Abstract

Cardiac complications are frequently seen in thrombotic thrombocytopaenic purpura related to ADAMTS13 deficiency. We describe the case of a 43-year-old woman who was diagnosed with an atypical haemolytic–uraemic syndrome (aHUS) associated with a pathogenic mutation in the factor H gene (C623S). After 15 days of treatment, she suffered a sudden cardiac arrest and died despite intensive resuscitation attempts. She showed only one cardiovascular risk factor, hypercholesterolaemia. Her sudden death was secondary to cardiac infarction related to a coronary thrombotic microangiopathy. This is the first case of aHUS related to a mutation in the factor H gene associated with cardiac microangiopathy. This case emphasizes the need to screen for cardiac complication during the treatment of aHUS.

Background

Thrombotic microangiopathy (TMA) is characterized by haemolytic anaemia, thrombocytopaenia and microvascular thrombi in multiple organs. Two entities are distinguished: haemolytic–uraemic syndrome (HUS) [1] and thrombotic thrombocytopaenic purpura (TTP) depending on the organs involved and von Willebrand factor-cleaving protease (ADAMTS13) activity. HUS is a triad of microangiopathic haemolytic anaemia, thrombocytopaenia and acute renal failure, whereas TTP is an association of thrombocytopaenia, haemolytic anaemia, fever and neurological disturbances and is linked in the majority of cases to ADAMTS13 low activity.

HUS can be classified into two types depending on the presence of verocytotoxin-producing Escherichia coli (VTEC or Stx) infection. VTEC-associated HUS is the most common cause of acute renal failure among children. Atypical haemolytic–uraemic syndrome (aHUS) is seen in adults and may be familial or sporadic. It often affects native kidneys but can also affect transplanted kidneys. An association between aHUS and uncontrolled complement activation has been well established [1]. More than 50% of patients have heterozygous loss-of-function mutations in genes encoding inhibitors of the alternative pathway of the complement system: factor H (CFH) [2,3], factor I (CFI) [4], membrane cofactor protein (MCP) [5] and thrombomodulin (THBD) [6]. Infrequently, gain-of-function mutations have been described in genes encoding factor B [7] and C3 [8], which promote alternative-pathway activation. 10 to 25% of patients with aHUS die. The cause is not always well identified.

Here, we report the case of an acute myocardial infarction in aHUS associated with mutation in the CFH gene.

Case report

A 43-year-old woman was admitted to the hospital for headaches and nausea. She had no significant past medical history apart from hypercholesterolaemia. She had no personal or family history of heart disease. Two months prior to her admission, her creatinine was 73 μmol/L (eGFR, 108 ml/min/1.73 m2).

On physical examination, the patient was pale and showed a malar rash. Her temperature was 37.3°C and blood pressure was 180/90 mmHg. Peripheral oedema with dyspnea was noted. Lung examination revealed pulmonary oedema. Biological data revealed anaemia with a red blood cell (RBC) count of 75 g/dl, thrombocytopaenia with 109 000 Giga/L platelets and acute renal failure with creatinine at 940 μmol/L. Total protein level was 57 g/L and serum albumin level was 28 g/L. Lactate dehydrogenase (LDH) level was 1498 UI/L (normal values, 200–400 UI/L). Serum haptoglobin was undetectable. Schistocytes were detected on blood smear (3% of RBC count). Urinalyses showed proteinuria with 11 g/L and no haematuria. Renal ultrasound scan revealed two large echogenic kidneys and no obstruction.

The association of a malar rash, haemolytic anaemia and nephrotic syndrome with acute renal failure suggested systemic lupus erythematous. Corticosteroid treatment was commenced with three pulses of 500 mg/kg followed by 1 mg/kg/j before a kidney biopsy was performed. Dialysis sessions were initiated. The patient was transfused with two RBC packs. No more transfusions were done. The corticosteroids initially corrected the platelet count. All immunological tests (antinuclear antibodies, anti-DNA antibodies, ANCA, cryoglobulinaemia, rheumatoid factor) were negative. Direct and indirect Coombs tests were negative. C3 antigen (Ag) was 638 mg/L (normal range, 660–1250 mg/L), C4 Ag was 298 mg/L (normal range, 93–380 mg/L), factor B Ag was 85 mg/L (normal range, 90–320 mg/L) and factor H Ag was 64% (normal range, 65–140%). Activity of ADAMTS13 was 60% with no antibodies against ADAMTS13.

A kidney biopsy was performed when platelet counts allowed it. The kidney biopsy revealed typical TMA (Figure 1).

Fig. 1

TMA in the kidney. Glomeruli show diffuse fibrin thrombi with early segmental mesangiolysis and acute ischemic changes are also seen in tubules (Jones staining, ×200).

Fig. 1

TMA in the kidney. Glomeruli show diffuse fibrin thrombi with early segmental mesangiolysis and acute ischemic changes are also seen in tubules (Jones staining, ×200).

Plasma exchanges were performed daily, 14 days after the onset of her symptoms, with 3 L of solvent detergent plasma (50 ml of plasma per kilogramme of body weight). The plasma exchanges were done with a femoral venous catheter of 14 Fr. We used an HF440 generator (Infomed SA) for plasma exchanges. Thirteen days after the beginning of daily plasma exchanges, haematological parameters improved with an increase in haptoglobin, normalization of LDH, correction of thrombocytopaenia and a decrease in schistocytes (1% of RBC count).

On day 15, after the beginning of plasma exchange, the patient suffered a sudden malaise with neck pain. Circulatory arrest associated was identified with pulse rate under 25/min. Heart massage was immediately initiated followed by mechanical ventilation. Rapidly, EKG showed non-electrical cardiac activity. Because heart activity did not resume after 10 boluses of 1 mg adrenalin, a cardiac ultrasound scan was performed. A pericardial effusion with tamponade was observed. Pericardial paracentesis allowed the evacuation of 300 cc of blood. However, the patient died, despite intra-thoracic cardiac massage. Troponin I-C taken at the beginning of resuscitation was 2.212 ng/ml (normal range, 0–0.04 ng/ml). A necropsy was performed. The delay between death and tissues sampling was <12 h. Necropsy revealed a myocardial infarction with no obstruction of the coronary arteries. In the heart, multiple microscopic areas of infarction (cardiomyocytes necrosis) were present in the myocardium of both ventricles dating 15 days to 24 h (Figure 2). No coronary thrombi were highlighted. There was no atherosclerotic lesion on coronary arteries. Pathology examination showed vessel wall thickening and sub-endothelial oedema with no vessel thrombi. The small vessels had endothelial swelling suggestive of TMA. Immunochemistry revealed an activation of the final pathway of complement in the small coronary vessels and in infarcted cardiomyocytes. C5b9 expression is an early marker of myocardial infarction, not specific of aHUS. It was specific of infarction. This staining is absent during autolytic changes [9]. The C5b9 positivity confirmed the myocardial infarction as the aetiology of death. Diffuse microscopic myocardial infarctions with normal coronary arteries are certainly secondary to aHUS.

Fig. 2

Myocardial infarctions. A Low power view showing three focal myocardial infarctions (arrows) (HES, ×50). B TMA in heart vessel. Acute oedematous intimal expansion with endothelial swelling and partial occlusion of the lumen without thrombosis (HES, ×400). C Activation of complement in heart vessel and myocardium. Complement activation is revealed by staining (brown) of anti-C5b9 antibody on damaged myocytes (C5b9 staining is an early marker of cardiomyocytes necrosis) and normal vessels within a deeper infraction are (immunohistochemistry, ×100).

Fig. 2

Myocardial infarctions. A Low power view showing three focal myocardial infarctions (arrows) (HES, ×50). B TMA in heart vessel. Acute oedematous intimal expansion with endothelial swelling and partial occlusion of the lumen without thrombosis (HES, ×400). C Activation of complement in heart vessel and myocardium. Complement activation is revealed by staining (brown) of anti-C5b9 antibody on damaged myocytes (C5b9 staining is an early marker of cardiomyocytes necrosis) and normal vessels within a deeper infraction are (immunohistochemistry, ×100).

Alternative complement pathway was studied and genetic mutations were explored. The patient showed alternative pathway activation with decreased plasma levels of C3 and factor B. The plasma concentration of FH protein was low (64% of normal value), suggesting a heterozygous FH deficiency. A nucleotide substitution leading to the change of a cysteine to another amino acid was found in SCR 10 at Position 623 in the factor H gene (TGT > TCT; Cys623Ser). This genetic abnormality was absent in a sample of more than 100 individuals (>200 chromosomes investigated) and was not previously reported in patients with aHUS.

Thirty years ago, her second cousin had suffered from aHUS with renal failure leading to dialysis. Renal transplantation was performed 2 years after the beginning of dialysis. She lost her graft 10 days after transplantation because of TMA recurrence. We identified the same mutation (C623S), which allowed us to make the diagnosis of aHUS related to CFH mutation, 30 years after the beginning of the disease.

Discussion

Sudden death can be seen in the course of TMA. Clinical and biological examinations can serve to exclude ionic abnormalities and non-cardiac causes. In our case, the final diagnosis was sudden death secondary to cardiac infarction related to a coronary TMA associated with a pathogenic mutation in factor H. We could not definitely affirm that infarction was related to aHUS because no microcirculatory thrombosis was detected within the myocardium contrary to the renal tissue, but intra-myocardial TMA was highly suggested by multifocal myocyte necrosis and endothelial swelling.

Besides neurological complications, cardiac injury in TTP is recognized as one of the leading causes of death [10]. A low level of ADAMTS13 with an accumulation of ultra large multimers of von Willebrant factor is associated with adverse outcome in myocardial infarction [11]. Furthermore, free haemoglobin due to haemolytic anaemia can capture nitric oxide (NO), which results in decreased NO. This decrease could be associated with vasoconstriction and platelet activation [12]. Although pathology findings often reveal microthrombi and infarction, clinical cardiac abnormalities are rarely seen [13].

Cardiac complications in HUS are not as well described as those in TTP. Yet, 10 to 25% of patients with aHUS die as a result of the syndrome. The heart could be an unrecognized target in aHUS. Only 16 patients were reported in nine reports (Table 1) [14–25]. Stx-associated HUS is the most frequent cause (certain, 63%). As it occurs during the course of Stx-associated HUS, children are over-represented (81% before 15 years old and 63% before 5 years old). Cardiac complications seem to be linked to severe HUS, as almost all patients required dialysis. This also seems to be the case for cardiac injury in TTP, which is associated with more severe disease, detected by elevated LDH or lower platelet count [26]. Cardiac complications resulted in acute injury with severe dilated cardiomyopathy in nine cases, myocardial infarction in four cases and cardiac tamponade in two cases. Cardiac injury often occurred in the first month of the disease (70%). Clinical presentation is atypical and the course of the cardiac disease is aggressive, given that most patients are in the intensive care unit (ICU) (69%). Troponin level, when available, is increased. The diagnosis is performed by ultrasound scan or necropsy. Pathology was reported in only four patients. Cardiac injuries due to consequences of microangiopathy in cardiac tissue were described in three cases.

Table 1

Case report of cardiac involvements in HUS course

Reference Patient Cause of HUS Sex Age (years) Time after onset (days) Cardiac disease Troponin level Cardiac outcome 
Eckart et al. [13PI 1.87 10 MI  Recovery 
VTEC DCM  Improvement 
VTEC 2.1 90 DCM 28 Recovery 
Thayu et al. [14VTEC MI 16 Recovery 
Nayak et al. [15Toxic 55 MI  Death 
Abu-Arafeh et al. [16VTEC 13 Myocarditis  Death 
Thomas et al. [17PI MI  Death 
VTEC DCM  Recovery 
Askiti et al. [18VTEC 1.8 Myocarditis 43 Recovery 
Tobias [1910 PI 0.75 DCM  Recovery 
Mohammed et al. [2011 VTEC Tamponade 7.8 Recovery 
Walker et al. [2112 VTEC 120 DCM  Recovery 
Poulton et al. [2213 VTEC 1.8 56 DCM  Improvement 
14 Unknown 25 DCM  Recovery 
Birk et al. [2315 VTEC Tamponade Death 
Leray et al. [2416 Post-partum 24 90 DCM  Improvement 
Reference Patient Cause of HUS Sex Age (years) Time after onset (days) Cardiac disease Troponin level Cardiac outcome 
Eckart et al. [13PI 1.87 10 MI  Recovery 
VTEC DCM  Improvement 
VTEC 2.1 90 DCM 28 Recovery 
Thayu et al. [14VTEC MI 16 Recovery 
Nayak et al. [15Toxic 55 MI  Death 
Abu-Arafeh et al. [16VTEC 13 Myocarditis  Death 
Thomas et al. [17PI MI  Death 
VTEC DCM  Recovery 
Askiti et al. [18VTEC 1.8 Myocarditis 43 Recovery 
Tobias [1910 PI 0.75 DCM  Recovery 
Mohammed et al. [2011 VTEC Tamponade 7.8 Recovery 
Walker et al. [2112 VTEC 120 DCM  Recovery 
Poulton et al. [2213 VTEC 1.8 56 DCM  Improvement 
14 Unknown 25 DCM  Recovery 
Birk et al. [2315 VTEC Tamponade Death 
Leray et al. [2416 Post-partum 24 90 DCM  Improvement 

PI, post infectious; MI, myocardial infarction; DCM, dilated cardiomyopathy.

The course of cardiac injury in our patient and in those cases was similar. Clinical presentation was severe and death occurred rapidly. Troponin level was high, and pathology results confirmed microangiopathy of small heart vessels. Myocardial tissue could be affected by the same anomalies of microvascular circulation as is those observed in the kidney during HUS. This is the first time that cardiac injury was described in aHUS associated with mutation in CFH (TGT > TCT; Cyst623Ser). It could be of great interest to systematically evaluate cardiac activity in a well-genotyped cohort of aHUS to identify whether cardiac injury is more frequently associated with particular mutated genes.

In the literature, it is unclear how cardiac injury of TMA could be detected and how it could be treated. Because of the atypical presentation and the severity of the prognosis of cardiac infarctions, we recommend monitoring cardiac enzymes like troponin I, as well as 12-lead EKG, daily. The monitoring should be very frequent particularly when platelet count is normalized. If troponin assay and/or EKG suggest cardiac injury, a cardiac sonogram is necessary to identify segmental or diffuse myocardial dysfunction. If patients have classical risk factors of atherosclerosis, a coronarography should be done rapidly to eliminate a stenosis on heart arteries. Management should include antiplatelet therapy, heparin and beta blockers, as that used for acute coronary syndrome of more typical aetiology.

In conclusion, this is the first report, to our knowledge, of a case of cardiac injury in aHUS due to genetic mutation in factor H gene with a poor outcome. Patients with aHUS and Stx-associated HUS, like patients with TTP, have to be monitored for cardiac injury. We believe that troponin and EKG monitoring is a good course of action and should be systematically performed. It should be of interest to study cardiac injury in genotyped aHUS to identify mutations.

We thank Prof. Gary Burkhart for his help in the language correction.

Conflict of interest statement. None declared.

References

1
Noris
M
Remuzzi
G
Atypical haemolytic–uremic syndrome
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
1676
-
1687
)
2
Noris
M
Ruggenenti
P
Perna
A
, et al.  . 
Hypocomplementemia discloses genetic predisposition to haemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. Italian Registry of Familial and Recurrent Haemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura
J Am Soc Nephrol
 , 
1999
, vol. 
10
 (pg. 
281
-
293
)
3
Perez-Caballero
D
Gonzalez-Rubio
C
Gallardo
ME
, et al.  . 
Clustering of missense mutations in the C-terminal region of factor H in atypical haemolytic uremic syndrome
Am J Hum Genet
 , 
2001
, vol. 
68
 (pg. 
478
-
484
)
4
Kavanagh
D
Richards
A
Noris
M
, et al.  . 
Characterization of mutations in complement factor I (CFI) associated with haemolytic uremic syndrome
Mol Immunol
 , 
2008
, vol. 
45
 (pg. 
95
-
105
)
5
Fremeaux-Bacchi
V
Kemp
EJ
Goodship
JA
, et al.  . 
The development of atypical haemolytic–uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts
J Med Genet
 , 
2005
, vol. 
42
 (pg. 
852
-
856
)
6
Delvaeye
M
Noris
M
De Vriese
A
, et al.  . 
Thrombomodulin mutations in atypical haemolytic–uremic syndrome
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
345
-
357
)
7
Goicoechea de Jorge
E
Harris
CL
Esparza-Gordillo
J
, et al.  . 
Gain-of-function mutations in complement factor B are associated with atypical haemolytic uremic syndrome
Proc Natl Acad Sci U S A
 , 
2007
, vol. 
104
 (pg. 
240
-
245
)
8
Fremeaux-Bacchi
V
Miller
EC
Liszewski
MK
, et al.  . 
Mutations in complement C3 predispose to development of atypical haemolytic uremic syndrome
Blood
 , 
2008
, vol. 
112
 (pg. 
4948
-
4952
)
9
Piercecchi-Marti
MD
Lepidi
H
Leonetti
G
Vire
O
Cianfarani
F
Pellissier
JF
Immunostaining by complement C9: a tool for early diagnosis of myocardial infarction and application in forensic medicine
J Forensic Sci
 , 
2001
, vol. 
46
 (pg. 
328
-
334
)
10
McCarthy
LJ
Danielson
CF
Skipworth
EM
, et al.  . 
Myocardial infarction/injury is relatively common at presentation of acute thrombotic thrombocytopenic purpura: the Indiana University experience
Ther Apher
 , 
2002
, vol. 
6
 (pg. 
2
-
4
)
11
Matsukawa
M
Kaikita
K
Soejima
K
, et al.  . 
Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction
Am J Cardiol
 , 
2007
, vol. 
100
 (pg. 
758
-
763
)
12
Thachil
J
The role for adjunctive treatment to plasma exchange in thrombotic thrombocytopenic purpura
Nephrol Dial Transplant
 , 
2008
, vol. 
23
 (pg. 
2701
-
2702
author reply 2702–2703
13
Hosler
GA
Cusumano
AM
Hutchins
GM
Thrombotic thrombocytopenic purpura and haemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases
Arch Pathol Lab Med
 , 
2003
, vol. 
127
 (pg. 
834
-
839
)
14
Eckart
P
Guillot
M
Jokic
M
, et al.  . 
Cardiac involvement during classic haemolytic uremic syndrome
Arch Pediatr
 , 
1999
, vol. 
6
 (pg. 
430
-
433
)
15
Thayu
M
Chandler
WL
Jelacic
S
, et al.  . 
Cardiac ischemia during haemolytic uremic syndrome
Pediatr Nephrol
 , 
2003
, vol. 
18
 (pg. 
286
-
289
)
16
Nayak
SG
Satish
R
Gokulnath
An unusual toxic cause of haemolytic–uremic syndrome
J Toxicol Sci
 , 
2007
, vol. 
32
 (pg. 
197
-
199
)
17
Abu-Arafeh
I
Gray
E
Youngson
G
, et al.  . 
Myocarditis and haemolytic uraemic syndrome
Arch Dis Child
 , 
1995
, vol. 
72
 (pg. 
46
-
47
)
18
Thomas
NJ
Messina
JJ
DeBruin
WJ
, et al.  . 
Cardiac failure in haemolytic uremic syndrome and rescue with extracorporeal life support
Pediatr Cardiol
 , 
2005
, vol. 
26
 (pg. 
104
-
106
)
19
Askiti
V
Hendrickson
K
Fish
AJ
, et al.  . 
Troponin I levels in a haemolytic uremic syndrome patient with severe cardiac failure
Pediatr Nephrol
 , 
2004
, vol. 
19
 (pg. 
345
-
348
)
20
Tobias
JD
Haemolytic–uremic syndrome and myocardial dysfunction in a 9-month-old boy
Paediatr Anaesth
 , 
2007
, vol. 
17
 (pg. 
584
-
587
)
21
Mohammed
J
Filler
G
Price
A
, et al.  . 
Cardiac tamponade in diarrhoea-positive haemolytic uraemic syndrome
Nephrol Dial Transplant
 , 
2009
, vol. 
24
 (pg. 
679
-
681
)
22
Walker
AM
Benson
LN
Wilson
GJ
, et al.  . 
Cardiomyopathy: a late complication of haemolytic uremic syndrome
Pediatr Nephrol
 , 
1997
, vol. 
11
 (pg. 
221
-
222
)
23
Poulton
J
Taylor
CM
De Giovanni
JV
Dilated cardiomyopathy associated with haemolytic uraemic syndrome
Br Heart J
 , 
1987
, vol. 
57
 (pg. 
181
-
183
)
24
Birk
PE
Chakrabarti
S
Lacson
AG
, et al.  . 
Cardiac tamponade as a terminal event in the haemolytic uremic syndrome in childhood
Pediatr Nephrol
 , 
1994
, vol. 
8
 (pg. 
754
-
755
)
25
Leray
H
Mourad
G
du Cailar
G
, et al.  . 
Dilated cardiomyopathy during post-partum haemolytic and uremic syndrome (HUS)
Nephrologie
 , 
1991
, vol. 
12
 (pg. 
237
-
240
)
26
Patschan
D
Witzke
O
Duhrsen
U
, et al.  . 
Acute myocardial infarction in thrombotic microangiopathies—clinical characteristics, risk factors and outcome
Nephrol Dial Transplant
 , 
2006
, vol. 
21
 (pg. 
1549
-
1554
)

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