http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(1): 69–70 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2013.868801
LETTER TO THE EDITOR
Ovarian hyperstimulation syndrome in systemic amyloidosis Andrea Piccin1, Norberto Vezzali2, Norbert Pescosta1, Michael Steurer3, Giovanni Palladini4,5, and Atto Billio1 1
Haematology Department, San Maurizio Regional Hospital, Bolzano, South Tyrol, Italy, 2Radiology Department, San Maurizio Regional Hospital, Bolzano, South Tyrol, Italy, 3Division of Hematology & Oncology, Innsbruck Medical University, Innsbruck, Austria, 4Amyloidosis Research and Treatment Center, Foundation ‘‘Istituto di Ricovero e Cura a Carattere Scientifico’’ (IRCCS) Policlinico San Matteo, and 5Department of Molecular Medicine, University of Pavia, Pavia, Italy Abstract
Keywords
We report on the case of a young woman with a diagnosis of amyloidosis who developed severe portal and splenic venous thrombosis shortly after hormonal follicle stimulation therapy for oocyte preservation. The clinical implications are discussed.
Hormone therapy, portal vein thrombosis, systemic amyloidosis History Received 4 October 2013 Revised 20 November 2013 Accepted 20 November 2013 Published online 16 January 2014
Address for correspondence: Andrea Piccin, MD, PhD, Haematology Department and Bone Marrow Transplant Unit, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy. Tel: +39 347 2736692. Fax: +39 0471 908703. E-mail: [email protected]
1.6–7.0), platelets 591.000 109/l. Bone marrow aspirate showed 6% plasma cells. FISH analysis identified del 13q14 and t (11;14). Bone marrow biopsy showed an infiltrate of 20% of plasma cells. Serum immunofixation showed monoclonal chains. Free light chains study showed 5.49 mg/L, 1892 mg/L, / ratio ¼ 0.003. Monoclonal free light chains were detectable in serum and in the urine at immunofixation. Abdominal fat test showed green birefringence in polarized light after staining with Congo red. A diagnosis of AL amyloidosis with cardiac and liver involvement was made. After communicating the diagnosis to the patient, the possibility of oocyte cryo-preservation, prior to chemotherapy or stem cell transplantation (SCT) was discussed with her. The patient decided to undergo oocyte cryopreservation as soon as possible. She was therefore treated (May 2013) with a course of 300 UI of follitropine-a and cetrotide 0.25 mg/day. She also received prophylaxys with low-molecular weight heparin 2000UI/die and euthyroxine 25 mg. On dayþ 4 post oocyte hormonal stimulation, she developed bilateral lung oedema and ascites. Due to progressive cardiac failure, on day þ 10 (30 May 2013) she underwent the first course of chemotherapy with bortezomib 1.3 mg/m2 sub cutis and cyclophosphamide 300 mg/m2 i.v. On day 1, 8, 15, 22 another 3 similar courses were planned before cardiac restaging. On day þ21post-hormonal stimulation, the patient developed severe hepatomegaly with ascites and constipation. An abdominal ultrasound revealed a massive venous portal thrombosis involving also the splenic and mesenteric branches. Furthermore, large abdominal ascites was seen in her pelvis. The patient developed cardiac failure with pro BNP 5981 pg/ml, BP 65/40 mmHg, heart rate 110 p/m and
20 14
Systemic immunoglobulin light-chain amyloidosis (AL) is characterized by the presence of clonal non-proliferative plasma cells that produce a monoclonal light chain protein that misfolds, causing the formation of b-pleated sheets which are insoluble and which deposit into parenchymal organs, causing over time severe organ failure. AL amyloidosis has already been associated with multiple arterial and venous thrombosis [1,2]. We report on the case of a young woman with a diagnosis of AL amyloidosis, who developed severe portal and splenic venous thrombosis shortly after hormonal follicle stimulation therapy for oocyte preservation. The clinical implications are discussed. A 31-year-old female first came to our attention in May 2013 during diagnostic screening for multiple myeloma. On this occasion cardiac amyloidosis (stage III) and liver amyloidosis were detected. Family history was unremarkable. The patient’s past medical history revealed that she had been diagnosed as suffering from Hashimoto thyroiditis one month previously. The diagnosis of AL was made following a hospital admission in April 2013 due to incipient dyspnoea. On this occasion N-terminal prohormone of brain natriuretic peptide (NT pro BNP) was 2365 pg/ml, troponine T (TnT) 98 ng/l. However, echocardiogram was unremarkable and did not show any wall ventricle thickening, and EF was 56%. Blood tests revealed: Hb 13.5 g/dl, Hct 40.7%, WBC 9.600 109/l (n.v 4.0–10.0), neutrophils 5.900 109/l (n.v
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room air oxygen saturation (SPO2) 89% and was therefore transferred to a specialist cardiac transplantation center, where she died a few days later before receiving any further chemotherapy treatment. Patients with AL have a high risk of developing thrombosis, particularly intra-cardiac thrombosis. This risk is further increased when a chemotherapy regimen with melphalan or bortezomib is used. Therapeutic prophylactic anticoagulation has been proven to reduce this risk [3]. The case presented here also highlights the potential risk associated with follicle hormonal stimulation in patients with AL. We believe that our patient developed an ovarian hyperstimulation syndrome (OHSS) despite already being on prophylactic anticoagulation with low-molecular weight heparin. The OHSS syndrome has been recently classified by the Royal College of Obstetricians & Gynaecologists [4]. According to this classification our patient developed severe OHSS as she had clinical ascites. OHSS is a severe complication of controlled ovarian hyperstimulation. This syndrome has been associated with increased permeability of blood vessels in response to excessive vasoactive substances of ovarian origin, vasoconstrictive effects of some other agents of ovarian origin, hemoconcentration and hypovolemia with resulting arterial hypotension, gonadotropin administration, supraphysiological concentrations of 17b-estradiol following ovulation induction, and inherited thrombophilias [5]. Arterial events are predominantly cerebrovascular accidents, usually occurring concurrently with the onset of OHSS. Venous thrombosis occurs several weeks later [6]. Previous reports on AL and OHHS are lacking. A report by Ricci G et al. showed that some natural occurring anticoagulants, such as antithrombin (AT), Protein S (PS) and tissue plasminogen activator (t-PA) were decreased after such hormone stimulation and returned to pre hormone stimulation value within 4 weeks time [7]. Unfortunately, we do not have any measurements of anticoagulants in our patient, however it is intriguing that the thrombosis developed exactly within 4 weeks of hormone stimulation. In conclusion, we describe the
Amyloid, 2014; 21(1): 69–70
first reported case of AL and OHHS after follicle stimulation for oocyte preservation. We also show that although the patient was already on anticoagulation before any ovary stimulation, this syndrome was extremely severe and the patient developed a massive portal vein thrombosis and died shortly afterwards. This case highlights the high risk of developing OHHS in AL, possibly because a prothrombotic state is already present. Considering that the current prognosis for AL patients is poor, we believe that oocyte preservation in AL patients should not be recommended.
Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
References 1. Freeman B, Sloan JM, Seldin DC, Cowan AJ, Ruberg FL, Sanchorawala V. Multiple arterial and venous thromboembolic complications in AL amyloidosis and cardiac involvement: a case report and literature review. Amyloid 2012;19:156–60. 2. Nakagawa M, Tojo K, Sekijima Y, Yamazaki KH, Ikeda S. Arterial thromboembolism in senile systemic amyloidosis: report of two cases. Amyloid 2012;19:118–21. 3. Feng D, Syed IS, Martinez M, Oh JK, Jaffe AS, Grogan M, Edwards WD, et al. Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis. Circulation 2009;119:2490–7. 4. Jenkins JM, Drakeley AJ, Mathur RS. The management of ovarian hyperstimulation syndrome. United Kingdom Guidelines of the Royal College of Obstetricians and Gyaneacologists. Green-top Guideline 2006;5:1–11. 5. Jo´z´wik M. The mechanism of thromboembolism in the course of ovarian hyperstimulation syndrome. Med Wieku Rozwoj 2012;16: 269–71. 6. Alper MM, Smith LP, Sills ES. Ovarian hyperstimulation syndrome: current views on pathophysiology, risk factors, prevention, and management. J Exp Clin Assist Reprod 2009;6:3. 7. Ricci G, Cerneca F, Simeone R, Pozzobon C, Guarnieri S, Sartore A, Pregazzi R, et al. Impact of highly purified urinary FSH and recombinant FSH on haemostasis: an open-label, randomized, controlled trial. Hum Reprod 2004;19:838–48.
Copyright of Amyloid is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
LETTER TO THE EDITOR
Ovarian hyperstimulation syndrome in systemic amyloidosis Andrea Piccin1, Norberto Vezzali2, Norbert Pescosta1, Michael Steurer3, Giovanni Palladini4,5, and Atto Billio1 1
Haematology Department, San Maurizio Regional Hospital, Bolzano, South Tyrol, Italy, 2Radiology Department, San Maurizio Regional Hospital, Bolzano, South Tyrol, Italy, 3Division of Hematology & Oncology, Innsbruck Medical University, Innsbruck, Austria, 4Amyloidosis Research and Treatment Center, Foundation ‘‘Istituto di Ricovero e Cura a Carattere Scientifico’’ (IRCCS) Policlinico San Matteo, and 5Department of Molecular Medicine, University of Pavia, Pavia, Italy Abstract
Keywords
We report on the case of a young woman with a diagnosis of amyloidosis who developed severe portal and splenic venous thrombosis shortly after hormonal follicle stimulation therapy for oocyte preservation. The clinical implications are discussed.
Hormone therapy, portal vein thrombosis, systemic amyloidosis History Received 4 October 2013 Revised 20 November 2013 Accepted 20 November 2013 Published online 16 January 2014
Address for correspondence: Andrea Piccin, MD, PhD, Haematology Department and Bone Marrow Transplant Unit, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy. Tel: +39 347 2736692. Fax: +39 0471 908703. E-mail: [email protected]
1.6–7.0), platelets 591.000 109/l. Bone marrow aspirate showed 6% plasma cells. FISH analysis identified del 13q14 and t (11;14). Bone marrow biopsy showed an infiltrate of 20% of plasma cells. Serum immunofixation showed monoclonal chains. Free light chains study showed 5.49 mg/L, 1892 mg/L, / ratio ¼ 0.003. Monoclonal free light chains were detectable in serum and in the urine at immunofixation. Abdominal fat test showed green birefringence in polarized light after staining with Congo red. A diagnosis of AL amyloidosis with cardiac and liver involvement was made. After communicating the diagnosis to the patient, the possibility of oocyte cryo-preservation, prior to chemotherapy or stem cell transplantation (SCT) was discussed with her. The patient decided to undergo oocyte cryopreservation as soon as possible. She was therefore treated (May 2013) with a course of 300 UI of follitropine-a and cetrotide 0.25 mg/day. She also received prophylaxys with low-molecular weight heparin 2000UI/die and euthyroxine 25 mg. On dayþ 4 post oocyte hormonal stimulation, she developed bilateral lung oedema and ascites. Due to progressive cardiac failure, on day þ 10 (30 May 2013) she underwent the first course of chemotherapy with bortezomib 1.3 mg/m2 sub cutis and cyclophosphamide 300 mg/m2 i.v. On day 1, 8, 15, 22 another 3 similar courses were planned before cardiac restaging. On day þ21post-hormonal stimulation, the patient developed severe hepatomegaly with ascites and constipation. An abdominal ultrasound revealed a massive venous portal thrombosis involving also the splenic and mesenteric branches. Furthermore, large abdominal ascites was seen in her pelvis. The patient developed cardiac failure with pro BNP 5981 pg/ml, BP 65/40 mmHg, heart rate 110 p/m and
20 14
Systemic immunoglobulin light-chain amyloidosis (AL) is characterized by the presence of clonal non-proliferative plasma cells that produce a monoclonal light chain protein that misfolds, causing the formation of b-pleated sheets which are insoluble and which deposit into parenchymal organs, causing over time severe organ failure. AL amyloidosis has already been associated with multiple arterial and venous thrombosis [1,2]. We report on the case of a young woman with a diagnosis of AL amyloidosis, who developed severe portal and splenic venous thrombosis shortly after hormonal follicle stimulation therapy for oocyte preservation. The clinical implications are discussed. A 31-year-old female first came to our attention in May 2013 during diagnostic screening for multiple myeloma. On this occasion cardiac amyloidosis (stage III) and liver amyloidosis were detected. Family history was unremarkable. The patient’s past medical history revealed that she had been diagnosed as suffering from Hashimoto thyroiditis one month previously. The diagnosis of AL was made following a hospital admission in April 2013 due to incipient dyspnoea. On this occasion N-terminal prohormone of brain natriuretic peptide (NT pro BNP) was 2365 pg/ml, troponine T (TnT) 98 ng/l. However, echocardiogram was unremarkable and did not show any wall ventricle thickening, and EF was 56%. Blood tests revealed: Hb 13.5 g/dl, Hct 40.7%, WBC 9.600 109/l (n.v 4.0–10.0), neutrophils 5.900 109/l (n.v
70
A. Piccin et al.
room air oxygen saturation (SPO2) 89% and was therefore transferred to a specialist cardiac transplantation center, where she died a few days later before receiving any further chemotherapy treatment. Patients with AL have a high risk of developing thrombosis, particularly intra-cardiac thrombosis. This risk is further increased when a chemotherapy regimen with melphalan or bortezomib is used. Therapeutic prophylactic anticoagulation has been proven to reduce this risk [3]. The case presented here also highlights the potential risk associated with follicle hormonal stimulation in patients with AL. We believe that our patient developed an ovarian hyperstimulation syndrome (OHSS) despite already being on prophylactic anticoagulation with low-molecular weight heparin. The OHSS syndrome has been recently classified by the Royal College of Obstetricians & Gynaecologists [4]. According to this classification our patient developed severe OHSS as she had clinical ascites. OHSS is a severe complication of controlled ovarian hyperstimulation. This syndrome has been associated with increased permeability of blood vessels in response to excessive vasoactive substances of ovarian origin, vasoconstrictive effects of some other agents of ovarian origin, hemoconcentration and hypovolemia with resulting arterial hypotension, gonadotropin administration, supraphysiological concentrations of 17b-estradiol following ovulation induction, and inherited thrombophilias [5]. Arterial events are predominantly cerebrovascular accidents, usually occurring concurrently with the onset of OHSS. Venous thrombosis occurs several weeks later [6]. Previous reports on AL and OHHS are lacking. A report by Ricci G et al. showed that some natural occurring anticoagulants, such as antithrombin (AT), Protein S (PS) and tissue plasminogen activator (t-PA) were decreased after such hormone stimulation and returned to pre hormone stimulation value within 4 weeks time [7]. Unfortunately, we do not have any measurements of anticoagulants in our patient, however it is intriguing that the thrombosis developed exactly within 4 weeks of hormone stimulation. In conclusion, we describe the
Amyloid, 2014; 21(1): 69–70
first reported case of AL and OHHS after follicle stimulation for oocyte preservation. We also show that although the patient was already on anticoagulation before any ovary stimulation, this syndrome was extremely severe and the patient developed a massive portal vein thrombosis and died shortly afterwards. This case highlights the high risk of developing OHHS in AL, possibly because a prothrombotic state is already present. Considering that the current prognosis for AL patients is poor, we believe that oocyte preservation in AL patients should not be recommended.
Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
References 1. Freeman B, Sloan JM, Seldin DC, Cowan AJ, Ruberg FL, Sanchorawala V. Multiple arterial and venous thromboembolic complications in AL amyloidosis and cardiac involvement: a case report and literature review. Amyloid 2012;19:156–60. 2. Nakagawa M, Tojo K, Sekijima Y, Yamazaki KH, Ikeda S. Arterial thromboembolism in senile systemic amyloidosis: report of two cases. Amyloid 2012;19:118–21. 3. Feng D, Syed IS, Martinez M, Oh JK, Jaffe AS, Grogan M, Edwards WD, et al. Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis. Circulation 2009;119:2490–7. 4. Jenkins JM, Drakeley AJ, Mathur RS. The management of ovarian hyperstimulation syndrome. United Kingdom Guidelines of the Royal College of Obstetricians and Gyaneacologists. Green-top Guideline 2006;5:1–11. 5. Jo´z´wik M. The mechanism of thromboembolism in the course of ovarian hyperstimulation syndrome. Med Wieku Rozwoj 2012;16: 269–71. 6. Alper MM, Smith LP, Sills ES. Ovarian hyperstimulation syndrome: current views on pathophysiology, risk factors, prevention, and management. J Exp Clin Assist Reprod 2009;6:3. 7. Ricci G, Cerneca F, Simeone R, Pozzobon C, Guarnieri S, Sartore A, Pregazzi R, et al. Impact of highly purified urinary FSH and recombinant FSH on haemostasis: an open-label, randomized, controlled trial. Hum Reprod 2004;19:838–48.
Copyright of Amyloid is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
