556

Thrombosis, Microangiopathies, and Inammation

Karen Matevosyan, MD1 Ravi Sarode, MD1

1 Division of Transfusion Medicine and Hemostasis, Department of Address for correspondence Ravi Sarode, MD, Department of
Pathology, UT Southwestern Medical Center, Dallas, Texas Pathology, University of Texas Southwestern Medical Center, 5909
Harry Hines Boulevard, HA2.179, Dallas, TX 75390-9234
Semin Thromb Hemost 2015;41:556562. (e-mail: ravi.sarode@utsouthwestern.edu).

Abstract Thrombotic microangiopathy (TMA) is characterized by the presence of microangio-

pathic hemolytic anemia and thrombocytopenia. There are several disorders with varied
Keywords etiopathogenesis, both genetic and acquired, that result in TMA. The neutrophils play an
ADAMTS-13 important role in inammation and thrombosis through the formation of neutrophil
complement extracellular traps (NETs). NETs are formed in response to a variety of stimuli including
endothelium infections, chemical factors, and platelet activation. The classic TMA, thrombotic
hemolytic uremic thrombocytopenic purpura (TTP) is caused by a severe deciency of ADAMTS-13 (a
syndrome disintegrin and metalloproteinase with a thrombospondin type-I motif, member 13),

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neutrophils mostly acquired due to autoantibodies, whereas atypical hemolytic uremic syndrome
microangiopathic (aHUS) is mostly attributed to genetic defects in complement pathway regulatory
hemolytic anemia proteins. The management of these well-known disorders has evolved over the last
thrombocytopenia decade. Similarly, there is also better understanding of diverse and unusual clinical
thrombotic presentations of both of these conditions. Since there are many other causes of TMAs,
microangiopathy which may mimic some of the clinical features of TTP or aHUS, it is essential to
thrombotic thoroughly investigate each patient so that appropriate therapy can be offered. This
thrombocytopenic review focuses on some important developments in understanding of etiopatho-
purpura genesis, diagnosis, and treatment of more commonly encountered TMAs.

Thrombotic microangiopathy (TMA) represents a nal com-
mon pathway of a diverse group of disorders characterized by
microvascular occlusive thrombosis and vasculopathy. It
manifests as microangiopathic hemolytic anemia (MAHA)
and thrombocytopenia. The severity of clinical manifestations
depends on the degree of tissue ischemia and damage to
target organs. Despite the similarity of clinical manifestations,
the etiopathogenic factors are diverse.
There are four types of lesions that have been described in
TMA1: (1) von Willebrand factor (VWF)platelet thrombi
with no or minimal microangiopathythis mechanism is
seen in thrombotic thrombocytopenic purpura (TTP); (2)
brinplatelet thrombi, as seen in disseminated intravascular
coagulation (DIC); (3) inammatory or proliferative micro-
angiopathy accompanied with variable brin thrombi, as seen
in hemolytic uremic syndrome (HUS), systemic lupus eryth-
ematosus (SLE), or scleroderma renal crisis; and (4) intravas-
cular clusters of cancer cells, a manifestation of metastatic
tumor spread. TTP is the most important cause of TMA that
continues to have high morbidity and mortality. Other
important causes of TMA include classic HUS (Shiga toxin
associated) or atypical HUS (aHUS), secondary to complement
pathway dysregulation. Table 1 shows broad classication
of TMAs.
Recently, there have been advances in understanding of
the role of the neutrophils in inammation and possibly
thrombosis through the formation of neutrophil extracellular
traps (NETs). The process of NETs formation is called netosis,
which is a specic type of cell death different from necrosis
and apoptosis.2 The NETs consist of neutrophil nuclear DNA
bers in extracellular space and are formed in response to
infection, acute and chronic inammation, and activated
platelets. The NETs have been shown to be elevated in stroke,
myocardial infarction, and TTP.3 The organisms are trapped in

published online Issue Theme Inammation, Endothelial
August 15, 2015 Dysfunction, and Thromboembolism;
Guest Editors: Bashir A. Lwaleed, PhD,
FRCPath, Rashid S. Kazmi, MRCP,
FRCPath, and Alan J. Cooper, PhD.
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 Thrombosis, Microangiopathies, and Inflammation
Table 1 Classication of thrombotic microangiopathy
Autoimmune
A. ADAMTS-13 autoantibody (TTP)
a. Idiopathic
b. Drug inducedTiclopidine
B. Complement factor H autoantibody (aHUS)
C. Systemic lupus erythematosus
D. Catastrophic antiphospholipid antibody syndrome
Abbreviations: aHUS, atypical hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.
these NETs and killed by the action of myeloperoxidase
(MPO), neutrophil elastase, reactive oxygen species, histone,
cathepsin G, and other enzymes. Ineffective clearance or
excessive formation of NETs can cause pathological effects.
Thrombotic Thrombocytopenic Purpura
Although the rst description of TTP was in 1924 by
Moshcowitz, until the introduction of empiric plasma
exchange therapy in the 1970s, the mortality was > 90%.4
In 1982, Moake et al reported the presence of unusually
large VWF multimers (ULVWF) in the plasma of patients
with congenital chronic relapsing TTP during remission. 5
They suggested a depolymerase deciency being respon-
sible for the persistence of ULVWF in the circulation result-
ing in platelet clumping in the microvasculature. In 1996,
Furlan et al and Tsai simultaneously isolated a metallopro-
teinase responsible for physiologic processing/cleaving of
the VWF (VWF-cleaving protease).6,7 In 1998, an immuno-
globulin G (IgG) autoantibody causing a severe deciency of
VWF-cleaving metalloproteinase was identied.8,9 The
only randomized prospective trial demonstrated superior-
ity of therapeutic plasma exchange (TPE) over simple
plasma transfusion, and the TPE remains the rst-line
standard-of-care therapy.10
The VWF-cleaving protease was later identied as an
ADAMTS-13 (a disintegrin and metalloproteinase with a
thrombospondin type-I motif, member 13) enzyme, which
was found to be decient in patients with congenital TTP (also
known as UpshawSchulman syndrome) due to genetic
mutations.11 Severe ADAMTS-13 deciency (< 10%) causes
accumulation of ULVWF in plasma, which progressively gets
activated by shear stress in the microcirculation, leading to
VWFplatelet aggregation and microvascular thrombosis.1
Although demonstration of ADAMTS-13 deciency is essen-
tial in the diagnosis of TTP, the deciency may persist even in
the absence of clinical and laboratory features of TTP, suggest-
ing that a second hit is probably necessary to precipitate an
acute event. Ticlopidine-induced TTP had a very high mortal-
ity most likely due to delayed recognition of this disorder
resulting from drug-induced autoantibodies against
ADAMTS-13.12,13
Matevosyan, Sarode 557
Nonautoimmune or toxic
A. Congenital
a. ADAMTS-13 gene defect (TTP)
b. Complement factor gene defects (aHUS)
B. Acquired
a. Shiga toxinmediated HUS
b. Neuraminidase-mediated HUS
c. Disseminated intravascular coagulation
d. Hemolysis, elevated liver enzymes, and low platelet syndrome
e. Hematopoietic stem cell transplantation
f. Drugs: gemcitabine, calcineurin inhibitors, mitomycin C
g. Malignant hypertension
Recent Advances in Thrombotic Thrombocytopenic
Purpura
Pathogenesis
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In addition to ADAMTS-13 deciency, activation of endothe-
lial cells by various noxious stimuli (inammatory cytokines,
bacterial toxins, phosphodiesterase inhibitors) may play an
important role in the pathogenesis of TTP. A prospective
multicenter study investigated biological markers of endo-
thelial activation in autoimmune TTP.14 They observed that
the soluble P-selectin, VWF, and circulating endothelial cells
(CEC) were increased during the acute phase of the disease
but normalized during remission. The CEC are injured endo-
thelial cells detached from the endothelial monolayer of the
vessel wall, which correlated with the presence of initial
neurological symptoms and with the patients outcome.
Recently increased plasma levels of circulating DNA-
histone complexes have been shown in patients with acute
TTP and other TMAs.15 These complexes are released from
necrotic tissues as well as from inammatory cells such as
neutrophils in the form of nucleosomes (NETs) in response to
infection or inammatory stimuli. These NETs contain DNA,
histones, and neutrophil proteases. NETs can promote throm-
bosis by stimulating platelet aggregation and thrombin gen-
eration. Extracellular DNA can serve as scaffolding for platelet
adhesion and promote brin deposition.3 TTP acute events
are often preceded by infection that may promote formation
of NETs which might play an important role in pathogenesis
(second hit). Fuchs et al demonstrated that inammatory
molecules such as MPO, S100A8/A9, and nucleosomes are
concomitantly elevated in plasma of patients with acute TTP
and other TMAs. Their levels reected and correlated with the
disease activity in TTP patients before, during, and after the
therapy.15
The complement activation in TTP patients has been
demonstrated in some studies.16,17 ULVWF multimers
anchored to endothelial cells were found to serve as activat-
ing surfaces for alternative complement pathway assembly.
Endothelial cells activated by noxious stimuli secrete ULVWF
multimers at an accelerated rate; in patients with severe
ADAMTS-13 deciency, this leads to an increase in endothe-
lium-anchored ULVWF multimers, causing prolonged
Seminars in Thrombosis & Hemostasis Vol. 41 No. 6/2015
558 Thrombosis, Microangiopathies, and Inflammation Matevosyan, Sarode
activation of the alternative complement pathway.18 This
nding may have an implication for the use of eculizumab
(described later) in refractory or relapsing TTP.
Clinical Presentation
Clinical presentation of TTP is diverse, from minimal symptoms
to critically ill patients presenting with coma.19 The presence of
MAHA, thrombocytopenia, with or without neurologic symp-
toms (present in two-thirds of acute TTP episodes), is sufcient
to make a diagnosis of TTP and warrant initiation of TPE.20 Renal
injury, if present, is usually very mild, and oliguric renal failure
rules out a diagnosis of TTP. There are several recent case reports
of TTP, presenting with acute neurologic decits that precede
severe hematological derangements.2123 These cases had evi-
dence of acute cortical or subcortical infarcts without occlusion
of major cerebral vessels on magnetic resonance imaging. They
all had a severe ADAMTS-13 deciency at the time of the stroke
without hematological features of TTP; however, they did
develop MAHA and thrombocytopenia later. Therefore, in a
young patient who presents with an unexplained stroke, a
differential diagnosis of severe ADAMTS-13 deciency should
be entertained.
A long-term follow-up has shown that 63% of TTP patients
have neurocognitive decits.24 Whether these are related to
subclinical ongoing microthrombosis in the presence of nor-
mal hematological features and persistence of severe
ADATMTS13, deciency needs to be investigated.
Diagnosis
ADAMTS-13 activity < 10% is diagnostic of TTP in real-life
situations.25 Comparison of various ADAMTS-13 assays have
demonstrated good concordance in detection of severe
ADAMTS-13 deciency (< 5%) as well as good correlation
between observed and expected ADAMTS-13 levels in the
< 20% range.26
There are several tests for determination of ADAMTS-13
activity, including commercial assays. The principle of these
assays is based on the proteolysis of puried, plasma-derived
or recombinant VWF multimers, or synthetic VWF peptides
by ADAMTS-13 in patient plasma. The VWF cleavage product
is then detected by electrophoresis, platelet aggregation
techniques, uorescence resonance energy transfer tech-
nique, or immunoassay.27 The surface-enhanced laser
desorption/ionization time-of-ight mass spectrometry
(SELDI-TOF-MS) is the most recent method that involves
Protein Chip Array technology.28 The assay uses a recombi-
nant VWF peptide containing the ADAMTS-13 cleavage site
and a 6X histidine tag at the N-terminus (rVWF73). VWF is
cleaved by ADAMTS-13 in the patients plasma, generating a
peptide product containing a histidine tag. This product
bound to an immobilized metal afnity capture Protein
Chip is then quantied by SELDI-TOF-MS. It allows for rapid
evaluation of functional activity of ADAMTS-13 in patient
plasma with the detection of a level as low as 1%.
The ADAMTS-13 autoantibodies are found in 80 to 90% of
patients with TTP at the time of presentation, as determined
by Bethesda-like assays or by enzyme-linked immunosorbent
assay. ADAMTS-13 activity/inhibitor levels have not been
Seminars in Thrombosis & Hemostasis Vol. 41 No. 6/2015
demonstrated to be of prognostic value in guiding therapy
because of poor correlation between ADAMTS-13 results and
clinical-hematologic progression of TTP course.20
Treatment
Recently, denitions related to management of TTP have been
published that help dene various clinical responses.20 A treat-
ment response is dened as a platelet count above 150
109/L
for 2 consecutive days accompanied by normal or normalizing
lactate dehydrogenase (LDH) and stable or improving neurolog-
ical decits. A durable treatment response is dened as a lasting
response to therapy for at least 30 days after discontinuation of
TPE. An exacerbation is dened as a recurrence of TTP within
30 days after achievement of the treatment response, whereas a
relapse is dened as a recurrence of TTP 30 days after achieve-
ment of the treatment response. The refractory disease is
dened as no treatment response by day 30 and/or no durable
treatment response by day 60. Current evidence suggests that 30
to 50% of TTP patients have exacerbations, relapses, or refractory
disease despite adequate TPE and corticosteroid treatment. The
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management of refractory TTP is challenging; hence, various
immunosuppressive agents have been tried.29,30
Rituximab use in refractory/relapsing TTP has been gain-
ing widespread acceptance and is currently supported by
most experts.20 Rituximab (anti-CD20) acts via depletion of
antibody-producing B-cells. In a prospective study, rituximab
therapy has demonstrated decreased time to durable remis-
sion, as well as fewer relapses in the 1st year following
rituximab therapy. A sustained decrease in CD20 B-cells
was observed for up to 9 months.31 Another retrospective
study showed relapse-free rates of 92% in the 1st year and 75%
at 3 and 5 years after rituximab.32 The serial measurement of
ADAMTS-13 during remission may help identify patients who
may benet from prophylactic rituximab therapy to prevent
impending TTP relapse.1
Recent case reports show that bortezomib (Velcade) was
successful in obtaining remissions in refractory TTP patients
who had failed treatment with concurrent TPE and rituxi-
mab.3335 The rationale behind the use of bortezomib is that it
probably affects antibody producing plasma cells. Similarly,
reports of successful use of N-acetylcysteine (NAC) in refrac-
tory TTP are based on the NACs ability to inhibit platelet
binding to ULVWF multimers. NAC decreases the size of VWF
by breaking disulde bonds in VWF multimers, thus prevent-
ing VWFplatelet thrombi formation.36,37
Nanobodies are small functional fragments derived from
naturally occurring heavy chains. ALX-0081 is a bivalent
nanobody that selectively blocks VWF interaction with pla-
telets at the glycoprotein (GP)Ib-binding site of VWF (A1
domain). It was shown to be effective in blocking VWF
platelet-mediated thrombosis under high-shear rates, ob-
served in normal arteriolar conditions.38 A recently complet-
ed international Phase II TITAN study showed promising
preliminary results with caplacizumab (ALX-0681).39 The
single-blinded, randomized (1:1), placebo-controlled trial
evaluated 75 patients treated with drug or placebo. All
patients received TPE. The patients in the active drug arm
received caplacizumab concurrently per day with TPE and up
 Thrombosis, Microangiopathies, and Inflammation
to a month after discontinuation of TPE. Patients treated with
caplacizumab in conjunction with the standard of care
achieved normalization of platelet counts in half the time
compared with placebo group (p 0.013). A complete remis-
sion was achieved in 81% in the caplacizumab group com-
pared with 46% in the placebo group. Also, patients treated
with caplacizumab had 73% fewer exacerbations compared
with the placebo group.39
Aptamers are nucleic acid macromolecules that bind with
high afnity and specicity to specic molecular protein
targets. A pilot study assessed safety, pharmacokinetics and
pharmacodynamics of ARC1779, a pegylated anti-VWF DNA/
RNA aptamer. ARC1779 inhibits VWFplatelet interaction by
binding to the A1 domain of VWF.40,41 These are some
promising alternate therapies desperately needed for relaps-
ing and refractory patients.
Availability of these rapid-acting drugs to prevent ongoing
microthromboses may be a very important treatment strate-
gy to possibly prevent late neurocognitive complications
observed in many TTP patients.
Hemolytic Uremic Syndrome
As the name suggests, this type of TMA is characterized by
predominant renal affection. Traditionally, HUS has been
divided into diarrhea-associated, typical/pediatric, and non-
diarrhea-associated aHUS. Diarrhea-associated HUS results
from Shiga toxinproducing Escherichia coli or Shigella dys-
enteriae (type 1) due to direct endothelial cytotoxicity medi-
ated by shigatoxin-Gb3 receptor binding. Gb3 is concentrated
in the endothelial cells, particularly in the glomeruli, and is
the main target of Shiga toxin. Endothelial damage by Shiga
toxin causes tissue factor release and activation of coagulation
and platelets with resultant microthrombosis.42
aHUS is caused by dysregulation of the alternate complement
pathway, resulting in uncontrolled complement activation.1
Mutations in various genes coding for regulatory factors of the
alternative complement pathway (complement inhibitor factors
H, I, membrane cofactor protein [MCP]), thrombomodulin, and
complement factor Hrelated protein 1(CFHR1) are responsible
for most familial aHUS. Inhibiting autoantibodies to complement
factor H have been implicated in 10% of cases of aHUS.42 CFH
serves as a cofactor for complement factor I and also regulates C3
convertase and C5 convertase. Patients with autoantibodies to
CFH show increased incidence in homozygous deletions of
CFHRPs (CFHRP15) genes, likely a predisposing factor for
development of autoantibodies to CFH.43 Patients with CFHR3/
1 deletion demonstrate worse renal outcomes.44 Although
oliguric renal failure is characteristic of aHUS, the clinical
presentation of aHUS can be very diverse and may affect a single
or multiple organs.1 A high degree of suspicion after excluding a
TTP diagnosis (ADAMTS-13 > 10%) is essential for prompt diag-
nosis and specic treatment. Currently only up to 50% of aHUS
patients have documented complement defect.1
Treatment
Shiga toxinassociated HUS is managed conservatively with-
out TPE. TPE is generally initiated in most cases of aHUS with
Matevosyan, Sarode 559
variable responses; however, once severe ADAMTS-13 de-
ciency is ruled out, TPE should be discontinued and a diag-
nosis of aHUS should be entertained. Eculizumab was
recently approved for the treatment of aHUS. Eculizumab is
a chimeric humanized monoclonal IgG2/4 antibody that
binds to complement factor 5, inhibiting the conversion of
C5 to C5a and C5b by C5 convertase. This prevents the
formation of C5b-9, the membrane attack complex.42 The
patients generally need a long-term therapy to prevent
permanent end organ damage. Close monitoring of renal
function, platelet counts, and hemolysis markers is recom-
mended following discontinuation of eculizumab.
Drug-Induced Thrombotic Microangiopathy
Drugs may cause TMA by immunologic or nonimmune (toxic)
mechanisms.
Autoimmune mechanism is implicated in quinine-induced
TMA, whereas the nonimmune mechanism is responsible for
the TMA caused by clopidogrel, calcineurin inhibitors (cyclo-
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sporine, tacrolimus), gemcitabine, mitomycin C, murmonab-
CD3 (OKT3), bevacizumab, and others.45,46 Quinine was the
rst drug implicated in immune-mediated TMA due to qui-
nine-dependent antibodies causing endothelial damage and
platelet activation.47,48 Gemcitabine and quetiapine have
been reported to cause recurrent TMA with repeated expo-
sure.44 Patients usually present with the sudden onset of
anuric kidney injury, TMA, and often symptoms of systemic
illness. History reveals prior exposure to the drug, and
sometimes quinine-containing beverages, for example, tonic
water. Prompt causal identication of the implicated drug, its
discontinuation, and further avoidance of the implicated drug
are essential parts of the management.
Transplant-Associated Thrombotic
Microangiopathy
Posttransplant TMA is a well-known complication of the
hematopoietic stem cell as well as some solid organ transplants
(e.g., liver or kidney transplant). The pathogenesis is likely
multifactorial related to endothelial injury, possibly secondary
to chemotherapy, radiotherapy, antirejection immunosup-
pressive medications, acute GVHD, angioinvasive viral, or
fungal infections. Most likely, cytokines (interleukin (IL)-1,
tumor necrosis factor- [TNF-], interferon-) release and
complement activation in response to the above factors (alone
or in combination) initiate changes leading to TMA.49 Because
there is no severe deciency of ADAMTS-13 in transplant-
associated TMA, TPE is not indicated. Recently, eculizumab has
been shown to be effective in such conditions.50
Pregnancy-Associated Thrombotic
Microangiopathy
HELLP (hemolysis, elevated liver enzymes, low platelets)
syndrome is a severe form of preeclampsia characterized by
TMA. Preeclampsia is a serious complication of pregnancy
and an important cause of maternal and neonatal morbidity
Seminars in Thrombosis & Hemostasis Vol. 41 No. 6/2015
560 Thrombosis, Microangiopathies, and Inflammation Matevosyan, Sarode
and mortality. HELLP complicates 0.2 to 0.8% of pregnan-
cies.51 Its pathogenesis is not completely understood, but
thought to be related to inadequate placentation secondary to
maternal immune response to invading trophoblast. Direct
liver damage by various placental factors released into the
maternal circulation leads to release of TNF- causing wide-
spread inammation with endothelial cell damage and dys-
function.52 The complement system, a key mediator of
systemic inammatory response, is also excessively activated
in HELLP syndrome.53 Endothelial activation leads to the
release of large multimers of VWF in a GPIb binding
conformation. Moderate deciency of ADAMTS-13 activity
(2050% of normal) due to liver dysfunction may explain
thrombocytopenia and platelet-rich thrombi in HELLP
syndrome.54
The denitive treatment of HELLP syndrome is urgent
delivery when possible. Intravenous steroids (dexametha-
sone), magnesium sulfate, and prevention of sustained severe
systolic hypertension to arrest disease progression are the
mainstay of therapy.51 TPE may have a role if the clinical
condition does not get better within 24 to 48 hours of delivery,
especially with severe coagulopathic bleeding. Due to altered
nitric oxide (NO) physiology in HELLP syndrome, NO donors
have been tried, such as glyceryl trinitrate, nitroglycerine,
isosorbide dinitrate, S-nitrosoglutathione, and nitrosoaspir-
ins.52 A case of successful use of eculizumab to treat severe
preeclampsia/HELLP syndrome was reported recently.55
Other Systemic Autoimmune/Inammatory
Conditions
Antiphospholipid syndrome (APS) is an acquired hypercoagu-
lable state in patients with laboratory evidence of antiphos-
pholipid antibodies (lupus anticoagulant, anticardiolipin, and/
or anti-2-GPI antibodies) and clinical evidence of venous/
arterial thrombosis or pregnancy losses. Catastrophic APS
(CAPS) is dened as an acute onset of multiple thromboses
in at least three organs/systems over periods of days to weeks.
In addition to end organ damage, CAPS manifests by systemic
inammatory response syndrome (SIRS). DIC complicates
approximately 20% of CAPS with marked thrombocytopenia
and occasionally with schistocytosis. Patients with relapsing
CAPS have shown increased evidence of MAHA.56 The man-
agement of CAPS is aimed at prevention and control of
thrombosis (therapeutic anticoagulation), treatment of pre-
cipitating factors (infection, necrotic tissue), and control of
autoantibody production as well as excessive cytokine produc-
tion (steroids, plasma exchange). TPE is used as adjunct
therapy, likely beneting by removing autoantibodies, cyto-
kines, and activated complement factors as well as by replen-
ishing natural anticoagulants with the plasma replacement.
Septic Shock and Multisystem Organ Failure
Severe infection with sepsis may result in SIRS, which occurs
when there is an imbalance between proinammatory and
anti-inammatory responses. Activation of complement
pathway, endothelial cells, platelets, coagulation, and bri-
Seminars in Thrombosis & Hemostasis Vol. 41 No. 6/2015
nolytic systems by bacterial toxins induces a proinamma-
tory and prothrombotic state.57 This cytokine storm leads to
consumptive coagulopathy with TMA and multisystem organ
failure syndrome associated with high mortality (70%).58
Patients with severe sepsis demonstrate elevated plasma
levels of various proinammatory cytokines, such as TNF-,
IL-1, and IL-6. Acquired moderate ADAMTS-13 functional
deciency is seen in certain patients with severe sepsis and is
associated with poor outcomes.59,60 Its mechanism is poten-
tially related to IL-6mediated inhibition. ADAMTS-13 func-
tional deciency was suggested as a prognostic factor for
mortality in patients with septic shock, independent of DIC.61
There is a signicant reduction in antithrombin and protein C
levels secondary to consumption, severe inammation, im-
paired synthesis, and degradation by neutrophil elastase.62
Therapy is aimed at the eradication of infection and
supportive care. Early initiation of TPE benets these patients
possibly by removing cytokines, NETs, activated clotting
factors and complement components, brin-split products,
and by supplementation of normal plasma factors.57
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Disseminated Intravascular Coagulation
Manifestation of TMA in DIC is the result of a widespread
systemic activation of the coagulation system seen in
various clinical settings, usually involving systemic inam-
matory reaction. The activated coagulation system, inef-
ciently counteracted by the natural anticoagulant system
and enhanced by impaired brin-degrading potential,
leads to widespread brinplatelet clots in microvascula-
ture. In acute decompensated DIC, there is sustained
thrombin generation with consumption of coagulation
factors and platelets resulting in bleeding up to 64%
patients.63 Chronic DIC is usually compensated with coag-
ulation factors being replenished.64
The patients with acute decompensated DIC are usually
critically ill patients. Laboratory diagnosis is based on dem-
onstration of prolonged prothrombin time, activated partial
thromboplastin time, thrombin time, increased D-dimers,
hypobrinogenemia, and thrombocytopenia. Schistocytosis
may be present on a peripheral blood smear, a manifestation
of MAHA. The management of DIC is directed toward treat-
ment of the underlying disorder (e.g., infection, severe wide-
spread inammation, shock). Transfusion of plasma,
cryoprecipitate, and/or platelets may be necessary to control
clinical bleeding. However, transfusions in nonbleeding pa-
tients should be avoided to prevent adding fuel to the re.
Conclusion
Recently, there have been signicant improvements in our
understanding of various TMAs. Because of better diagnostic
capabilities and the availability of specic treatment options,
the management of TMAs has improved tremendously.
Systemic complement activation and NETs formation appear
to be important mechanisms in many of these syndromes.
A long-term follow-up is warranted for evaluating sequelae in
TMAs like TTP and aHUS.
 Thrombosis, Microangiopathies, and Inflammation
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