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Hematologic Changes in Sepsis and Their Therapeutic Implications

Article  in  Seminars in Respiratory and Critical Care Medicine · January 2005


DOI: 10.1055/s-2004-860979 · Source: PubMed

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Hematologic Changes in Sepsis and Their
Therapeutic Implications
Richert E. Goyette, M.D.,1 Nigel S. Key, M.D.,2 and E. Wesley Ely, M.D., M.P.H.3

ABSTRACT

The blood and bone marrow constitute the hematologic organ system. Unlike
other organ systems, hematologic organs are distributed in space and provide for a variety
of seemingly unrelated functions. The hematologic system has both cellular and fluid-phase
elements. Cellular elements include erythrocytes, leukocytes, and platelets; fluid phase
elements include coagulation factors, natural antithrombotics, and proteins of the fibri-
nolytic system. The most common abnormalities of the hematologic system in patients
with sepsis are anemia, leukocytosis, thrombocytopenia, and activation of the hemostatic
system. Dysfunction of the hematologic organ system is an early manifestation of severe
sepsis and is seen in virtually all patients with this disease. In concert with alterations in the
endothelium, hematologic changes reflect both the body’s reaction to an infectious insult as
well as attempts to restore homeostasis. Dysfunction of the hematologic organ system can
contribute to multiple organ dysfunctions and death. Recognizing these sepsis-associated
changes and understanding the underlying pathophysiology are key to improving outcomes
in patients with this deadly disease.

KEYWORDS: Coagulation, erythrocytes, hematology, inflammation, leukocytes,


platelets, sepsis

Objectives: After reading this article, the reader should be able to: (1) recognize the blood and bone marrow as an organ system; (2)
understand the key role played by the endothelium in the septic process; (3) discuss alterations in red blood cells, white blood cells, and
platelets that occur in sepsis; and (4) describe the therapeutic implications of alterations in formed elements during sepsis.
Accreditation: The University of Michigan is accredited by the Accreditation Council for Continuing Medical Education to sponsor
continuing medical education for physicians.
Credits: The University of Michigan designates this educational activity for a maximum of 1 category 1 credit toward the AMA
Physician’s Recognition Award.

S epsis with acute organ dysfunction (severe sep- sepsis ranges from 28 to 50% or greater. Angus et al
sis) is common, frequently fatal, and associated with report that each organ dysfunction increases the mortal-
significant use of health care resources. In the United ity rate of severe sepsis by  20%. It has been estimated
States alone, there are more than 800,000 cases of severe that with the increase in the elderly population, use of
sepsis each year.1 The mortality in patients with severe more invasive diagnostic and therapeutic interventions,

Management of Shock; Editor in Chief, Joseph P. Lynch, III, M.D.; Guest Editors, Arthur P. Wheeler, M.D., Gordon R. Bernard, M.D. Seminars
in Respiratory and Critical Care Medicine, volume 25, number 6, 2004. Address for correspondence and reprint requests: E. Wesley Ely, M.D.,
M.P.H., Center for Health Services Research, #6109 MCE, Vanderbilt University Medical Center, Nashville, TN 37232-8300. E-mail:
wes.ely@vanderbilt.edu. 1Consultant, hematology and oncology, private practice, Knoxville, Tennessee; 2Department of Medicine, Division of
Hematology, Oncology, and Transplantation, University of Minnesota Medical School, Minneapolis, Minnesota; 3Department of Medicine,
Division of Allergy/Pulmonary/Critical Care Medicine and Center for Health Services Research and the VA Tennessee Valley Geriatric Research,
Education, and Clinical Center (GRECC), all at the Vanderbilt University School of Medicine, Nashville, Tennessee. Copyright # 2004 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 1069-3424,p;2004,25,06,645,659,
ftx,en;srm00336x.
645
646 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 6 2004

and increasing numbers of immunocompromised pa- endothelial cells. For example, a single injection of
tients, the incidence of severe sepsis will increase at least endotoxin in rabbits produces desquamation of  25%
1.5% per year for the next 50 years. The hematologic of the aortic endothelial surface area within 5 days.6
organ system is a major element in the response to a Alternately, organisms such as Rickettsiae can directly
septic insult and plays a pivotal role in the resolution infect endothelial cells and disrupt cellular homeostasis.
phase of severe sepsis.2 Therefore, it is important for Severe endothelial injury from a variety of etiologies can
critical care specialists to be aware of the manifestations produce microvascular coagulopathy and acute organ
and consequences of hematologic dysfunction in patients dysfunction.7
with severe sepsis. Elevated circulating levels of the soluble (s) forms
of thrombomodulin (TM), ICAM-1 (intercellular adhe-
sion molecule-1), E-selectin, and von Willebrand factor
THE HEMATOLOGIC ORGAN (vWF) are frequently measured markers of endothelial
SYSTEM DEFINED dysfunction and injury.8 In children with septic shock,
Organ systems consist of anatomically and/or physiolo- soluble TM levels are increased and the levels correlate
gically related components. Because the activity of most with survival status and the extent of organ dysfunction.9
organ systems is focused on a single goal (e.g., gas In a population of patients with sepsis, plasma levels of
exchange), the concept is easy to understand. Unlike vWF, ICAM-1, and sE-selectin were significantly in-
the heart or the lungs, however, the hematologic system creased within 8 hours of the development of the acute
is diffuse, has both cellular and fluid phase elements, and respiratory distress syndrome (ARDS).10 Sepsis is asso-
serves a variety of unrelated functions. Consequently, its ciated with apoptosis of various cell types.11 In patients
role as an organ system is often underappreciated. with severe sepsis, endothelial cell apoptosis may produce
Cellular elements of the hematologic system originate abnormalities in trafficking of blood cells into an infected
in the bone marrow, transit the blood, and then either focus, vasoregulation, and the antithrombosis–thrombo-
exit the body or are cleared by the reticuloendothelial sis balance that may contribute to the pathogenesis of
system. Cellular elements include red blood cells, white septic manifestations such as multiple organ dysfunction,
blood cells, and platelets. Fluid-phase components in- impaired microvascular blood flow, and inability of the
clude coagulation factors, natural anticoagulants, and body to restore homeostasis.
proteins of the fibrinolytic system. Disparate physiolo-
gical functions of the hematologic system include gas
ALTERATIONS OF THE ERYTHRON
exchange, acid–base balance, innate and adaptive im-
IN SEPSIS
munity, and hemostasis. Hematologic changes are al-
The erythron is the organ responsible for the production
most universal in patients with severe sepsis. Although
of erythrocytes. It is composed of committed red blood
sepsis-associated hematologic changes can be beneficial,
cell progenitors, developing erythrocytes, reticulocytes,
dysfunction, evidenced by alterations in the number of
and mature red blood cells. Mature red blood cells are
cells, the properties of cells, fluidity of the blood, and/or
anucleate, hemoglobin (Hb)-containing sacs, with en-
integrity of the vasculature, can contribute to both
zyme systems necessary to maintain the integrity of the
morbidity and mortality.
sac (red blood cell membrane) and prevent oxidative
damage to the contents (Hb).
THE ENDOTHELIUM
Endothelial cell function is tightly integrated with the Physiology
physiology of the hematologic system, and dysfunction The sole function of Hb is oxygen transport; when fully
plays a key role in many of the hematologic manifesta- saturated, each gram of Hb can bind 1.39 mL of oxygen.
tions of sepsis. Therefore, a brief discussion of endothe- Oxygen delivery is a critical physiological process that is
lial cell physiology is warranted before sepsis-related a function of microcirculatory blood flow, oxygen con-
changes in the hematologic organ system are discussed. centration in the blood, and oxyhemoglobin dissociation.
With  1011 endothelial cells and a surface area Because the absolute amount of oxygen physically dis-
estimated to exceed 1,000 m2, the endothelium surpasses solved in the blood is minimal, the arterial oxygen
the skin as the largest organ in the body.3,4 The great saturation (SaO2) essentially describes the oxygen that
majority of the endothelium is located in the microvas- is bound to Hb. The oxygen affinity of Hb is a measure
culature where the endothelial surface area per unit of of the pO2 at which Hb is 50% saturated with oxygen
blood volume is 2 to 3 thousand times greater than in the (P50). In nonsmokers, the P50 is normally 26.6 mm Hg
larger blood vessels.5 Endothelial dysfunction is a key and varies with the concentration of 2,3-DPG (2,3-
element in the pathogenesis of severe sepsis. This may be diphosphoglycerate), temperature, and pH.
secondary to the effects of endotoxin, proinflammatory The Hb concentration is a function of patient age,
cytokines, reactive oxygen species, or other substances on gender, race, activity level, and altitude above sea level.
HEMATOLOGIC CHANGES IN SEPSIS/GOYETTE ET AL 647

Following puberty, Hb levels are  2.0 g/dL higher in include damage to membrane proteins from reactive
men than in women, a difference that is a function of the oxygen species generated by inflammatory cells and
physiological effects of testosterone on the erythron. ischemic tissues. Thus, in addition to its negative effect
African Americans have Hb levels that are  0.5 g/dL on oxygen delivery, decreased red blood cell deform-
lower than Caucasians. A recumbent posture for 1 hour ability may contribute to organ dysfunction outside of
will result in a 6% decrease in HCT (hematocrit), with a the hematologic system. Although its clinical utility has
return of the value to normal  15 minutes after resum- not been established, altered red blood cell deformability
ing an upright posture. These changes are the result of has been proposed as a tool to detect sepsis before the
postural fluid shifts between the intra- and extravascular appearance of more classical signs and symptoms.13
components of the extracellular fluid space. Over time, Experimentally, red blood cell aggregates that
altitude-dependent increases in erythropoiesis in indivi- could impair microcirculatory blood flow have also
duals residing at 15,000 feet can produce a ‘‘normal’’ Hb been reported in sepsis.14 This tendency to form aggre-
that may be as much as 4 g/dL greater than that gates likely has a nonimmunologic etiology and may be a
observed in healthy adults residing at sea level. consequence of increased acute phase proteins such as
fibrinogen that can decrease the erythrocytes’ negative
charge (zeta potential), the electrical potential that
Pathophysiology promotes mutual red blood cell repulsion. Although
Alterations in the properties of individual red blood cells the significance of red cell aggregates in sepsis patho-
may contribute to the pathophysiology of sepsis. These physiology is unclear, one laboratory manifestation of
alterations include abnormalities of oxygen carrying the decrease in erythrocyte zeta potential is an increased
capacity and changes in red cell mechanical properties erythrocyte sedimentation rate (ESR).
that may alter the rheology of the microcirculation. In
addition, changes in the erythron can affect other com-
ponents of the hematologic system. For example, the Clinical and Laboratory Manifestations
HCT level is inversely correlated with the bleeding time, Extravascular leak of fluids at the onset of sepsis has the
a test that reflects both platelet function and microvas- potential to produce hemoconcentration. This situation
cular integrity. can result in a relative erythrocytosis during the initial
phase of sepsis. With time, however, the most common
ALTERATIONS IN OXYGEN CARRYING CAPACITY alteration in the erythron in patients with sepsis is
The capacity of the blood to carry oxygen can be anemia. Anemia results in a decrease in the oxygen-
impaired by changes in Hb’s oxygen affinity or its carrying capacity of the blood. Although anemia can be
concentration or both. Fever and acidosis in patients identified by decreases in the number of erythrocytes or a
with sepsis shift the oxygen dissociation curve to the fall in the HCT, the diagnosis is best established by the
right. As a consequence of the decreased oxygen affinity, Hb concentration. This does not reflect superiority of
red blood cells release oxygen to the tissues more readily. one parameter or another; instead, the Hb concentration
Increased levels of erythrocyte 2,3-DPG also favor oxy- is preferred because it most closely reflects the blood’s
gen release. Unfortunately, 2,3-DPG is depleted in oxygen carrying capacity.
banked blood and is not restored to normal levels for
 6 to 12 hours following transfusion. Consequently,
immediately following transfusion the Hb in transfused Diagnostic Considerations
red blood cells fails to release oxygen as readily and at Apart from hemodilution, anemia may be the result of
the same pO2 levels as Hb in metabolically intact blood loss, decreased production (hypoproliferative ane-
erythrocytes. mia), or increased destruction (hemolytic anemia) of red
blood cells. In most instances, therefore, the anemia in
ALTERATIONS IN PROPERTIES OF ERYTHROCYTES patients with sepsis is multifactorial in origin.
In patients with sepsis, alterations in the mechanical
properties of the red blood cells may impair microcircu- BLOOD LOSS
latory blood flow, which may in turn decrease tissue Anemia in patients with severe sepsis may be a conse-
oxygen delivery. Cellular deformability, the ability of a quence of bleeding. In most instances, the diagnosis and
cell to change its shape in response to applied forces, is source of blood loss are readily apparent. The source of
an important determinant of microcirculatory blood the anemia may be less evident in patients who become
flow. Decreased red blood cell deformability occurs early septic following major trauma with bleeding into the soft
in sepsis and has the potential to reduce blood flow and tissues of the thigh or the retroperitoneum, for example.
increase the time required for cells to transit the micro- Significant blood loss can also occur as a result of
circulation.12 Alterations in the red blood cell membrane multiple phlebotomies necessary to obtain blood to
responsible for increased cellular rigidity probably diagnose and monitor patients with critical illnesses
648 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 6 2004

such as severe sepsis. It has been estimated that repeated


phlebotomies result in a loss of 24 to 41 mL of blood
daily.15–17 In a study of patients with arterial lines
hospitalized in the intensive care unit (ICU), the mean
blood loss was 944 mL.18 This is equivalent to almost
20% of the blood volume of a 70 kg man and contributed
to transfusion requirements in this population.

ANEMIA OF SYSTEMIC INFLAMMATION


Patients with the systemic inflammatory response syn-
drome (SIRS) may be anemic. The anemia of systemic
inflammation has also been called the anemia of chronic
disease. However, the latter term is a misnomer because
this syndrome can develop within days of the inciting Figure 1 Peripheral blood smear from a patient with dissemi-
event in patients with sepsis and other inflammatory nated intravascular coagulation. Important manifestations include
disorders.19 Characteristic pathophysiological features of the presence of schistocytes (fragmented erythrocytes) and the
relative absence of platelets.
this hypoproliferative anemia include a reticuloendothe-
lial block in iron transport, decreased sensitivity of the with underlying glucose-6-phosphate dehydrogenase
erythron to erythropoietin, and shortened red blood cell (G6PD) deficiency (more common in those of Medi-
survival.20 It is tempting to speculate that because this terranean or African descent) or an unstable hemoglo-
cytokine-mediated process effectively sequesters iron bin. In addition, endogenous oxidants and acid
required for microbial growth (as well as erythropoiesis), metabolites produced during acute infection may con-
it may have evolved as a protective mechanism.21 tribute to hemolysis in susceptible patients. During the
The anemia is generally mild with Hb and HCT values workup of suspected hemolysis in a patient with sepsis, it
of 8 g/dL and 24% or greater, respectively. The block in is important to bear in mind the possibility that a
reticuloendothelial iron transport is significant enough positive direct antiglobulin (Coombs’) test may be pro-
in approximately one third of patients to produce micro- duced not only by autoantibodies but also by adsorption
cytic red blood cell indices suggestive of iron deficiency. of certain antibiotics (e.g., cephalosporins) onto the
Other laboratory features include low serum iron and surface of red blood cells. In most cases of severe sepsis,
iron-binding capacity and increased serum ferritin. infection-associated hemolysis plays only a minor role in
Multiorgan dysfunction in patients with severe sepsis clinical manifestations and outcome. However, experi-
can contribute to the onset or progression of the anemia mental evidence suggests that hemoglobinemia can in-
of systemic inflammation. crease lethality of endotoxemia through a tumor necrosis
factor (TNF)-mediated mechanism.23
HEMOLYSIS
Sepsis may precipitate disseminated intravascular coa-
gulation (DIC) with hemolysis due to red blood cell Treatment Considerations
fragmentation. Approximately 25% of patients with Critically ill patients typically receive multiple transfu-
DIC will have clinical evidence of microangiopathic sions of packed red blood cells (PRBCs). In one study,
hemolysis manifested by the presence of schistocytes 85% of patients hospitalized in the ICU for more than 1
on their peripheral blood smear (Fig. 1). Although the week received blood transfusions (9.5  0.8 U per pa-
clinical presentation is usually not that of severe sepsis, tient).24 These were not single-unit transfusions nor
babesiosis, bartonellosis, leishmaniasis, and malaria can were they generally administered because of bleeding.
also be associated with a prominent hemolytic compo- Instead, patients were transfused a constant 2 to 3 units
nent. Clinically significant hemolysis can occur in pa- of PRBCs per week with approximately one third of the
tients with sepsis due to Clostridium perfringens or type B units administered in the absence of a clear indication.
Haemophilus influenzae. In the former, intravascular Packed red blood cells are prepared by differential
hemolysis is due to the effects of bacterial lysolecithins centrifugation, which removes  80% of the plasma
that directly lyse red blood cell membranes. In the latter, resulting in a volume and HCT of  350 mL and
polyribosyl ribosyl phosphate (PRP) from bacterial cap- 60%, respectively. When transfused into a 70 kg adult,
sular polysaccharides is released during infection and one unit of packed red blood cells will increase the Hb
binds to the red cell surface.22 Subsequently, these and HCT by  1 g/dL and 3%, respectively. Obviously,
patients may develop antibodies to PRP, which may continued bleeding or aggressive fluid resuscitation will
result in complement-mediated hemolysis. Treatment of blunt this response.
infections with sulfonamides and other antibiotics can Until recently, many critical care specialists chose
precipitate Heinz body hemolytic anemia in patients a relatively liberal transfusion strategy based upon the
HEMATOLOGIC CHANGES IN SEPSIS/GOYETTE ET AL 649

assumption that a more normal oxygen-carrying capacity transfused red blood cells and other appropriate mea-
would benefit the recovery process.25 Despite its life- sures can help to restore the balance between oxygen
saving benefits, however, transfusion of red blood cells is delivery and oxygen demand.
associated with several potential complications. In addi-
tion to alloimmunization and transmission of infectious
disease, complications of particular importance in the ALTERATIONS OF LEUKOCYTES IN SEPSIS
ICU setting include acute hemolytic transfusion reac- Leukocyte alterations are common in patients with
tions, transfusion-related acute lung injury (TRALI), severe sepsis. In fact, white blood cells  12.0  109 /L,
and nosocomial infections secondary to transfusion-  4.0  109 /L, or a left shift with > 10 immature
mediated immunomodulation.26 Hébert et al recently neutrophils (bands) are one of the four SIRS criteria
compared restrictive and liberal transfusion strategies in employed to establish a diagnosis of sepsis in patients
a population of critically ill subjects.27 They reported with infection.31
that a restrictive transfusion strategy with a Hb trigger of
< 7 g/dL was as effective as a more liberal strategy that
used a Hb of < 10 g/dL to trigger transfusion of red cells Pathophysiology and Background
in patients without an acute coronary syndrome. How- The initial response to a septic challenge is met by
ever, the mortality benefit of this intervention remains to elements of the innate limb of the immune system. In
be confirmed by a large-scale, randomized clinical trial. humans, cellular effectors of innate immunity include
One strategy to improve oxygen carrying capacity neutrophils, monocytes/macrophages, natural killer
without transfusion is the administration of recombinant (NK) cells, and platelets. Neutrophils play important
human erythropoietin (rHuEPO). Exogenous rHuEPO roles by phagocytosing infectious organisms, crystalline
compensates for the body’s relatively blunted erythro- material (e.g., uric acid), and immune complexes. Cyto-
poietic drive produced by the anemia of systemic in- kines released during inflammation and infection pro-
flammation. In a recent randomized controlled trial of mote migration of bands and mature neutrophils from
critically ill patients, administration of 40,000 units of the maturation-storage pool in the bone marrow into the
rHuEPO decreased the total number of transfused units circulation, whereas metamyelocytes are not released
of PRBCs by 19% compared with placebo.28 In addition, into the blood except in extreme circumstances. Follow-
patients who received rHuEPO had higher Hb levels, ing release, granulocytes randomly enter either the
despite receiving fewer transfusions than the control circulating or the marginating pools; the concentration
group. However the outcomes were similar between of cells in each pool is approximately equal. A neutro-
the groups, and a cost–benefit analysis of this strategy philic leukocytosis is an appropriate response to many
is not available at this time. types of infections. However, when the neutrophilic
The complex systems that balance tissue oxygen response is exaggerated, lysosomal enzymes and toxic
delivery with tissue oxygen demand are impaired and can oxygen metabolites released by the excess of inflamma-
produce tissue hypoxia in patients with sepsis and other tory cells can damage host tissue adjacent to the inflam-
critical illnesses. Given the importance of oxygen avail- matory focus. Oxidants released from granulocytes may
ability to the tissues, several randomized, controlled also inactivate tissue protease inhibitors and thereby
clinical trials have evaluated the role of increased global contribute to injury of endothelial and parenchymal cells
oxygen delivery (DO2). Surprisingly, trials of supranor- by allowing unchecked enzymatic activity of elastase,
mal DO2 have reported conflicting results, with some collagenase, and other matrix metalloproteinases. In
showing decreased mortality, others showing no change, addition, leukocyte counts in excess of 50  109 /L in-
and one reporting increased mortality.29 Recently, Rivers crease blood viscosity with the potential to impair
et al reported that early goal-directed therapy (EGDT) microcirculatory blood flow.
consisting of standard measures to optimize the central The monocyte/macrophage is the human analog
venous pressure (CVP), mean arterial pressure (MAP), of the invertebrate amoebocyte: an innate immune cell
and urine output (UOP) plus treatment to increase that is involved in response to pathogens, wound repair,
central venous oxygen saturation (SCVO2) to 70% or and hemolymph clotting. By virtue of their ability to
greater significantly decreased mortality in patients with upregulate synthesis and release of cytokines such as
severe sepsis.30 Critical elements of the process included tumor necrosis factor alpha (TNF-a), as well as expres-
initial treatment for 6 or more hours in the emergency sion of tissue factor (TF), monocytes provide one of
department, continuous monitoring of SCVO2, transfu- the critical links between inflammation and coagulation.
sions of PRBCs to a target HCT of at least 30%, and Monocytes originate in the bone marrow and then
inotropic support with dobutamine if the SCVO2 re- transit the peripheral blood to lodge in tissues as long-
mained < 70% despite optimized CVP, MAP, UOP, lived macrophages, such as Kupffer’s cells and
and HCT. Thus early identification and treatment of other reticuloendothelial elements. Monocytes possess
global tissue hypoxia despite stable vital signs with pathogen-associated molecular pattern signaling
650 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 6 2004

receptors such as toll-like receptors that are a key include splenomegaly, granulocyte counts > 50  109 /L,
component of the innate immune system.32 Unlike the basophilia, and the presence of small numbers of circu-
antigen receptors of B- and T-cells, these receptors are lating blasts and promyelocytes. Additional laboratory
encoded in the germline and trigger an immediate studies are not usually required. However, unlike the
effector function. septic patient who has a normal or elevated leukocyte
alkaline phosphatase (LAP), decreased or absent stain-
able LAP is a feature of granulocytes in CML. Other
Clinical and Laboratory Manifestations laboratory studies that can establish the diagnosis of
Neutrophilic leukocytosis is a common manifestation of CML but are rarely required on an emergent basis
sepsis. It appears to result from a combination of factors, include identification of the Philadelphia chromosome
including recruitment of mature neutrophils from the by cytogenetic analysis or fluorescent in situ hybridiza-
marginating pool into the circulating pool, mobilization tion, or the presence of the bcr-abl fusion oncogene, the
of mature and developing neutrophils from the bone Philadelphia chromosome’s molecular equivalent.
marrow, and eventually increased leukopoiesis. In most
instances, the leukocytosis is moderate. Examination of
the peripheral blood smear in patients with sepsis may Treatment Considerations
show persistence of the primary granules that first appear White blood cell changes of sepsis resolve with effective
at the stage of the promyelocyte (toxic granulation), therapy of the primary disorder. Although the use
residual blue-gray areas of ribonucleic acid (RNA)-rich of hematopoietic growth factors such as granulocyte-
cytoplasm (Döhle’s bodies), and cytoplasmic vacuoles colony-stimulating factor (G-CSF) or granulocyte
(i.e., phagolysosomes, autophagic vacuoles). In some macrophage-colony-stimulating factor (GM-CSF) to
instances, intracellular bacteria can be identified in a activate leukocytes and increase their numbers is theo-
stained buffy-coat smear. Neutropenia in patients with retically attractive, particularly for patients with sepsis
sepsis can be the result of depletion of bone marrow and neutropenia, there is no evidence that this approach
granulocyte precursors, a granulocytic ‘‘maturation ar- improves outcomes.34
rest,’’ or migration of leukocytes into the infected focus
in numbers in excess of the bone marrow’s ability to
replace them in a timely fashion. Although neutropenia ALTERATIONS OF PLATELETS IN SEPSIS
can occur in adult patients with severe sepsis, it is more Thrombocytopenia is a frequent accompaniment of
common in the pediatric population.33 critical illness and is commonly employed in clinical
trials of severe sepsis therapies as a marker of hemato-
logic organ system dysfunction.35,36 In the ICU setting,
Diagnostic Considerations platelet counts < 100,000/mm3 (< 100  109/L) are
Sepsis may be the presenting manifestation of a primary identified in 20 to 40% of patients.37–39 In a study of
hematologic disorder. For example, infection may be the an ICU population, sepsis was identified as a major risk
first clue to the neutropenia of aplastic anemia, agranu- factor for thrombocytopenia.37 Platelet counts in criti-
locytosis, or acute leukemia. In most instances, the cally ill patients are also related to prognosis independent
etiology of the white blood cell changes is obvious. For of the Simplified Acute Physiology Score II (SAPS II)
example, patients with aplastic anemia are pancytopenic, and Acute Physiology and Chronic Health Evaluation II
and the typical patient with sepsis will not have the (APACHE II) severity scores. In addition, a blunted rise
circulating blasts, promyelocytes, myelocytes, or baso- in previously depressed platelet counts is associated with
philia that may be variably present depending on the type poorer outcomes in acutely ill patients.40
of leukemia.

LEUKEMOID REACTION Pathophysiology and Background


A patient with sepsis may sometimes present with Megakaryocytes are derived from multipotential hema-
leukocyte counts in excess of 50  109/L. This extreme topoietic progenitor cells. Acting under the influence of
nonneoplastic leukocytosis is known as a leukemoid thrombopoietin (TPO) and other cytokines, such as
(leukemia-like) reaction. Although infection secondary stem cell factor, interleukin (IL)-3, IL-6, IL-11, and
to granulocyte dysfunction is uncommon in patients erythropoietin, progenitor cells progressively differenti-
with chronic myelogenous leukemia (CML), patients ate into promegakaryoblasts and mature megakaryo-
with previously undiagnosed CML may also develop cytes.41 Platelet formation results from a combination
sepsis. In this case, it is important to differentiate a of budding of platelets from the megakaryocytes’ surface,
leukemoid reaction secondary to sepsis from CML in a release of platelets from small preformed regions of
septic patient. Clues from the initial examination and the mature megakaryocyte, and by formation of propla-
laboratory studies that are suggestive of coexistent CML telets, long filaments of megakaryocyte cytoplasm.42
HEMATOLOGIC CHANGES IN SEPSIS/GOYETTE ET AL 651

Proplatelets enter the circulation and progressively 4 days following heparin exposure in 10 to 20% of
fragment to yield individual platelets. In a healthy adult, patients.49 The disorder is transient, non–immune media-
the normal platelet count is  150,000 to 450,000/mm3 ted, and reversible despite ongoing heparin exposure. In
(150–450  109 /L). general, patients with type I HIT are asymptomatic and
platelet counts do not drop below 100  109 /L.
On the other hand, type II HIT is a potentially
Clinical and Laboratory Manifestations fatal disorder that is associated with significant morbid-
Sepsis-associated thrombocytopenia is multifactorial in ity that may be confused with thrombotic DIC in a
origin. In experimental models of sepsis, platelets adhere patient with severe sepsis. As an immune-mediated
to activated endothelium in multiple organs.43,44 Fol- clinicopathological syndrome, it typically develops 5 to
lowing adhesion, activated platelets may either dislodge 14 days after heparin exposure—a time interval that can
and return to the circulation or release their granule be as short as several hours in patients who have been
contents and undergo irreversible aggregation with vis- recently exposed to the drug. Type II HIT develops in 1
cous metamorphosis. Inflammatory mediators and bac- to 5% of patients treated with unfractionated heparin,
terial products such as endotoxin can contribute to and in a much lower proportion of patients exposed to
sepsis-associated thrombocytopenia by enhancing plate- low molecular weight heparin (LMWH). Thrombocy-
let reactivity and adhesivity.45 Phagocytosis of platelets topenia is more severe with platelet counts below 60 
by reticuloendothelial elements may also contribute to 109 /L (although usually not below 20  109 /L) and
the cytopenias of sepsis. Microscopy of bone marrow unlike type I HIT, the thrombocytopenia persists for
aspirates of patients with sepsis often demonstrates days after heparin has been discontinued. Paradoxically,
hemophagocytic histiocytes.46 In a prospective study of bleeding in patients with HIT II is rare. Instead,  50%
50 patients with sepsis and thrombocytopenia, hemo- of patients present with arterial and venous thrombosis
phagocytosis was identified in 32 patients (64%). This that may be isolated or develop in multiple vessels. The
process appears to be a function of elevated levels of mortality and limb loss rate from amputation in patients
macrophage-colony-stimulating factor and is correlated with HIT II have each been estimated to be as high as
with the presence and extent of multiorgan dysfunc- 30%. Pathophysiologically, HIT II results from antibo-
tion.47 However, a cause and effect relationship has not dies, predominantly immunoglobulin G (IgG), that
been demonstrated. Instead, hemophagocytosis of plate- develop in response to an antigen formed by a complex
lets may represent a mechanism through which non- between platelet factor-4 (PF-4) and heparin. Binding of
pathogenic immunoglobulin bound to bacterial products antibody to the PF-4-heparin complex induces platelet
on the surface of platelets is cleared.46 In some patients aggregation with thrombocytopenia and platelet activa-
with sepsis, however, antibodies to specific platelet anti- tion with release of platelet microparticles, which are
gens such as GP IIb/IIIa or GP Ib/IX have been believed to be responsible for the thrombotic diathesis.50
detected.48 Because similar antibodies have been impli- When clinically suspected, HIT II should be treated
cated in the pathogenesis of immune thrombocytopenic accordingly. However, the diagnosis requires subsequent
purpura (ITP), these autoantibodies may contribute to laboratory confirmation, preferably with both a func-
sepsis-associated thrombocytopenia in some patients. tional assay of serotonin release from normal donor
platelets exposed to patient plasma in the presence of
heparin, and an assay for the presence of the PF-4-
Other Diagnostic Considerations heparin antibody; for example, by enzyme-linked im-
munosorbent assay (ELISA). In practice, the ELISA
HEPARIN-INDUCED THROMBOCYTOPENIA assay (which has a moderately high sensitivity with low
Critically ill patients, including those with severe sepsis, specificity) is widely used as a screening test, whereas the
are often exposed to heparin administered for thrombo- ‘‘gold standard’’ serotonin release assay is offered by
prophylaxis or to maintain patency of indwelling lines or relatively few laboratories. Treatment of confirmed cases
to coat vascular catheters. Although the prophylactic of HIT II (with or without confirmed thrombosis)
value of unfractionated heparin and its low-molecular should include cessation of all heparin and administra-
weight derivatives has in general a very favorable benefit– tion of a direct thrombin inhibitor such as lepirudin or
risk profile, even minimal amounts of these drugs may argatroban by continuous infusion. In Canada and
induce heparin-induced thrombocytopenia (HIT) that Europe, danaparoid is another alternative agent that
may be mistaken for the thrombocytopenia of sepsis. may be used. LMWH should be avoided because anti-
Although thrombocytopenia can also be induced by other bodies can cross-react with the PF-4–LMWH complex.
drugs (e.g., quinidine), HIT is unique because the throm- Warfarin anticoagulation should be avoided until the
bocytopenia can be associated with significant morbidity platelet count has recovered to at least > 100  109 /L on
and mortality resulting from thrombosis. Two types of antithrombin therapy because the drug may diminish
HIT have been identified. Type I HIT presents 1 to circulating protein C levels in the short term, which may
652 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 6 2004

in turn exacerbate the procoagulant state and result in incorporated into clinical practice for patients with and
venous limb gangrene.51 without malignancy. Since that time, and due to the
more accurate automated methods of determining plate-
PSEUDOTHROMBOCYTOPENIA let count and subsequent risk of spontaneous bleeding,
Pseudothrombocytopenia should be suspected when a most clinicians now use a threshold of < 10  109 /L to
low platelet count is reported by the clinical laboratory in trigger prophylactic platelet transfusion in a nonbleed-
a patient without clinical manifestations of thrombocy- ing, nonseptic patient with hypoproliferative thrombo-
topenia or when other organ dysfunctions are absent. cytopenia. However, platelet counts of 15 to 20  109 /L
Artifactually low platelet counts may be due to several are recommended in patients with concomitant fever or
causes. They include platelet aggregation in finger-stick infection.55 During the study of treatment of patients
samples, giant platelets not recognized as thrombocytes with severe sepsis with activated protein C, the safety
by automated cell counters, platelet satellitosis, or platelet data were generated with platelet counts maintained
clumping. The latter is produced by the presence of above 30  109 /L.
anticoagulant-dependent platelet agglutinins.52 Although
it is most commonly seen with EDTA, platelet clumping WATCHFUL WAITING
can also occur with other anticoagulants. A septic patient with a low absolute risk for thrombo-
cytopenic bleeding with a stable platelet count of
HYPOPROLIFERATIVE THROMBOCYTOPENIA  20  109 /L may be carefully observed. However,
The bone marrow of some patients with severe sepsis other risk factors commonly associated with sepsis such
and thrombocytopenia may be hypocellular with de- as fever, increased platelet consumption, a declining
creased numbers of megakaryocytes. Several processes platelet count, renal failure, and/or treatment with drugs
can be responsible for hypoproliferative thrombocytope- that inhibit platelet function or an anticoagulant warrant
nia. For example, it may be a consequence of the effects prophylactic platelet transfusion.
of cytokines, drug-induced injury, preexisting disease, or
an acute folic acid deficiency. PLATELET TRANSFUSIONS
Platelet transfusions remain the ‘‘gold standard’’ for the
OTHER CAUSES treatment of clinically significant thrombocytopenia.
Thrombocytopenia due to accelerated platelet destruc- However, their use is associated with several complica-
tion may be due to immunologic or nonimmunologic tions, including pyrogenic reactions, allergic reactions,
causes in infected patients. Immunologic disorders pro- and disease transmission.56 In fact, the risk of transmis-
ducing thrombocytopenia can be autoimmune (e.g., sion of viral diseases is the same as that associated with
collagen vascular disorders, drugs, etc.) or alloimmune transfusion of a single unit of PRBCs (in the case of a
(e.g., posttransfusion purpura). Nonimmunologic etiol- single donor platelet pheresis unit) or five to eight donor
ogies include microangiopathic disorders such as DIC exposures (in the case of pooled random donor platelets).
and thrombotic thrombocytopenic purpura (TTP). One unit of platelets contains the number of platelets in
a unit of fresh whole blood in a volume of  50 mL. In
the absence of a consumptive process (e.g., fever, DIC,
Treatment Considerations bleeding, or alloimmunization) or sequestration (e.g.,
As the platelet count progressively falls below 150  splenomegaly), one unit of platelets should increase the
109 /L, the risk of bleeding increases; however, platelet platelet count by  10  109 /L/m2 ( 7  109 /L in a
counts above 60  109 /L enable patients to withstand 70 kg adult). A pheresis pack contains the equivalent of 6
most minor hemostatic challenges. Risk–benefit assess- to 10 units of platelets, and is obtained from a single
ment should be employed when considering the admin- donor by platelet pheresis. In general, one platelet
istration of anticoagulants or drugs that impair platelet pheresis pack will increase the platelet count of a stable
function when counts are less than 30  109 /L. Platelet 70 kg adult by  60  109 /L.
counts below 20  109 /L can be accompanied by pete-
chiae, ecchymoses, epistaxis, and serious internal bleed-
ing. The relationships between platelet count and ALTERATIONS OF THE HEMOSTATIC
bleeding risk are largely derived from observations of SYSTEM IN SEPSIS
patients with untreated acute leukemia in the early
1960s.53,54 Although no clear threshold for bleeding Pathophysiology and Background
was identified, the percentage of days in which patients The coagulopathy of sepsis results from the effects of
experienced thrombocytopenia-associated hemorrhage cytokines, bacterial products, and in some cases, direct
rose steadily after platelet counts dropped below a range endothelial cell injury. In addition to the thrombocyto-
of 20  109 /L to 50  109 /L. This ‘‘trigger’’ for prophy- penia described earlier, hemostatic changes of
lactic platelet transfusions of  20  109 /L was widely sepsis-induced coagulopathy include prothrombotic
HEMATOLOGIC CHANGES IN SEPSIS/GOYETTE ET AL 653

manifestations and impairment of the body’s natural receptor (EPCR) and circulating protein S, protein C is
fibrinolytic potential. converted to its active form and exerts several antiin-
flammatory, antithrombotic, and profibrinolytic proper-
ACTIVATION OF PROCOAGULANT PATHWAYS ties. Levels of protein C decrease 12 hours (median)
The initial step in the coagulopathy of sepsis involves before the onset of the clinical symptoms of severe sepsis
activation of the tissue factor pathway of coagulation and septic shock and are low in more than 90% of
(formerly known as the ‘‘extrinsic pathway’’). Tumor patients with severe sepsis.65,66 The Protein C World-
necrosis factor and IL-1 are believed to play a crucial wide Evaluation in Severe Sepsis (PROWESS) trial
role in the activation of coagulation during sepsis. demonstrated that treatment with recombinant human
Animal models of sepsis have established that enhanced APC (rhAPC), drotrecogin alfa (activated), significantly
TF expression occurs in vivo, and that blockade of its decreases all-cause 30-day mortality in patients with
procoagulant activity prevents the development of coa- severe sepsis.33 Failure of clinical trials to demonstrate
gulopathy, organ dysfunction, and death.57–60 The pri- that either AT or TFPI can improve outcomes in
mary role of the contact pathway in sepsis is probably to patients with severe sepsis suggests that drotrecogin
activate fibrinolysis and generate vasoactive kinins.61,62 alfa (activated) not only possesses antithrombotic prop-
Although multiple cytokines (TNFa, IL-1a, IL1-b, erties but also modulates endothelial cell function—a
IL-6, IL-8) and endotoxin itself are capable of upregu- property supported by experimental evidence.67,68
lating TF synthesis by endothelial cells and monocytes in TNF-a and IL-1 have been shown to down-
vitro, it has not been established that these cells are the regulate endothelial TM and EPCR expression in vitro.
dominant source of TF in vivo. Endotoxin and cytokine- EPCR, which binds to protein C, enhances thrombin-
induced activation of endothelial cell TF synthesis ia TM dependent activation of protein C. Whether im-
another possibility, although detectable expression of TF pairment of protein C activation on the endothelial cell
was limited to splenic endothelium in animals dying surface actually occurs in vivo during sepsis has only
from Escherichia coli sepsis.63 While inhibitors targeted recently been studied, but the data do not allow a firm
at enzymes ‘‘downstream’’ from TF/VIIa (such as factor conclusion to be drawn. In meningococcemia, decreased
Xa and thrombin) are capable of inhibiting the coagulo- immunohistochemical expression of TM and EPCR in
pathic response, they do not prevent organ damage the microvasculature of purpuric skin biopsy specimens
or death.64 Laboratory changes associated with this has been demonstrated. These findings were interpreted
prothrombotic diathesis include elevated levels of pro- to indicate that protein C activation is impaired, a
thrombin (PT) fragment F1.2 and increased concentra- conclusion supported by in vivo data in two patients
tions of thrombin-antithrombin (TAT) complexes. PT treated with protein C concentrate.69 However, a recent
fragment F1.2 is a peptide that is cleaved when PT is post hoc analysis of data from the PROWESS study, in
converted to thrombin; elevated plasma levels of PT which the ratio of plasma concentrations of zymogen
fragment F1.2 are evidence of a prothrombotic diathesis. protein C to APC was measured in individuals with
Increased TAT complexes result from binding and severe sepsis, suggested that the ability to activate
inactivation of thrombin by circulating antithrombin. protein C may be quite variable.70 Some individuals
Because D-dimers are formed by plasmin-mediated had no apparent defect in protein C activation because
cleavage of cross-linked fibrin, elevated levels of D- their elevated APC levels mirrored the plasma levels of
dimer also support the presence of enhanced intravas- thrombin (measured indirectly as F1.2). Others had lower
cular activation of the coagulation system. APC levels than expected for the F1.2 levels, likely
indicative of a relative failure to activate protein C.71
DOWNREGULATION OF ANTICOAGULANT PATHWAYS
The body possesses several natural antithrombotic pro- INHIBITION OF FIBRINOLYSIS
teins that modulate hemostasis and help to localize Inhibition of fibrinolysis promotes persistence of micro-
coagulation to areas of tissue injury. They include vascular clots, a consequence that may significantly
antithrombin (AT), tissue factor pathway inhibitor impair oxygen delivery and lead to organ dysfunction.
(TFPI), and activated protein C (APC). Antithrombin Experimental animal and human models of sepsis have
inactivates several serine proteases formed during coa- demonstrated an early and transient activation of fibri-
gulation and is the substrate required for heparin to exert nolysis, probably due to release of plasminogen activa-
its anticoagulant activity. TFPI first binds and inacti- tors, followed by prolonged inhibition. This inhibition is
vates factor Xa; subsequently, the TFPI-Xa complex probably explained by a sustained TNFa, IL-1, and
inhibits factor VIIa within the factor VIIa/ TF complex. lipopolysaccharide-mediated stimulation of plasmino-
Protein C is a vitamin K-dependent zymogen synthe- gen activator inhibitor-1 (PAI-1) synthesis by endothe-
sized in the liver. APC is formed from protein C by lium and monocytes, and is independent of the
thrombin bound to TM, an endothelial cell transmem- coagulation response. In meningococcemia, higher
brane protein. In concert with the endothelial protein C PAI-1 levels have been shown to correlate with the
654 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 6 2004

development of septic shock rather than meningitis, and sepsis. Therefore, it may be important to differentiate
a higher risk of death. Furthermore, PAI-1 levels are at sepsis-associated coagulopathy from overt DIC.
least partly genetically determined, with higher values Although there is no single clinical manifestation or
identified in individuals homozygous for the 4G/4G laboratory value that is diagnostic of overt DIC, the
polymorphism of the PAI-1 gene.72,73 These clinical following changes are reasonably consistent with the
observations agree with in vitro experiments using cul- diagnosis: (1) presence of a disorder that is known to
tured cell lines, in which basal and inducible levels of be linked with DIC (such as severe sepsis), (2) mucocu-
PAI-1 are higher in cell lines expressing this polymorph- taneous bleeding and dysfunction of one or more organ
ism. A similar observation regarding the prognostic systems, and (3) ongoing consumption of platelets and
relevance of inhibited fibrinolysis in nonmeningococcal coagulation factors. The first two criteria are detected by
sepsis has been presented.74 clinical examination, whereas the third will be manifest
as thrombocytopenia and/or prolongation of one or
more global tests of coagulation. On behalf of the
Clinical and Laboratory Manifestations International Society of Thrombosis and Haemostasis,
A sepsis-associated coagulopathy is a sign of dysfunction Taylor et al have proposed a scoring system for the
of the hematologic organ system. In the Ibuprofen in diagnosis of DIC77 (Table 1). This system utilizes the
Sepsis Trial, a coagulopathy with elevated levels of D- features already described to provide a DIC score; values
dimer and decreased levels of protein C was almost  5 are characteristic of DIC. Currently, the prognostic
universal in patients with severe sepsis (Fig. 2).66 The value of this system is undergoing prospective validation.
coagulopathy in patients with this disease is linked to
endothelial cell dysfunction and fibrin deposition, SEVERE LIVER DISEASE
pathological processes that contribute to multiple organ Severe liver disease can produce alterations in the hemo-
system dysfunction and death. For example, involvement static system that can resemble sepsis coagulopathy or
of the pulmonary vasculature is a prominent pathological DIC. In fact, in the absence of clinical features it is
manifestation of pulmonary dysfunction in patients with difficult to differentiate the two disorders with hemo-
severe sepsis and ARDS.75,76 The first manifestations static assays alone. Patients with severe liver disease may
occur at the level of the endothelial cell and include have hematologic changes similar to those of severe
increased capillary permeability. Diffuse alveolar damage sepsis including anemia, thrombocytopenia, and elevated
subsequently follows and bronchoalveolar lavage at this PT and aPTT values. Results of factor VII and VIII
time demonstrates the presence of procoagulants and functional assays can assist in the differential diagnosis.
decreased fibrinolytic activity. Vascular lesions correlate Metabolic alterations in severe liver disease usually result
with the temporal phase of diffuse alveolar damage and in a low level of factor VII and increased concentrations
include thrombotic, fibroproliferative, and obliterative of factor VIII. Because factor VIII is consumed during
changes. clotting, patients with severe sepsis and a coagulopathy,
on the other hand, are more likely to have decreased
concentrations of factor VIII.78,79
Diagnostic Considerations

DISSEMINATED INTRAVASCULAR COAGULATION General Treatment Considerations


Thrombocytopenia, prolongation of the PT and/or In the absence of bleeding, patients with severe sepsis-
activated partial thromboplastin time (aPTT) or any associated coagulopathy can simply be monitored. In
combination thereof is common in patients with severe most instances, once the infection is controlled the

Figure 2 Coagulopathy is
common in patients with
severe sepsis. Note that ele-
vated D-dimers and de-
creased levels of protein C
are present in the great ma-
jority of patients with the dis-
ease. Classical markers of
disseminated intravascular
coagulation occur in only
 20% of patients with the
disease. (Illustration cour-
tesy of the National Initiative
in Sepsis Education.)
HEMATOLOGIC CHANGES IN SEPSIS/GOYETTE ET AL 655

Table 1 Scoring Criteria for Overt Disseminated whose members are involved in the treatment of severe
Intravascular Coagulation73 sepsis, have recently strongly endorsed the administra-
Does the patient have severe sepsis or another disorder tion of drotrecogin alfa (activated) to patients with
known to be associated with DIC?. If so, proceed to scoring severe sepsis at high risk of death.81 Consequently, we
global coagulation test results and calculate score will briefly review hematologic issues related to drotre-
Parameter Score cogin alfa (activated) administration.
PLATELET COUNT 0
BLEEDING
> 100,000/mm3 (> 100  109 /L) 1
3 9 As an antithrombotic agent, drotrecogin alfa (activated)
< 100,000/mm (< 100  10 /L) 2
3 9 is associated with an increased risk of bleeding. In the
< 50,000/mm (< 50  10 /L)
PROWESS trial, serious bleeding was reported in 2.0%
ELEVATED MARKER OF FIBRIN DEGRADATION* 0
of placebo recipients and 3.5% of subjects who were
No increase 1
treated with the drug.35 Risk factors for bleeding include
Moderate increase 2
Strong increase
platelet counts < 30  109 /L; concomitantly adminis-
tered medications that increase the risk of bleeding such
PROLONGED PROTHROMBIN TIME 0
as GP IIb/IIIa inhibitors, oral anticoagulants, therapeu-
< 3 seconds 1
tic (not thromboprophylactic) doses of heparin; surgical
> 3 seconds and < 6 seconds 2
interventions; and other disorders that increase the risk
> 6 seconds
of bleeding in any candidate for systemic anticoagulation
FIBRINOGEN CONCENTRATION 0
or thrombolysis. Importantly, the increased rate of
> 100 mg/dL (> 1.0 g/L) 1
bleeding in patients treated with drotrecogin alfa (acti-
< 100 mg/dL (< 1.0 g/L)
vated) is primarily procedure-related and predominantly
*D-dimers, fibrin split products (FSPs), fibrin degradation products
(FDPs).
develops during drug infusion. Because of its short half-
Scores of 5 or more are compatible with overt DIC and should be life, there is no significant residual drug effect if the
followed on a daily basis.
Scores < 5 are suggestive of nonovert DIC or another disorder and
infusion is temporarily interrupted 2 hours prior to any
should be repeated in the next 1–2 days or as clinically indicated. surgical procedure. The decision as to when to restart
the infusion should be based upon the nature of the
abnormal laboratory parameters return toward normal. procedure and assessment of the patient.82 Cases of
In patients who are bleeding despite active treatment of intracranial hemorrhage, a potentially life-threatening
their infection, a careful examination should be con- complication, are rare and are most often associated with
ducted to rule out a discrete and correctable anatomic platelet counts < 30  109 /L or meningitis.
lesion (e.g., peptic ulcer) as the cause of the bleed. If
bleeding is from multiple sites, treatment is that of DIC USE IN PATIENTS WITH DIC
and is generally subdivided into three general areas: (1) A study by Aoki et al reported that low-dose rhAPC
treatment of the primary disease, (2) platelets and corrected the clinical and laboratory abnormalities in
coagulation factor replacement, and (3) antithrombotics. patients with DIC more effectively than unfractionated
Platelet transfusions are often used to maintain the heparin.83 The 28-day all-cause mortality rates in pa-
platelet count above 20  109 /L, though the risk of tients treated with APC and heparin were 20.4% and
spontaneous bleeding in the absence of anticoagulants 40%, respectively (p < 0.05). In addition, patients treated
usually occurs at platelet counts below 10 to 20  109 /L. with APC had significantly less bleeding (p ¼ 0.009).
Platelets should be administered to patients with throm- Joyce et al performed a retrospective subgroup analysis to
bocytopenia who are bleeding. Low-dose unfractionated determine the effect of drotrecogin alfa (activated) in
heparin has been used in the past to interrupt the vicious patients with severe sepsis and DIC.84 Treatment with
cycle of accelerated activation of coagulation, thrombo- drotrecogin alfa (activated) produced a 42% reduction in
sis, and factor depletion in patients with DIC. However, the relative risk of death compared with placebo (95%
its efficacy has not been demonstrated in large-scale, confidence interval: 58 to 19).
randomized clinical trials.80 Fibrinolytic inhibitors are
also not recommended in patients with severe sepsis and USE IN THE ELDERLY
DIC because they may convert a hemorrhagic form of The incidence of sepsis and associated mortality in-
DIC to a microvascular thrombotic form with worsened creases significantly with age. As pointed out by Ely
end organ perfusion. et al, there are age-related inflammatory and coagulo-
pathic changes that may increase vulnerability of older
Drotrecogin Alfa (Activated) Treatment-Related patients to sepsis-associated hematologic changes and
Considerations adverse outcomes.85 Advancing age is accompanied by
Practice guidelines from the Surviving Sepsis Campaign, both prothrombotic and impaired fibrinolytic activity. In
an international collaboration of professional societies a comparative study of healthy centenarians with healthy
656 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 25, NUMBER 6 2004

adult controls, hypercoagulability could be identified in Because drotrecogin alfa (activated) inactivates coagula-
the very elderly by significant increases in coagulation tion factors Va and VIIIa, treatment has been shown to
factor VIIa, activation peptides of factors IX and X, F1.2, prolong the aPTT by a mean of 7 seconds. The PT tests
and TAT complexes.86 These changes are accompanied the tissue factor and final common pathways of coagula-
by a balanced and significant increase in fibrinolytic tion. Inactivation of factor Va by the drug can lead to a
activity reflected in elevated D-dimers and plasmin– prolongation of the PT. However, in the PROWESS
antiplasmin complexes. These hemostatic alterations enrollees, a median of only 1 second separated the
may be linked to increased frailty and functional impair- placebo and intervention groups. Therefore, the PT
ment in the elderly.87 cannot be expected to be an accurate surrogate of drug
Further activation of the hemostatic system of the effect.
aged can be produced by bacterial products released In the PROWESS trial, drotrecogin alfa (acti-
during sepsis. Yamamoto et al have demonstrated ex- vated) benefited patients with normal and depressed
perimentally that with age there is enhanced lipopoly- levels of protein C. Following treatment with the drug,
saccharide signaling.88 The result may be increased levels levels of zymogen protein C increased in PROWESS
of inflammatory cytokines and upregulation of the PAI- enrollees, reflecting restoration of homeostasis. Antith-
1 gene. When the hemostatic alterations of advanced age rombin is consumed during the coagulopathy of sepsis.
are coupled with the coagulopathy of sepsis, the elderly Treatment with drotrecogin alfa (activated) also in-
population is placed at significant increased risk for creased levels of this natural antithrombotic protein.
mortality. However, clinical benefit from drotrecogin alfa (acti-
Ely et al evaluated the short- and long-term vated) was seen even in subjects with normal baseline AT
outcomes of drotrecogin alfa (activated) therapy of 386 activity. Thus there is no scientific basis to assay protein
adult PROWESS enrollees aged 75 years and older with C or AT levels to stratify patients for treatment or to
severe sepsis.85 Subjects treated with drotrecogin alfa monitor therapy. The antithrombotic properties of dro-
(activated) had absolute risk reductions in 28-day and trecogin alfa (activated) produce significant improve-
in-hospital mortality of 15.5% and 15.6%, respectively ments in sepsis-associated elevations of the markers of
(for both), compared with placebo recipients (p ¼ 0.002). intravascular thrombin generation such as concentra-
Long-term follow-up data indicated that survival rates tions of PT fragment F1.2 and TAT complexes. Analo-
for patients treated with drotrecogin alfa (activated) gously therefore, routine assay of these substances is not
recipients were significantly higher over a 2-year period indicated or clinically useful.
(p ¼ 0.02). The incidences of serious bleeding events
during the 28-day study period were 3.9% and 2.2%
(p ¼ 0.34), slightly higher than the overall PROWESS CONCLUSIONS
population. However, there was no interaction between The hematologic organ system is a central player in the
age and bleeding rates (p ¼ 0.97). Presumably as a result clinical manifestations of sepsis, sepsis pathophysiology,
of the drug’s antithrombotic properties, elderly patients and recovery from sepsis. Identification of hematologic
treated with drotrecogin alfa (activated) had significantly organ dysfunction in a patient with two or more SIRS
fewer thrombotic events than controls (p ¼ 0.019). In criteria and infection indicates that the diagnosis is
the presence of a favorable benefit/risk profile, this study severe sepsis. Knowledge of the hematologic manifesta-
supports the use of the drug in the elderly at high risk of tions of sepsis can improve diagnosis and therapy of
death when the patient, family, and health care team patients with this common and frequently fatal disorder.
have chosen aggressive care.
FINANCIAL SUPPORT
EFFECT OF DROTRECOGIN ALFA (ACTIVATED) Dr. Ely is a recipient of the Paul Beeson Faculty Scholar
ON TESTS OF HEMOSTASIS Award from the Alliance for Aging Research. He is a
There is no need to monitor drotrecogin alfa (activated) recipient of a K23 from the National Institute of Health
therapy with tests of hemostasis including protein C (#AG01023–01A1) and is the Associate Director of
assays. However, because both the sepsis coagulopathy Research for the VA Tennessee Valley Geriatric
and the drug can alter routine tests of hemostasis, Research and Education Clinical Center (GRECC).
relevant drug-related effects on coagulation parameters No other external funding was provided.
are briefly described.82
Drotrecogin alfa (activated) has no direct effect
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