< Brief History >
A 36-year-old
woman who denied any systemic disease developed fever 6 days
prior to admission. She had been quiet well-being before this
admission and no abnormality was detected in previous annual
health examinations. In additional to the fever, she also
found that many purpura lesions involving the extremities and
trunk. The size was around 1 to 2 cm in diameter with
irregular shape. Besides, pale face was also noted by her
family. There was no history of trauma, headache, blurred
vision, epistaxis or focal neurologic symptoms. One day before
admission, she was found to have intermittent confusion and
lethargy. Progressive dyspnea was also noted. Because of the
altered consciousness, she was brought to our Emergency
Service subsequently. On arrival, the Glasgow Coma Score was
E4V5M6. Physical examination showed a woman of 159 cm in
height and 65 kg in weight. Her body temperature was 37.8 oC,
blood pressure 152/86 mmHg, and pulse rate was 122 beats per minute. No
focal neurologic deficit was detected but mild confusion was
noted. Her conjunctiva was remarkably pale, and some
scattered painless purpura were found on the trunk.
According to her family's statement, she was not a vegetarian.
She had no recent history of taking medicines or
travel. Because of severe anemia, she was transfused with I unit of
packed RBC at the Emergency Service after the lab data were
available.
< Laboratory and Image
Study >
1. CBC:
Day after admission |
WBC K/μL |
Hgb g/dL |
Hct % |
MCV fL
|
Plt K/μL |
ER |
9.51 |
7.3 |
21.9 |
104 |
65 |
2nd |
9.54 |
7.9 |
23 |
104 |
50 |
3rd |
8.98 |
8.7 |
25.3 |
102 |
48 |
5th |
9.03 |
9.3 |
28.8 |
102 |
45 |
7th |
10.3 |
8.9 |
25.0 |
101 |
54 |
10th |
12.1 |
9.2 |
28.6 |
102 |
55 |
15th |
10.4 |
9.3 |
28.0 |
100 |
78 |
25th |
9.6 |
10.4 |
30.4 |
98 |
150 |
2.
Biochemistry:
Day after admission |
BUN mg/dl |
Cre mg/dl |
Na mmol/l |
K mmol/l |
GOT U/l |
LDH U/l |
T-Bil mg/dl |
I-Bil mg/dl |
ER |
29.3 |
2.9 |
141 |
4.8 |
104 |
1288 |
1.6 |
1.2 |
2nd |
48 |
3.3 |
138 |
4.6 |
123 |
1250 |
1.6 |
1.2 |
3rd |
54 |
4.8 |
136 |
4.4 |
158 |
1365 |
|
|
5th |
76 |
5.9 |
135 |
4.5 |
204 |
1402 |
1.4 |
1.0 |
7th |
95 |
8.1 |
133 |
4.9 |
356 |
1532 |
|
|
10th |
93 |
8.2 |
136 |
4.5 |
365 |
1280 |
1.4 |
1.1 |
15th |
67 |
7.2 |
137 |
4.3 |
254 |
767 |
|
|
25th |
34 |
2.5 |
137 |
4.2 |
45 |
150 |
1.0 |
0.4 |
3. Urine analysis:
Day after admission |
Appearance |
Sp. gr |
pH |
Protein mg/dL |
Glu g/dL |
Ketones |
O.B |
Urobil EU/dL |
Bil |
ER |
R;Cloudy |
1.02 |
6.5 |
>300 |
- |
- |
+ |
0.1 |
- |
5th |
R;Cloudy |
1.02 |
6.5 |
>300 |
- |
- |
+ |
0.1 |
- |
25th |
Y;C |
1.01 |
7.0 |
Trace |
- |
- |
- |
0.1 |
-
|
Day after admission
|
Nitrite |
WBC |
RBC /HPF |
WBC /HPF |
EpithCell /HPF
|
Cast /LPF |
Crystal |
Bact |
ER |
- |
- |
10-15 |
0-1 |
0-3 |
- |
- |
- |
5th |
- |
- |
10-15 |
0 |
3-5 |
- |
- |
- |
25th |
- |
- |
3-5 |
0 |
0 |
- |
- |
- | PT & aPTT: Both were within normal range
4. Renal sonography:
Size |
R't 10.5 cm ; L't 10.9 cm |
Shape |
Bilaterally normal |
Cortical thinkness |
R't: 10 mm; L't: 9 mm (within normal limit) |
Central sinus |
No hydronephrosis |
Solid or cystic lesion |
Nil |
5. CXR: Normal heart size and clear lung fields.
6. Coombs' Test: Negative
< Course and Treatment
>
After admission, antibiotics were prescribed
for presumed sepsis. Because of the fever, profound renal failure,
highly elevated LDH, low platelets, skin purpura and fluctuating
neuroloic symptoms, TTP was highly suspected. Because
of the bleeding tendency, renal biopsy was postponed,
and plasmapheresis was instituted immediately 5 days after
admission. She also underwent packed RBC transfusion
for severe anemia. Ten days after the initiation of
plasmapheresis, her platelet number and LDH improved gradually.
After the platelet levels and LDH were normal, plamapheresis was suspended.
Because urine out was adequate, no hemodialysis was
needed. She still had impairment of renal function 30 days
after admission. Two months after discharge, the hemogram
and renal function were normalized.
< Analysis
>
Thrombotic
thrombocytopenic purpura (TTP) is more
common in women than in men, with a female-to-male ratio of 3:2.
TTP is most common in adults, and the peak age occurs
in the fourth decade of life, with a median age at diagnosis
of 35 years. TTP can be divided into idiopathic and acquired
forms. Some drugs like quinine, mitomycin-C, calcineurin inhibitors,
and ticlopidine are the most common. And
antibodies against vWF cleaving protein have ever been reported. Cancers
and infection (mostly HIV infection) have also been reported
to be associated with TTP. Pregnancy and the postpartum
state also account for 10-25% of the cases of TTP. However,
for many patients with acquired TTP, no underlying cause
can be established. It belongs to
thrombotic microangiopathies, a group of diverse disorders that
are classified based on common morphologic features. The
most common types are TTP and hemolytic uremic syndrome (HUS).
TTP and HUS have several similar presentations, but they
are different somehow in the involvement of end organs.
Besides, the pathogenesis underlying these two diseases is
actually distinct. TTP is characterized by diminished activity of
von Willebrand factor (vWF) cleaving protein, whereas HUS
has defective vWF cleaving protein. When there is a defect
or deficiency of vWF cleaving protein resulting in unusual
large vWF which binds to extracellular matrix and platelets, it
will induce platelets aggregation and activation, which leads to
platelets consumption, thrombi formation, organ ischemia and
erythrocyte fragmentation (ie, schistocytes). The vWF cleaving
protein is a member of a family of zince metalloproteinases
named “a disintegrin and metalloprotease with thrombospondin
type 1 repeat” (ADAMTS). Mutations of ADAMTS-13 were observed
in patients with familial and recurrent TTP. Based on the
pathogenesis, some clinical symptoms can be expected.
There is a clinical
pentad of TTP: renal failure (88%), fever (60%),
fluctuating central nervous system symptoms (36%),
thrombocytopenic purpura and microangiopathic hemolytic anemia
(MAHA). The thrombocytopenic purpura and MAHA are always present, but the
other three are not. Other non-specific
symptoms like fatigue/generalized malaise and arthralgias may be present.
TTP is a clinical diagnosis with no
pathognomonic laboratory test findings. Current clinical
practical diagnostic criteria of TTP
include thrombocytopenia, schistocytosis, and significant elevations in serum LDH levels. Measuring
protease activity as a single test to distinguish TTP from HUS
is not practical at this time. The absence of in vitro tests
capable of detecting abnormalities in all the molecular
interactions required for the cleavage of unusual large vWF
multimers by ADAMTS-13 in vivo is a limitation. Typical
abnormal lab results are thrombocytopenia, severe anemia,
elevated LDH, impaired renal function, microscopic hematuria
and proteinuria but normal PT/aPTT tests.
Because the underlying pathogenesis
of TTP is ongoing in patients with active status, it's never
too early to treat them with fresh frozen plasma (FFP)
infusion or plasmapheresis. FFP infusion is the mainstay of
therapy to provide deficit vWF cleaving enzyme. Plasmapheresis
or plasma exchange may provide synergism by removing any
circulating vWF cleaving protein inhibitor and by facilitating
the infusion of large amount of FFP. Steroids might be useful
sometimes. Supportive dialysis might also be needed when
uremic status is present. Platelet infusions and aspirin are
contradicted even though patients have thrombocytopenia and
microthrombi, because the platelet aggregation worsens with
platelet transfusions which is associated with rapid
deterioration and bleeding tendency. In some studies,
extensive platelet aggregates were found throughout the CNS on
postmortem examination. Desmopressin (DDAVP) is
contraindicated because it acts by releasing ULVWF from the
endothelium into the circulating blood. The response of the
therapy is monitored by platelet and LDH levels. Treatment of
refractory or relapsing TTP includes vincristine, a
second-line therapy with an unknown mechanism of action.
< Reference
>
- Harrison's principles of internal
medicine 15 edition
- Comprehensive Clinical Nephrology
2nd edition
- eMedicine, Thrombotic Thrombocytopenic Purpura. Last
Updated: Nov 30, 2005
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