You Make the Call: How would you treat this 38-year-old patient with sickle cell trait and end-stage renal disease?

This month, Maureen Achebe, MD, MPH, discusses treatment for a patient with sickle cell trait and end-stage renal disease.

And don’t forget to check out next month’s clinical dilemma – send in your responses for a chance to win an ASH Clinical News-themed prize!

I am taking care of a 38-year-old man with sickle cell trait (SCT) and end-stage renal disease (ESRD). He was started on dialysis about 15 years ago and developed joint pains and priapism at that time associated with a drop in his hemoglobin level. He eventually got a renal transplant, after which his symptoms resolved and his hemoglobin level normalized. I first saw him about six months ago, after he had been restarted on dialysis for complaints of joint pain. He also reports occasional priapism. He has been hospitalized frequently for severe pain over the past couple of months. I sent his blood for extended hemoglobinopathy testing to see if there was a variant that was potentially interacting with the S trait, but all that was found was the trait. He has significant anemia (hemoglobin ranging from 6 to 8 g/dL), but has no evidence of hemolysis, and his reticulocyte count has been quite low (20,000-30,000). A bone marrow biopsy came back normal. I have been working with nephrology when adjusting his erythropoietin supplementation, as this is the only explanation for his hypoproliferative anemia that I can come up with. I am struggling to improve either his anemia or his pain symptoms. Are there alternative explanations or interventions I am missing? I don't see how sickle cell−directed therapy would make sense in this setting, but I can't think of anything else to offer.

Individuals with sickle cell disease (SCD), and to a lesser extent SCT, have a faster decline in renal function than the general population.1 Individuals with SCT do not usually present with complications of SCD despite having ESRD, so this case is unique. Nevertheless, I assume that something other than SCT is responsible for this patient's early onset ESRD.

Conditions of increased oxygen demand may trigger sickle-related complications in SCT, but this is not usually seen in ESRD. Having said that, the fact that the patient's symptoms resolved after he received a renal transplant, only to reoccur when he was again on dialysis, is compelling. Similar to patients with SCD, his two main problems are anemia and pain.

I agree that a hemoglobin level of 6-8 g/dL is low. I would check a serum erythropoietin level just before the next dose. Anecdotally, I have found that much higher doses of erythropoietin are needed in patients with SCD on dialysis. I don't know that this is the case for individuals with SCT, but the patient is behaving like a patient with SCD, so I would try that. There is no systematic data that identifies the optimal epoetin alfa doses on dialysis in patients with SCD. The 2019 American Society of Hematology (ASH) Clinical Practice Guidelines on SCD recommended future studies to evaluate dosing of epoetin alfa in SCD and chronic kidney disease, target hemoglobin levels in this setting, and the use of erythropoietin in combination with hydroxyurea,2 so we anticipate having data on this in the future. Our colleagues in nephrology are reluctant to give doses in excess of what is typically used in the setting of ESRD, so we often have to give it weekly through our clinic.

I am concerned that increasing the patient's hemoglobin may not have an impact on his pain. I agree that sickle cell−directed therapy targeting erythrocytes does not seem warranted. I would suggest clarifying whether the patient is able to identify a trigger for priapism or pain crises. His symptoms may be related to vasculopathy. You could have the rheology of the patient's cells tested at Functional Fluidics, a certified CLIA lab, and if the red blood cell rheology is abnormal, maybe a case can be made for trying a P-selectin inhibitor. I would also ask our colleagues in nephrology whether aspects of the patient's dialysis can be optimized (so that his electrolytes and pH, etc., are as close to normal as possible).

References

1. Olaniran KO, Allegretti AS, Zhao SH, et al. Kidney function decline among black patients with sickle cell trait and sickle cell disease: An observational cohort study. J Am Soc Nephrol. 2020; 31(2):393-404.
2. Liem RI, Lanzkron S, Coates TD, et al. American Society of Hematology 2019 guidelines for sickle cell disease: Cardiopulmonary and kidney disease. Blood Adv. 2019; 3(23):3867-3897.

How did readers respond? Check out You Make the Call – Readers’ Response.

I am evaluating a 65-year-old woman with newly diagnosed breast cancer for possible bleeding diathesis.

Her bleeding history is as follows:

• Epistaxis as a child
• History of heavy menstrual cycles requiring ablation and iron supplementation
• Heavy bleeding with first intercourse requiring vaginal packing and vitamin K administration
• No bleeding after a vaginal delivery in 1973
• Postpartum hemorrhage after a vaginal delivery in 1976
• Easy bruising

She has undergone several procedures including port-a-cath placement, breast biopsy, bilateral breast reduction, knee surgery, tonsillectomy, and routine dental work all without significant or unexpected bleeding.

However, after her breast cancer diagnosis, she underwent a partial mastectomy with sentinel lymph node biopsy in January. During the surgery, her estimated blood loss was 58 mL. A few days later, she reported extensive bruising of the breast and surrounding tissues. During a visit in early February, she had extensive ecchymosis and hematoma over the left breast wound site that extended down the left side of her chest. Her bleeding was so extensive she was anemic, underwent a red blood cell transfusion, and required ventriculoperitoneal drain placement. Similarly, she had a history of extended bleeding for a few days after a laparoscopic hysterectomy in 2011.

Blood work in early February showed a hemoglobin level of 12.6 g/dL, mean corpuscular volume of 89.7 fL, red cell distribution width of 14.1%, and a platelet count of 280 x 109/L. Her prothrombin and partial thromboplastin times were 10.9 and 27 seconds, respectively. She had a fibrinogen level of 169 mg/dL, factor XIII functional level of 82%, factor XI activity of 119%, factor IX activity of 125%, factor VIII activity of 99%, and negative test for factor VIII inhibitor. A von Willebrand panel was normal. Her comprehensive metabolic panel and lactate dehydrogenase were also normal.

A repeat fibrinogen level two weeks later was 157 mg/dL. Additional bloodwork from March showed a thrombin time of 25.9 seconds, fibrinogen activity of 130 mg/dL, fibrinogen antigen of 155 mg/dL, fibrin degradation products of <5 mcg/mL, a reptilase time of 18.2 seconds, and chromogenic factor VIII activity of 106%.

I think she might have a congenital hypofibrinogenemia. Although her fibrinogen levels are not terribly low, challenges such as surgery could have tipped the scale and led to bleeding a few days later. She is currently doing well with CMF chemotherapy (cyclophosphamide, methotrexate, and fluorouracil).

Would you recommend any further testing? How would you treat with surgery? The patients' parents died when she was a toddler. Would you recommend that her children/grandchildren be tested? If so, with which test?

Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.