CASE REPORT

A Congenital Variant of Thrombotic ThrombocytopenicP urpura in Two SiblingsYoichi Azuno, Kohei Kaku, Kazuko Shino*, Shinji Kamei, Manabu Nishimura,

Koichiro Okafuji, Yasushi Inoue, Noboru Matsumoto** and Toshio Kaneko

Wedescribe two siblings affected by chronic relapsing thrombotic thrombocytopenic purpurafrom infancy. The elder brother, a 12-year-old boy had 50 such episodes characterized by acuteonset of fever, headache, drowsiness, vomiting, dark urine, thrombocytopenia and anemia. Theyounger sister, a 6-year-old girl, had 8 episodes with the same clinical manifestations. Petechiae andecchymoses on the extremities were present throughout their lives. Furthermore, anemia withevidence of red blood cell fragmentation and thrombocytopenia were present chronically. Periodi-cal transfusion offrozen fresh plasma prevented recurrent episodes. These cases suggest that thereis a congenital variant of thrombotic thrombocytopenic purpura.(Internal Medicine 33: 752-758, 1994)

Key words: thrombotic thrombocytopenic purpura, sibling, fresh frozen plasma

Introduction

Thrombotic thrombocytopenic purpura (TTP) , first describedby Moshcowitz in 1924 (1), is characterized by a pentad ofclinicalmanifestations including microangiopathic hemolyticanemia,thrombocytopenia, fever, fluctuating neurological signsand renal dysfunction. Until the early 1960s, TTP had been afulminant,fatal disease and fewer than five percent of patientswith acute episodes survived (2). Once the efficacy of wholeblood exchange transfusions, plasma infusions, or plasma ex-changes had been demonstrated, the survival rate of TTPincreasedto about eighty percent (3-7). It was also revealed thata considerable number of patients who survive the first episodeof the disease frequently relapse (8).

This report presents two siblings affected by an unusualvariant of TTP. Both siblings have suffered from frequentepisodes of TTP with clinical manifestations of headache,vomiting,drowsiness and dark urine since early childhood. Theclinicalsymptoms were temporarily improved by whole bloodorplasma infusions. Once the diagnosis ofTTP was made, theyreceivedplasma transfusions to supplement the missing plasmafactor. Periodical transfusions of fresh frozen plasma (FFP)controlledtheir disease. Reports of siblings affected by chronicrelapsingTTP since early childhood are quite rare because TTPwas usually a fulminant and fatal disease. The present cases

mayrepresent an important variant of the disease.

Case Report

Case1A 10-year-old Japanese boy was admitted to the Yamaguchi

University Hospital on the 20th of August 1990. He was bornafter an uncomplicated 38-week pregnancy with a birth weightof3,030 g to 30-year-old, gravida 2, para 2 mother. Thirty-eighthours after birth he received exchange transfusions because ofhyperbilirubinemia. From the age of 3 months to 10 years he

experienced 50 similar episodes characterized by the acuteonsetoffever, headache, drowsiness associated with vomiting,darkurine, severe thrombocytopenia and anemia. At an earlyage, episodes had been preceded by an upper respiratory infec-tion,however, the recent episodes had no apparent precipitatingevent. Petechiae and ecchymoses were present throughout hisclinicalcourse. Recent episodes necessitated his receiving

transfusions of either whole blood or packed red cells to which

he always responded dramatically, being clinically well within2 days. Occasionally he recovered spontaneously from someepisodes without a blood transfusion, although this recoverywasslower than when he received blood transfusions.On admission, physical examination revealed a well devel-oped, well nourished, slightly pale boy, who had several

From the Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, *the Department of Pediatrics, Momoyama Civil Hospital and **the School of Allied Health Science, Yamaguchi University, YamaguchiReceived for publication December 16, 1993; Accepted for publication July 28, 1994Reprint requests should be addressed to Dr. Yoichi Azuno, the Third Department of Internal Medicine, Yamaguchi University School of Medicine, 1 144 Kogushi, Ube, Yamaguchi 755

752 InternalMedicineVol. 33, No. 12 (December 1994)

Congenital Variant of TTP

ecchymoses on the extremities. The enlarged liver and spleenwere each palpable to two finger-breadths below the costalmargin. There was no lymph node enlargement, jaundice,hypertension, neurological abnormalities, or any sign of renalinsufficiency.

Laboratory data on admission are summarized in Table 1.The peripheral blood smear showed abnormal red blood cellmorphology characterized by anisocytosis, poikilocytosis,spherocytosis, reticulocytosis and fragmentation (Fig. 1A).Urinalysis was weakly positive for occult blood and negativefor proteinuria. Serum electrolytes were normal. A bone mar-row aspirate revealed hyperplastic marrow with a 0.28:1 ofmyeloid to erythroid ratio and numerous megakaryocytes. Theosmotic fragility test of red blood cells was normal. All studiesof the activities in the red cells of enzymes in the Embden-Myerhof pathway, pentose phosphate pathway and those in-volved in glutathione metabolism were normal. Screening testfor abnormal hemoglobins was negative. Platelet aggregationtests revealed that his platelets did not respond at all to adenosine

diphosphate, epinephrine or collagen. The chest film and elec-

trocardiogram disclosed no abnormality. A computed tomogram

of the brain showed no abnormality, however, the electroen-cephalogram revealed increased whole brain theta waves. Abiopsy specimen obtained from his left auricle failed to demon-strate microthrombi or any abnormality of endothelial cells.Although lacking histological proof or evidence of renal in-

sufficiency, we diagnosed the patient as having an unusual

c

ongenital form of TTP.

Five days after admission, he complained suddenly of head-ache and general fatigue, followed by drowsiness, dark urineandfever. As before, there was no apparent precipitating factor.Neurological examination revealed no abnormality associatedwith the drowsiness. The urine was "Coca-Cola"-like in colorand contained hemoglobin and protein. Microscopic examina-tion of the urine revealed no white blood cells, a few red bloodcells and many red blood cell casts. Six hours after the onset ofthis episode, we initiated a 200 ml fresh frozen plasma (FFP)transfusion. When one half of the volume of FFP was trans-

Table 1. Laboratory Data on Admission

Normal Range Case 1 Case 2

Peripheral Blood

R

BC C? 4.5-5.5xlO12/l 2.65 3.89

9 4.0-4.5xl0I2/l

Hematocrit cf 40-50%, 9 37^7% 23.9 32. 1

Hemoglobin Cf 14-18g/dl, 9 12-16g/dl 8.0 10.6

Reticulocyte 0.5-1,5% 1 1.9 9.4White blood cells 4-10xl09/l 2.8 3.6

Platelet 1 50-400x l 09/l 1 9 43

Blood Chemistry

Total bilirubin 0.3-1.Omg/dl 1.5 1.4

Direct bilirubin 0.6 0.5

Blood urea nitrogen 8-15mg/dl 25.0 1 6.0

Creatinine 0.7-1.5mg/dl 1.0 0.7

24-hour creatinine clearance I/day 1 50.6 75.2

Glutamate oxaloacetate transaminase 1 -20U 30 1 9

Glutamate pyruvate transaminase 1-1 7U 1 6 9

Lactate dehydrogenase 1 30-240U 835 535

C-reactive protein less than 0.25mg/dl 0.24 0.24

Serological Test

Haptoglobin 6 1-200mg/dl < 1 0 < 1 0

Antinuclear factor (-) (-)

CH50 25-40 40.4 34. 1

Direct Coombs ' test (-) (-)

Ham 's test (-) (-)

Sugar water test (-) (-)

Bleeding Tendency and Coagulation

Bleeding time 1-6 min >10 >10

Prothrombin time (PT) control 1 1.8 sec 13.3 13.3

Partial thromboplastin time (PTT) control 28.2 sec 28.5 42.5

Fibrinogen 1 20-308mg/dl 247 1 75

Fibrinogen degradation product (FDP) less than lOOng/ml 4 1 42Antithrombin III 82-1 32% 1 36 83

6-keto prostaglandin F l a 1 2-33pg/ml 6.7 1 0von Willebrand factor activity 60-170% 32 32VWF multimer pattern Normal Normal

Internal MedicineVol. 33, No. 12 (December 1994) 753

Azuno et al

Fig. 1. Red blood cell morphology characterized with anisocytosis,poikilocytosis, spherocytosis, reticulocytosis and fragmentation in the periph-eral blood smear of case 1 (A) and case 2 (B). The milder morphologicalchanges were seen in the second sister, who had no episodes of TTP (C)(Wright stain, x600).

fused, his consciousness level improved dramatically, as head-ache and general fatigue disappeared at once. The urine was no

longer dark at 6 hours after initiating the FFP. The bodytemperature rose to 38.2°C at 6 hours after the onset of the

episode and then fell rapidly. The platelet count began toincrease beginning at 24 hours after FFP infusion, reached apeak of 126xlO9/l at 5 days after FFP, and decreased gradually

thereafter. The hemoglobin level, which decreased to 5.9 g/dlfrom7.8 g/dl during this episode, also began to increasebeginning at 24 hours after FFP infusion to reach the peak of10.9 g/dl at 7 days after FFP, and thereafter decreased gradually(Fig. 2). However, the red blood cell abnormality persisted inspite of dramatic improvement of the clinical symptoms. Thepatient was discharged on the 1st of September, 1990. Ten daysafter discharge, the next episode occurred and was treatedsuccessfully with 100 ml of FFP. Thereafter, we began to give

preventive 100 ml FFP at regular three-week intervals, and have

continued preventive transfusion of FFP. As shown in Fig. 3,

this procedure causes characteristic fluctuation in the peripheralbloodcell count, especially in the platelet count, and it de-

creases, or prevents altogether, further episodes. When theplatelet count reached a peak of 126xlO9/l after FFP, platelet

aggregation test revealed the following; the maximum responserate of adenosine diphosphate (3 |LiM) was 17%, epinephrine (3jLig) was 10%, and collagen (2 jag) was 0%.

Although the clinical course suggested a chronic activecourse, the patient has not had any significant clinical symptomsince January 1991 and appears to be very well as of December

1993.

Case2A 4-year-old girl, the younger sister of patient 1, was

admitted to our hospital on the same day as patient 1. She wasborn in 1986 after an uncomplicated 38-week pregnancy witha birth weight of 2,782 g. The patient received exchangetransfusions on the first and the second days after birth becauseofhyperbilirubinemia. From the age of 8 months to 4 years, she

experienced 8 episodes characterized by preceding upper respi-ratory infection associated with high fever, followed by head-ache, general fatigue, drowsiness and dark urine. Each episodewas treated with 100 ml or 200 ml of whole blood orpacked redcells and some antibiotics providing dramatic relief from herclinical symptoms. However, abnormalities in the peripheral

blood counts and the abnormal appearance of the red cellspersisted even during asymptomatic periods as in case 1.On admission, physical examination revealed a well devel-oped, well nourished, slightly pale girl, exhibiting several

ecchymoses on the extremities. No evidence of hepatospleno-megaly, lymphadenopathy, jaundice, hypertension, neurologi-calabnormalities, or renal insufficiency was observed. Thelaboratory data are summarized in Table 1 , and are similar tothose abnormalities seen in case 1. The red blood cell morphol-ogy was also abnormal as there was anisocytosis, poikilocytosis,spherocytosis, reticulocytosis and fragmentation (Fig. I B). The

urine was weakly positive for occult blood and negative forprotein. A bone marrow aspirate revealed hyperplasia with a0.5:1 of myeloid to erythroid ratio and numerous mega-

karyocytes. Studies of red blood cell osmotic fragility andactivities of enzymes in the red cells were normal and no

abnormal hemoglobin was evident. The platelet aggregation

754 Internal Medicine Vol. 33, No. 12 (December 1994)

Congenital Variant of TTP

150-1 15-I ^u . .. ,, . r30 ^K Hemolytic attack

^ FFP 2U

i 100-\10- / Sxy/^j+---^\ -20? fci ^ A --'''' ^*+y' \

! °"V-V / ° o |

1 50"45~ JT -iog

o I I i I i | i | | 8/24 25 26 27 28 29 30 31 9/1 day

Fig. 2. Hospital course of case 1. After transfusing 2 U of frozen fresh plasma (FFP), a significant recovery of thehemoglobin (Hb) concentration, platelet (PLT) number, and percent reticulocytes (Retic) was seen.

Hemolytic attack2001 å  å  å  å  r20

£ 2U 1U 1U 1U 1U 1U 1UA *

^ ^L ^L^ vlv vlv ^L ^L ^L- J T *^ 150- V TTTTT \\ "15?

10°" a\J'\ v\à"' v'i v/l y -w

I | | | |'90.9 10 ll 12 '91.1 month

Fig. 3. Clinical course of case 1 afterdischarge. Cyclic changes in hemoglobin (Hb) andplatelet (PLT) levels in peripheralblood were evident with preventive use of 100 ml (1 U) of frozen fresh plasma (FFP) given every 3 weeks.

test gave the same results as in case 1. The chest film, electro-cardiogram and the computed tomogram of the brain disclosedno abnormality. However, the electroencephalogram revealeddiffusely increased theta waves. Histological examination of

t

he skin was not performed.Wehad no opportunity to observe any episode in the hospi-

tal. The laboratory data, however, demonstrated clearly that thepatient had a chronic active disease resembling TTP as did her

elderbrother. Weresigned to give prophylactic transfusions ofFFP because we could not obtain her parents' consent. She wasdischarged with her elder brother (case 1) on the 1 st of Septem-ber, 1990. At 6 months after discharge, she had a relativelysevere episode associated with an intracranial hemorrhage.Afterthat, she received preventive transfusions of 100 ml FFPand has not since experienced any similar episode. Thus, weconcluded that both siblings had the same disease, a variant of

Internal Medicine Vol. 33, No. 12 (December 1994) 755

Azuno et al

apoplexy apoplexy

»>[7f q rn Q)^T Y V T

I i

-å¡ O DD (>(HLAlI I A24 Bw61 Cw3 DR4

A2 B51 DR1

blee^0 Q ( A4days 12y lOy ^^ 4y ^^

à" TTP (HLA) (HLA)

All Bw62 Cw4 DR4 A24 Bw61 Cw3 DR4

O A2B51 DR1 Bw52 DR2

probably TTP

Fig. 4. Pedigree chart. Ages of family members at the time of admission.

TTP, although they differed in a few respects in the onset,frequency and clinical manifestations of their diseases.

T

he family

The two affected siblings were born into a family of fourchildren (Fig. 4). The eldest sister died at 4 days after birth witha diagnosis of''Melena neonatorum''. The details ofherperinatalhealthcould not be obtained, but suggested that she too hadTTP.The second sister, a 14-year-old, has had no episode ofTTP and has normal peripheral blood counts and normal bloodchemistries.However, a low serum haptoglobin level (34 mg/

dl), mild poikilocytosis and red blood cell fragmentation in thissubject suggests a mild variant of TTP (Fig. 1C). The parentswere unrelated and had no history of anemia, thrombocytopeniaorjaundice. Screening tests of the parents, including peripheralbloodcounts, blood chemistries, and serum haptoglobin levelsrevealed no abnormality. The other family members were notexamined. Human leukocyte antigen (HLA) typing was per-formed for subjects 1 and 2 and their mother and revealed thatthey shared at least DR4.

Discussion

Among a number of reports regarding thromboticmicroangiopathic hemolytic anemia designated as TTP,hemolytic uremic syndrome (HUS), and other pathogenic

microvascularthrombotic conditions, a very unusual subset of

a congenital variant has also been reported by several investi-gators. Schulman and his associates reported a female patient

who had frequent episodes of severe epistaxis, purpuric skinlesions, jaundice and precipitous thrombocytopenia usually

preceded by an infection (9, 10). They disclosed marked im-

provement by plasma transfusion of the platelet count as itceased the hemorrhaging during each episode in this patient.Thereafter, on a trial basis they transfused plasma at regularintervals of 20 to 23 days, and were able to eliminate thehemorrhagic manifestations. It was noted that the patient had achronic active disease ofthrombotic microangiopathic hemolyticanemia throughout her life time, even when she was notexperiencing an acute episode. Upshow reported a female

patient who experienced 32 episodes from the age of 6 monthsto 1 1 years, which were characterized by high fever, general-ized petechial rash, thrombocytopenia, hemolytic anemia and,usually, a prior clinically evident infection although 5 of the 32

episodes occurred spontaneously (1 1). Shinohara et al pre-sented a Japanese female patient with recurrent episodes ofpetechial bleeding, thrombocytopenia and anemia due to

microangiopathic hemolytic anemia ( 1 2). These three patients

had several important, commoncharacteristics that were docu-mented clinically and on laboratory analysis, such as onset

during infancy, chronic active disease with frequent episodes ofthrombotic microangiopathic hemolytic anemia, and an excel-lent reproducible response to each plasma transfusion. Rennardand Abe proposed the name "Upshow-Schulman syndrome"

f

or the disease condition exemplified by these subjects (13).The cases described presently are very similar and probably

identical to the three patients reported previously. In case 1 ofthe present report, however, there were several unique clinical

756 Internal MedicineVol. 33, No. 12 (December 1994)

Congenital Variant of TTP

manifestations. The first was the presence ofneurological signs,such as headache, vomiting and drowsiness during each epi-sode, suggesting the occurrence ofmicrothrombi on intracranialvascular lesions as evidenced indirectly by increased thetawave activity on the electroencephalogram. The second was thepresence of dark urine during each episode, direct proof ofmassive intravascular hemolysis. Schulman et al describedmicroscopic hematuria in their patient (9). The third uniquefeature was the absence of any precipitating factor or premoni-tory symptom by which we could predict an episode. Althoughthe first several episodes in case 1 were preceded by an upperrespiratory infection, the most recent episodes had no apparentprecipitating event. Furthermore, in contrast to Upshow's pa-tient who had compensated hemolysis between episodes, theabnormal appearance of red cells in the present case 1 did notimprove during symptom-free intervals. Again, the peaks of theplatelet count were almostalways below normal in case 1 , whilein the three patients reported previously, reactive thrombocytosiswas seen after plasma infusions. The disease in case 2 appearedto be milder than in case 1, although the laboratory datademonstrated that active disease was present in both. Historicalconsiderations suggest that patient 2 is at an early phase of adisease identical to that seen in case 1. We expect that she willfollow a progressive clinical course similar to that seen in case1. Indeed, she experienced an intracranial hemorrhage within 6months of discharge. Although there are several unique clinicalcharacteristics in our sibling cases distinct from those of thethree patients described previously, we conclude that our casescan be diagnosed as having "Upshow-Schulman syndrome", acongenital variant of TTP. There are some other case reports probably belonging to"Upshow-Schulman syndrome" in the previous literature. If thepatient does not survive the first few attacks, it is not possibleto document its chronic clinical course. Elias et al presentedthree siblings, at least one of which was affected by "the chronicfatal variant ofTTP" who died before the age of two years (14).Wallace et al reported four siblings affected with fatal TTP fromearly childhood (15). Kaplan et al also reported three HUSsiblings with onset during infancy, all of which died before theage of one year (16). These patients appeared to have beenaffected from birth by chronic thrombotic microangiopathichemolytic anemia. These patients may be included in thedisease category of "Upshow-Schulman syndrome".

The pathogeneses of TTP and HUS, while thought to beidentical ( 17), have not yet been elucidated. Several hypotheseshave been proposed. These include a quantitative abnormalityin large multimer von Willebrand factor (18), reducedprostacyclin synthesis by endothelial cells (19), reduced tissueplasminogen activator (20), presence of platelet aggregatingprotein (21), presence of antibody to endothelial cells (22), andhyperadhesion by neutrophilic leukocytes to endothelial cells(23). In the 2 present cases, we found decreased von Willebrandfactor activities with normal multimer distribution and de-creased levels of 6-keto prostaglandin Flot, a degradative prod-uct of prostacyclin. On the other hand, a considerable number of reports regard-

ing familial occurrence of.TTP and/or HUS (24-26) and ourdemonstration of a congenital variant in siblings stronglysuggest that genetic predisposition plays an important role inpathogenesis. Some investigators have indicated that familymembers affected by TTP and/or HUS have common humanleukocyte antigens (HLA) (27, 28). Pirson et al however, foundno relationship between familial HUS and any specific HLAphenotype (29) as demonstrated by the present cases. It is ofinterest that the parents appear normal although genetic predis-position is suggested. A single autosomal recessive segregationmay be causative as speculated by Wallace et al to explain how4 children of 7 with normal parents were affected (15). In thepresent cases , however, all four children were somehow affected.Therefore, it is unlikely that a single autosomal recessivemutation is responsible for their condition. Our cases suggestthe possibility that environmental factors may operate in addi-tion to a genetic factor. To exclude any environmental factor,such as a toxic agent, we carefully obtained the history of eachfamily member but did not find any prominent characteristics.The mother had no unusual history of drug use. Thus, the factthat our cases are siblings and were affected from infancysuggests ambiguously a genetic cause to their condition. Recently, Byrnes and Moake classified TTP into threesubgroups, mainly according to the frequency of episodes;single episode, intermittent and chronic relapsing TTP (30).Interestingly, Rose and Eldor suggested using their uniquescoring system that the episodes in frequently relapsing patientswere milder than those in patients with a single episode ofTTP(8). The present subjects also have normal renal function, whichis the most important prognostic factor in TTP and HUS (3 1),in spite of frequent episodic hemoglobinuria. Furthermore, ourpatients have experienced neither growth or mental retardation. In conclusion, we report a congenital variant of TTP,"Upshow-Schulman syndrome" in two siblings. Periodicaltransfusions of FFP were effective for preventing recurrences.Although the present cases suggest that there is a genetic basisfor this disease, an etiologic mechanism remains to be clarified.It will be important to follow carefully the clinical course ofthese patients as it may provide added insight into thepathogenesis

of TTP and HUS.

References

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IntemalMedicineVol・33，No．12（December1994）