Thrombotic thrombocytopenic purpura

Description of the diagnosis and management of an infrequent

entity with high mortality

Thrombotic thrombocytopenic purpura

Description of diagnosis and management of a rare entity with a high
mortality

Viviana Olaya 1
, Juan Pablo Montoya 2 , Ángela María Benjumea 3 , Kenny Gálvez 4
,
Juan Felipe Combariza 5 : Medellín (Colombia)

1
Dr. Viviana Olaya: Internist Universidad Pontificia Bolivariana and Hospital Pablo
Tobón Uribe;
2
Dr. Pablo Montoya: Resident of the Second Year of Internal Medicine, Universidad
Pontificia Bolivariana;
3
Dr. Ángela María Benjumea Salgado: Second Year Resident in Internal Medicine and
Geriatrics, Universidad de Caldas;
4
Dr. Kenny Gálvez: Internist at the University of Caldas. Hematologist University
Foundation of Health Sciences. Hematologist Hospital Pablo Tobón Uribe;
5
Dr. Juan Felipe Combariza: Internist at Javeriana University. Hematologist National
University. Hematologist Hospital Pablo Tobón Uribe. Medellin Colombia).

Correspondence. Dr. Viviana Olaya. E mail: viviolayac@hotmail.com

Received: 04 / VIII / 2011 Accepted: 25 / X / 2012

Summary

We present two cases with idiopathic thrombotic thrombocytopenic purpura refractory

to treatment with plasma exchange and in which it was necessary to use additional
treatment. In one of the cases there was an adequate response with rituximab. We
also analyzed the role of ADAMTS 13 levels in the management and diagnosis of this
disease. (Acta Med Colomb 2012; 37: 201-206) .

Key words: thrombotic thrombocytopenic purpura, plasma exchange, rituximab .

Abstract

We report two patients diagnosed as having thrombocytopenic idiopathic purpura

refractory to plasma exchange in which the use of additional treatment was
necessary. In one case there was an adequate response to rituximab. We also analyze
the role of ADAMTS 13 levels for the management and diagnosis of this disease.(Acta
Med Colomb 2012; 37: 201-206) .

Keywords: thrombotic thrombocytopenic purpura, plasma exchange, rituximab.

Introduction

Thrombotic thrombocytopenic purpura (TTP) is a rare disease with an incidence of 4.4

patients per million inhabitants per year and in those associated with ADAMTS 13
deficiency it is 1.76 per million inhabitants (1) according to epidemiological statistics of
the United States, in Colombia there are no data on this, and there are no case reports
published in the country of this disease.

It belongs to the group of thrombotic microangiopathies of which other diseases such

as haemolytic uraemic syndrome, disseminated intravascular coagulation, HELLP
syndrome (hemolysis, increased liver enzymes and thrombocytopenia) and malignant
hypertension, among others. It is necessary to have a high clinical suspicion of the
diagnosis, because the disease has a 90% mortality if an opportune treatment is not
started.

In this article, we present two patients with a PTT diagnosis managed in the Pablo
Tobón Uribe Hospital, who behaved as refractory to the treatment with plasma
exchange and required additional management with a second line therapy.

Description of the cases

First case

A 46-year-old woman with no history of importance who was admitted due to a 20-day
history consisting of general malaise, unquantified fever, occasional headache, initially
managed as sinusitis with analgesia and oral antibiotic without clinical
improvement. The patient consulted again and a complete blood count was performed
in which they documented severe anemia and thrombocytopenia, started transfusion
support with platelets, and referred with suspicion of myelodysplastic syndrome.

Upon entering our institution, it was documented that he had presented disorientation,
without evidence of an infectious clinical focus in the physical examination or
alterations in the neurological examination, no focalization, or other abnormalities.

In the paraclinical admissions, anemia is documented with high reticulocytes, elevated

lactic dehydrogenation, indirect hyperbilirubinemia and direct negative Coombs. In the
peripheral blood smear, multiple schistocytes are documented. There was no alteration
in renal function.

Given the data of patients with non-immune hemolytic anemia classified as

microangiopathic due to the presence of schistocytes in peripheral blood, associated
with severe thrombocytopenia, fever and neurological alterations, the diagnosis of TTP
is considered; studies of HIV, hepatitis B and hepatitis C were requested, which were
negative and ADAMTS 13 levels were requested, which were reported as less than 5%
(reaching the institution after the patient's death). Management was started with
methylprednisolone in boluses for three days, followed by prednisone at a dose of 1
mg / kg daily, and plasma exchanges with a volume of 1.5 volemia during the first
three days and subsequently a volemia per day.
Restriction of platelet transfusion support was performed only when there was
documented bleeding independent of the number of platelets and transfusion of red
blood cells if the hemoglobin was less than 8 g / dL.

He presented a torpid clinical course, remaining with severe thrombocytopenia and

active hemolysis, without improvement of the neurological symptoms and progressive
deterioration of renal function. After the eighth cycle of plasma exchange presented
convulsive crisis associated with hypotension, simple skull tomography was performed
documenting bleeding to the right occipital region with edema and erasure of the brain
grooves, with scanographic control at 24 hours showing great hypointensity right
temporoparietal compatible with cerebrovascular disease of the ischemic type in the
territory of the middle cerebral artery with improvement of the area of occipital
hemorrhage.

Due to refractoriness to the treatment after eight days of plasma exchange, evidenced
by persistence of high LDH, thrombocytopenia, de novo cerebral ischemic events and
progressive azoate increase was added to the management of vincristine and
cyclosporin without any improvement ( Table 1 ).
Second case

Male patient of 20 years of age without any important antecedent who enters due to
presenting eight days of evolution consisting of fever, nausea, vomiting, changes in
behavior and that later presents seizures to status, requiring sedation and orotracheal
intubation.

A clinical diagnosis of TTP was made and 1.5 plasma vole exchange was started for
three days, followed by a volemia per day associated with methylprednisolone until the
recovery of the symptoms.

He received seven days of plasma exchange with partial response evidenced by

improvement of the neurological picture without new convulsive episodes and
extubation was achieved. He presented an increase in the platelet count to 56,000 and
subsequently fell again to 26,000 remaining with active hemolysis with high LDH, so
that 375 mg / m 2 was added to the weekly rituximab treatment.

After the start of treatment with rituximab the patient presents a slow but progressive
improvement remaining with low platelet counts between 20 thousand and 30
thousand during the first seven days, but after day eight and after the second
application of rituximab, increases the platelet count up to normal levels and without
evidence of hemolysis, progressively increasing hemoglobin with decreased levels of
LDH. He received a total of three doses of rituximab, remaining in complete response
and without the need for additional treatment. When achieving the complete answer,
he continued with the plasmatic exchanges interdiarially for two more episodes and
later they were suspended. The patient completed a total of 15 plasma exchanges and
three infusions of rituximab.

The observation continued on an outpatient basis without any evidence of relapse of

the disease remaining with normal platelet count, without any evidence of hemolysis
and without presenting any neurological alterations.

After discharge from the patient, levels of ADA-MTS 13 with activity lower than 5% are
received, which confirms the clinical diagnosis of idiopathic PTT ( Table 2 ).
Discussion

We present two clinical cases of TTP, a low frequency entity with a high mortality in
which there are no laboratory tests, or single images to confirm the diagnosis and
there must be a high clinical suspicion for selective examinations and before The
presence of microangiopathic hemolytic anemia associated with thrombocytopenia
should be initiated quickly with plasma replacement, which is the initial standard
management; the delay of onset of the same can lead to a mortality higher than 90%
(2).

The initial description of this disease was made in 1924 by Dr. Moschcowitz in a
previously healthy 16-year-old woman who presented fever, malaise and joint pain,
her symptoms worsened after 10 days so she was admitted to the hospital finding
anemia, leukocytosis and petechiae, subsequently presents hemiparesis, coma and
finally dies. Autopsy revealed hyaline thrombi in the terminal arterioles and capillaries
of the heart, spleen kidney, liver and lungs (3).

Subsequently, cases were described with improvement after the infusion of plasma,
considering that there was probably a deficit in some of the plasma proteins that could
be replaced when transfusing the same, only until 1976 began to talk about
management with plasma exchange (4-7). ).

The diagnosis of the disease is clinical and five key elements for diagnosis have been
proposed, including the presence of:

1. Microangiopathic hemolytic anemia.

In which there is an intravascular hemolysis of non-immune cause and is
confirmed by the presence of schistocytes in peripheral blood, elevated
dehydrogenated lactic acid, high reticulocytes and indirect hyperbilirubinemia
but with direct negative coombs.
 2. Thrombocytopenia
3. Neurological alterations.
4. Fever.
5. Increase in creatinine.

However, in view of the poor prognosis of the disease and the high mortality and
because only 20% of the patients classified as PTT comply with the pentade, it was
considered that having microangiopathic hemolytic anemia associated with
thrombocytopenia could lead to its management ( 8). These diagnostic criteria are not
specific for the diagnosis of idiopathic PTT associated with ADAMTS 13 deficiency
(activity less than 5%). Studies have found that patients with clinical appearance of
idiopathic PTT may have ADAMTS 13 deficit less than 5% between 33 and 100% of
cases (9,16).

Pathophysiology

In 1982, the relationship of Von Willebrand factor with the pathogenesis of PTT was
documented (17), finding in these patients unusually large von Willebrand multimers,
which were absent in healthy people. The presence of this unusually large factor
causes intravascular aggregation of platelets and thrombosis which subsequently leads
to microangiopathic anemia and ischemic organ damage due to platelet hyaline
thrombosis.

In 1996, a protease was found to be responsible for cleaving Von Willebrand factor in
human plasma, and was named ADAMTS 13 by the English acronym of the family of
metalloproteases ( a disentigren-like and metalloprotease with thrombospondin
repeats ) and it has been found that Patients who have a deficit of this protease with
activity less than 5% develop TTP (18,19).

The clinical manifestations develop basically due to the severe deficiency (less than
5%) of the activity of ADAMTS 13, metalloprotein responsible for fractionating the very
high molecular weight Von Willebrand molecules newly synthesized mainly by
endothelial cells and to a lesser extent for the platelets. These large molecules of Von
Willebrand factor circulate freely in different organs producing platelet adhesion with
subsequent aggregation of them and intravascular erythrocyte destruction, generating
microthrombosis that give rise to microangiopathic hemolytic anemia with the classic
schistocytes visualized in peripheral blood. All of the above generates a deficient
supply of nutrients and O 2 at the body's historical level, which is why the findings at
the renal and central nervous system (CNS) levels are produced (20-21).

Patients without severe deficiency of ADAMTS 13 can not be cataloged with a diagnosis
of PTT, the other importance of the determination of ADAMTS 13 is that the activity
levels of ADAMTS 13 are prognostic indicators;levels higher than 10% are associated
with clinical and hematological improvement, otherwise they are less than 10% (22).

Driving

Plasmatic exchange
Plasma exchange is the initial standardized treatment for the management of TTP,
before its introduction mortality was close to 90% but with early diagnosis and
subsequent onset of plasma exchange, mortality decreased to 20% (4-8) .

The initial study comparing the transfusion of plasma against plasma exchange as
initial management of TTP included 102 patients. The first group was randomized to
receive plasma replacement (1 to 1.5 times the plasma calculated for that patient),
and the other group received plasma infusion (30 ml / kg / day). On the seventh day,
47% of the first group had platelet counts greater than 150000 / mm 3 and absence of
neurological phenomena, versus 25% in the control group (p = 0.02). Six-month
survival was 78% in the first group, versus 63% in the control group (p = 0.04) (8).

A meta-analysis that included seven randomized studies comparing the use of plasma
exchange and plasma transfusion, concludes that the relative risk of mortality of the
first group was 0.31 (0.12-0.79). (2. 3)

The duration of plasma exchange is widely variable and it is generally accepted that it
takes place at least two days after achieving complete remission of the patient, which
is defined as obtaining

platelet count within the range of normality, in addition to normalization of the LDH
figures and of course the clinical improvement of the patient, in terms of total days of
plasma exchange, the average is 15 days but time ranges have been published that go
from three days to 35 days (24-25).

When is a patient considered refractory to plasma exchange?

It is defined as a platelet count of less than 150000 or persistently elevated LDH or

clinical deterioration of the patient, all after at least seven days of treatment with daily
plasma exchange associated with the use of systemic steroids (22).

In patients who by day seven do not have a good response to plasma exchange, some
additional behavior should be taken because larger responses from this day without a
change in management is difficult to find; Among the therapeutic alternatives are
increased frequency of plasma exchange twice a day, replacement with plasma
supernatant, addition of vincristine, cyclosporine, cyclophosphamide, platelet
antiaggregation and rituximab.

The increase in the frequency of plasma exchanges to twice a day has been evaluated
in the Oklahoma registry in which plasma exchanges were made in 31 episodes of 28
patients evaluated with some response in 27 patients but only complete response in
three patients ( 26).

In the case of cyclophosphamide alone, it has been used in refractory patients with
close 50% responses. It has been used together with splenectomy and / or
rituximab. Relapses are frequent after the same (27, 28).

Another therapeutic option is the use of cryoprecipitate supernatant. It has low

amounts of Von Willebrand multimers and its usefulness in plasma exchange has been
explored instead of plasma. Two randomized studies found no differences in the use of
one or the other product in the response to plasma exchange (29, 30).
When patients with PTT do not respond to management with plasma exchange, other
therapeutic options have been considered, such as the use of cyclosporine, or
vincristine, previously used in immune thrombocytopenic purpura. With respect to
these two drugs, there are reports of case series with variable responses. In the
majority of reported cases, they report a response with these medications, even
knowing that cyclosporine itself can cause PTT (31-40).

Use of rituximab

Because PTT was considered a disease of immune origin when documenting inhibitory
antibodies against ADAMTS 13, rituximab was used. This medication is a monoclonal
antibody against CD20, which is used in the management of several types of
lymphomas and in some autoimmune diseases. Since 2002 there have been reports of
response to refractory TTP with the use of this drug, the first articles in this regard
were series of cases (41-46), with encouraging results in some of them.

Taking into account the previous results with rituximab, a Canadian group conducted a
Phase II study with rituximab in refractory or relapsing TTP in order to determine the
role of this drug in this condition (47). In this study, it was observed that the use of
rituximab decreased the likelihood of relapse with respect to the control group and was
also related to an increase in the activity of ADAMST13. This study demonstrated that
the weekly use of rituximab associated with standard plasma exchange therapy plus
steroids is safe, effective and well tolerated in patients with TTP (47). There are other
studies that have also demonstrated the effectiveness of rituximab in combination with
other therapies (48-52), which make this drug a useful tool to manage this complex
pathology and with a high mortality rate.

At the moment the analysis of the phase 3 study (STAR) that assesses the
effectiveness of the addition of rituximab to standard therapy is ongoing (53).

Conclusions

In only one of our patients based on the literature available at the time, we decided to
administer rituximab with encouraging results, given the clinical improvement and the
remission of the disease. The patient is currently in follow-up without relapse of the
disease seven months after the debut of this one.

This is our experience in the management of this complex disease, both from a
diagnostic and therapeutic point of view. Emphasizing that the most important thing is
to have a great clinical suspicion and initiate an immediate treatment, because the
result of the ADAMST13 levels that confirm the diagnosis are very delayed in our
environment. Therefore, with only clinical suspicion, treatment should be established
to try to reduce mortality in this devastating disease and with sometimes not so
favorable results.

Financing and conflict of interests

There is no conflict of interests. No funding source

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