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Thrombotic

Thrombocytopenic Purpura
Serena Ezzeddine
Morning Report
September 8, 2008
Epidemiology
Suspected TTP-HUS- 11cases/million/yr
Idiopathic TTP-HUS- 4.5 cases/million/yr
Severe ADAMTS13 deficiency- 1.7
cases/million/yr
Incidence rates were greater for women
and African-Americans
Prior to plasma exchange, mortality rate
was as high as 90%, now less than 20%
Terminology
TTP and HUS (hemolytic uremic syndrome) are
both acute syndromes with abnormalities in
multiple organ systems and evidencing
microangiopathic hemolytic anemia and
thrombocytopenia. Although some studies
appear to distinguish these two entities the
presenting features are essentially the same in
most adult patients. Furthermore, the pathologic
changes are the same and so is the initial
treatment.
Definitions and Diagnosis
The Classic Pentad of TTP
Microangiopathic hemolytic anemia
Thrombocytopenia
Renal insufficiency or abnormalities
Neurologic abnormalities that can be fluctuating
Fever
Most common symptoms at presentation are
nonspecific and include abdominal pain, nausea,
vomiting and weakness.


Definitions and Diagnosis
In the era before effective treatment, it
was common for all five features of the
pentad to be present, but now it is rare
for all to be present in same patient.
Now, only thrombocytopenia and
microangiopathic hemolytic anemia
WITHOUT another clinically apparent
cause is required to suspect TTP-HUS and
initiate treatment.
Definitions Continued
MAHA-nonimmune hemolysis (negative coombs) with
prominent red cell fragmentation (schistocytes) on
peripheral blood smear. Will exhibit increased LDH and
indirect bili.
Schistocytes-in the appropriate clinical setting
schistocyte count>1% was strongly suggestive of TTP-
HUS, ie 2 or more schistos in microscopic field at 100x
magnification.
Thromoboctyopenia- mean in a series was 25,300
prior to treatment.
Renal disease- due to renal thrombotic
microangiopathy, which is usually associated with a UA
that is often near normal with only mild proteinuria
(between 1-2 g/day) and few cells or casts
Definitions Continued
Neurologic symptoms - most are subtle, such
as transient confusion or severe headache.
Focal, objective abnormalities are less common,
but grand mall seizures and coma can occur.
Fever- less frequent finding, but the presence
of chills and high spiking fever should suggest
dx of sepsis or DIC.
Cardiac involvement- incidence is difficult to
determine, but diffuse platelet thrombi and
associated hemorrhage in cardiac tissues can
lead to arrythmias, MIs, sudden death, shock, or
heart failure.

SCHISTOCYTES!
Pathophysiology and ADAMTS13
Before 1998, there was a lack of knowledge of the pathophysiology
of TTP. In that year, adults with idiopathic TTP were reported to
have acquired antibodies that inhibit VWF cleaving protease, which
is normally present in plasma. In 2001, VWF cleaving protease was
purified and cloned by several groups, shown to be a new member
of the a disintegrin and metalloprotease with thrombospondin type
1 repeats-aka ADAMTS13.


In initial studies with Furlan et al, in 1997, no inhibitor of the
enzyme was found, and the deficiency was ascribed to an
abnormality in the production, survival or function of protease, but
then in 1998, concomitant studies showed that the protease activity
was decreased during acute episode of TTP, but returned to normal
in recovery, so there was a transient autoantibody produced against
the enzyme during acute episodes.
Pathogenesis
VWF is synthesized in endothelial cells and assembled in
large multimers that are present in normal plasma. The
large multimers, ie unusually large von willebrand factor
(ULVWF) are rapidly degraded in the circulation into
normal size range of VWF multimers by ADAMTS13.

ADAMTS13 deficiency could lead to accumulation of
ULVWF multimers, platelet aggregation, and platelet
clumping. ULVWF multimers accumulate in patients with
TTP being found in platelet thrombi and serum. The
ULVWF can attach to activated platelets thereby
promoting aggregation.


Copyright 2006 American Society of Hematology. Copyright restrictions may apply.
Sadler, J. E. Hematology 2006;2006:415-420
Figure 1. Pathogenesis of idiopathic thrombotic thrombocytopenic purpura (TTP) caused by
ADAMTS13 deficiency

ADAMTS13
An inhibitory autoantibody to ADAMTS13 has
been found at varying titers among high
percentage of patients with idiopathic TTP who
have severe ADAMTS13 deficiency, and the
inhibitory IgG is directed at various elements of
the protease.
It has been suggested that levels of ADAMTS13
less than 5% with or without an inhibitor
antibody may be part of a larger autoimmune
response. Non-inhibitory antibodies to
ADAMTS13 have also been demonstrated.
ADAMTS13 and prognosis
So usually, in acute idiopathic TTP, there is a severe
deficiency in ADAMTS13 activity (undetectable or <5%),
although senstivity/specificity remains controversial.
Severe deficiency is less common in secondary TTP.
For most patients, a complete response to plasma
exchange is accompanied by normalization of ADAMTS13
activity and disappearance of inhibitors, if present.
Persistently undetectable ADAMTS13 in plasma during
remission was found to be highly predictive of
recurrence, and also the higher the antibody titers,
clinical manifestations were more severe and responses
to plasma exchange were delayed
Treatment
PLASMA EXCHANGE -do NOT wait!
Usually done daily until platelet count
has normalized (150K for 2 days) and
hemolysis has largely ceased, ie
normalized LDH. Exchange 1 to 1.5
plasma volumes daily
1/3 to of patients have prompt
exacerbation of thrombocytopenia and
hemolysis when plasma exchanged stopped
or tapered. In these cases re-institute daily
exchange, or even twice daily exchange with
a planned tapering schedule
Plasma Exchange continued
Serial observations indicate that neurologic
symptoms and serum LDH improve first, then
platelet count, and improvement of renal
function also occurs but is unpredictable
FFP is used usually four units per liter plasma
removed. Most commonly used.
Cryo-poor plasma (VWF largely removed), but
can lead to deficiency of fibrinogen and Factor
VIII
Plasma infusion without exchange can serve
as emergencv treatment if exchange not
readily available.


Treatment
Corticosteroids (prednisone 1mg/kg) or
methylprednisolone 125mg IV BID) either
adjunctively immediately or if platelet counts do
not increase within several days of plasma
exchange, or if thrombocytopenia recurs when
plasma exchange treatments are diminished or
stopped.
There is little evidence for this strategy, but is
used on the justifiable assumption that TTP is
immune mediated.
Treatment
RITUXIMAB
Humanized monoclonal antibody against CD20, which
is expressed on B cells, and it rapidly clears B cells
from circulation, preventing replenishment of
pathological plasma cells.
Remission associated with disappearance of
ADAMTS13 inhibitors and normalization of activity
levels
Should be considered in TTP patients who fail to
respond to daily PE and corticosteroids after 7-14
days
Dose 375 mg/m2 IV qweek for minimum of four
weeks and maximum of 8 weeks.

TTP and Lupus
TTP is a known complication in SLE and 1-4% of
patients with SLE may experience an episode of TTP
during their life.
Possibly, the occurrence of TTP in SLE pts is
underestimated because of overlapping symptoms
In vast majority of SLE-related TTP, SLE dx first, 13-15%
TTP dx first, and 12-26% dx concomitantly
Pts with active vasculitis esp with severe HTN and renal
involvement may be difficult to distinguish from ITTP,
and may represent true overlap syndrome between
TTP and SLE.

TTP and SLE

References
NEJM 2006; 354:1927-35 George, James MD-Thrombotic Thrombocytopenic Purpura.
Uptodate. Diagnosis, Causes, and Treatment of TTP-HUS
Hematology 2004:407-423.Recent Advances in Thrombotic Thrombocyotopenic
Purpura, Sadler Et al
Hematology 2007. TTP and ADAMTS13: When is testing appropriate? Mannucci et al
Hematology 2006.Thrombocytopenic Purpura:A moving Target. Sadler
Hoffman:Hematology: Basic Principles and Practice fourth edition. Chapters 42 and
132
Swiss Med Wkly 2007;137:518-524. Rituximab for acute plasma refractory thrombotic
thrombocyotopenic purpura.
Eur J Haematology 2005;75:436-440. Acquired TTP as presenting symptom of SLE.
Successful treatment with plasma exchange and immunosuppression-report of 2
cases
Blood cells, Molecules and Diseases (2002) 28(3) May/June:385-391. Ritux Therapy
for Refractory TTP
Thrombotic Thrombocytopenic Purpura and Systemic Lupus Erythematous:Distinct
entities or overlapping syndromes. Internet Journal of Internal Medicine; Cheung