DESCRIPTION OF THE NEPHROLOGY TRAINING PROGRAM-UNIVERSITY OF IOWA COLLEGE OF MEDICINE

The Nephrology Division at the University of Iowa was formally inillated in 1970 as the Renal-Hypertension-Electrolyte Division under the diredion of Dr. Walter Kirkendall. Since that beginning, the Division has assumedaddillonal responsibilities for the medical diredion of organ transpiantallon and has simplified its name. Its current16 faculty members share clinical responsibilliles for the care of patients at the University of Iowa Hospitals andClinics and the Iowa City VA Medical Center. Postdoctoral fellows having trained in the Iowa nephrology programnumber over 75 with about one fourth of The fellows being involved in only research training. The current I I traineeshave interests That reflect the diverse areas of expertise of the Nephrology Division: membrane transport, cell andmolecular biology, integrated renal physiology, clinical trials, and epidemiology.

The clinical programs in nephrology at the University of Iowa offer a full and vigorous opportunity for clinicaltraining. The dialysis program offers a balanced populallon of 44 center hemodialysis pallents, 43 home hemodi-alysis patients, and 42 home peritoneal dialysis patients. Last year, nephrology transplant physicians assisted inThe care of 77 patients receiving a kidney transplant in addition to caring for others who received heart, lung, liver,and pancreas transplants. Division physicians performed over 100 renal biopsies and 1, 500 consultation visits andattended to over 600 admissions to the Renal/Medicine inpallent unit. We are pleased to have The opportunity tobe a part of this educallonal initiallve by JASN.

Journal of the American Society of Nephrology 35

Tomas Berl, EditorDenver, CO

William HenrichDallas, TX

EDITORIAL COMMITTEE

Mark PallerMinneapolis, MN

Fred SilvaOklahoma City, OK

Thrombotic Microangiopathy: A Case Report and Reviewof the Literature1

David L. Sommerfeld, Daniel C. Brennan, and Joel A. Gordon2

DL. Sommerfeld, J.A. Gordon. Division of Nephrology,

University of Iowa College of Medicine, Iowa City, IA

Daniel C. Brennan. Division of Nephrology. Brigham andWomen’s Hospital, Harvard University School of Medi-cine, Boston, MA

(J. Am. Soc. Nephrol. 1992; 3:35-41)

A 26-year-old white woman (three pregnancies,three births, no abortions) was transferred to

the University of Iowa Hospitals and Clinics 4 wk

postpartum for the evaluation and management of

I Received December 2, 1991. Accepted March 10. 1992.2 Correspondence to Dr. J. Gordon, Department of Internal Medicine, E 300G

GH, University of Iowa College of Medicine, Iowa City, IA 52242.

1046-6673/030 I-0035$03.00/0Journal of the American Society of NephrologyCopyright © 1992 by the American Society of Nephrology

acute renal failure. Her pregnancy had been compli-cated by mild proteinunia and hypertension, treatedwith methyldopa, during the last 3 wk of pregnancy.

Her physical exam was remarkable for a bloodpressure of 160/100 mm Hg, 1+ pedal edema, andhyperreflexia with 6 beats of clonus. Laboratory find-

ings included sodium, 1 26 mEq/L (1 26 mmol/L); po-tassium, 4.4 mEq/L (4.4 mmol/L); chloride, 90 mEq/L (90 mmol/L); CO2 content, 1 1 mEq/L (1 1 mmol/L);

BUN, 1 70 mEq/L (6,0 1 7 mmol/L); creatinine, 24.8mg/dL (2, 1 92 jzmol); total protein, 4.9 g/dL (49 gIL);albumin, 2.8 gIdL (28 g/L): calcium, 6.2 mg/dL (1.55

mmol/L); phosphorus, 16.4 mg/dL (5.30 mmol/L);

and lactate dehydrogenase (LDH) 895 lU/L (14.92mkat/L). A complete blood count showed a hemoglo-bin, 8.5 g/dL; and hematocnit, 26% (after 4 U ofpacked red blood cells [RBC) before transfer); plate-lets, 121 x 103/mm3, and haptoglobmn, <5 mg/dL(0.05 g/L). Schistocytes were seen on the peripheralsmear. Direct and indirect Coombs tests were nega-

tive, prothrombin time was 13 s, and partial throm-

4,4, 4,30

0

30

at20

Ea,C

� 1015

a,0

700

ceo0

:�

E i .soo

0� 300a,

�200CS

0.100

10 20 30 40 50 �o 70 80 90 100

12P!e�me Exchange

30 40 50 60 70 80 90 100

Time (Days)

Figure 1 . Alterations in the patient’s serum creatinine concentration (top) and platelet count and hemoglobin concentration(bottom) during the first 100 days of her illness. The days of high-dose iv. ‘y-globulin therapy (0.4 g/kg/day) are denoted byIgG. The days of plasma exchange therapy are indicated in the right half of both the top and bottom portions. Hemodialysistreatments are denoted by the j in the top portion of the figure on the days she received this therapy.

Thrombotic Microangiopathy

36 Volume 3 ‘ Number I ‘ 1992

boplastin time was 34 s. Fibninogen was 380 mg/dL,fibnin degradation products were 80 mg/dL, andthromboplastin time was 26 s with a control time of1 7 s. Urinalysis revealed sp gr of 1 .009, pH 5, 2+protein, and 2+ blood. There were 1 to 2 white bloodcells pen high power field, 1 to 2 RBC per high powerfield, and no evidence of casts on microscopic cx-amination of the urine sediment. A renal ultrasoundrevealed normal-sized kidneys with slightly in-

creased parenchymal echogenicity without hydrone-phrosis. A diagnosis of postpartum acute renal fail-

ure secondary to thrombotic microangiopathy wasmost consistent with her clinical picture. Treatmentwas begun with high-dose i.v. -y-globulin at 0.5 g/kg/

day over the first 5 days of her admission. No anti-platelet agents, corticosteroids, hepanin, plasma-

pheresis, or plasma exchange was used.The patient required hemodialysis three times per

week without ultrafiltration for control of uremic

symptoms. On day six of her admission, she received3 U of packed RBC and underwent suction curettageof the uterus for the persistence of heavy uterine

bleeding. One week after completion of immunoglob-ulin G (IgG) treatment, schistocytes were no longerpresent on peripheral smear, platelets had risen

sharply, and LDH normalized. She remained dialysisdependent until the 27th day after initial presenta-tion, at which time her creatinine was 6. 1 mg/dL(539.2 �mol/L). Forty-four days after initial pnesen-tation, a laboratory analysis showed hemoglobin, 9.0g/dL; platelets, 319 x 103/mm3.LDH, 196 lU/L (3.26mkat/L); and creatininc, 3.9 mg/dL (344.8 mmol/L)

(Figure 1).On the 67th day after initial presentation, she

complained of headache, fever, and fatigue, and lab-oratory findings revealed hemoglobin, 8.5 g/dL and

platelets, 1 73 x 1 03/mm3 with evidence of schisto-cytes on peripheral smear. LDH was 376 lU/L (6.27mkat/L), and creatinine was 9.0 mg/dL (795.6 �mol/

L). She was felt to have a recurrence of thromboticmicroangiopathy and was treated again with high-dose IgG with prompt resolution of schistocytosis,increase of hemoglobin to 9.0 g/dL, and increase inplatelets to approximately 250 x 1O�3/mm3 (Figure 1).Her urine output remained more than 2,500 mL/24

h, but because of significant reduction in hen GFR,plasmapheresis and plasma exchange were initiated

in an attempt to improve her renal status. After theinstitution of this therapy, urticania developed, schis-tocytes returned, platelets decreased to 157 x 1 0�/

C-)-I(D5)

20�

T(Dl�

10 i.�

0.

I

:fI

Sommerfeld et al

Journal of the American Society of Nephrology 37

mm3, and hemoglobin decreased to 6.5 g/dL. Despite

this, plasma exchange was continued three times perweek empirically for 2 wk (Figure 1).

On day 22 after her second presentation, plasmaexchange was discontinued and levels of hemoglobinand platelets rose (Figure 1 ). Her subsequent coursewas complicated by the development of non-A, non-

B hepatitis. Six months after her initial presentation,a renal biopsy was performed showing chronicthrombotic microangiopathic changes affecting bothglomeruli and vessels, consistent with prior throm-

botic microangiography (Figure 2). After 3 yr of closefollow-up, she has not had any further recurrences.

Hypertension is controlled with enalapnil, 5 mg twicedaily, and her most recent serum creatinine level was

2.6 mg/dL.

BACKGROUND

Thrombotic thrombocytopenic purpura (TTP) and

hemolytic uremic syndrome are rare clinical entitiescharacterized by platelet thrombi occluding the ml-crovasculature. TTP was first described by Mosch-

cowitz in 1 924 when he reported the abrupt onset offever, bleeding. hemolytic anemia, renal failure, andneunologic impairment in a 1 6-yr-old girl (1 ). Post-mortem examination revealed hyalinc thrombi in theterminal arterioles and capillaries, particularly in theheart, liver, and kidneys. The hyaline thrombi have

since been determined to be composed primarily ofagglutinated platelets and little fibrin (2). Hemolyticuremic syndrome was first described by Gasser et at.

(3) in 1 955 as a triad composed of acute renal failure,hemolytic anemia with schistocytosis, and thrombo-cytopenia. Historically, these two entities were distin-guished by neurologic symptoms in the former andsevere renal failure in the latter. In the adult, theoverlap of these two syndromes can make them dif-ficult to distinguish clinically. They have both beenlinked to similar precipitating factors, leading manyto favor the notion that they actually represent dif-ferent clinical expressions of the same disease thatis currently referred to as thrombotic microangiopa-

thy. In early reports, the mortality from thromboticmicroangiopathy was nearly 100%. Since the advent

of plasma therapy, effective treatment has ap-

proached 90% survival (4).

CLINICAL AND PATHOLOGICAL PRESENTATION

Thrombotic microangiopathy can occur in eithersex at any age but has a peak incidence in women in

their thirties. The childhood form of thrombotic mi-croangiopathy differs in several respects from theadult form. In children, renal involvement is bothmore frequent and more severe. The mortality rate

for children given only symptomatic treatment is less

Figure 2. Chronic thrombotic microangiopathic changes ofglomeruli and vessels in percutaneous renal biopsy. (A) Asingle glomerulus demonstrating mesangial sclerosis andwidespread capillary loop basement membrane redupli-cation. Jones methenamine silver, x265. (B) An intralobularartery demonstrates mucoid intimal thickening with suben-dothelial myointimal cells. Hematoxylin and eosin, x285.Inset: two arterioles are occluded by granular material.Hematoxylin and eosin, x450.

than 10% (5), a striking difference when comparedwith the 50% rate reported in adults (6).

Clinical presentation of patients with thromboticmicroangiopathy can be quite variable, depending onthe organ systems involved (Table 1 ). Often, a flulikeprodrome with fatigue, abdominal pain, fever, nau-sea, and vomiting may be obtained in the history.Bleeding is a presenting feature nearly 85% of thetime and may be manifested in the skin with pete-

chiae or purpura, gross or microscopic hematunia,vaginal bleeding, or gastrointestinal bleeding (5).

Nearly all patients will develop neunologic symptoms

Thrombotic Microangiopathy

38 Volume 3 ‘ Number I #{149}1992

TABLE I . Clinical and laboratory manifestations ofthrombotic microangiopathy

%Reference

No.

Flulike prodrome 70 5Fever

Neurologic Manifestations I 00 5Minor Irritability 92

JerkinessSomnolenceTremorMyoclonic dischargeConfusion

Seizures 35Headache 20Coma 11Hemiparesis 3

Renal Manifestations 88 7Hematuria 78Proteinuria 75Azotemia 69Hypertension I 2

Hematologic Manifestations 5Thrombocytopenia I 00Microangiopathic Hemolytic IOU

AnemiaHemorrhage 85 5

Gastrointestinal tract 57Skin 38Retinal 18

such as headaches, paresthesias, confusion, sei-zures, or even coma as a presenting symptom orshortly after presentation. Renal involvement ap-proaches 90% of patients and is usually manifestedas hematunia and proteinunia (7). Elevations of serumurea nitrogen and creatinine are seen more fre-

quently in severe cases and have even been 1mph-cated in predicting a poor outcome (7). Other organs

such as lungs, pancreas, and heart are less fre-quently involved and may only be manifestedthrough abnormal laboratory values.

Laboratory findings will invariably reflect a

Coombs negative intravascular hemolytic anemiawith elevated bihirubin and LDH, neticulocytosis, andlow haptoglobin. RBC indices will usually be normo-

chromic and normocytic, whereas a review of theperipheral blood smear will demonstrate schisto-cytes. Thrombocytopenia is found nearly 1 00% of thetime with increased megakaryocytes on examinationof the bone marrow. Coagulation studies are oftennormal, although prothrombin time and fibrin deg-radation products may be elevated.

The typical pathologic lesion in thrombotic mi-

croangiopathy is microvascular hyaline thrombosis,

composed primarily of agglutinated platelets and lit-

the fibnin. These microvasculan lesions can produce

ischemic organ dysfunction in any tissue. It is pre-dominantly manifested in those organs dependent onthe microcircuhation such as the brain, heart, pan-

creas, adrenals, and kidney. In the kidney, the mi-croangiopathic changes may involve the glomeruhus,the interhobulan arteries, or both (7). Intravascularhemohysis and RBC fragmentation occur because ofthe mechanical damage of the RBC during their pas-

sage across fibnin strands in the damaged small yes-sets.

ETIOLOGY AND PATHOGENESIS

The etiology and pathogenesis of thrombotic mi-croangiopathy have not yet been determined, at-

though a number of conditions have been associatedwith the syndrome. In children, the clinical settingand occasional epidemic presentations suggest aninfectious cause. Serologic evidence of Coxsackic vi-

rus, echovirus, and adenovirus infections have allbeen reported in children with thrombotic microan-

giopathy (6). Several cases have also been noted inchildren and adults after infections with Shtgelta,

Salmonella, or Streptococcus species or Eschertchlacolt (6).

In adults, a wider variety of conditions have been

associated with thrombotic microangiopathy. Severalcases have been reported accompanying systemicdiseases such as malignant hypertension, systemic

hupus erythematosus, and scheroderma (6). A geneticpredisposition has been suggested by several reports

of relapsing thrombotic microangiopathy occurringin members of the same family (8). The disease haslong been recognized in pregnant or postpartum fe-males, along with women taking oral contraceptives.Finally, a number of drugs have been associated withthe occurrence of thrombotic microangiopathy, es-pecially cyclosponine and mitomycin (8).

The mechanism by which these various entities

may cause thnombotic microangiopathy has not yetbeen established. One feature common to all of theseclinical entities is that they injure vascular endothe-

hal cells. Normally, the endothehium prevents throm-

bogenesis through several mechanisms. Endothelialcells secrete prostacychin (prostaglandin 12) [PGI2]),which is the most potent substance known to inhibitplatelet aggregation. In addition to the inhibition ofplatelet aggretation, PG!2 is an important antagonistof thromboxane A2, a potent vasoconstrictor. Endo-

thehial cells also synthesize and secrete plasminogenactivator, which dissolves thrombi by activating theproteolytic enzyme plasmin. Finally, endothehial cells

synthesize, store, secrete, and process von Wille-brand Factor (vWF), a glycoprotein that regulates

platelet interaction with injured vessel walls. It hastherefore been hypothesized that by inducing endo-

Sommerfeld et al

Journal of the American Society of Nephrology 39

thehial cell damage, a cascade of events would ensuein the microcinculation, leading to the formation ofthrombi and the clinical manifestations of the syn-

drome of thrombotic microangiopathy (6).There are several theories as to the possible path-

ogenesis of thrombotic microangiopathy. They pni-marily focus upon ( 1 ) decreased production of endo-

thelial cell PG!2 or excessive lability of PGI2 due to adeficiency of PGI2-stimulating or -stabilizing factorpresent in normal plasma; (2) defective fibrinolysisdue to inadequate production of endothehial cell plas-minogen activator; (3) the presence of a substancecapable of promoting intravascular platelet clump-ing; and (4) abnormal metabolism of vWF, multimers

leading to increased platelet aggregation (8).

PGI2 synthesis has been noted to be reduced inpatients during active thrombotic microangiopathy(6). It has also been shown experimentally that endo-

thelial cell damage stimulates rather than suppresses

PGI2 production (9), leading to the theory that PGI2synthesis is initially stimulated in the early phaseof TTP and depressed later when more pronouncedvascular damage takes place (6). It has also beendemonstrated that patients with TTP lack a factornormally present in plasma that stimulates PG!2 pro-duction (1 0). Despite this information about PG!2. theinfusion of PG!2 has not been demonstrated as an

effective therapeutic modality in thrombotic ml-

croangiopathy (8).Plasminogen activator activity has been reported

to be absent in vessels occluded by thrombi in pa-

tients with TTP but is present in normal amounts inuninvolved vessels in the same patient ( 1 1 ). It hastherefore been suggested that local endothelial celldamage may inhibit plasminogen activator activity,decreasing fibrinolysis and potentiating thrombusgeneration. However, because fibrin formation is notnecessary for the development of platelet thrombi,the role of decreased plasminogen activator activity

and subsequent decreased fibninolysis in the patho-genesis of thrombotic microangiopathy is unclear.

Streptokinase infusion, which should increase fi-brinolysis, has not been shown to be effective in thetreatment of thrombotic microangiopathy (8).

The presence of a platelet-agglutinating factor has

been detected in the plasma of some patients withactive TTP (12). When mixed, plasma from patientswith TTP has been shown to cause aggregation ofplatelets from normal donors. This agglutination is

not inhibited by heparin, aspirin, antithrombin III,

apyrase, or hirudin but could be abolished whenincubated with normal plasma ( 1 0) and, more specif-ically, with normal human IgG (13).

Finally, unusually large vWF (ULvWF) multimershave been recovered from the plasma of patients withchronic relapsing thrombotic microangiopathy (14).

These factors are much larger than those normally

found in plasma and have an extraordinary ability to

aggregate platelets (8). They are abundant in thecirculation during remission and disappear during

relapse, suggesting that some putative factor appearsin the plasma, causes the unusually large vWF mul-timers to attach to platelets, and then causes them

to aggregate. This aggregation can be blocked by theinfusion of fresh frozen plasma, but not by albuminon IgG alone (8).

TREATMENT

Thrombotic microangiopathy in adults has beenpreviously associated with a nearly 1 00% mortality

nate. Because of the rapidly progressing fulminant

course associated with the disease, various treatmentmodalities have been employed simultaneously. Thismakes it impossible to determine which treatment is

specifically beneficial. Because of the poor outcomein untreated thrombotic microangiopathy, no pla-cebo-controlled trials have been performed. Earlyrecognition of this disease entity and supportivemeasures such as blood transfusion and hemodi-alysis are crucial for survival. The following sum-manizes the therapeutic modalities reported in theliterature along with their rationale and efficacy(Table 2).

Supportive Measures

Much of the improved survival over the past three

decades can be attributed to earlier recognition of thedisease and efficient use of supportive measures.Many of the life-threatening symptoms such as dcc-trolyte abnormalities and volume overload can beadequately controlled by hemodialysis. Severe and-mia can be corrected through proper blood transfu-

sions, and newer pharmacological agents allow bettercontrol of hypertension. Although these measuresalone cannot account for the dramatic increase inpatient survival, they allow time to implement thevarious therapeutic modalities listed below. They are

TABLE 2. Therapeutic modalities used in thromboticmicroangiopathy

TherapyResponse

( /0)Reference No.

Plasma Exchange 80 16, 18Plasma Infusion 60-70 16, 18‘y-Globulin ?? 19Vincristine 100 20Splenectomy 51 16Antiplatelet Agents 54 16Corticosteroids I I 4, 8, 16

Thrombotic Microangiopathy

40 Volume 3’ Number I ‘ 1992

also quite important for the long-term managementof patients with residual end organ damage.

Plasma Therapy

Although four survivors were described after treat-ment with whole blood transfusion in Moschowitz’soriginal description of thnombotic micnoangiopathy

in 1 924 (1), this treatment modality was ignored until1 959 when Rubenstein et at. reported survival in a

patient treated with exchange transfusions ( 1 5). Over

the years, it has been demonstrated that normalplasma infusion, in combination with other agents,

has been associated with improved recovery rates.Plasma exchange and plasma infusion have beenreported to have 60 to 80% response rates and sun-

vival rates over 90% (1 6). Theoretically, plasma in-fusion supplies a factor deficient in patients withthrombotic microangiopathy. This missing factor

could be an inhibitor of a platelet-activating factor, asubstrate necessary for the formation of PGI2, or a

substance required for the normalization of vWF me-tabohism (1 7). Plasma exchange is efficacious, inprinciple, because not only is the missing factor re-

plenished but the toxic substances are also removedduring the exchange procedure. A recent prospectivetrial comparing response in patients with thrombotic

microangiopathy to antiplatelet agents and eitherplasma infusion or plasma exchange showed a 78%successful response rate to plasma exchange andonly a 3 1 % response rate to plasma infusion alone(1 8). Patients who failed to respond to plasma infu-sion initially and were subsequently treated with

plasma exchange also achieved a high (78%) nate ofresponse, suggesting exchange therapy is more effec-tive than infusion alone. Many different schedules

have been reported for plasma exchange, but mostauthors recommend an initial 7 days of therapy fol-lowed by alternate-day treatment until hematologicimprovement. Recommended exchange volumes are1 to 1 .5 times the predicted plasma volume (18).Complications of plasma therapy include congestiveheart failure and pulmonary edema if administeredtoo fast, because renal insufficiency frequently ac-

companies this disorder. Long-term complicationscould include possible transmission of infectious

agents such as non-A, non-B hepatitis as seen in thispatient and, theoretically, exposure to the humanimmunodeficiency virus.

lgG

Recently, several case reports have appeared in theliterature where i.v. y-globulin was associated with

remission of thrombotic micnoangiopathy (19). Withthe exception of the case reported here, all otherswere used in combination with other agents. Theexact mode of action of high-dose �y-globuhin is un-

clear, although it is based on the findings of Lian et

at. that IgG inhibits the platelet-agglutinating factorpresent in patients with thrombotic microangiopathy

(1 3). Its relative safety and suggested effectivenesshave prompted several authors to suggest that con-tnolled trials be performed ( 1 9). The current recom-

mended dose is 0.5 mg/kg body wt/day given paren-terally for 5 consecutive days. Although problemscan still arise with volume management during IgGinfusion, the risk of infectious complications isgreatly reduced.

Vincristine

The ymca alkaloids are immunosuppressive agents

that disrupt the polymerization of microtubules as-sociated with platelet membranes. It has been usedfrequently in combination with other agents, espe-

cially in protracted cases, although response is oftennot as rapid as that typically seen with plasma then-apy. Recommended dose is 2 mg i.v. initially followedby 1 mg i.v. every 4 days for 4 to 6 wk or for at least2 wk after hematologic remission (20).

Splenectomy

Splcncctomy has been used in several cases of

relapsing thnombotic microangiopathy with variableresults. A number of patients have achieved remis-

sion after the removal of the spleen. However, it hasbeen argued that these patients also receive a signif-

icant number of blood products and dextnans duringthe procedure, which may account for its apparentefficacy. In a retrospective review of 92 patients ne-ceiving splenectomy in addition to various otheragents, 5 1 % achieved remission (1 6). Its use shouldbe reserved for patients who fail to respond to otherforms of therapy.

Glucocorficoids

Corticostenoids have been one of the earliest formsof therapy used in patients with thrombotic microan-giopathy. In high doses, they have been shown toincrease platelet survival in patients with thnomboticmicnoangiopathy and other vasculitides (1 6). The hy-pothesized mode of action has been through thesuppression of autoantibody production and the en-hanccmcnt of suppressor T-lymphocyte activity.Their role is largely historical, and many authorsnow consider steroids ineffective.

Antiplatelet Agents

The possibility that thnombotic microangiopathy ismanifested by diffuse platelet aggregation has led to

the use of inhibitors of platelet function extensivelyoven the past several years. Because of their frequent

Sommerfeld et al

Journal of the American Society of Nephrology 41

use with other agents and the lack of controlled trials,

their true efficacy remains unclean. Most authorities(4, 8, 16) do not advocate their use, because they arebelieved to be ineffective and because they tend toincrease bleeding complications.

SUMMARY

Thrombotic microangiopathy most likely repre-sents a spectrum of diseases consisting of multipleetiologies that has a final common pathway of mul-tiorgan microvascular thrombosis. The variable re-sponses to several different modes of therapy wouldsuggest that more than one pathogenetic mechanismis involved. Untreated, it has been associated withvery high morbidity and mortality rates. A poor un-derstanding of the basic disease process has pre-

vented specific treatment modalities, although early

diagnosis and availability of dialysis and blood prod-

uct transfusion services remain crucial. Severalmodes of therapy have been used to date, with plasmaexchange being the most effective method studiedand shown to improve survival. On the basis of cur-rent knowledge, this form of treatment should beinstituted promptly in severe cases. Anecdotal re-ports of recovery with vincristine or IgG alone or with

the use of IgG after the apparent failure of plasmatherapy appear promising and deserve further inves-

tigation as initial therapeutic measures used inthrombotic microangiopathy. Although the majorityof patients recover with normal renal function, thosewith severe thnombotic microangiopathy may healthrough sclerosis with residual hypertension andchronic renal impairment requiring continual mcdi-

cal therapy.

ACKNOWLEDGMENTS

We thank Dr. S. Bonsib, Department of Pathology. University of

Iowa College of Medicine, for interpretation of the renal biopsy.

REFERENCES

1 . Moschcowitz E: Hyahine thrombosis of the ten-minal arterioles and capillaries in a hitherto un-described disease. Proc NY Pathol Soc 1924:24:21-24.

2. Baehr G, Kiemperer P. Schifrin A: An acutefebnile anemia and thnombocytopenic punpurawith diffuse platelet thromboses of capillariesand arterioles. Assoc Am Physicians 1936:65:43-58.

3. Gasser C, Gautier E, Steck A, et al.: Haemoly-tisch-Uramische syndrome: bilaterale Nierennin-denncknosen bei akuten enworbenen haemoly-tischen Anamien. Schweizenische MedizinischeWochenschnift. 1955:85:905-909.

4. Bell WR, Hayden GB, Ness PM, Kickler TS:Improved survival in thrombotic thrombocyto-

penic punpura-hemolytic uremic syndrome. NEngl J Med 1991:325:398-403.

5. Gianantonio CA, Vitacco M, Mendilaharzu F,Gallo GE, Sojo ET: The hemolytic-uremic syn-drome. Nephron 1973:11:174-192.

6. Remuzzi G: HUS and TTP: Variable expressionof a single entity. Kidney tnt 1987:32:292-308.

7. Eknoyan G, Riggs SA: Renal involvement inpatients with thrombotic thrombocytopenic pun-puna. Am J Nephnol 1986;6:1 17-131.

8. Byrnes JJ, Moake JL: Thrombotic thrombocy-topenic purpura and haemolytic-uraemic syd-rome: Evolving concepts of pathogenesis andtherapy. Chin Haematol 1 986; 15:413-442.

9. Goldsmith JC: Contribution of the subendothe-hum to prostacychin release after vascular in-jury. J Lab Clin Med 1982:100:574-584.

1 0. Remuzzi GR, Misiani R, Mecca G, de GaetanoG, Donati MB: Thrombotic thrombocytopenicpurpura-a deficiency of plasma factors regu-lating platelet-vessel-wall interaction [letter]. NEngl J Med 1978:299:311.

1 1 . Kwaan HC, Gallo G, Potter E, et at. : The natureof the vascular lesion in thnombotic thrombocy-topenic purpura. Ann Intern Med 1968;68:1169-1170.

12. Lian ECY, Harkness DR. Byrnes JJ, WallachH, Nunez R: The presence of a platelet ag-gregating factor in the plasma of patients withthrombotic thrombocytopenic purpura and itsinhibition by normal plasma. Blood 1979;53:333-338.

13. Lian ECY, Mui PTK, Siddiqui FA, Chiu AYY,Chiu LLS: Inhibition of platelet-aggregating ac-tivity in thrombotic thnombocytopenic purpunaplasma by normal adult immunoglobuhin G. JClin Invest 1984:73:548-555.

1 4. Moake JL, Rudy CK, Troll JH, et at. : Unusuallylarge plasma factor VIII: von Willebrand factormultimers in chronic relapsing thromboticthrombocytopenic purpura. N Engl J Med 1982;307:1432-1435.

1 5. Rubenstein MA, Kagan BM, MacGiliviray MH,Merliss R, Sacks H: Unusual remission in a caseof thnombotic thrombocytopcnic purpura syn-drome following fresh blood exchange transfu-sions. Ann Intern Med 1959:51:1409-1419.

16. Bukowski RM, Hewlett JS, Reimer RR, GroppeCW, Weick JK, Livingston RB: Therapy ofthrombotic thrombocytopenic purpura: an over-view. Semin Thromb Hemostasis 1 98 1 :7: 1-8.

1 7. Shepard KV, Bukowski RM: The treatment ofthrombotic thrombocytopenic purpura with cx-change transfusions, plasma infusions, andplasma exchange. Semin Hematol 1987:24:178- 193.

1 8. The Canada Apheresis Study Group: Compari-son of plasma exchange with plasma infusion inthe treatment of thrombotic thrombocytopenicpurpura. N Engh J Med 1991:325:393-397.

1 9. Raniele DP, Opsahi JA, Kjellstrand CM: Shouldintravenous immunoghobuhin G be first-linetreatment for acute thrombotic thrombocyto-penic purpuna? Case report and review of theliterature. Am J Kidney Dis 1991;18:264-268.

20. Gutterman LA, Stevenson TD: Treatment ofthrombotic thrombocytopcnic purpura with yin-cnistine. JAMA 1 982:247: 1 433- 1436.