Brief Report

Post-transfusion Hypertension and Seizure in Congenital Hemolytic anemia: A Case Report and Literature Review by Chin Fang Ngim,1 Chen Siew Ng,2 and Nai Ming Lai3 1 Department of Paediatrics, School of Medicine and Health Sciences, Monash University, Johor Bahru, 80100 Johor, Malaysia 2 Department of Nuclear Medicine, Sultanah Aminah Hospital, Johor Bahru, 80100 Johor, Malaysia 3 Paediatrics and Child Health Research Group, Department of Paediatrics, University of Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia

Summary A rare syndrome of hypertension, seizures and intracranial bleed has been reported among patients with congenital hemolytic anemia who underwent multiple blood transfusions. We report this syndrome in a 12-year-old Malay girl with hemoglobin E-beta-thalassemia, who underwent intensive transfusion and subsequently had headache, visual loss, severe hypertension and seizures. A comprehensive literature review revealed 30 patients with this syndrome, of whom 15 had intracranial bleed and 12 among these 15 died. A less-intensive transfusion regimen among patients with chronic hemolytic anemia and prompt detection and management of hypertension may prevent this potentially fatal syndrome. Key words: hemolytic anemia, hypertension, seizures, intracranial bleed, transfusion.

Introduction Thalassemia is a common inherited disorder of hemoglobin synthesis with significant short- and long-term complications. In 1978, Wasi et al. [1] reported a rare and potentially fatal syndrome of systemic hypertension, convulsion and intracranial bleed (ICB) affecting eight thalassemic patients who had received multiple blood transfusions. We report this syndrome in a 12-year-old Malay girl who has hemoglobin E-beta-thalassemia and review the literature in the PubMed database. Using the keywords anemia, hypertension and seizure, fit or convulsion, nine publications with 30 patients were identified in the English literature [1–9]. Case Report Our patient is a Malay female who was diagnosed with hemoglobin E-beta-thalassemia at 5 years of age. She had no family or personal history of hypertension, seizures or renal disease. After four visits for blood transfusions, she did not come for follow-up until 12 years of age, when she presented with fever, vomiting and drowsiness. She had severe growth retardation, pallor and massive hepatosplenomegaly. Her hemoglobin was 3.3 g/dl, leukocyte count 6.1  109/l and platelet count 15.2  109/l. C-reactive

protein was elevated to 117 mg/dl. Brain computed tomography (CT) was normal. Echocardiogram revealed slightly reduced function with left ventricular ejection fraction recorded as 58%. Intravenous cefotaxime and transfusion with pack cells were commenced with improvement in her clinical condition. Over the first 11 days of admission, she underwent transfusion with packed red cells nine times, with a total volume of 70 ml/kg, and by the 11th day, her hemoglobin was 11.9 g/dl, leukocyte count 10.1  109/l and platelet count 171  109/l. Her systolic blood pressure (BP) ranged from 101 to 127 and diastolic BP was 58–73 during this period. Eight hours after the last transfusion, the patient developed severe headache and vomiting, followed by visual loss and generalized seizure. Her BP was 165/ 122. Although her seizure ceased after intravenous diazepam treatment, her BP remained elevated at 135/89. She was intubated for airway protection. An urgent brain CT was normal. Cerebrospinal fluid microscopy, biochemistry and culture were normal, except for mild elevation of protein concentration to 0.67 g/l. A repeat echocardiogram was similar to the one conducted on admission, with left ventricular ejection fraction recorded as 58%. Kidney ultrasonography and Doppler studies,

ß The Author [2014]. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] doi:10.1093/tropej/fmu003 Advance Access published on 27 January 2014


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Correspondence: Chin Fang Ngim, School of Medicine and Health Sciences, Monash University Malaysia, 8, Jalan Masjid Abu Bakar, Johor Bahru, 80100 Johor, Malaysia. Tel: þ60 127613459. Fax: þ60 72190601. .

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Sickle cell anemia Sickle cell anemia Sickle cell anemia Sickle cell anemia Hb E-beta thalassemia

M/20 M/10 M/6 M/12 M/4

M/5 M/5 F/10 M/13 M/14 M/8 F/8 F/5 F/11 M/7 F/6 M/14 M/3 M/6

– – – – – *4 *4.31 *6.39 *5 *3.9 *5.6 *4.1 *5.7 *3

*3.9 *1.6 *7.4 – –

24 15.3


7 16 9 10 15

12 15 10


– – – – – – *10.9 – 11.9 *8.5 *8.9 *9.6 *10.2 *8.3

*8.7 *10.8 – *10.8 –

40 33.6


40 33 40 20 27

33 28 33

During attack

Hct % or (*) Hb g/dl

– – – – – – 153 – 138 118 59 134 79 177

123 575 – – –

67 120


471 106 344 100 80

175 87 230

Percent increase in Hct or Hb

– – – 90/50 110/70 – – – – 112/70 114/68 120/67 102/66 –

120–138/54–78 110/60 110/70 – –

104/60 –


120/50 100/60 110/70 90/50 90/50

122/80 90/60 90/40

Before transfusion

160/110 120/80 170/110 150/100 210/130 200/140 140/90 140/95 Normal 154/97 143/87 165/98 137/84 160/100

170/110 200/100 170/120 200/130 140/90

140/80 130/80


Unknown 104/80 160/90 Sys > 200 170/130 170/100 210/50 160/100 150/100

During attack

Blood pressure (mm Hg)

(–), Not documented; M, male; F, female; Hct, hematocrit; Hb, hemoglobin; ICB, intracranial bleed. a brain CT conducted. * Hemoglobin g/dL.

Masood [9]

Assadi [8]

Gurgey et al [7]

Sonakul and Fucharoen, [6] Beta-thalassemia major Hb E-beta thalassemia Hb E-beta thalassemia Hb E-beta thalassemia Hb E-beta thalassemia Beta-thalassemia intermedia Thalassemia intermedia Thalassemia intermedia Thalassemia intermedia Beta-thalassemia Beta-thalassemia intermedia Sickle cell disease Hereditary spherocytosis Thalassemia major

Sickle cell anemia Beta-thalassemia major

F/8 M/3.5 months

Yetgin and Hicsonmez [3] Warth [4] Hamdan et al [5]


Hb H-Constant Spring Hb E-beta thalassemia Hb E-beta thalassemia Hb E-beta thalassemia Hbs A þ E þ Barts þ Constant Spring Sickle cell anemia

F/24 M/20 M/14 M/20 M/13

Royal and Seeler [2]

Hb E-beta thalassemia Hb E-beta thalassemia Hb E-beta thalassemia

M/16 M/16 F/24

Wasi et al [1]

Underlying hematological condition

Sex/age (years)

ˇ ˇ ˇ ˇ ˇ ˇ ˇ

ˇ ˇ ˇ ˇ ˇ ˇ

ˇ ˇ ˇ ˇ ˇ



ˇ ˇ ˇ


ˇ ˇ ˇ ˇ ˇ

ˇ ˇ




ˇ ˇ

ˇ ˇ

ˇ ˇ ˇ ˇ



Presentation during attack

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Author(s), year of publication

TABLE 1 Details of patients with post-transfusion hypertension and seizure

3 11 10 hours 2 14 2 4 4 1 3 2 2 4 15


7 7 9

1.7 2


9 0 (same day) 15 6 2

6 2 0 (same day)

Interval from last transfusion to attack (days)

Dieda Died Died Died Died Recovereda Recovered Recovered Recovereda Recovereda Recovereda Recovereda Recovereda Dieda

Recovereda Recovered Recovered Died Died

Died Recovered


Recovered Died Died Recovereda Died

Recovered Recovered Recovered




Discussion Our case illustrated the rare syndrome of severe hypertension, convulsion and, in some cases, ICB that occurs in patients with congenital hemolytic anemia who receive blood transfusions. Of 30 patients reported in this review (Table 1), 23 had thalassemia [1, 3, 6–9], 7 had sickle cell anemia [2, 4, 5, 8] and 1 had hereditary spherocytosis [8]. Their age ranged from 3.5 months to 24 years (mean  SD: 11.2  6.2 years). Mortality rate was high, with 15 cases reported to suffer from ICB, which was diagnosed by brain CT, cerebrospinal fluid analysis or during autopsy; of these 15 patients, 12 died and only 3 survived. The remainder 15 patients without ICB survived without complications. The mechanism that causes this syndrome remains unclear. The postulation that patients may have an ICB first that caused the hypertension as a result of Cushing reflex [10] has not been supported by subsequent observations, as half the patients reviewed did not have ICB despite suffering from severe hypertension and seizures. Brain pathology for nine Thai patients who died from this syndrome demonstrated changes of hypertensive cerebral hemorrhage and hypertensive encephalopathy [11]. Thus, it appeared that the episode starts with severe hypertension that led to hypertensive encephalopathy and sometimes ICB. The cause of hypertension in this syndrome is still unknown. Many patients experienced this syndrome only on receiving blood transfusion, and therefore, the relationship to blood transfusion was suggested. As the syndrome may occur hours to up to 15 days from the last transfusion, it is unlikely due to volume overload, and as seen in our case, no deterioration of cardiac function was detected on echocardiogram. A marked increase in hematocrit/hemoglobin compared with the pre-transfusion values appeared to be a risk factor, where the values ranged from 59 to 575% (mean 171%) in this review. This observation may support the theory that the sudden increase in Journal of Tropical Pediatrics

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the hematocrit levels altered the rheologic state of the blood and adversely affects kidney perfusion and hence activation of the renin–angiotensin system [4]. However, studies on the role of vasoconstrictors and the renin–angiotensin system that were conducted among these patients have so far yielded variable results [5, 8, 12]. Host factors such as chronic severe anemia appear to increase the susceptibility to this syndrome, where mean pre-transfusion hematocrit was only 13.9% (first 11 cases) and mean pre-transfusion hemoglobin for the remainder cases was 4.6 g/dl. In addition, many of the thalassemic patients, including our case, had marked splenomegaly [5, 7–9] and severe growth retardation [1] because of chronic severe anemia. The long-standing anemia is known to increase endogenous overproduction of endothelin-1, a potent vasoconstrictor among patients with thalassemia [13] and sickle cell disease [14]. Only 10 patients had brain CT in this series because this imaging modality was probably more accessible in the later years. Two patients had abnormal scans, where one had right frontal subarachnoid hemorrhage [6] and the other had parenchymal, intra-ventricular and subarachnoid hemorrhage [9], and they both died. The remainder eight patients with normal scans survived, thus suggesting the value of imaging in prognosis for these patients. The lack of reports of cerebral white matter edema classically described in imaging of patients with hypertensive encephalopathy [15] could be because the imaging was conducted at an earlier stage of presentation or because of lack of sensitivity in detecting these changes. The small number of patients reported may be owing to the rarity of this condition with improvement in transfusion practices or owing to poor recognition, as illustrated in our case where our patient underwent intense transfusion. In conclusion, patients with chronic severe anemia due to congenital hemolytic anemia who underwent blood transfusions that increase their erythrocyte volume considerably over a short period are at risk from hypertension and seizures, which can progress to fatal ICB. A less-intensive transfusion regimen, early recognition and prompt antihypertensive therapy may prove to be life-saving in these patients. References 1. Wasi P, Na-Nakorn S, Pootrakul P, et al. A syndrome of hypertension, convulsion, and cerebral haemorrhage in thalassaemic patients after multiple bloodtransfusions. Lancet 1978;2:602–4. 2. Royal JE, Seeler RA. Hypertension, convulsions, and cerebral haemorrhage in sickle-cell anaemia patients after blood-transfusions. Lancet 1978;2:1207. 3. Yetgin S, Hicsonmez G. Hypertension, convulsions, and purpuric skin lesions after blood-transfusion. Lancet 1979;1:610. 255

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cortisol levels, connective tissue screen and renal and thyroid function were normal. Her recovery was complicated by vocal cord edema and nosocomial pneumonia. When transfused with packed red blood cells again, she had hypertensive episodes on the first (BP 139/75), third (BP 158/ 76) and fourth day after transfusion (BP 165/61), in which the last episode was associated with generalized seizure. Her hypertension was treated with spironolactone, captopril and nifedipine. She gradually recovered and was discharged with nifedipine and captopril, which were discontinued within 2 weeks. She underwent splenectomy uneventfully 4 months later, and there were no hypertension, seizure or neurological deficits reported in the following 6 years.



11. Wiwanitkit V. Brain pathology in a syndrome of hypertension, convulsion, and cerebral haemorrhage in thalassaemic patients after multiple blood-transfusions: a summary in reported Thai autopsy cases. J Hypertens 2006;24:601. 12. Thirawarapan SS, Snongchart N, Fucharoen S, et al. Study of mechanisms of post-transfusion hypertension in thalassaemic patients. Southeast Asian J Trop Med Public Health 1989;20:471–8. 13. Viprakasit V, Kankirawatana S, Akarasereenont P, et al. Baseline levels of plasma endothelin-1 (ET-1) and changes during transfusion in thalassemic patients. Am J Hematol 2002;70:260–2. 14. Gonzalez EG, Doherty JC, Bergreen EW, et al. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood 1998;92:2551–5. 15. Schwartz RB, Jones KM, Kalina P, et al. Hypertensive encephalopathy: findings on CT, MR imaging, and SPECT imaging in 14 cases. Am J Roentgenol 1992; 159:379–83.

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4. Warth JA. Hypertension and a seizure following transfusion in an adult with sickle cell anemia. Arch Intern Med 1984;144:607–8. 5. Hamdan JM, Mallouh AA, Ahmad MS. Hypertension and convulsions complicating sickle cell anaemia: possible role of transfusion. Ann Trop Paediatr 1984;4: 41–3. 6. Sonakul D, Fucharoen S. Brain pathology in 6 fatal cases of post-transfusion hypertension, convulsion and cerebral hemorrhage syndrome. Southeast Asian J Trop Med Public Health 1992;23(Suppl 2):116–19. 7. Gu¨rgey A, Kalayci O, Gu¨mru¨k F, et al. Convulsion after blood transfusion in four beta-thalassemia intermedia patients. Pediatr Hematol Oncol 1994;11:549–52. 8. Assadi F. Vasoconstrictor-induced hypertension following multiple blood transfusions in children with congenital hemolytic anemia. Iran J Kidney Dis 2008;2: 132–6. 9. Masood SA, Zaidi A. Post-transfusion hypertension, convulsion and intracranial haemorrhage in -thalassemia major. J Coll Physicians Surg Pak 2012;22:473–5. 10. Sinniah D, Ekert H, Bosco J, et al. Intracranial hemorrhage and circulating coagulation inhibitor in beta-thalassemia major. J Pediatr 1981;99:700–3.

Post-transfusion hypertension and seizure in congenital hemolytic anemia: a case report and literature review.

A rare syndrome of hypertension, seizures and intracranial bleed has been reported among patients with congenital hemolytic anemia who underwent multi...
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