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Thrombotic Microangiopathies in the 1980s: Clinical Features, Response to
Treatment, and the Impact of the Human Immunodeficiency Virus Epidemic
By Clinton E. Thompson, Lloyd E. Damon, Curt A. Ries, and Charles A. Linker
We reviewed the medical records of 44 adults with 50
consecutive episodes of thrombotic thrombocytopenia purpura (TTP) or hemolytic uremic syndrome (HUS) seen at the
University of California, San Francisco affiliated hospitals
during the past decade. Patients were treated according to a
uniform plan in which initial therapy included daily large
volume plasmapheresis using fresh frozen plasma. Patients
not responding completely to initial therapy were treated
with a salvage regimen including splenectomy, dextran, and
corticosteroids. At the time of diagnosis, the lactate dehydrogenase (LDH) was elevated in 98% of cases, with a median
value of 1,208 U/L. Other clinical features were present
inconsistently, and only 34% of "TTP episodes involved the
classic pentad of hemolytic anemia, thrombocytopenia, neurologic disorders, noninfectious fever, and renal impairment.
Primary treatment with plasma exchange produced complete remission in 56% (27 of 48) of the episodes. Previously
splenectomized patients uniformly responded to plasma
therapy (12 of 12). In patients not responding completely t o
primary therapy, salvage splenectomy produced complete
responses in 81% (13 of 16) of the cases. The pattern of
clinical response t o therapy was consistent, with initial
resolution of neurologic dysfunction (median, 3 days) followed by normalization of LDH levels (5 days) and platelet
count (7 days). Normalization of renal function occurred
significantly later (15 days). Although short-term responses
t o plasma therapy in human immunodeficiency virus (HIV)seropositive patients did not differ from other patients, no
HIV-positive patient survived more than 2 years from diagnosis of thrombotic microangiopathy (TMA). We conclude that
the diagnosis of TMA requires a high degree of clinical
suspicion and that the diagnostic criteria should consist of
microangiopathic hemolytic anemia, thrombocytopenia, and
an elevated LDH. Initial therapy with plasma exchange leads
to disease control in the majority of cases, but an optimal
treatment strategy requires the use of alternative methods if
initial remission is transient or not achieved. Salvage therapy
with splenectomy, steroids, and dextran is highly effective in
this setting.
0 1992by The American Society of Hematology.
T
We reviewed our experience treating TMA in an effort to
describe the clinical spectrum of these disorders, as well as
to define the efficacy of plasmapheresis as primary therapy
and the role of splenectomy as salvage therapy. The natural
history of HIV-associated TMA and the outcome of treatment in HIV-positive patients was also reviewed.
HE THROMBOTIC microangiopathies (TMA) are a
spectrum of clinical syndromes, including thrombotic
thrombocytopenic purpura (TT'P) and hemolytic uremic
syndrome (HUS), that are characterized by the presence of
microangiopathic hemolytic anemia, thrombocytopenia, microvascular thrombosis, and multiple organ dysfunction.
TTP has been classically defined by the pentad of thrombocytopenia, anemia, renal dysfunction, neurologic deficit,
and fever'; HUS is defined as thrombocytopenia, anemia,
and renal dysfunction.2However, it has been observed that
many patients with TTP lack one or more of these criteria,
while some HUS patients exhibit fever and neurologic
dysfunction. Hence, these two disorders appear to be
closely related and part of a disease continuum. In the past
decade, human immunodeficiency virus (HIV) infection
has emerged, and cases of both TT'P and HUS in HIVinfected patients have been re~orted,~-'O
raising the question of a relationship between HIV and TMA.
Although the pathogenesis of these disorders remains an
enigma," the introduction of plasma exchange in the late
1970s has markedly improved survival for these once fatal
diseases.12-ls There remains controversy concerning the
best primary therapy for TMA, and whether any effective
salvage therapy exists for patients failing initial treatment.
From the Department of Medicine, Division of Hematology and
Oncology, The University of Califomia, San Francisco.
Submitted February 14,1992; accepted June 19, 1992.
Address reprint requests to Lloyd E. Damon, MD, Department of
Medicine, Cancer Research Institute, Box M-0128, Rm 1282, MofittLong Hospital, Third and Pamassus Ave, San Francisco, CA 94143.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1992 by The American Society of Hematology.
0006-497119218008-0034$3.00/0
1890
MATERIALS AND METHODS
We retrospectively examined the records of adult patients with
thrombotic microangiopathies admitted to the University of California at San Francisco (UCSF) affiliated hospitals (Moffitt-Long, San
Francisco General, and San Francisco Veterans Administration
hospitals) between January 1980 and April 1991. TMAs were
defined by the presence of thrombocytopenia and a peripheral
blood smear showing microangiopathic hemolysis not explained by
disseminated intravascular coagulation (DIC). Patients with TMA
related to cyclosporin A or mitomycin C were excluded from
analysis. Clinical parameters associated with TMA were defined as
the following: (1) Fever was defined as an unexplained oral
temperature greater than 38.0"C. (2) Neurologic dysfunction was
defined as any new abnormality in neuropsychiatric exam. (3)
Renal dysfunction was defined as a serum creatinine (Cr) 2 1.5
mg/dL and/or a blood urea nitrogen (BUN) 2 3 0 mg/dL, or either
value 50% greater than previously established elevated baseline
values. (4)Thrombocytopenia was defined as a platelet count less
than 150,00O/pL. TTP was defined as TMA with neurologic
dysfunction out of proportion to renal impairment, or with the
absence of both neurologic and renal dysfunction. HUS was
defined as TMA with significant renal impairment and little or no
neurologic dysfunction.
Primary therapy consisted of daily large volume plasma exchanges, 60 to 80 mL/kg/procedure, replaced with equal volumes
of fresh frozen plasma (FFP), or with half FFP and half liquid
plasma. Adjunctive therapies administered with primary plasma
exchange at the discretion of the treating physician included
intravenous (IV) vincristine (1 to 2 mg weekly; 4 episodes);
high-dose corticosteroids ( 21 mglkgld; 14 episodes); oral dipyridamole (75 mg, three times daily; 12 episodes) plus aspirin (325
mg/d; 11 episodes); IV Ig (5 to 30 gld; 4 patients); and oral
Blood, Vol80, No 8 (October 15). 1992: pp 1890-1895
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THROMBOTIC MICROANGIOPATHIES
1891
azothioprine (1.5 mg/kg/d; 1 episode). Complete remission was
defined as 2 1 month of normalization of platelet count, resolution
of red blood cell (RBC) transfusion requirements, and resolution
of acute neurologic events. Generally, patients received two plasma
exchanges after achievement of a complete clinical response (CR).
Patients not achieving complete response to initial therapy, or
rapidly ( 5 2 weeks) relapsing despite initial response, were treated
with the combination of splenectomy, IV dextran-70(500 mL every
12 hours), and high-dose corticosteroids. Patients not responding
quickly (24 to 48 hours) to this regimen were additionally treated
with postoperative daily plasma exchange and, occasionally (8
episodes), IV vincristine. Patients referred for care after failing
splenectomy were treated with plasma exchange.
Follow-up data were obtained through UCSF clinic records, as
well through phone contact with patients or their primary community physicians.
Statistical evaluation of predictors of clinical outcome was
assessed via the two-by-twocontingency table method (x2analysis).
RESULTS
We reviewed 50 consecutive separate episodes in 44
patients. Nine of these patients have been reported previously in the medical l i t e r a t ~ r e . Seventy
~ ~ . ~ ~ percent of the
patients (31 of 44) were women and an equal number were
Caucasian. The median age was 43 years, with a range of 20
to 78. There were 41 episodes of "TP: 22 were primary
disease (15 without prodromal illness, 3 postdiarrheal, and
4 occurring in the peripartum period); 11 episodes occurred
in five patients as relapsing disease (occurring from 1 month
to 15 years after a previous episode); 7 additional episodes
occurred in patients who were seropositive for HIV, and 1
episode was seen in a patient with metastatic parathyroid
adenocarcinoma. Nine episodes were classified as HUS: 6
were primary disease (3 without prodromal illness and 3
after diarrheal illness); 3 were secondary disease (2 in
patients with scleroderma, and 1 in a patient with metastatic adenocarcinoma of the lung).
Table 1 shows the initial clinical presentation of our
patients compared with previously reported ~ e r i e s . ~ J ~ , ~ O - ~ ~
Seventy-eight percent of TTP episodes presented with the
triad of anemia, thrombocytopenia, and neurologic dysfunction, and only 34% with the classic pentad. The most
frequent neurologic abnormalities were alteration in mental status (18 episodes), seizures (8 episodes), hemiplegia (6
episodes), and aphasia (6 episodes). Paresthesias (2 episodes) and visual disturbance (1 episode) were also seen.
More than one neurologic abnormality was seen in 6
episodes. Seizures were late events, occurring in the setting
of advanced disease. In one case, seizures and hemiplegia
became manifest after the onset of hematologic response.
Twelve patients with TTP presented with bleeding (3
each with epistaxis, hematuria, gastrointestinal hemorrhage, and menorrhagia); three others subsequently developed life-threatening hemorrhagic events (subarachnoid
hemorrhage, postoperative ovarian rupture, and massive
hemoptysis). Twelve patients presented with significant
abdominal pain, although in no case was there evidence of
pancreatitis or other identifiable abdominal pathology.
Laboratory parameters at presentation are shown in
Table 2. Serum lactate dehydrogenase (LDH) levels were
markedly elevated in all but one case (range, 191 to 4,700
U/L; normal range, 88 to 230 U/L). Plasma Cr levels were
elevated in 18 of the TTP episodes (range, 0.7 to 6.4 mg/dL;
normal range, 0.5 to 1.4 mg/dL). Cr levels ranged from 2.7
to 11.9 mg/dL in the HUS patients. Only one patient
presented with an abnormality in any coagulation parameter (prothrombin time, partial thromboplastin time, fibrinogen, or D-dimers); this patient had a prolonged prothrombin time secondary to chronic active hepatitis. Liver function
abnormalities, defined by elevations (greater than or equal
to twice normal) in alkaline phosphatase and/or direct
bilirubin, were present in 24% (12 of 50) of the episodes.
Table 1. Clinical Presentation of TMA Patients
Parameters(% of episodes)
Study
Fever
Neurologic
Dysfunction
Current series
Overall (n = 50)
TTP (n = 41)
HUS (n = 9)
Amorosi and Ultmannl
Ridolfi and Be1113
Kennedy et a122
Petin23
Cunner21
Myers24
Taft and BaldwinZ5
Byrnes26
Rose and EldorZ7
Shepard et aI2O
Bell et a128
Rock et a129
60 (n = 30)
61 (n = 25)
56 (n = 5)
98
59
14
a7
100
100
NS
61
37
55
NS
24
70 (n = 35)
78 (n = 32)
33 (n = 3)
60
52
71
100
95
92
NS
89
94
63*
NS
63
Renal
Dysfunction
Triad*
Pentadt
54 (n = 26)
44 (n = 18)
100 (n = 9)
50
45
58
18
55
45
NS
89
73
NS
NS
52
70 (n = 35)
78 (n = 32)
33 (n = 3)
NS
52
NS
100
95
92
NS
89
94
NS
NS
63
30 (n = 15)
34 (n = 14)
11 (n = 1)
NS
40
NS
NS
55
45
NS
Abbreviation: NS, data not stated.
*Historical triad of anemia, thrombocytopenia, and neurologic dysfunction.
tClassic pentad of anemia, thrombocytopenia, neurologic dysfunction, fever, and renal dysfunction.
*Data approximated from report.
44
37
NS
77
NS
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1892
THOMPSON ET AL
Table 2. Laboratory Parameters at Diagnosis of TMA [median values1
~~
Study
Current series
Overall (n = 50)
TTP (n = 41)
HUS (n = 9)
Amorosi and Ultmann'
Ridolfi and Bell13
Kennedy et aIz2
Petin23
Cunner21
MyersZ4
Taft and Baldwin25
Byrnes26
Rose and Eldor27
Shepard et alZo
Bell et a P t
Female
Male
Rock et a P t
Plasma exchange
Plasma infusion
Hemoglobin
IgldLI
Hematocrit
8.7
8.7
8.8
"<10.4"
"<10.4"
7.9
8.8
7.2
26
26
27
(04
NS
NS
NS
NS
NS
PIateIets
(10 3 1 ~ ~ )
49
44
67
"10-120
"'< 6 0
22
44
20
25
25
LDH
(U/L)
BUN
(mgldL1
1,208
1,222
1,215
39
30
72
50%*
45%*
58%*
NS
NS
loo%*
NS
NS
NS
NS
Cr
ImddLI
2.5
1.8
5.2
NS
45%'
58%*
18%*
23
NS
1.6
1.8
8.5
8.8
NS
NS
NS
35
20.5
NS
NS
NS
NS
NS
NS
1,358
29
1.5
NS
NS
21
22
16.5
22
1,139
913
25
31
1.7
1.8
8.8
9.1
26
25
22
24
1,407
1.248
27
34
1.4
1.7
NS
NS
NS
29
26
NS
1,924
NS
NS
Abbreviation: NS, data not stated.
'Values not given, reported as percent abnormal.
tMean values.
There were 41 episodes of TTP in 35 patients. One
patient died before initiation of treatment. One patient
with relapsing TTP (previously treated in this series) in the
third trimester of pregnancy was emergently delivered by
Ceasarian section with complete hematologic resolution.
Thirty-nine episodes in 34 patients were treated with
plasma exchange. A CR was achieved in 22 episodes (56%).
The number of plasma exchanges required ranged from 3 to
32, with a median number of 9. The response to plasmapheresis was better in previously splenectomized patients. All 11
episodes in asplenic patients achieved CR with plasmapheresis. Three patients had just undergone splenectomy at the
time of initial diagnosis of TTP and were transferred to
UCSF after failure to respond. Eight patients had been
splenectomized in the past, one during staging for Hodgkin's
disease, two after abdominal trauma, and five during prior
episodes of TTP. In contrast, only 11 of 28 (39%) episodes
in nonsplenectomized patients achieved a CR with plasma
exchange (P= .002).
Other than splenectomy status, no other clinical features
at diagnosis predicted for poor response. Six of seven
episodes in HIV-positive patients responded to initial
plasmapheresis. All three peripartum patients treated responded to primary plasma exchange. One patient with
metastatic parathyroid adenocarcinoma achieved CR with
plasma exchange.
Of the 14 patients treated with salvage splenectomy, 7
had had a partial response to initial plasma exchange
therapy, but then worsened and failed despite continued
plasma exchange; 7 other patients never responded to
initial plasma exchange therapy. Twelve of 14 (86%)
patients responded completely to the salvage splenectomy
program; 2 patients died despite salvage therapy, 1 of
postoperative staphylococcal infection (in complete hematologic remission), and l (HIV-positive) of unresponsive
disease.
Five of 9 patients with HUS treated with primary plasma
exchange achieved CR. The number of plasma exchanges
required ranged from 2 to 11, with a median number of 7.
One patient was previously asplenic (posttraumatic) and
responded to primary plasma exchange. Four of the remaining eight patients responded to primary plasmapheresis.
Two of four patients who failed plasmapheresis underwent
salvage splenectomy. One of these patients had had an
initial response to plasma therapy, but relapsed both
hematologically and neurologically while on therapy. This
patient had a CR to salvage splenectomy. One patient with
metastatic adenocarcinoma of the lung did not respond to
plasma exchange and had a transient response to splenectomy before dying of bacterial pneumonia. Two patients
died after failing primary plasmapheresis without salvage
therapy (both with sepsis of unknown origin). One of two
patients with scleroderma responded hematologically to
primary therapy, although she remained chronically dialysisdependent.
The pattern of response to therapy in the TTP patients is
summarized in Fig 1. Neurologic resolution occurred earliest, with a median time to onset of improvement after
initiation of therapy 2 days (range, 1 to 7), and median time
to neurologic resolution 3 days (range, 1 to 7). Five patients
experienced permanent neurologic sequelae despite hematologic CR (2 with hemiplegia, 2 with seizure disorder, and
1 with aphasia, seizure disorder, and hemiplegia). LDH
levels were the first laboratory parameter to show improvement, with median time to 50% decrease in LDH 3 days
after initiating therapy (range, 1 to 20) and to normalization
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1893
THROMBOTIC MICROANGIOPATHIES
Neurologic
Abnormalities*
Serum LDH
Platelet count*
Renal
Function
s
0
4
10
15
20
25
30
Tone (days post-initiation of therapy)
ImproveFig 1. Mean time to clinical response in TMA patients. (0)
ment;).( normalization. (*) Neurologic improvement and resolution
by objective exam, with absence of new abnormalities. (t)Serum LDH
improvement when LDH 550% peak level and normalization when
LDH in normal range. (*) Platelet count improvementwhen the count
was a50,000/pL and normalizationwhen the count was r150,000/
pL. (I) Renal improvement when creatinine values decreased a2
sequential days with no further deterioration and normalized with
return to normal range/ baseline values.
5 days (range, 2 to 22). The median time to a sustained
increase in platelet count was 5 days after initiating therapy
(range, 1 to 23), to a platelet count of 50,000 7 days (range,
3 to 28), and to a platelet count of 150,000 10 days (range, 3
to 32). Renal response to therapy was slowest, with medium
time to sustained improvement in serum creatinine 5 days
after initiating therapy (range, 2 to 25), and a median time
to return to baseline/normal levels of 15 days (range, 8 to
36).
Overall, 82% (41 of 50) of TMA episodes fully resolved,
and 80% (35 of 44) of patients survived. For patients
treated with plasma therapy, 83% (40 of 48) of the episodes
resolved and 81% (35 of 43) of the patients survived. In the
acute setting, HIV positivity did not adversely affect outcome, with resolution in 87% (6 of 7) of the episodes, as
opposed to 83% (34 of 41) of the episodes in HIV-negative
patients. Similarly, there was no difference in short-term
survival (6 of 7 v 29 of 36). However, with follow-up
(median, 23 months; range 1 to 124 months), striking
survival differences have emerged. No HIV-positive patient
has survived for 2 years. Causes of death were pulmonary
toxoplasmosis (1 month), central nervous system (CNS)
lymphoma (6 months), pneumocystis pneumonia (7, 9, and
11 months), and relapsed refractory TTP (20 months;
episode not included in acute treatment data). In the
HIV-negative group, there has been one late death, a fatal
complication of acquired immunodeficiency syndrome
(AIDS) acquired during plasma therapy of the initial TTP
episode. Long-term survival is 78% (28 of 36) in HIVnegative TMA patients (81% [22 of 271 in HIV-negative
TTP patients).
DISCUSSION
The treatment of TMA has remained empiric since
Moschowitz's first report in 1924.30Until the 1960s, fewer
than 5% of adult patients with TTP-HUS survived.' With
the introduction of corticosteroids, splenectomy, and anti-
platelet agents, survival improved13J4x21,31s32;
in the 1970s,
with the advent of first whole blood e ~ c h a n g eand
~ ~ later
-~~
plasma therapy,15.16,20
significant advances were made in
long-term outcome. Recently, combination therapies including IV vincristine have been shown to be e f f i c a c i ~ u s . ~ ~ . ~ ~
Controversy continues regarding the therapy of choice in
these disorders, and the relative roles of corticosteroids,
vincristine, antiplatelet agents, and splenectomy remain to
be defined.
The diagnosis of a TMA requires a high degree of clinical
suspicion. We found that 70% of episodes in TMA patients
presented with the triad of thrombocytopenia, hemolytic
anemia, and neurologic dysfunction, and only 30% of
episodes presented with the clinical pentad. While the first
large reviews of TTP suggested that the absence of fever
was rare,' we found fever present at diagnosis in only 61%
of cases. Neurologic abnormalities are often subtle at
diagnosis and changes in personality or mental status may
become evident in retrospect only after response to treatment. More severe neurologic findings usually occur during
disease progression. Given the lack of consistent nonhematologic findings (fever, neurologic, or renal), the diagnosis
of TMA/TTP should be made by the presence of a
microangiopathic hemolytic anemia and thrombocytopenia
in the absence of a good alternative diagnosis (such as
DIC). Waiting for the onset of neurologic or other organ
dysfunction to begin treatment may be hazardous given the
potentially catastrophic course of some patients with TTP,
and is not advisable.
The serum LDH level is greatly elevated in patients with
TMA, and can be helpful in increasing the degree of
suspicion for these disorders. The median LDH level in our
patients was greater than 1,200 U/L, almost six times the
upper limit of normal. This elevation is much greater than
that seen in other hemolytic anemias, suggesting a source of
LDH other than (or in addition to) RBC hemolysis. The
LDH appears to be a valuable clinical tool in recognizing
and diagnosing TMA. Serum LDH levels also decrease
early in response to therapy, and are a sensitive marker of
clinical disease activity. The presence of an extraordinarily
high LDH in the presence of microangiopathic hemolysis
and thrombocytopenia, in the presence or absence of fever
and neurologic or renal abnormalities, should prompt a
diagnosis of TMA.
Our patients were treated in a generally uniform manner,
and permit an estimation of the efficacy of plasma exchange
primary therapy with splenectomy salvage therapy for the
TMAs. Fifty-six percent of the episodes achieved CR with
plasma exchange alone. This is consistent with other studies
in the l i t e r a t ~ r e .The
~ ~response
. ~ ~ ~ to
~ ~initial
~ ~ plasmapher~
esis in episodes classified as either TTP or HUS is similar
(22 of 39 TT'P; 5 of 9 HUS). A recent large series of TTP
patients in Canada treated with plasma exchange or plasma
infusion showed a similar response rate in those patients
receiving plasma exchange.29Forty-seven percent of TTP
patients responded to plasma exchange when analyzed at
the end of one cycle of therapy (a cycle was defined as 7
days of treatment or the time to death/rapid deterioration/
rapid response if one of these events occurred before 7
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
THOMPSON ET AL
1894
days). However, the response to plasma exchange was
better (78%) when response was determined at 6 months.29
This suggests that prolonged plasma exchange might benefit some patients we defined as plasma exchange failures. If
so, then one must consider the relative risks and benefits of
prolonged plasma exchange versus splenectomy in patients
not responding well to plasma exchange therapy. When we
combine our responses to plasma exchange followed by
salvage splenectomy (82%), the outcome in our patients is
similar to the Canadian plasma exchange patients (mean,
15.8 exchanges). However, patients having no initial response to plasma exchange, or those clearly deteriorating
despite continued daily large-volume plasma exchange,
would probably not benefit from continuation of the same
therapy and require an alternative approach. The Canadian
series also proved the superiority of plasma exchange over
plasma infusion as initial therapy for TTP (6-month survival, 78% v 63%; P = .036).29
Splenectomy appears to have a beneficial role in the
treatment of TMA. Previously splenectomized patients
uniformly responded to treatment with plasma exchange
(12 of 12 episodes), whereas patients with intact spleens
responded less often (11 of 28 TTP episodes; 4 of 8 HUS
episodes). Furthermore, splenectomy combined with steroids and dextran proved to be effective as salvage therapy.
The addition of splenectomy in patients not responsive to
plasma exchange alone produced responses in 81% (13 of
16) of the episodes, including one HUS patient. This
finding extends our previous observations on the value of
this salvage splenectomy regimen'* and indicates that
failure to respond completely to initial plasma exchange
does not necessarily indicate a dire prognosis. A recent
series of TMA patients treated with corticosteroids or
corticosteroids plus plasma exchange used salvage splenectomy in six patients failing primary therapy.28Because one
patient died perioperatively and the others had hematologic and clinical deterioration soon after splenectomy,
these investigators did not recommend splenectomy as
salvage therapy. However, the five surviving patients had
plasma exchange restarted, as is our practice, and all
responded.28 This result supports our belief that splenectomy is an effective salvage therapy, but often requires
continued plasma exchange support until the effect of
splenectomy becomes clinically evident.
TMA are presently eminently treatable with CRs expected in most patients. Overall, the response rate to
therapy in our patients was 82%, comparable to recently
published series using plasma exchange therapy20 TTP and
HUS may be considered for purposes of therapy as related
d i s e a ~ e s , 3and
~ , ~should
~
be treated as such in adults.
Although presently the clinical response to therapy
cannot be predicted in the individual
we found
that the pattern of response to therapy is predictable.
Neurologic abnormalities are the most sensitive to therapy,
resolving in the first hours to days in patients responding to
therapy. The earliest laboratory sign of clinical response is a
decrease in the serum LDH, which may improve days
before there is an improvement in the platelet count. The
slowest clinical abnormality to respond is that of renal
abnormalities, which may persist for days to weeks after
other abnormalities have normalized.
The recent emergence of the HIV epidemic and numerous case reports of classic HUS and TTP in patients with
both symptomatic and asymptomatic HIV infection has
suggested a possible relationship between TMA and HIV.
This present series represents the largest single series of
HIV-positive patients reported in the literature. First
reported in 1987,3 to date a total of 15 HIV-positive
patients have been previously reported in the English
l i t e r a t ~ r e . ~The
- ' ~ pooled literature and the patients in this
series are summarized in Table 3. In the short term,
HIV-positive patients with TMA respond equally well to
plasma exchange as non-HIV-positive patients, with a
response rate in this series of 86% and in the pooled
literature of 80%. In both the current patients and pooled
literature, the majority of patients were not previously
diagnosed with Center for Disease Control (CDC)-defined
AIDS-related complex (ARC) or AIDS. While long-term
outcomes are unavailable for the previously reported cases,
in the present series only one of the six patients achieving
CR survived more than 1 year after CR and none survived
to 2 years. This suggests that TMA syndromes may occur
late in the natural history of HIV-related diseases.
Although the TMAs are likely to be a pathogenically
heterogeneous group of diseases, the treatment of these
disorders with plasma exchange therapy has significantly
improved the prognosis for such patients. Primary therapy
with plasma exchange alone can be expected to achieve a
CR in at least half of the episodes. Patients who fail to
respond or who rapidly relapse are still salvageable and can
benefit from alternative therapy. The combination of splenectomy, steroids, and dextran provides effective salvage
therapy in the majority of patients, and, overall, a CR
should be achieved in greater than 80% of cases. With rapid
diagnosis and an aggressive approach to therapy, the
mortality rate from these disorders should continue to decline.
Table 3. TMA in HIV-Positive Patients
CRlNo Treated
Pre-Existing
-
Current series
Pooled literature*
"References 3 through IO.
N
Male
ARC/AIDS
Plasma
Infusion
Plasma
Exchange
7
15
7
13
2
3
1I 2
-
617
11/11
Splenectomy
CR
01 1
86%
80%
-
1-yr
SuNlval
16%
-
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1895
THROMBOTIC MICROANGIOPATHIES
REFERENCES
1. Amorosi EL, Ultmann JE: Thrombotic thrombocytopenic
purpura: Report of 16 cases and review of the literature. Medicine
45:139,1966
2. Gasser VC, Gauter E, Steck A, Siebenmann RE: Hamolytischuramische Syndrome: Bilaterale Nierenindenneckrosen bei akuten
envorben hemolytischen anamien. Schweiz Med Wochenschr 85:
905,1955
3. Jokela J, Flynn T, Henry K Thrombotic thrombocytopenic
purpura in a human immunodeficiency virus (H1V)-seropositive
homosexual man. Am J Hematol25:341,1987
4. Leaf AN, Laubenstein LJ, Raphael B, Hochster H, Baez L,
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1992 80: 1890-1895
Thrombotic microangiopathies in the 1980s: clinical features,
response to treatment, and the impact of the human
immunodeficiency virus epidemic
CE Thompson, LE Damon, CA Ries and CA Linker
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