Download Iron Deficiency Anemia Related to Hereditary Hemorrhagic

CASE REPORT
Iron Deficiency Anemia Related to Hereditary Hemorrhagic
Telangiectasia: Response to Treatment With Bevacizumab
Jessica M. Fleagle, DO, Ravi K. Bobba, MD, Carl G. Kardinal, MD
and Carl E. Freter, MD, PhD
H
organ systems such as the liver, lungs and brain. When on the
skin, telangiectasias are generally more common on the face,
chest and hands appearing bright red to purple and blanch
with pressure. Mucosal telangiectasias exhibit similar characteristics. In the gastrointestinal tract, AVMs and telangiectasias can be difficult to see during endoscopy as the
location may be distal to an esophagogastroduodenoscopy
(EGD) or cephalad to a colonoscope. They also may be
missed with capsule endoscopy.
Bevacizumab was the first antiangiogenic agent approved for the treatment of nonsmall cell lung cancer, breast
cancer and colorectal cancer.11 Bevacizumab has also been
effective in treating retinal disorders, often used as repeated
injections to control neovascularity.12,13 Furthermore, multiple
treatments with bevacizumab by intranasal submucosal injection (100 mg) are effective in treating epistaxis in HHT patients; this has been shown to result in less emergency room
visits, blood transfusions, iron infusions and potassium titanyl
phosphate laser treatments.14 Although a previous case report
described the use of bevacizumab in the primary treatment of
mesothelioma and occult gastrointestinal bleeding secondary to
HHT,15 the use of bevacizumab as a primary treatment for
gastrointestinal bleeding alone in patients with HHT has not
been reported. Herein, we describe our experience in the
treatment of this rare disorder with iron deficiency anemia.
From the Division of Hematology and Medical Oncology, Department
of Internal Medicine, Ellis Fischel Cancer Center, University of Missouri
School of Medicine, Columbia, Missouri.
Submitted May 23, 2011; accepted in revised form November 17, 2011.
Correspondence: Carl G. Kardinal, MD, Hematology and Medical
Oncology, Ellis Fischel Cancer Center, University of Missouri-Columbia,
115 Business Loop 70 West, DC 116.71, Columbia, MO 65203 (E-mail:
[email protected]).
A 52-year-old woman presented to the University of
Missouri Medical Center with HHT after failed responses to
iron sucrose infusions every 2 months, frequent blood transfusions and hospitalizations for gastrointestinal bleeding and
occasional hospitalizations for epistaxis. She failed cautery on
multiple endoscopy procedures for at least 2 prominent gastric
body vascular ectasias and 5 small vascular ectasias in the
second/third portion of the duodenum. In the past, she also had
a resection for a large pulmonary AVM. After presenting to our
center, she was hospitalized for epistaxis once, gastrointestinal
bleeding and epistaxis once and 2 separate hospitalizations for
acute gastrointestinal bleeding alone. Two were life-threatening
episodes of hemorrhage. She had also presented with bacteremia secondary to a port infection. The port had been placed for
frequent transfusions and iron infusions. Her nadir for hemoglobin in our center was 6.4 g/dL (Figure 1). Despite the
maximal treatment of her disease with iron infusions, she
required repeated blood transfusions and cauterization of the
ectasias, was doing very poorly and remained at risk for fatal
hemorrhage or complications from her treatments (ie, the bacteremia secondary to the vascular access port).
The patient was treated with bevacizumab at a dose of 5
mg/kg infusion every 2 weeks and was given 4 cycles.15 Before
the initiation of bevacizumab, her iron studies revealed low
serum iron of 22 ␮g/dL and low ferritin of 6.9 ng/mL. She was
also started on supplemental oral ferrous sulfate. Within 1
Abstract: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant condition associated with arteriovenous malformations (AVMs) or telangiectasias of the pulmonary, gastrointestinal or
hepatic circulations. The authors present a case of a 52-year-old woman
with a known diagnosis of HHT who presented for evaluation of
anemia. She had an extensive history of iron sucrose infusions, frequent
blood transfusions and hospitalizations for anemia related to gastrointestinal bleeding and epistaxis. The patient was treated with bevacizumab at a dose of 5 mg/kg infusion every 2 weeks for 4 cycles. In the
next 4 months, her hemoglobin improved to 13.7g/dL and she did not
require iron or packed red blood cell transfusions for the next 8 months.
Abnormal angiogenesis primarily due to mutations in the transforming
growth factor ␤ receptor endoglin and the activin receptor-like kinases
is a central contributor to the formation of AVMs in HHT. Bevacizumab is a monoclonal antibody against vascular endothelial growth
factor and therefore may be a useful treatment against AVM formation
in patients with HHT. The authors do caution that therapy has to be
individualized as there are no randomized trials regarding its usage in
patients with HHT.
Key Indexing Terms: Iron deficiency anemia; Hereditary hemorrhagic
telangiectasia; Bevacizumab. [Am J Med Sci 2012;343(3):249–251.]
ereditary hemorrhagic telangiectasia (HHT), also known
as Osler-Weber-Rendu disease, is a rare, autosomal dominant condition occurring in 1 in 5000 to 8000 people.1– 4. The
major presenting complaint in 90% of patients with HHT is
epistaxis which when coupled with the varying degrees of
penetrance of HHT may lead to misdiagnosis.3–5 The majority
of patients actually are not aware that they have the disease.
Other presenting symptoms include massive hemoptysis and
epistaxis, anemia and iron deficiency, massive gastrointestinal
bleeding or hemorrhagic stroke.6 HHT may also be associated
with other diseases such as juvenile polyposis syndrome and
primary pulmonary hypertension.7 Available evidence demonstrates that patients with HHT exhibit arteriovenous malformations (AVMs) or telangiectasias of the pulmonary (15%–30%),
gastrointestinal (⬃30%) or hepatic (⬃30%) circulations although no study has determined the prevalence of AVMs in
multiple vasculatures of patients with HHT.8,9 The Curacao
criteria for diagnosing HHT were developed in 1999.10 A
helpful review of current screening recommendations has recently been published.6
Telangiectasias and AVMs occur on mucocutaneous
surfaces (ie, nose, gastrointestinal tract and skin) or in large
CASE REPORTS
The American Journal of the Medical Sciences • Volume 343, Number 3, March 2012
249
Fleagle et al
FIGURE 1. Hemoglobin graph showing the initiation of bevacizumab and the trend in the hemoglobin.
month of the infusions, her hemoglobin reached 11 g/dL, the
highest on record including outside hospital records even with
no transfusion. She was hospitalized for methicillin-resistant
staphylococcal aureus sepsis and was treated with vancomycin.
Her hemoglobin trended down during that time to 9.4 g/dL but
did not require any transfusions. In the next 8 months, she had
not presented to an emergency room or was hospitalized for
bleeding and did not require iron infusions or transfusions. The
hemoglobin was 13.7 g/dL at 4 months and 11.7 g/dL at 8
months from the initiation of the bevacizumab infusions. Repeat esophagogastroduodenoscopy was considered but withheld due to clinical improvement.
DISCUSSION
Abnormal angiogenesis primarily due to mutations in the
transforming growth factor ␤ (TGF-␤) receptors endoglin and
the activin receptor-like kinases (ALKs) is a central contributor
to the formation of AVMs in HHT.3,4,16 TGF-␤ is an upstream
regulator of the well-described angiogenic mediator vascular
endothelial growth factor (VEGF), and circulating concentrations of both TGF-␤ and VEGF are significantly elevated in
patients with HHT.17,18 The degree of VEGF elevation correlates with the severity of bleeding from any site.19 Bevacizumab is a monoclonal antibody against VEGF and therefore
may be a useful treatment against AVM formation in patients
with HHT.3,4 The differential stimulation of ALK-1 and ALK-5
is thought to regulate different phases of angiogenesis, activating the angiogenic process, subsequently increasing the production of VEGF. VEGF stimulates the proliferation of vascular endothelial cells and increases vascular permeability and
thus is a central mediator in early angiogenesis.18 As the initial
phase is characterized by VEGF-dependent formation and the
sprouting of vessels consisting of endothelial cells, the microenvironmental concentrations of VEGF seem to determine
the normal or aberrant angiogenesis induction.20
250
From a trial done with HHT and epistaxis in local
injections of bevacizumab, a case report of bevacizumab reversing need of transplantation in HHT and a case report of
reduced gastrointestinal bleeding with the treatment of mesothelioma in a patient with HHT, it was shown that patients who
received bevacizumab had a significant reduction in bleeding.14,15,21 The current patient was treated with bevacizumab at
a dose of 5 mg/kg infusion every 2 weeks, similar to a previous
report.15 Within 1 month of the infusions, her hemoglobin
reached 11 g/dL, the highest on record including outside
hospital records even without transfusion. In the next 6 months,
she did not present to an emergency room or require hospitalization for bleeding and did not require iron infusions or
transfusions other than for sepsis. In a reported case with
bevacizumab infusion and local injection in the nose, there was
no change in the visualization of the AVMs.14,22 Flieger et al15
had used bevacizumab in a patient with recurrent bleeding from
HHT and progression in a patient with mesothelioma. For
patients with epistaxis, submucosal nasal injections with bevacizumab resulted in an effect lasting 7.3 months on the
average.14 In addition to saving recurrent life-threatening hemorrhage in this patient, bevacizumab has improved some additional parameters: lifestyle, hospital costs and decreased exposure to health care-associated pathogens and potential
complications related to procedures such as conscious sedation
and repeated cauterizations and blood products.23
As with all treatments, there are side effects and complications. There have been some common side effects noted in
association with bevacizumab treatment in the oncology literature including hypertension, proteinuria, hypophosphatemia,
thrombocytopenia, gastrointestinal perforation, cardiac dysfunction, bleeding and thrombosis; all of which tend to be
mild to moderate and manageable.11 When used for patients
older than 65 years with renal cell cancer, the risk of arterial
thrombotic events increased from 2% to 18%.11 Our patient
Volume 343, Number 3, March 2012
Treatment of Iron-Deficient Anemia With Bevacizumab
has had worsening hypertension requiring more frequent
monitoring of her blood pressure and titration of her antihypertensive medications.
In conclusion, bevacizumab may be a useful alternative
in patients with HHT with uncontrolled gastrointestinal bleeding, but this should be individualized as there are no randomized trials regarding its usage in patients with HHT.
11. Boehm S, Rothermundt C, Hess D, et al. Antiangiogenic drugs in
oncology: a focus on drug safety and the elderly—a mini-review.
Gerontology 2010;56:303–9.
REFERENCES
1. Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet 1992;29:527–30.
14. Simonds J, Miller F, Mandel J, et al. The effect of bevacizumab
(Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope 2009;119:988 –92.
2. Westermann CJ, Rosina AF, De Vries V, et al. The prevalence and
manifestations of hereditary hemorrhagic telangiectasia in the AfroCaribbean population of the Netherlands Antilles: a family screening.
Am J Med Genet A 2003;116A:324 – 8.
15. Flieger D, Hainke S, Fischbach W. Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab. Ann Hematol
2006;85:631–2.
3. Johnson DW, Berg JN, Gallione CJ, et al. A second locus for
hereditary hemorrhagic telangiectasia maps to chromosome 12. Genome Res 1995;5:21– 8.
16. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet
2006;43:97–110.
4. McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGFbeta binding protein of endothelial cells, is the gene for hereditary
haemorrhagic telangiectasia type 1. Nat Genet 1994;8:345–51.
17. Sadick H, Riedel F, Naim R, et al. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high
ALK1 tissue expression. Haematologica 2005;90:818 –28.
5. Romer W, Burk M, Schneider W. [Hereditary hemorrhagic telangiectasia (Osler’s disease)]. Dtsch Med Wochenschr 1992;117:669 –75.
6. Olitsky SE. Hereditary hemorrhagic telangiectasia: diagnosis and management. Am Fam Physician 2010;82:785–90.
7. Trembath RC, Thomson JR, Machado RD, et al. Clinical and
molecular genetic features of pulmonary hypertension in patients with
hereditary hemorrhagic telangiectasia. N Engl J Med 2001;345:325–34.
8. Begbie ME, Wallace GM, Shovlin CL. Hereditary haemorrhagic
telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st
century. Postgrad Med J 2003;79:18 –24.
9. Kjeldsen AD, Oxhøj H, Andersen PE, et al. Pulmonary arteriovenous
malformations: screening procedures and pulmonary angiography in
patients with hereditary hemorrhagic telangiectasia. Chest 1999;116:
432–9.
10. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria
for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000;91:66 –7.
© 2012 Lippincott Williams & Wilkins
12. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab
for treatment of neovascular age-related macular degeneration: a oneyear prospective study. Am J Ophthalmol 2008;145:249 –56.
13. Lynch SS, Cheng CM. Bevacizumab for neovascular ocular diseases.
Ann Pharmacother 2007;41:614 –25.
18. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its
receptors. Nat Med 2003;9:669 –76.
19. Cirulli A, Liso A, D’Ovidio F, et al. Vascular endothelial growth
factor serum levels are elevated in patients with hereditary hemorrhagic
telangiectasia. Acta Haematol 2003;110:29 –32.
20. Ozawa CR, Banfi A, Glazer NL, et al. Microenvironmental VEGF
concentration, not total dose, determines a threshold between normal
and aberrant angiogenesis. J Clin Invest 2004;113:516 –27.
21. Mitchell A, Adams LA, MacQuillan G, et al. Bevacizumab reverses
need for liver transplantation in hereditary hemorrhagic telangiectasia.
Liver Transpl 2008;14:210 –3.
22. Bose P, Holter JL, Selby GB. Bevacizumab in hereditary hemorrhagic
telangiectasia. N Engl J Med 2009;360:2143– 4.
23. Fleagle JM, Bobba RK, Khozouz RF, et al. Iron deficiency anemia
related to hereditary hemorrhagic telangiectasia: response to treatment
with bevacizumab. J Clin Oncol 2011;29(suppl):abstract e13521.
251