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A horse-riding accident and haemolytic anaemia
Case Report
A horse-riding accident and haemolytic anaemia Lancet 2004; 364: 1728 Texas Tech University Health Sciences Center, Department of Pharmacology and Neuroscience (C C Bittle Jr MD), Lubbock, TX, USA
Charles C Bittle Jr
In July, 2001, a 39-year-old woman was thrown from and stamped on by a horse. She had multiple fractures of her ribs, pelvis, and left humerus, and a deep laceration of her left elbow. Diagnostic imaging including an MRI of her head with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) was done. A declining haemoglobin (Hb) was attributed to blood loss from her fractured pelvis. She was transfused with 1–2 units 310–620 mL of packed cells per week. 4 months after injury a second MRI with Gd-DTPA was done to assess the pelvic fracture for soft-tissue sequestration of blood. This was followed by immediate exacerbation of her anaemia requiring transfusion of 4–8 units of packed cells a week to maintain an Hb of 70–90 g/L. A Coomb’s test and a bone-marrow biopsy specimen were negative. She was given erythropoietin, steroids, and her fiftieth unit of packed red cells. Her prognosis was considered to depend on continued availability of compatible packed red cells. 5 months after her accident, a 24 h heavy-metal screen to rule out lead intoxication was positive for arsenic from two independent laboratories 118 g and 128 g in 24 h urine (normal range 0–62 g). She was referred to a local physician for intravenous sodium magnesium edetic acid (IV-NaMgEDTA+) treatment for arsenic chelation. Tests of her hair, nails, and well-water from her home were all negative for arsenic. On examination, she was obviously Control E+8 RBC 290 osm Gd CI3–75 mg/mL 1117 osm
1·10
Gd CI3–50 mg/mL 771 osm Gd CI3–40 mg/mL 672 osm
1·00
Gd CI3–37·5 mg/mL 593 osm Gd–DTPA 235 mg 948 osm
0·90
Optical density 700 nm
0·80 0·70 0·60 0·50 0·40 0·30 0·20 0·10 0 0
3000
6000
9000 Time in seconds
12 000
15 000
18 000
anaemic. She was tender over the sites of her fractures, which were not internally fixed and she had serous drainage from her elbow laceration. Her spleen was palpable 2–3 cm below the costal margin without hepatomegaly or abdominal tenderness. There was no history of anaemia, thalassaemia, sickle-cell disease, or glucose-6-phosphate dehydrogenase deficiency. A provoked 24 h urine heavy-metal screen with intravenous NaMgEDTA+ (1 g Na2EDTA, 500 mg MgCl2, 8 g vitamin C, 5 mL 8% NaHCO3, in 250 mL of water) infused over 90 min, induced release of 202 g Gd3+, 404 times the normal threshold of 0·5 g with an accompanying provoked release of zinc and manganese. Normal amounts of arsenic and low concentrations of lead, cadmium, nickel and bismuth were released. She was given twice-weekly intravenous MgEDTA+ (3 g Na2EDTA, 1 g MgCl2, 8 g vitamin C, and 10 mL of 8% NaHCO3 in 500 mL water) infused over 3 h to remove extracellular Gd3+. After 5 weeks the wound on her left elbow healed and her Hb stabilised at 90 g/L. Her gait improved with reunion of the pelvic fracture and resolution of posttraumatic osteitis. At 20 weeks, her Hb increased to 120 g/L with no need for further packed-cell transfusions. 18 months after her injury a third MRI with Gd-DTPA was done at another facility without recurrence of anaemia. She is currently well after convalescing from an elective total hysterectomy in July, 2004. Arsenic released from stored deposits in inflamed bone can be transiently detected on unprovoked heavy metal screen. Dissociated Gd3+ ions released from metal-ligand complexes like Gd-DTPA can precipitate as salts in serum to be sequestered in macrophages damaging the Kupffer cells or can be deposited in tissues by transmetallation.1,2 The mechanism behind induction and sustained decrease in erythrocyte survival in this anaemia and the rapid dissociation of Gd-DTPA may be linked to osteitis. This speculation is based on the absence of a recurrence of anaemia after this patient was re-exposed to Gd-DTPA in the absence of osteitis and by a report of retention of Gd in bone.3 Recent finding from our laboratory of the effect of ionic Gd and complexed Gd on the rate of lysis (by change in turbidity) of serum-free rabbit erythrocytes by continuous cytolytic assay is shown in the figure. References 1 Spencer A, Wilson S, Harpur E. Gadolinium chloride toxicity in the mouse. Hum Exp Toxicol 1998 Nov; 17: 633–37. 2 Puttagunta NR, Gibby WA, Smith GT. Human in vivo comparative study of zinc and copper transmetallation after administration of magnetic resonance imaging contrast agents. Invest Radiol 1996; 31: 739–42. 3 Gibby WA, Gibby KA, Gibby WA. Comparison of Gd-DTPA-BMA (Omniscan) verse Gd HP-DO3A (ProHance) retention in human body by Inductively Coupled Plasma Atomic Emission Spectroscopy. Invest Radiol 2004; 39: 138–42.
Figure: Rate of erythrocyte lysis with Gd CI3 and Gd-DTPA
1728
www.thelancet.com Vol 364 November 6, 2004
A horse-riding accident and haemolytic anaemia Lancet 2004; 364: 1728 Texas Tech University Health Sciences Center, Department of Pharmacology and Neuroscience (C C Bittle Jr MD), Lubbock, TX, USA
Charles C Bittle Jr
In July, 2001, a 39-year-old woman was thrown from and stamped on by a horse. She had multiple fractures of her ribs, pelvis, and left humerus, and a deep laceration of her left elbow. Diagnostic imaging including an MRI of her head with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) was done. A declining haemoglobin (Hb) was attributed to blood loss from her fractured pelvis. She was transfused with 1–2 units 310–620 mL of packed cells per week. 4 months after injury a second MRI with Gd-DTPA was done to assess the pelvic fracture for soft-tissue sequestration of blood. This was followed by immediate exacerbation of her anaemia requiring transfusion of 4–8 units of packed cells a week to maintain an Hb of 70–90 g/L. A Coomb’s test and a bone-marrow biopsy specimen were negative. She was given erythropoietin, steroids, and her fiftieth unit of packed red cells. Her prognosis was considered to depend on continued availability of compatible packed red cells. 5 months after her accident, a 24 h heavy-metal screen to rule out lead intoxication was positive for arsenic from two independent laboratories 118 g and 128 g in 24 h urine (normal range 0–62 g). She was referred to a local physician for intravenous sodium magnesium edetic acid (IV-NaMgEDTA+) treatment for arsenic chelation. Tests of her hair, nails, and well-water from her home were all negative for arsenic. On examination, she was obviously Control E+8 RBC 290 osm Gd CI3–75 mg/mL 1117 osm
1·10
Gd CI3–50 mg/mL 771 osm Gd CI3–40 mg/mL 672 osm
1·00
Gd CI3–37·5 mg/mL 593 osm Gd–DTPA 235 mg 948 osm
0·90
Optical density 700 nm
0·80 0·70 0·60 0·50 0·40 0·30 0·20 0·10 0 0
3000
6000
9000 Time in seconds
12 000
15 000
18 000
anaemic. She was tender over the sites of her fractures, which were not internally fixed and she had serous drainage from her elbow laceration. Her spleen was palpable 2–3 cm below the costal margin without hepatomegaly or abdominal tenderness. There was no history of anaemia, thalassaemia, sickle-cell disease, or glucose-6-phosphate dehydrogenase deficiency. A provoked 24 h urine heavy-metal screen with intravenous NaMgEDTA+ (1 g Na2EDTA, 500 mg MgCl2, 8 g vitamin C, 5 mL 8% NaHCO3, in 250 mL of water) infused over 90 min, induced release of 202 g Gd3+, 404 times the normal threshold of 0·5 g with an accompanying provoked release of zinc and manganese. Normal amounts of arsenic and low concentrations of lead, cadmium, nickel and bismuth were released. She was given twice-weekly intravenous MgEDTA+ (3 g Na2EDTA, 1 g MgCl2, 8 g vitamin C, and 10 mL of 8% NaHCO3 in 500 mL water) infused over 3 h to remove extracellular Gd3+. After 5 weeks the wound on her left elbow healed and her Hb stabilised at 90 g/L. Her gait improved with reunion of the pelvic fracture and resolution of posttraumatic osteitis. At 20 weeks, her Hb increased to 120 g/L with no need for further packed-cell transfusions. 18 months after her injury a third MRI with Gd-DTPA was done at another facility without recurrence of anaemia. She is currently well after convalescing from an elective total hysterectomy in July, 2004. Arsenic released from stored deposits in inflamed bone can be transiently detected on unprovoked heavy metal screen. Dissociated Gd3+ ions released from metal-ligand complexes like Gd-DTPA can precipitate as salts in serum to be sequestered in macrophages damaging the Kupffer cells or can be deposited in tissues by transmetallation.1,2 The mechanism behind induction and sustained decrease in erythrocyte survival in this anaemia and the rapid dissociation of Gd-DTPA may be linked to osteitis. This speculation is based on the absence of a recurrence of anaemia after this patient was re-exposed to Gd-DTPA in the absence of osteitis and by a report of retention of Gd in bone.3 Recent finding from our laboratory of the effect of ionic Gd and complexed Gd on the rate of lysis (by change in turbidity) of serum-free rabbit erythrocytes by continuous cytolytic assay is shown in the figure. References 1 Spencer A, Wilson S, Harpur E. Gadolinium chloride toxicity in the mouse. Hum Exp Toxicol 1998 Nov; 17: 633–37. 2 Puttagunta NR, Gibby WA, Smith GT. Human in vivo comparative study of zinc and copper transmetallation after administration of magnetic resonance imaging contrast agents. Invest Radiol 1996; 31: 739–42. 3 Gibby WA, Gibby KA, Gibby WA. Comparison of Gd-DTPA-BMA (Omniscan) verse Gd HP-DO3A (ProHance) retention in human body by Inductively Coupled Plasma Atomic Emission Spectroscopy. Invest Radiol 2004; 39: 138–42.
Figure: Rate of erythrocyte lysis with Gd CI3 and Gd-DTPA
1728
www.thelancet.com Vol 364 November 6, 2004