-
longed, monitoring using anti-Xa levels should be
considered. Low molecular weight can also be considered
in a stable patient without renal dysfunction and risk fac-
tors for hemorrhage and who is not on vasopressor agents;
absorption from subcutaneous injections may be impaired
during shock [15]. Direct oral anticoagulants (DOACs) are
not recommended due to variable gut absorption of oral
medications in critical illness and the potential for renal
dysfunction.
The presence of thrombocytopenia can complicate the use
of therapeutic anticoagulants. While we acknowledge that
good studies are lacking, it is commonly accepted that a plate-
let count of 50 × 109
/L or greater permits the use of full-dose
anticoagulation. Inferior vena cava (IVC) filters should only
be used if full-dose anticoagulation is prohibitively risky; in
this case, we would insert a filter only if the heparin infusion
had to be stopped, either for bleeding or for a surgical inter-
vention [16].The patient with a platelet count between 30 and
50 × 109
/L who requires therapeutic anticoagulation provides
a challenge to the treating intensivist. In that setting, a
retrievable IVC filter plus a reduced dose of unfractionated
heparin, targeting an aPTT of 45–60 s, could be considered.
Prophylactic dose unfractionated heparin plus a retrievable
IVC filter may need to be considered for patients with a
platelet count less than 30 × 109
/L.
Systemic thrombolysis for the treatment of pulmonary
embolus is considered only for patients with hypotension
due to pulmonary vascular obstruction. In patients with sub-­
massive pulmonary embolism, systematic thrombolysis
results in earlier hemodynamic improvement but causes
D. S. Houston and R. Zarychanski

13. 311
increased major bleeding with uncertain difference in mor-
tality [17]. We would be further dissuaded from thrombolysis
in this patient because of her recent major hemorrhage.
Outcome
The patient clinically improved on unfractionated heparin.
After 5 days of treatment,she was on 2 liters of oxygen via nasal
prongs with an oxygen saturation of 98%. Due to concerns
regarding oral absorption, on the medical ward, the patient
transitioned first to therapeutic LMWH for 4 additional days.
Prior to discharge, she was prescribed a direct oral anticoagu-
lant to complete a 3-month course of therapeutic anticoagula-
tion, as is appropriate for a provoked pulmonary embolus.
Key Points
• Multiple causes of both bleeding and thrombosis
may coexist in a critically ill patient. Arriving at the
causes(s) of each requires the integration of a
patient’s past history, present illness, and the results
of laboratory testing.
• Management of DIC is to treat the underlying dis-
ease and to manage either bleeding or thrombosis if
present.
• Multiple mechanisms for thrombocytopenia in the
ICU can be present. Although drugs are often sus-
pected, they are rarely the cause.
• In septic shock, platelet recovery lags behind clinical
recovery.
• Plasma is the product of choice for bleeding in the
setting of DIC or liver failure.
• In the setting of acute venous thromboembolism,
effective anticoagulation is the priority.An IVC filter
should only be used if anticoagulation is
contraindicated.
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14. 312
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Chapter 16. Bleeding and Thrombosis in the ICU