case report

Sirolimus-Induced Severe Hypertriglyceridemia Presenting with Signs of Hyperviscosity Syndrome and as Pink Colored Blood: A Case Report

Authors: Sascha T Bender*, Maximilian J Ganz, Peter R Mertens, Christian R Gross

*Corresponding Author: Sascha T Bender, Clinic for Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Leipziger Str. 40, 39120 Magdeburg, Germany

Clinic for Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Germany

Received Date: 28 April 2022

Accepted Date: 02 May 2022

Published Date: 05 May 2022

Citation: Bender ST, Ganz MJ, Mertens PR, Gross CR (2022) Sirolimus-Induced Severe Hypertriglyceridemia Presenting with Signs of Hyperviscosity Syndrome and as Pink Colored Blood: A Case Report. Ann Case Report 7: 837. DOI:


Background: Inhibitors of the mammalian target of rapamycin have proven as potent immunosuppressive drugs effective in prevention of graft-versus-host-disease (GvHD). However severe disturbances of lipid metabolism are possible with the risk of developing hypertriglyceridemia-induced hyperviscosity syndrome. Clinical experience in the management of this potentially life-threatening complication is limited. Case presentation: We report a case of a patient with myelodysplastic syndrome complicated by chronic GvHD after allogeneic hematopoietic stem cell transplantation on second line sirolimus maintenance therapy while developing hyperviscosity syndrome due to severe hypertriglyceridemia of 138mmol/l presenting as pink colored blood. Plasmapheresis was initiated alongside fenofibrates to lower triglycerides. Importantly only serial therapeutic intervention with daily plasmapheresis over five days resulted in persistent therapeutic success. Triglyceride levels dropped to 7.02 mmol/l on day 8 after admission. Conclusions: The index case is notable due to symptomatic sirolimus-induced excessive hypertriglyceridemia with signs of hyperviscosity syndrome. Furthermore, we provide evidence that only after repeated plasma exchanges a satisfying decrease of lipid levels is achieved.

Keywords: Hypertriglyceridemia; Pink blood; Sirolimus; Hyperviscosity; Plasmapheresis; Graft-versus-host-disease (GvHD)

Abbreviations: GvHD: Graft-versus-Host-Disease; HSCT: Hematopoietic Stem Cell Transplantation; JAK: Janus-Associated Kinase; MDS: Myelodysplastic Syndrome; MMF: Mycophenolate Mofetil; mTOR: Mammalian Target of Rapamycin; TPE: Therapeutic Plasma Exchange


Inhibitors of the mammalian target of rapamycin (mTOR) have proven as potent immunosuppressive drugs that are derived from actinomycete Streptomyces hygroscopius [1]. The most prominent, sirolimus, has entered the transplant field following successful clinical trials that demonstrated effective prevention of graft-versus-host-disease (GvHD) in bone marrow allograft recipients, especially with corticosteroid-dependent or refractory chronic GvHD [2-4]. Mechanistically sirolimus interacts with immunophilins such as FK-binding protein 12 in order to complex with the kinase enzyme mTOR and hereby blocks interleukin-2 synthesis and T-cell proliferation [5,6]. A cell cycle arrest between G1 and S phase is observed in T-cells [7]. Sirolimus expands the repertoire of immunosuppressive armamentarium which is especially needed in transplant medicine with bone marrow and organ transplantation. Given an overall favorable profile of side-effects, especially no diabetogenic, nephrotoxic and neurotoxic sequelae, and in some cases anticancerogenic effect, sirolimus has become a popular treatment option in patients with co-morbidities such as diabetes and refractory arterial hypertension [8-10]. However sirolimus is associated with adverse metabolic reactions concerning lipid metabolism, dose-dependent leukocytopenia and thrombocytopenia and exaggeration of proteinuria [11]. Well-known changes in the lipid metabolism include a steady increase in triglyceride levels accompanied by less pronounced increases in cholesterol levels in long-term sirolimus

therapy regimens [12,13]. There are only a few cases in the literature that report on sirolimus-dependent severe hypertriglyceridemia, that is defined as triglyceride level >11.4 mmol/l (> 1000mg/dl) by the Common Terminology Criteria for Adverse Events (CTCAE) from the National Cancer Institute [14]. Urgent therapeutic interventions are indicated in these patients, since due to the highly lipemic blood they are at risk of developing either hypertriglyceridemia-induced acute pancreatitis or hyperviscosity syndrome. There are no general approved guidelines for best management under these conditions. The aim of this case report is to depict a case of a patient suffering from chronic GvHD after bone marrow transplantation developing critical hypertriglyceridemia under sirolimus treatment.

Case presentation

A 28-year-old female patient with history of myelodysplastic syndrome (MDS) underwent allogeneic hematopoietic stem cell transplantation (HSCT) in 2019. MDS has been in complete remission thereafter, but the disease course was complicated by chronic GvHD involving the skin and liver. Since other immunosuppressive medications were not tolerated, the patient received sirolimus as second line therapy. She was started two weeks prior to hospital admission on sirolimus at a starting dose of 1,5 mg per day combined with mycophenolate mofetil (MMF) bid 1000 mg and prednisolone bid 10 mg. The first trough level control was determined at 34 μg/l, thereafter the dose was lowered to 1 mg per day. The patient presented on the day of admission for a regular control in our outpatient hematological ward with nonspecific abdominal discomfort, diminished appetite, slight headache and dizziness. On admission, her medication included acyclovir, allopurinol, amlodipine, amphotericin B, cholecalciferol, cotrimoxazole, levetiracetam, magnesium, metoprolol, mirtazapine, MMF, pantoprazole, posaconazole, prednisolone, quetiapine, ramipril, sirolimus, and torasemid.

On clinical examination her neurologic status did not show focal deficits, however her overall mood was depressed. The blood appeared with a milky opaque pink color (Figure 1). Blood viscosity appeared distinctly increased. Initial laboratory work-up revealed triglycerides >138 mmol/l [ref. range <1.70 mmol/l], total cholesterol levels at 35.4 mmol/l [ref. range <5.2 mmol/l]. High-density lipoprotein and low-density lipoprotein were not measurable under these lipid levels. Over time lipemic blood showed separation into two layers with a milky opaque supernatant resulting triglycerides (Figure 2). Liver enzymes such as aspartate aminotransferase at 0.82 μmol/l [ref. <0.6 μmol/l], amino alanine transferase at 1.68 μmol/l [ref. <0.58 μmol/l], total bilirubin (within normal range), γ-GT 29.9 μmol/l [ref. <0.7 μmol/l] and lipase at 2.2 μmol/l [ref. <1.0 μmol/l] were not markedly altered. Total blood cell counts revealed macrocytic hyperchromic anemia with hemoglobin of 5.2 mmol/l [ref. 7.2 -9.6 mmol/l] due to vitamin B12 deficiency, coagulation was balanced with international normalized ratio for prothrombin time and activated partial thromboplastin time were measured in normal range. Due to the apparent neurological symptoms and suspected hyper viscosity syndrome plasmapheresis was initiated and repeated five times in exchange for

albumin. Plasmapheresis decreased triglyceride levels effectively without adverse events. Additionally fen fibrate 200 mg daily was administered, sirolimus discontinued. Triglyceride levels over time dropped to 7.02 mmol/l on day 8 (Table 1). Blood samples thereafter showed no longer the initially depicted hypertriglycerid phenomena. Following discontinuation of sirolimus the patient was put on MMF 1000 mg bid and prednisolone, thereafter the selective Janus-associated kinase 1 (JAK1) and JAK2 inhibitor ruxolitinib was initiated.


Sirolimus-induced hyperlipidemia has been described in up to 50 % of patients [15,16]. Hyperlipidemia is foremost characterized by a prominent hypertriglyceridemia that make up around 50 to 95% of lipids [12,13,17,18]. The pathophysiology of hypertriglyceridemia associated with mTOR-inhibition is not entirely understood. Potential mechanisms relate to interference with lipoprotein lipase activity by antagonizing insulin-dependent effects and diminished apolipoprotein C-III synthesis [19,20]. Additionally the enhancement of hormone-sensitive lipase activity, leading to elevated free fatty-acid release from adipose tissue has been described [21]. Furthermore sirolimus may interfere in lipogenesis by reduction of free fatty acids and expression of key enzymes [22]. Reports on severe hypertriglyceridemia associated with sirolimus treatment are rare, however have to be considered amongst the differential diagnoses (Box 1). Literature searches revealed that levels that high as in our index case have not been observed before [23–25]. Comingling of the red blood cells with the white appearing triglycerides are responsible for the phenomenon of pink colored blood [26].

Other differential diagnoses of severe hypertriglyceridemia include adverse drug reactions (Table 2) [27]. Uncontrolled diabetes mellitus may be accompanied by severe hypertriglyceridemia, however was not present in the index case. Especially the close temporal link with the newly prescribed drug and high trough levels link the excessive hypertriglyceridemia with sirolimus. Potentially aggravating factors elevating additionally lipid levels in this case are chronic kidney disease with mild proteinuria, medication with glucocorticoids and quetiapine [28,29]. Proteinuria leads to renal loss of lipoproteins and hence to hypertriglyceridemia, whereas administration of glucocorticoids increases triglyceride synthesis and stimulates lipoprotein lipase activity [30,31]. There is no generally consented standard of care regime to treat patients with excessive hypertriglyceridemia exceeding 10g/l. Expert opinion and anecdotal case reports provide hints on how to proceed [22]. Kido et al. reported on a pharmacological approach in an index patient without signs of hyperviscosity syndrome [32]. Furthermore triglyceride levels were lower (4425 mg/dl). Repeated laboratory testing in our patient revealed a steady fall of triglycerides following therapeutic plasma exchange (TPE) treatment, as reported in others [33-35]. The procedure is recommended in cases with suspected hyperviscosity syndrome or acute pancreatitis [27,36,37]. In the literature reports on TPE demonstrate lowered triglyceride levels by 66 to 84% after a single session [35,38]. In our reported

case this efficacy was not achieved and several sessions had to be performed. This observation may be explained with the hyperviscous blood, which has been demonstrated to reduce the efficiency of triglyceride removal [39].


The index case is notable due to symptomatic sirolimus-induced excessive hypertriglyceridemia with signs of hyperviscosity syndrome. The reddish pink color of the blood and lipid separation in two phases is impressive to the care provider in the dialysis unit as well on the wards. Early and regular testing of the lipid status is mandatory following sirolimus treatment initiation. Furthermore, we provide evidence that only after repeated plasma exchanges a satisfying decrease of lipid levels is achieved.


Ethics approval and consent to participate: Ethical approval is not appropriate. The authors obtained patient´s consent to participate.

Consent for publication: The authors obtained informed consent from the patient to publish information on her disease and clinical course.

Availability of data and materials: The authors did not use any datasets, databases, or special software in writing this manuscript.

Authors' contributions: STB collected the patient´s data and drafted the manuscript along with MJG, PRM and CRG. All authors read and approved the final manuscript.

Authors' information: Clinic for Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg, Germany.


Figure 1: Blood appearance on admission day. A bright pink color is seen which contrasts to normal blood appearance with therapeutic plasma exchange. (Colors have not been digitally processed).

Figure 2: Blood sedimentation into two layers. The milky opaque supernatant results from aggregated triglycerides.

Box 1: Differential diagnosis of bright pink colored blood.


Days after Admission

Triglyceride Level in mmol/l [ref. < 1.7]

Therapeutic Intervention

Triglyceride Removal rate in %

Total Cholesterol in mmol/l [ref. < 5.2]

HDL in mmol/l

LDL in mmol/l



1. TPE1, stopping of sirolimus, prescription of fibrates







2. TPE1







3. TPE1







4. TPE1







5. TPE1

































Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; NA, not available; TPE, therapeutic plasma exchange. 1 Plasma exchange volume 4l. 2 Unmeasurable due to lipemic blood.

Table 1: Lipid panels since hospital admission in relation to therapeutic interventions.

Genetic (Primary Hypertriglyceridemias)

  • Familial Chylomicronemia Syndrome
  • Familial Hypertiglyceridemia


  • Uncontrolled Diabetes Mellitus
  • Obesity
  • Pregnancy
  • Alcohol


  • Estrogene
  • Tamoxifen
  • Sirolimus
  • Protease Inhibitors
  • Interferon
  • Propofol

Table 2: Selected disorders reported as causative for severe hypertriglyceridemia.


  1. Sehgal SN. (2003) Sirolimus: its discovery, biological properties, and mechanism of action. Transplantation Proceedings. 35: S7-14.
  2. Jurado M, Vallejo C, Pérez-Simón JA, Brunet S, Ferra C, et al. (2007) u. a. Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant. 13:701-706.
  3. Johnston LJ, Brown J, Shizuru JA, Stockerl-Goldstein KE, Stuart MJ, et al. (2005) u. a. Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 11: 47-55.
  4. Couriel DR, Saliba R, Escalón MP, Hsu Y, Ghosh S, et al. (2005) u. a. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol. 130: 409-417.
  5. Zaza G, Granata S, Caletti C, Signorini L, Stallone G, et al. (2018) mTOR Inhibition Role in Cellular Mechanisms. Transplantation. 102: S3-16.
  6. Neuhaus P, Klupp J, Langrehr JM. (2001) mTOR inhibitors: an overview. Liver Transpl. 7: 473-484.
  7. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, et al. (1994) u. a. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 30. 369: 756-758.
  8. Chang GJ, Mahanty HD, Quan D, Freise CE, Ascher NL, et al. (2000) u. a. Experience with the use of sirolimus in liver transplantation--use in patients for whom calcineurin inhibitors are contraindicated. Liver Transpl. November 6: 734-740.
  9. Boffa DJ, Luan F, Thomas D, Yang H, Sharma VK, et al. (2004) u. a. Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res. 1. 10: 293-300.
  10. Luan FL, Ding R, Sharma VK, Chon WJ, Lagman M, et al. (2006) Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int. 63: 917-926.
  11. Murgia MG, Jordan S, Kahan BD. (1996) The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int. 49: 209-216.
  12. Firpi RJ, Tran TT, Flores P, Nissen N, Colquhoun S, et al. (2004) u. a. Sirolimus-induced hyperlipidaemia in liver transplant recipients is not dose-dependent. Aliment Pharmacol Ther. 1. 19: 1033-1039.
  13. Morrisett JD, Abdel-Fattah G, Kahan BD. (2003) Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients. Transplant Proc. 35: 143S-150S.
  14. Common Terminology Criteria for Adverse Events (CTCAE). 2017;155.
  15. Kasiske BL, de Mattos A, Flechner SM, Gallon L, Meier-Kriesche H-U, et al. (2008) u. a. Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients. Am J Transplant. 8: 1384-1392.
  16. MacDonald AS, RAPAMUNE Global Study Group. (2001) A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation. 71: 271-280.
  17. Brattström C, Wilczek HE, Tydén G, Böttiger Y, Säwe J, et al. (1998) Hypertriglyceridemia in renal transplant recipients treated with sirolimus. Transplant Proc. Dezember 30: 3950-3951.
  18. Meier-Kriesche HU, Kaplan B. (2000) Toxicity and efficacy of sirolimus: relationship to whole-blood concentrations. Clin Ther. 22: B93-100.
  19. Kraemer FB, Takeda D, Natu V, Sztalryd C. (1998) Insulin regulates lipoprotein lipase activity in rat adipose cells via wortmannin- and rapamycin-sensitive pathways. Metabolism. 47: 555-559.
  20. Tur MD, Garrigue V, Vela C, Dupuy AM, Descomps B, et al. (2000) u. a. Apolipoprotein CIII is upregulated by anticalcineurins and rapamycin: implications in transplantation-induced dyslipidemia. Transplant Proc. Dezember 32: 2783-2784.
  21. Morrisett JD, Abdel-Fattah G, Hoogeveen R, Mitchell E, Ballantyne CM, et al. (2002) u. a. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res. August 43: 1170-1180.
  22. Bouillet B, Buffier P, Smati S, Archambeaud F, Cariou B, et al. (2018) Expert opinion on the metabolic complications of mTOR inhibitors. Ann Endocrinol (Paris). Oktober 79: 583-590.
  23. Kulkarni JD, Bhatia P, Pai SA. (2016) Strawberry Pink Blood. Indian J Hematol Blood Transfus. 32: 512-513.
  24. Tan TXZ, Lim SHC, Khoo J. (2021) Strawberry pink blood: hypertriglyceridaemia and diabetic ketoacidosis secondary to poorly controlled type 2 diabetes mellitus. BMJ Case Rep. 14: e243696.
  25. Susheela AT, Vadakapet P, Pillai L, Thampi S. (2021) Familial chylomicronemia syndrome: a case report. J Med Case Rep. 15: 5.
  26. Tsai DE, Mato A, Porter DL, Vogl DT. (2008) Hypertriglyceridemia presenting as „pink blood“ and elevated hemoglobin level. Am J Hematol. 83: 253.
  27. Simha V. (2020) Management of hypertriglyceridemia. BMJ. 371: m3109.
  28. Dubath C, Piras M, Gholam M, Laaboub N, Grosu C, et al. (2021) u. a. Effect of Quetiapine, from Low to High Dose, on Weight and Metabolic Traits: Results from a Prospective Cohort Study. Pharmacopsychiatry. 54: 279-286.
  29. Franco JM, Vallabhajosyula S, Griffin TJ. (2015) Quetiapine-induced hypertriglyceridaemia causing acute pancreatitis. BMJ Case Rep. 2015: bcr2015209571.
  30. Kosugi T, Eriguchi M, Yoshida H, Tasaki H, Fukata F, et al. (2021) u. a. Association between chronic kidney disease and new-onset dyslipidemia: The Japan Specific Health Checkups (J-SHC) study. Atherosclerosis. September 332: 24-32.
  31. Rahimi L, Rajpal A, Ismail-Beigi F. (2020) Glucocorticoid-Induced Fatty Liver Disease. Diabetes Metab Syndr Obes. 13: 1133-1145.
  32. Kido K, Evans RA, Gopinath A, Flynn JD. (2018) Severe Hypertriglyceridemia Induced by Sirolimus Treated With Medical Management Without Plasmapheresis: A Case Report. J Pharm Pract. 31: 104-106.
  33. Fernandez-Bussy S, Akindipe O, Baz M, Gosain P, Rosenberg A, et al. (2010) Sirolimus-induced severe hypertriglyceridemia in a lung transplant recipient. Transplantation. 89: 481-482.
  34. Ewald N, Kloer H-U. (2012) Treatment options for severe hypertriglyceridemia (SHTG): the role of apheresis. Clin Res Cardiol Suppl. 7: 31-35.
  35. Zeitler H, Balta Z, Klein B, Strassburg CP. (2015) Extracorporeal Treatment in Severe Hypertriglyceridemia-Induced Pancreatitis. Ther Apher Dial. 19: 405-410.
  36. Ärzteblatt DÄG Redaktion Deutsches. Diagnose und Therapie der Hypertriglyceridämie [Internet].
  37. Kyriakidis AV, Karydakis P, Neofytou N, Pyrgioti M, Vasilakakis D, et al. (2005) u. a. Plasmapheresis in the management of acute severe hyperlipidemic pancreatitis: report of 5 cases. Pancreatology. 5: 201-204.
  38. Yeh J-H, Chen J-H, Chiu H-C. (2003) Plasmapheresis for hyperlipidemic pancreatitis. J Clin Apher. 18: 181-185.
  39. Wu H-C, Lee L-C, Wang W-J. (2019) Plasmapheresis for hypertriglyceridemia: The association between blood viscosity and triglyceride clearance rate. J Clin Lab Anal. 33: e22688.

© by the Authors & Gavin Publishers. This is an Open Access Journal Article Published Under Attribution-Share Alike CC BY-SA: Creative Commons Attribution-Share Alike 4.0 International License. With this license, readers can share, distribute, download, even commercially, as long as the original source is properly cited. Read More.

Annals of Case Reports

pola slot gacor zeusslot gacor mudah jackpotslot sugar rushslot mahjong thailandmahjong scatter naga hitamslot mahjong ways 2slot pg soft gacorprediksi judi bola sbobetparlay sbobet euro 2024rtp pg softbocoran rtp dan pola gacoragen bola euro terpercayatrik slot mahjong ways 2trik menaklukkan slot mahjong waysbandar bola terpercayaslot gacor gampang menangslot olympus 1000jam gacor pragmaticslot gacor mudah maxwinagen judi bola resmimahjong ways pola jitu maxwinpola gacor starlight princessslot server kambojarahasia scatter hitam mahjong waysturbo spin slot mahjongrtp slot candy villagepola gacor mahjong wins terbaruslot server luar terbarurtp slot olympusslot mahjong waysrtp sweet bonanzaagen sbobet euro 2024judi bola parlay sbobetslot gates of olympus jepe maxwinrtp slot gacorslot starlight christmas pragmatic