Case Report Am J Nephrol 1992;12:126-133
Departments of Medicine, Gynecology and Pathology. Lutheran General Hospital. Park Ridge. 111., USA
Key Words Postpartum hemolytic uremic syndrome Anticardiolipin antibody Lupus anticoagulant Antiphospholipid antibody Plasmapheresis
Postpartum Hemolytic Uremic Syndrome Associated with Antiphospholipid Antibodies A Case Report and Review of the Literature
Abstract Postpartum hemolytic uremic syndrome (HUS) is described in a woman with a history of spontaneous abortions and both circulating lupus anticoagulant and anticardiolipin antibody (ACA). After termination of her pregnancy because of severe preeclampsia, ACA blood levels increased simultaneously with the onset of a microangiopathic process associated with severe hyperten sion and renal failure. Plasma exchange resulted in a rapid decline in ACA levels and immediate improvement in her clinical condition. This case strongly suggests an important causal relationship between ACA and postpar tum HUS. The possible mechanisms of ACA-related postpartum HUS and the potential role of plasmapheresis in its treatment are reviewed and discussed.
The hemolytic uremic syndrome (HUS) is a microan giopathic process primarily of the renal circulation be lieved to be mediated by platelet clumping. Renal isch emia. thrombocytopenia and disruption of erythrocytes occur as a result of microangiopathy [1], The association of renal dysfunction, thrombocytopenia and hemolytic anemia with schistocytes was first described by Gasser et al. [2] in 1955 and is now widely recognized [1. 3-5], Although more commonly described in children, the syn drome also occurs in adults [6- 8], In adults, the disease is usually triggered after a normal pregnancy [9-17] but is also observed in assocation with oral contraceptive thera py, infection, autoimmune disease, vaccination, cyclospo rine and certain chemotherapeutic agents [3, 7, 8, 18]. The relationship between pregnancy and HUS remains obscure, but numerous explanations have been suggested [10, 13, 19, 20]. A recent report noted an association of circulating lupus anticoagulant (LAC) and anticardiolipin
Received: Novembers, 1991 Accepted: March 16, 1992
antibody (ACA) with the development of postpartum HUS [21], However, the authors did not attempt to corre late levels of ACA with the onset and resolution of renal failure and other manifestations of HUS. We describe a woman with postpartum HUS in whom circulating anti phospholipids appeared to play a central role in the gener ation of clinical manifestations of HUS. This new associa tion is distinct from the occlusive vasculopathy pre viously described in patients with antiphospholipid anti bodies [22],
Case Report A 33-year-old Caucasian woman (G4 P0030) was admitted to Lu theran General Hospital on June 21.1990. at 22 weeks of gestation with epigastric and back pain, headache and hypertension. Past obstetrical history was significant for an uncomplicated elective abortion in September 1980 and two spontaneous abortions (9/88
Daniel Kniaz. MD Associate Director of Nephrology Department of Medicine Lutheran General Hospital 1775 Dempster Street. Park Ridge, 11.60068 (USA)
© 1992 S. Kargcr AG. Basel 0250-8095/92/0122-0126 $2.75/0
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Daniel Kniaz Gerald M. Eisenberg Haim Elrad Catherine A. Johnson Jonas Valaitis Harold Bregman
normal at 92 %. U rinalysis showed more than 100 mg protcin/dl. 1320 RBC/hpf and occasional granular cast. She was treated with phenvtoin. nitroprusside, diazepam and magnesium sulfate and admitted to intensive care with a presump tive diagnosis of eclampsia. HELLP syndrome and malignant hyper tension. Despite nitroprusside, labetalol, captopril, nifedipine and furosemide. her blood pressure remained elevated over the next 4 days, averaging 150/105 mm Hg(fig. 1). On hospital day 5, her blood urea nitrogen rose to 7.2 mntol/l (20 mg/dl) and serum creatinine rose to 186 pniol/1 (2.1 mg/dl: fig. 1). Hemoglobin was 99 g/l (9.9 g/dl), hematocrit 28.1%. platelet count 83.000/pl. reticulocyte count 5.2%. and peripheral blood smear revealed schistocytes. Prothrom bin time, partial thromboplastin time and antithrombin III were still normal, but fibrinogen increased to 5.2 g/l. and fibrin degradation products were > 40 mg/1. Urinalysis revealed 4+ protein, moderate hemoglobin and numerous red blood cells and red blood cell casts. A percutaneous renal biopsy was performed. On light microsco py. small arteries (intralobular) and preglomerular arterioles were focally occluded by fibrin thrombi without evidence of a related vas culitis (fig. 2). In several glomeruli, fibrin thrombi extended from occluded arterioles into the glomerular capillaries. Many glomeruli were ischemic and some were swollen with focally proliferative endo thelial cells that narrowed the capillary lumens (fig. 3). Several tubules were focally hemorrhagic with a few scattered neutrophils. Scattered tubules showed a large number of hyaline droplets and a few areas of tubular atrophy. Electron microscopy revealed occa sional areas with subendothelial widening with a translucent fine granular texture (fig. 4). Basement membranes were intact. Capillarylumens and urinary' spaces of the glomeruli were filled with schisto cytes (fig. 5). Immunofluorescent studies demonstrated focal, periph eral, finely granular deposits for Cj and IgM. but were negative for fibrinogen. She received her 1st of 4 plasma exchanges (3 liters) on the 8th hospital day, and dipyridamole (75 mg. 3 times a day) and aspirin (325 mg daily) were added. By the 9th hospital day. serum creatinine peaked at 248 pmol/l (2.8 mg/dl). platelet count rose to 173.000/pl. and blood pressure was finally controlled with minoxidil, labetalol. nifedipine, captopril. furosemide and clonidine(fig. I). Over the next 4 days, renal function improved and blood pressure remained con trolled despite discontinuation of several antihypertensives. She was discharged on the 17th hospital day with a blood pressure of 137/77 mm Hg, blood urea nitrogen of 9.6 mmol/1 (27 mg/dl), creatinine of 221 pmol/1 (2.5 mg/dl). platelet count of 331,000/pl. reticulocyte count of 3.2% and lactate dehydrogenase of 205 IU/1. Discharge medications were captopril. furosemide. nifedipine, dipyridamole and aspirin. Five months later, her blood pressure was normal off antihypertensive medications, and serum creatinine was 133 pmol/l (1.5 mg/dl). ACA was mesured by ELISA assay [24] before, during and after treatment with plasmapheresis. As shown in figure 1, levels of ACA increased postpartum and peaked immediately before treatment. Plasmapheresis resulted in a marked decrease in antibody levels coincident with clinical improvement. During the 2nd plasma ex change. ACA was measured in the removed plasma and contained 22,500 IU of IgG. 24.000 IU of IgM. and 3.300 IU of IgA.
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and 5/89) at 12 and 11 weeks of gestation. Prolonged partial throm boplastin time and LAC were first observed following the second miscarriage, yet she did not manifest features of SLE. and the antinu clear antibody (ANA) was negative. During the current pregnancy, she was treated with progesterone from the 4th to the 14th week of pregnancy and aspirin, 40 mg daily, from the 4th week onward. A maternal-fetal specialist recommended prednisone 30 mg daily, but the patient refused. LAC was 1.4 near conception. 1.6 at 15 weeks of gestation and 1.7 at 19 weeks of gestation (normal < 1.2). IgM and IgG ACA was present at 19 weeks but titers could not be performed because of other interfering antibodies. Blood pressure was 110/80 mm Hg at 7 weeks of gestation, but increased to 130/80 mm Hg at 9 weeks and to 140/90 mm Hg at 19 weeks of gestation. On admission, she appeared anxious and in moderate respiratory distress with a blood pressure of 150/110 mm Hg. pulse of 106 beats/min, respiration of 20 breaths/min and evidence of left-sided heart failure. Extremities revealed 2+ edema, hyperreflexia and 3- to 4-beat clonus. Fetal heart tones w'ere present. Her urinalysis was significant for 3+ protein. Blood urea nitrogen was 3.2 mmol/1 (9 mg/dl) and serum creatinine 88 pmol/l (1.0 mg/dl). Uric acid was 321 pmol/l(5.4 mg/dl). Hemoglobin was 106 g/1 (10.6 g/dl). hematocrit 28.8% and platelet count 61.000/pI. Serum hapto globin was 0.15 g/l (normal 0.25-1.80) and both direct and indirect Coombs were negative. Prothrombin and partial thromboplastin times and fibrinogen were normal. Serum aspartate aminotransfer ase was 302IU/1 (normal 5-30). serum alanine aminotransferase was 253IU/I (normal 5-40) and lactate dehydrogenase was 268IU/I (nor mal 65-155). Serum albumin was 24 g/l (2.4 g/dl). Complement lev els showed a decreased Cj of 0.60 g/l (normal 0.83-1.77) and a nor mal Cj and CHjo. ANA. SS-A. SS-B and RF were negative. The LAC ratio was only borderline positive (1.2). A presumptive diagnosis of preeclampsia with hemolysis, ele vated liver enzymes and low platelet count (HELLP syndrome) was made [23], She received intravenous magnesium sulfate and prosta glandin E; vaginal suppositories to induce delivery, and on the fol lowing morning, she delivered a 340-gram stillborn male. Placental pathology showed acute chorioamnionitis and degeneration of pla cental villi with focal infarction. On the 3rd hospital day. peripheral edema resolved and blood pressure averaged 140/95 mm Hg. blood urea nitrogen was 3.9 mmol/1 (11 mg/dl) and creatinine 71 pmol/l (0.8 mg/dl). Lactate dehydrogenase fell to 208 IU/1 and platelet count rose to 133.000/pl. She was discharged on the 4th hospital day. Twenty-four hours after discharge, she developed blurred vision, nausea and recurrent epigastric pain. En route to the emergency room, she had a generalized tonic-clonic seizure. A second seizure lasting 3 min occurred after arrival to the hospital. Blood pressure was 205/130 mm Hg. and heart rate was 136 beats/min. Physical examination revealed a lethargic, postictal, but responsive, Cauca sian female. Examination of the fundi demonstrated hemorrhages and papilledema. Bibasilar lung rales were present. A grade 1I1/V1 systolic ejection murmur and a summation gallop were heard on car diac examination. Trace bilateral pedal edema was noted as well as hyperreflexia with clonus and bilateral Babinski signs. Electrolytes, blood urea nitrogen and creatinine were normal. Lactate dehydrogenase was 536 IU/1, leukocyte count 23.600/pl. hemoglobin 137 g/l (13.7 g/dl), hematocrit 38.7% and platelet count was 80.000/pl. Direct and indirect Coombs remained negative. Hap toglobin was undetectable: prothrombin and partial thromboplastin times were normal. Fibrinogen was 3.50 g/l (normal 2.5-5.0). and fibrin degradation products were 25-40 mg/1. Antithrombin 111 was
Discussion
Fig. 1. Mean arterial pressure, platelet count, serum creatinine and ACA levels for IgG. IgM and IgA before and after treatment with plasmapheresis. Antibodies measured by ELISA using partial throm boplastin derived from the human brain as the antigen (Theratcst Co.. Chicago. Illinois). Each arrow represents a 3.0-liter plasma exchange.
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Days
ACA and circulating LAC arc immunoglobulins with antiphospholipid activity initially identified in patients with SLE [25]. These antibodies carry an increased risk of thromboembolic events in both the venous and arterial circulation [22], More recently, these antibodies have been associated with thrombotic events even in patients without SLE [25, 26], In pregnancy, circulating antiphos pholipids have been associated with increased risk of spontaneous abortions, fetal death and the development of early and more severe preeclampsia [27-30]. In addi tion. severe, life-threatening systemic thromboembolism, cerebral hemorrhage and other vasculopathies have been described in postpartum women with antiphospholipid antibodies [31. 32], Also, a postpartum autoimmune syn drome with myocarditis, pleuropulmonary disease and fever has been described in 3 patients with LAC or ACA [33], Thus, as assays for LAC and ACA have improved in sensitivity, specificity and availability, other clinical syn dromes have also been causally related to their presence in the circulation. This patient with circulating LAC and ACA developed preeclampsia early in pregnancy and subsequent HUS. The clinical distinction between the three microangio pathic disorders which occur in pregnancy, severe pre eclampsia, HUS and thrombotic thrombocytopenic pur pura (TTP), is not always possible [ 16], While most inves tigators have focused on the distinctions between these clinical entities [15. 16], some have concluded that the differences are more a matter of degree and have empha sized similarities in clinical presentation, renal pathology and underlying mechanisms [34], The progressive course seen in our patient from preeclampsia, thrombocytopenia and, finally, HUS lends credence to this belief. Our patient initially demonstrated typical features of a severe form of preeclampsia, often referred to as HELLP syn drome [23], which subsequently progressed to full-blown HUS postpartum. The diagnosis of preeclampsia alone is unlikely because of the degree of renal failure, the long term renal compromise and the striking microangiopathic features seen in the small arterioles. In addition, in con trast to the clinical improvement seen postpartum in patients with preeclampsia, this patient's illness worsened 3 days after delivery, and her ACA levels continued to rise until plasmapheresis was initiated. Also, in contrast to preeclampsia, where there may be clinical evidence of dis seminated intravascular coagulation, our patient had nor mal prothrombin and partial thromboplastin times, a normal fibrinogen level and normal antithrombin III
3
Fig. 2. Thrombus in small-sized artery of kidneys. HE. X 200. Fig. 3. Glomerulus with thrombi in capillary lumens, narrow lumens and swol len endothelial cells. Masson’s trichromc. X 200.
Fig. 4. Glomerular tuft with subendothelial widening with fine granular texture. EM. X 20.000. Fig. 5. Glomerulus with many schistocytes in urinary space. EM. X 3.750.
with lupus nephritis [36, 37]. Subsequently. Lockshin et al. [27] reported a high incidence of proteinuria, thrombo cytopenia. hypocomplementemia and a high incidence of fetal death in 7 pregnant women with SLE and LAC. None of these patients developed HUS and, unlike our patient, the syndrome disappeared quickly after termina tion of pregnancy. Kincaid-Smith [21] first reported a relationship be tween circulating LAC and the development of renal thrombotic microangiopathy in pregnant women who did not have lupus (table 1). All developed a syndrome simi lar to our patient. In that study. LAC was measured
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activity [15]. Finally, the low serum C3 level and C3 deposits seen on immunofluorescent staining of glomeru lar capillary walls have also been described in cases of postpartum HUS [17. 35], Thus, this patient presented with severe preeclampsia early in pregnancy and later developed postpartum HUS as evidenced by the progres sive hematologic alterations and kidney pathology. The original descriptions of the relation of ACA and renal disease were made in patients with systemic lupus. These reports suggested that lupus patients with LAC and ACA are more prone to develop thrombocytopenia and renal arteriolar and glomerular thrombosis in association
Table 1. Summary of the literature describing renal disease associated with antiphopholipid antibody without SLE Author
Patients
Hypo-
Connective tissue disease
Pregnancy BCP
Clinical manifestations
Microangiopathic hemolytic anemia
Thrombocytopenia
F
NR
7/1
fetal death spontaneous abortions hypertension (malignant) azotemia
yes
yes
no
26 42
M M
•SLE-like' Raynaud's
no
fever thrombophlebitis hypertension proteinuria azotemia
no
no
no
1
24
F
no
no
fever thrombophlebitis hypertension proteinuria azotemia
no
yes
no
Grave [40]
3
NR
NR
no
no
dementia hypertension proteinuria azotemia
NR
NR
no
Ingram [41]
1 1
43 22
M F
‘SLE-like’ + ANA (1:120, 1:240) + Shirmer’s
no
fever thrombophlebitis livedo reticularis cerebral infarct hypertension (malignant) proteinuria azotemia
no
yes
NR
total
age years
sex
Kincaid-Smith [21]
8
20-35
D’Agati [38]
1 1
Becquemont [39]
complementemia
ND = Not done; NR = not reported.
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broelastic intimal thickening. Thus, the features of this case as well as those recently described by Kincaid-Smith [21 ] suggest a distinct subset of patients with postpartum HUS associated with ACA. In our case, the correlation of ACA levels with the clinical course as well as the demon stration of high levels of ACA in the pheresate suggests a causal relationship. Future studies should address the incidence of antiphospholipid antibodies in presumed ‘idiopathic’ postpartum HUS. Other antiphospholipid-antibody-related renal diseases have been described in nonpregnant women and men with out SLE [38-41 ]. In each of these reports, antiphospholipid antibodies were associated with a renal thrombotic mi croangiopathy, although full-blown HUS has not been described (table 1). HUS in association with ACA has only been described in the setting of pregnancy [21 ],
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because of a history of recurrent abortions or fetal death, impaired renal function during pregnancy or because of a history of disseminated thrombotic manifestations. As in our patient, ages ranged from 20 to 35 years, and the syn drome was related to pregnancy in 7 cases. In another woman, it was related to the use of oral contraceptives. Four other women with a similar clinical picture had a history of systemic lupus and/or serologic markers for SLE. All of them had low platelet counts, increased fibrin degradation products and a microangiopathic hemolytic anemia. In addition, as in our patient. 3 had malignant hypertension, and most had moderate or severe renal impairment. Biopsies from these women were identical to that from our patient, showing fibrin thrombi in glomer uli and arterioles as well as ischemic necrosis. Biopsies from later periods showed intimal proliferation and fi-
LAC/ACA BINDING
thrombotic microangiopathy
Correlation Therapy of clinical course with ACA levels
Outcome
ND
most improved but persistent impaired renal function
heparin steroids ASA/dipyridamole plasmapheresis
ND thrombotic microangiopathy endocapillary proliferation fibrinous thrombi
NR steroids cyclophosphamide
ND thrombotic microangiopathy endothcliosis fibrinous thrombi
y-globulin improved fresh frozen plasma but severe ASA/dipyridamole persistent renal insufficiency
thrombotic microangiopathy subendothelial Ig and C deposits
ND
NR
yes
/
I
PLA T E LE T ACTIVATION
\
E N D O T H E L IA L IN JU R Y
v W F M U LT IM E R S
PLA TELET A G G R E G A T IO N
THROM BOCYTO PENIA
THROMBOSIS
NR
heparin/coumadin steroids cyclophosphamide ASA/dipyridamole plasmapheresis
NR
improved but persistent neurologic deficits
What is the relationship of ACA to the pathogenesis of fetal wastage, severe preeclampsia and postpartum HUS? These immunoglobulins possess antiphospholipid activ ity and are believed to bind and alter the structure of platelet and/or endothelial cell wall membranes, causing platelet aggregation [26. 28, 38.42] (fig. 6). Direct platelet activation could result in systemic thrombosis, while localized endothelial damage in the placenta during preg nancy could result in fetal wastage or prceclampsia. When the renal circulation is the primary site of endothelial damage and/or platelet activation, HUS may result. Alter natively, endothelial wall injury by ACA could alter the delicate balance between procoagulant and anticoagulant factors [43]. For example, ACA has been shown to decrease production or release of prostacyclin (PGL) [28. 29. 38], an endothelial-derived vasodilator and inhibitor
y CIRCULATION
• Venous and Arterial Thrombosis
/ PLACENTA
\
\
^
KIDNEY_________ ÇN S_______OTHER
• Fetal Growth • Renal Thrombotic Retardation Microangiopathy • Abortion • Hemolytic Uremic • Preeclampsia Syndrome • Hypertension
• Migraine • Livedo • Seizures reticularis • Infarcts • Myocardial • Dementia infarction • Monocular • Endocarditis Blindness
Fig. 6. Theoretical mechanisms whereby LAC and/or ACA result in focal or systemic vasculopathies. Pregnancy, normally a hypcrcoaguable state, is dependent on increased PGL and is associated with increased (+) release of large multimcrs of von Willebrand factor (vWF). both of which may amplify the thrombotic tendency of LAC and ACA (see text for details).
of platelet aggregation. In pregnancy, normally a hypercoagulable state, increased production of PGL may be important in preventing platelet aggregation [19], A rela tive deficiency of PGL during pregnancy has been pro posed as one explanation for fetal wastage, preeclampsia and postpartum HUS [13, 19, 20. 44], In support of this mechanism, lower plasma levels of PGL in the maternal and placental circulation have been described in women with ACA and LAC who develop these complications [28. 29], Another hypothesis is that circulating ACA or LAC act as a platelet-agglutinating factor (PAF) that interacts with large multimers of von Willebrand factor causing platelet aggregation. In pregnancy, an increased synthesis of large multimers of von Willebrand factor could in crease the susceptibility to developng HUS [1.45], The role of plasma infusion and plasma exchange ther apy in thrombotic microangiopathic diseases, particularly TTP. has been well established [1.4. 45. 46]. Successful use of this mode of therapy has also been described in severe HUS [8. 47], but its effectiveness is less certain. However, because of the similarities between HUS and
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Renal histology
TTP and the severity of our patient’s illness, we elected to proceed with plasma exchange therapy in addition to aspirin and dipyridamole [10, 48, 49], Plasmapheresis resulted in a rapid reduction in circulating ACA coinci dent with dramatic clinical improvement. While the benefit of plasma exchange in TTP and HUS is believed to stem either from the removal of a platelet activating factor (i.e„ abnormal von Willebrand factor, PAF. inhibitors of PGU) or infusion of inhibitors of plate let aggregation, in women with ACA-related postpartum HUS. removal of the antiphospholipid antibody is likely to be a key aspect of therapy. We did not. however, exam ine the effects of plasmapheresis on other regulators of platelet function. Previous reports also suggest a role for
plasmapheresis therapy in fulminant ACA-related vasculopathies [21, 22. 41], In one of those reports, the reduc tion in ACA levels also correlated with clinical improve ment [41], Thus, although the precise role of plasmapher esis in the treatment of ACA-related syndromes requires further investigation, early recognition of the role of ACA in renal and other severe vasculopathies should be sought and treatment with plasmapheresis considered.
Acknowledgment The authors would like to express their gratitude to Drs. Jose Arruda and Jeffrey Lakier for their advice and comments in prepar ing the manuscipt.
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32 Branch DW, Andres R, Digre KB. et at: The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol 1989:73:541-545. 33 Kochenours NK: A new postpartum syndrome associated with antiphospholipid antibodies. Obstet Gynecol 1987;69:460-468. 34 Kincaid-Smith P: The similarity oflesions and underlying mechanism in prc-eclamptic tox emia and postpartum renal failure - Studies in the acute stage and during follow-up: in Kincaid-Smith P. Mathew TH. Becker EL (eds): Glomerulonephritis. New York. Wiley. 1973, pp 1013-1025. 35 Sagawa N. Kariya M. Dan/.aki H. el at: A case of postpartum hemolytic uremic syndrome with severe elevations of liver enzymes. Obstet Gynecol 1985:65:761-764. 36 Kant KS. Pollack VE. Weiss MA. et al: Glo merular thrombosis in systemic lupus erythe matosus: Prevalence and significance. Medi cine 1981:60:71-86. 37 Glueck HI, Kant KS. Weiss MA. et al: Throm bosis in systemic lupus erythematosus: Rela tion to presence of circulatory' anticoagulants. Arch Intern Med 1985:145:1389-1395.
Departments of Medicine, Gynecology and Pathology. Lutheran General Hospital. Park Ridge. 111., USA
Key Words Postpartum hemolytic uremic syndrome Anticardiolipin antibody Lupus anticoagulant Antiphospholipid antibody Plasmapheresis
Postpartum Hemolytic Uremic Syndrome Associated with Antiphospholipid Antibodies A Case Report and Review of the Literature
Abstract Postpartum hemolytic uremic syndrome (HUS) is described in a woman with a history of spontaneous abortions and both circulating lupus anticoagulant and anticardiolipin antibody (ACA). After termination of her pregnancy because of severe preeclampsia, ACA blood levels increased simultaneously with the onset of a microangiopathic process associated with severe hyperten sion and renal failure. Plasma exchange resulted in a rapid decline in ACA levels and immediate improvement in her clinical condition. This case strongly suggests an important causal relationship between ACA and postpar tum HUS. The possible mechanisms of ACA-related postpartum HUS and the potential role of plasmapheresis in its treatment are reviewed and discussed.
The hemolytic uremic syndrome (HUS) is a microan giopathic process primarily of the renal circulation be lieved to be mediated by platelet clumping. Renal isch emia. thrombocytopenia and disruption of erythrocytes occur as a result of microangiopathy [1], The association of renal dysfunction, thrombocytopenia and hemolytic anemia with schistocytes was first described by Gasser et al. [2] in 1955 and is now widely recognized [1. 3-5], Although more commonly described in children, the syn drome also occurs in adults [6- 8], In adults, the disease is usually triggered after a normal pregnancy [9-17] but is also observed in assocation with oral contraceptive thera py, infection, autoimmune disease, vaccination, cyclospo rine and certain chemotherapeutic agents [3, 7, 8, 18]. The relationship between pregnancy and HUS remains obscure, but numerous explanations have been suggested [10, 13, 19, 20]. A recent report noted an association of circulating lupus anticoagulant (LAC) and anticardiolipin
Received: Novembers, 1991 Accepted: March 16, 1992
antibody (ACA) with the development of postpartum HUS [21], However, the authors did not attempt to corre late levels of ACA with the onset and resolution of renal failure and other manifestations of HUS. We describe a woman with postpartum HUS in whom circulating anti phospholipids appeared to play a central role in the gener ation of clinical manifestations of HUS. This new associa tion is distinct from the occlusive vasculopathy pre viously described in patients with antiphospholipid anti bodies [22],
Case Report A 33-year-old Caucasian woman (G4 P0030) was admitted to Lu theran General Hospital on June 21.1990. at 22 weeks of gestation with epigastric and back pain, headache and hypertension. Past obstetrical history was significant for an uncomplicated elective abortion in September 1980 and two spontaneous abortions (9/88
Daniel Kniaz. MD Associate Director of Nephrology Department of Medicine Lutheran General Hospital 1775 Dempster Street. Park Ridge, 11.60068 (USA)
© 1992 S. Kargcr AG. Basel 0250-8095/92/0122-0126 $2.75/0
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Daniel Kniaz Gerald M. Eisenberg Haim Elrad Catherine A. Johnson Jonas Valaitis Harold Bregman
normal at 92 %. U rinalysis showed more than 100 mg protcin/dl. 1320 RBC/hpf and occasional granular cast. She was treated with phenvtoin. nitroprusside, diazepam and magnesium sulfate and admitted to intensive care with a presump tive diagnosis of eclampsia. HELLP syndrome and malignant hyper tension. Despite nitroprusside, labetalol, captopril, nifedipine and furosemide. her blood pressure remained elevated over the next 4 days, averaging 150/105 mm Hg(fig. 1). On hospital day 5, her blood urea nitrogen rose to 7.2 mntol/l (20 mg/dl) and serum creatinine rose to 186 pniol/1 (2.1 mg/dl: fig. 1). Hemoglobin was 99 g/l (9.9 g/dl), hematocrit 28.1%. platelet count 83.000/pl. reticulocyte count 5.2%. and peripheral blood smear revealed schistocytes. Prothrom bin time, partial thromboplastin time and antithrombin III were still normal, but fibrinogen increased to 5.2 g/l. and fibrin degradation products were > 40 mg/1. Urinalysis revealed 4+ protein, moderate hemoglobin and numerous red blood cells and red blood cell casts. A percutaneous renal biopsy was performed. On light microsco py. small arteries (intralobular) and preglomerular arterioles were focally occluded by fibrin thrombi without evidence of a related vas culitis (fig. 2). In several glomeruli, fibrin thrombi extended from occluded arterioles into the glomerular capillaries. Many glomeruli were ischemic and some were swollen with focally proliferative endo thelial cells that narrowed the capillary lumens (fig. 3). Several tubules were focally hemorrhagic with a few scattered neutrophils. Scattered tubules showed a large number of hyaline droplets and a few areas of tubular atrophy. Electron microscopy revealed occa sional areas with subendothelial widening with a translucent fine granular texture (fig. 4). Basement membranes were intact. Capillarylumens and urinary' spaces of the glomeruli were filled with schisto cytes (fig. 5). Immunofluorescent studies demonstrated focal, periph eral, finely granular deposits for Cj and IgM. but were negative for fibrinogen. She received her 1st of 4 plasma exchanges (3 liters) on the 8th hospital day, and dipyridamole (75 mg. 3 times a day) and aspirin (325 mg daily) were added. By the 9th hospital day. serum creatinine peaked at 248 pmol/l (2.8 mg/dl). platelet count rose to 173.000/pl. and blood pressure was finally controlled with minoxidil, labetalol. nifedipine, captopril. furosemide and clonidine(fig. I). Over the next 4 days, renal function improved and blood pressure remained con trolled despite discontinuation of several antihypertensives. She was discharged on the 17th hospital day with a blood pressure of 137/77 mm Hg, blood urea nitrogen of 9.6 mmol/1 (27 mg/dl), creatinine of 221 pmol/1 (2.5 mg/dl). platelet count of 331,000/pl. reticulocyte count of 3.2% and lactate dehydrogenase of 205 IU/1. Discharge medications were captopril. furosemide. nifedipine, dipyridamole and aspirin. Five months later, her blood pressure was normal off antihypertensive medications, and serum creatinine was 133 pmol/l (1.5 mg/dl). ACA was mesured by ELISA assay [24] before, during and after treatment with plasmapheresis. As shown in figure 1, levels of ACA increased postpartum and peaked immediately before treatment. Plasmapheresis resulted in a marked decrease in antibody levels coincident with clinical improvement. During the 2nd plasma ex change. ACA was measured in the removed plasma and contained 22,500 IU of IgG. 24.000 IU of IgM. and 3.300 IU of IgA.
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and 5/89) at 12 and 11 weeks of gestation. Prolonged partial throm boplastin time and LAC were first observed following the second miscarriage, yet she did not manifest features of SLE. and the antinu clear antibody (ANA) was negative. During the current pregnancy, she was treated with progesterone from the 4th to the 14th week of pregnancy and aspirin, 40 mg daily, from the 4th week onward. A maternal-fetal specialist recommended prednisone 30 mg daily, but the patient refused. LAC was 1.4 near conception. 1.6 at 15 weeks of gestation and 1.7 at 19 weeks of gestation (normal < 1.2). IgM and IgG ACA was present at 19 weeks but titers could not be performed because of other interfering antibodies. Blood pressure was 110/80 mm Hg at 7 weeks of gestation, but increased to 130/80 mm Hg at 9 weeks and to 140/90 mm Hg at 19 weeks of gestation. On admission, she appeared anxious and in moderate respiratory distress with a blood pressure of 150/110 mm Hg. pulse of 106 beats/min, respiration of 20 breaths/min and evidence of left-sided heart failure. Extremities revealed 2+ edema, hyperreflexia and 3- to 4-beat clonus. Fetal heart tones w'ere present. Her urinalysis was significant for 3+ protein. Blood urea nitrogen was 3.2 mmol/1 (9 mg/dl) and serum creatinine 88 pmol/l (1.0 mg/dl). Uric acid was 321 pmol/l(5.4 mg/dl). Hemoglobin was 106 g/1 (10.6 g/dl). hematocrit 28.8% and platelet count 61.000/pI. Serum hapto globin was 0.15 g/l (normal 0.25-1.80) and both direct and indirect Coombs were negative. Prothrombin and partial thromboplastin times and fibrinogen were normal. Serum aspartate aminotransfer ase was 302IU/1 (normal 5-30). serum alanine aminotransferase was 253IU/I (normal 5-40) and lactate dehydrogenase was 268IU/I (nor mal 65-155). Serum albumin was 24 g/l (2.4 g/dl). Complement lev els showed a decreased Cj of 0.60 g/l (normal 0.83-1.77) and a nor mal Cj and CHjo. ANA. SS-A. SS-B and RF were negative. The LAC ratio was only borderline positive (1.2). A presumptive diagnosis of preeclampsia with hemolysis, ele vated liver enzymes and low platelet count (HELLP syndrome) was made [23], She received intravenous magnesium sulfate and prosta glandin E; vaginal suppositories to induce delivery, and on the fol lowing morning, she delivered a 340-gram stillborn male. Placental pathology showed acute chorioamnionitis and degeneration of pla cental villi with focal infarction. On the 3rd hospital day. peripheral edema resolved and blood pressure averaged 140/95 mm Hg. blood urea nitrogen was 3.9 mmol/1 (11 mg/dl) and creatinine 71 pmol/l (0.8 mg/dl). Lactate dehydrogenase fell to 208 IU/1 and platelet count rose to 133.000/pl. She was discharged on the 4th hospital day. Twenty-four hours after discharge, she developed blurred vision, nausea and recurrent epigastric pain. En route to the emergency room, she had a generalized tonic-clonic seizure. A second seizure lasting 3 min occurred after arrival to the hospital. Blood pressure was 205/130 mm Hg. and heart rate was 136 beats/min. Physical examination revealed a lethargic, postictal, but responsive, Cauca sian female. Examination of the fundi demonstrated hemorrhages and papilledema. Bibasilar lung rales were present. A grade 1I1/V1 systolic ejection murmur and a summation gallop were heard on car diac examination. Trace bilateral pedal edema was noted as well as hyperreflexia with clonus and bilateral Babinski signs. Electrolytes, blood urea nitrogen and creatinine were normal. Lactate dehydrogenase was 536 IU/1, leukocyte count 23.600/pl. hemoglobin 137 g/l (13.7 g/dl), hematocrit 38.7% and platelet count was 80.000/pl. Direct and indirect Coombs remained negative. Hap toglobin was undetectable: prothrombin and partial thromboplastin times were normal. Fibrinogen was 3.50 g/l (normal 2.5-5.0). and fibrin degradation products were 25-40 mg/1. Antithrombin 111 was
Discussion
Fig. 1. Mean arterial pressure, platelet count, serum creatinine and ACA levels for IgG. IgM and IgA before and after treatment with plasmapheresis. Antibodies measured by ELISA using partial throm boplastin derived from the human brain as the antigen (Theratcst Co.. Chicago. Illinois). Each arrow represents a 3.0-liter plasma exchange.
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Days
ACA and circulating LAC arc immunoglobulins with antiphospholipid activity initially identified in patients with SLE [25]. These antibodies carry an increased risk of thromboembolic events in both the venous and arterial circulation [22], More recently, these antibodies have been associated with thrombotic events even in patients without SLE [25, 26], In pregnancy, circulating antiphos pholipids have been associated with increased risk of spontaneous abortions, fetal death and the development of early and more severe preeclampsia [27-30]. In addi tion. severe, life-threatening systemic thromboembolism, cerebral hemorrhage and other vasculopathies have been described in postpartum women with antiphospholipid antibodies [31. 32], Also, a postpartum autoimmune syn drome with myocarditis, pleuropulmonary disease and fever has been described in 3 patients with LAC or ACA [33], Thus, as assays for LAC and ACA have improved in sensitivity, specificity and availability, other clinical syn dromes have also been causally related to their presence in the circulation. This patient with circulating LAC and ACA developed preeclampsia early in pregnancy and subsequent HUS. The clinical distinction between the three microangio pathic disorders which occur in pregnancy, severe pre eclampsia, HUS and thrombotic thrombocytopenic pur pura (TTP), is not always possible [ 16], While most inves tigators have focused on the distinctions between these clinical entities [15. 16], some have concluded that the differences are more a matter of degree and have empha sized similarities in clinical presentation, renal pathology and underlying mechanisms [34], The progressive course seen in our patient from preeclampsia, thrombocytopenia and, finally, HUS lends credence to this belief. Our patient initially demonstrated typical features of a severe form of preeclampsia, often referred to as HELLP syn drome [23], which subsequently progressed to full-blown HUS postpartum. The diagnosis of preeclampsia alone is unlikely because of the degree of renal failure, the long term renal compromise and the striking microangiopathic features seen in the small arterioles. In addition, in con trast to the clinical improvement seen postpartum in patients with preeclampsia, this patient's illness worsened 3 days after delivery, and her ACA levels continued to rise until plasmapheresis was initiated. Also, in contrast to preeclampsia, where there may be clinical evidence of dis seminated intravascular coagulation, our patient had nor mal prothrombin and partial thromboplastin times, a normal fibrinogen level and normal antithrombin III
3
Fig. 2. Thrombus in small-sized artery of kidneys. HE. X 200. Fig. 3. Glomerulus with thrombi in capillary lumens, narrow lumens and swol len endothelial cells. Masson’s trichromc. X 200.
Fig. 4. Glomerular tuft with subendothelial widening with fine granular texture. EM. X 20.000. Fig. 5. Glomerulus with many schistocytes in urinary space. EM. X 3.750.
with lupus nephritis [36, 37]. Subsequently. Lockshin et al. [27] reported a high incidence of proteinuria, thrombo cytopenia. hypocomplementemia and a high incidence of fetal death in 7 pregnant women with SLE and LAC. None of these patients developed HUS and, unlike our patient, the syndrome disappeared quickly after termina tion of pregnancy. Kincaid-Smith [21] first reported a relationship be tween circulating LAC and the development of renal thrombotic microangiopathy in pregnant women who did not have lupus (table 1). All developed a syndrome simi lar to our patient. In that study. LAC was measured
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activity [15]. Finally, the low serum C3 level and C3 deposits seen on immunofluorescent staining of glomeru lar capillary walls have also been described in cases of postpartum HUS [17. 35], Thus, this patient presented with severe preeclampsia early in pregnancy and later developed postpartum HUS as evidenced by the progres sive hematologic alterations and kidney pathology. The original descriptions of the relation of ACA and renal disease were made in patients with systemic lupus. These reports suggested that lupus patients with LAC and ACA are more prone to develop thrombocytopenia and renal arteriolar and glomerular thrombosis in association
Table 1. Summary of the literature describing renal disease associated with antiphopholipid antibody without SLE Author
Patients
Hypo-
Connective tissue disease
Pregnancy BCP
Clinical manifestations
Microangiopathic hemolytic anemia
Thrombocytopenia
F
NR
7/1
fetal death spontaneous abortions hypertension (malignant) azotemia
yes
yes
no
26 42
M M
•SLE-like' Raynaud's
no
fever thrombophlebitis hypertension proteinuria azotemia
no
no
no
1
24
F
no
no
fever thrombophlebitis hypertension proteinuria azotemia
no
yes
no
Grave [40]
3
NR
NR
no
no
dementia hypertension proteinuria azotemia
NR
NR
no
Ingram [41]
1 1
43 22
M F
‘SLE-like’ + ANA (1:120, 1:240) + Shirmer’s
no
fever thrombophlebitis livedo reticularis cerebral infarct hypertension (malignant) proteinuria azotemia
no
yes
NR
total
age years
sex
Kincaid-Smith [21]
8
20-35
D’Agati [38]
1 1
Becquemont [39]
complementemia
ND = Not done; NR = not reported.
130
broelastic intimal thickening. Thus, the features of this case as well as those recently described by Kincaid-Smith [21 ] suggest a distinct subset of patients with postpartum HUS associated with ACA. In our case, the correlation of ACA levels with the clinical course as well as the demon stration of high levels of ACA in the pheresate suggests a causal relationship. Future studies should address the incidence of antiphospholipid antibodies in presumed ‘idiopathic’ postpartum HUS. Other antiphospholipid-antibody-related renal diseases have been described in nonpregnant women and men with out SLE [38-41 ]. In each of these reports, antiphospholipid antibodies were associated with a renal thrombotic mi croangiopathy, although full-blown HUS has not been described (table 1). HUS in association with ACA has only been described in the setting of pregnancy [21 ],
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because of a history of recurrent abortions or fetal death, impaired renal function during pregnancy or because of a history of disseminated thrombotic manifestations. As in our patient, ages ranged from 20 to 35 years, and the syn drome was related to pregnancy in 7 cases. In another woman, it was related to the use of oral contraceptives. Four other women with a similar clinical picture had a history of systemic lupus and/or serologic markers for SLE. All of them had low platelet counts, increased fibrin degradation products and a microangiopathic hemolytic anemia. In addition, as in our patient. 3 had malignant hypertension, and most had moderate or severe renal impairment. Biopsies from these women were identical to that from our patient, showing fibrin thrombi in glomer uli and arterioles as well as ischemic necrosis. Biopsies from later periods showed intimal proliferation and fi-
LAC/ACA BINDING
thrombotic microangiopathy
Correlation Therapy of clinical course with ACA levels
Outcome
ND
most improved but persistent impaired renal function
heparin steroids ASA/dipyridamole plasmapheresis
ND thrombotic microangiopathy endocapillary proliferation fibrinous thrombi
NR steroids cyclophosphamide
ND thrombotic microangiopathy endothcliosis fibrinous thrombi
y-globulin improved fresh frozen plasma but severe ASA/dipyridamole persistent renal insufficiency
thrombotic microangiopathy subendothelial Ig and C deposits
ND
NR
yes
/
I
PLA T E LE T ACTIVATION
\
E N D O T H E L IA L IN JU R Y
v W F M U LT IM E R S
PLA TELET A G G R E G A T IO N
THROM BOCYTO PENIA
THROMBOSIS
NR
heparin/coumadin steroids cyclophosphamide ASA/dipyridamole plasmapheresis
NR
improved but persistent neurologic deficits
What is the relationship of ACA to the pathogenesis of fetal wastage, severe preeclampsia and postpartum HUS? These immunoglobulins possess antiphospholipid activ ity and are believed to bind and alter the structure of platelet and/or endothelial cell wall membranes, causing platelet aggregation [26. 28, 38.42] (fig. 6). Direct platelet activation could result in systemic thrombosis, while localized endothelial damage in the placenta during preg nancy could result in fetal wastage or prceclampsia. When the renal circulation is the primary site of endothelial damage and/or platelet activation, HUS may result. Alter natively, endothelial wall injury by ACA could alter the delicate balance between procoagulant and anticoagulant factors [43]. For example, ACA has been shown to decrease production or release of prostacyclin (PGL) [28. 29. 38], an endothelial-derived vasodilator and inhibitor
y CIRCULATION
• Venous and Arterial Thrombosis
/ PLACENTA
\
\
^
KIDNEY_________ ÇN S_______OTHER
• Fetal Growth • Renal Thrombotic Retardation Microangiopathy • Abortion • Hemolytic Uremic • Preeclampsia Syndrome • Hypertension
• Migraine • Livedo • Seizures reticularis • Infarcts • Myocardial • Dementia infarction • Monocular • Endocarditis Blindness
Fig. 6. Theoretical mechanisms whereby LAC and/or ACA result in focal or systemic vasculopathies. Pregnancy, normally a hypcrcoaguable state, is dependent on increased PGL and is associated with increased (+) release of large multimcrs of von Willebrand factor (vWF). both of which may amplify the thrombotic tendency of LAC and ACA (see text for details).
of platelet aggregation. In pregnancy, normally a hypercoagulable state, increased production of PGL may be important in preventing platelet aggregation [19], A rela tive deficiency of PGL during pregnancy has been pro posed as one explanation for fetal wastage, preeclampsia and postpartum HUS [13, 19, 20. 44], In support of this mechanism, lower plasma levels of PGL in the maternal and placental circulation have been described in women with ACA and LAC who develop these complications [28. 29], Another hypothesis is that circulating ACA or LAC act as a platelet-agglutinating factor (PAF) that interacts with large multimers of von Willebrand factor causing platelet aggregation. In pregnancy, an increased synthesis of large multimers of von Willebrand factor could in crease the susceptibility to developng HUS [1.45], The role of plasma infusion and plasma exchange ther apy in thrombotic microangiopathic diseases, particularly TTP. has been well established [1.4. 45. 46]. Successful use of this mode of therapy has also been described in severe HUS [8. 47], but its effectiveness is less certain. However, because of the similarities between HUS and
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Renal histology
TTP and the severity of our patient’s illness, we elected to proceed with plasma exchange therapy in addition to aspirin and dipyridamole [10, 48, 49], Plasmapheresis resulted in a rapid reduction in circulating ACA coinci dent with dramatic clinical improvement. While the benefit of plasma exchange in TTP and HUS is believed to stem either from the removal of a platelet activating factor (i.e„ abnormal von Willebrand factor, PAF. inhibitors of PGU) or infusion of inhibitors of plate let aggregation, in women with ACA-related postpartum HUS. removal of the antiphospholipid antibody is likely to be a key aspect of therapy. We did not. however, exam ine the effects of plasmapheresis on other regulators of platelet function. Previous reports also suggest a role for
plasmapheresis therapy in fulminant ACA-related vasculopathies [21, 22. 41], In one of those reports, the reduc tion in ACA levels also correlated with clinical improve ment [41], Thus, although the precise role of plasmapher esis in the treatment of ACA-related syndromes requires further investigation, early recognition of the role of ACA in renal and other severe vasculopathies should be sought and treatment with plasmapheresis considered.
Acknowledgment The authors would like to express their gratitude to Drs. Jose Arruda and Jeffrey Lakier for their advice and comments in prepar ing the manuscipt.
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23 Weinstein L: Syndrome of hemolysis, elevated liver enzymes and low platelet count: A severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982:142:15 9-167. 24 Branch DW. Rote NS. Scott JR: Demonstra tion of lupus anticoagulant by an enzymelinked immunoabsorbent assay. Clin Immunol Immunopalhol 1986:39:298-307. 25 Harris EN. Hughes GRV. Gharavi AE: Anti cardiolipin antibodies and the lupus anticoagu lant. Clin Exp Rheumatol 1986:4:187-190. 26 Love PS. Santoro SA: Antiphospholipid anti bodies. anticardiolipin and the lupus anticoag ulant in systemic lupus erythematosus (SLE) and non-SLE disorders. Ann Intern Med 1990: 112:682-698. 27 Lockshin MD. Harpel PC, Druzin ML. et al: Lupus pregnancy - Unusual pattern of hvpocomplementemia and thrombocytopenia in the pregnant patient. Arthritis 1985:28:58-66. 28 Carreras LO. Vermylen J. Spitz B. et al: Lupus anticoagulant and inhibition of prostacyclin formation in patients with repeated abortion, intrauterine growth retardation and intrauter ine death. Br J Obstet Gynaecol 1981:88:890894. 29 Branch DW. Scott JP. Kochcnour NK. el al: Obstetric complications associated with lupus anticoagulant. N F.ngl J Med 1985:313:1322— 1326. 30 Lockshin MD. Druzin ML. QamarT: Predni sone does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet Gynecol 1989; 160:439-443. 31 Clauvel JP. Tchobroutsky C. Danon F. et al: Spontaneous recurrent fetal wastage and auto immune abnormalities. Clin Immunol Immu nopalhol 1986:39:523-530.
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