Pathways Case Record: Novel Insights Into Clinical Severity in Sickle Cell Disease

A 28-year-old woman with sickle cell disease (SCD) and eczema was admitted to an outside hospital with a fever, productive cough, and joint pain lasting four days. Her history was notable for one prior hospitalization for cholecystitis (inflammation in the gallbladder), no prior need for blood transfusions, and normocytic anemia (low number of red blood cells). She was initially treated with hydromorphone and a red blood cell (RBC) transfusion. During this hospitalization, she developed tachycardia and hypoxia. Evaluations then were notable for ground-glass opacities suggesting acute chest syndrome and high white blood cell (WBC) count. She was transferred to Massachusetts General Hospital due to concern for acute respiratory failure, where she was started on empiric antibiotic therapy for hospital-acquired pneumonia.

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Four days after initiating antibiotics, the patient developed a new fever, and her WBC count remained high. While her infectious workup was unrevealing, her hypercoagulability examination was remarkable for heterozygous mutation of Factor V Leiden (FVL). An ultrasound revealed bilateral deep vein thrombosis in her distal femoral and right subclavian veins. She was treated with hydromorphone for pain and anticoagulants.

The Pathways Consult Service in the Department of Medicine at Mass General was consulted and focused on the course of SCD in our patient, driven by two questions:

1. What protected our patient from episodes of vaso-occlusive crisis until this time?
2. What prompted her profound and sudden vaso-occlusive crisis during this hospitalization?

Background and Diagnosis

In SCD, the aberrant beta-globin chain in hemoglobin (HgbS) has an exposed hydrophobic region that interacts to form chains of hemoglobin that lead to cell sickling. Sickling leads to increased RBC turnover, fragility, RBC rupturing, and interaction with endothelium and immune cells. This inevitably causes intravascular thrombosis, leading to microvascular occlusion and frequent ischemic events. This process can be disrupted by preventing the beta-globin chain regions from interacting. Indeed, gamma-globin prevents beta-globin chains from interacting as they do not have the requisite hydrophobic region. To date, the most well-described mechanism of natural sickle cell disease protection is the persistence of fetal hemoglobin (HgbF). In adults without known hemoglobinopathies, the percentage of HbgF usually does not rise above 1% (Blood). Patients with mild hemoglobinopathies and high HgbF (~30%) demonstrate alleviated clinical symptoms (Blood). Interestingly, our patient's hemoglobin electrophoresis revealed that her HbgF was relatively low (for patients with SCD) at 5.2%, making it less likely that HgbF was a mitigating element of her mild disease. This further raises the question of what other factors may be contributing to her protection.

While our patient has a normal HgbF, it is worth considering whether she has a concurrent "protective" hemoglobinopathy. We hypothesize that our patient has concurrent alpha-thalassemia, an inherited blood disorder that reduces the production of RBCs and normal hemoglobin. Indeed, comorbid alpha-thalassemia has been demonstrated to prevent interaction between hydrophobic beta-globin regions (Br J Haematol). While less profound than HgbF, patients with this benefit from decreased sickling and subsequent reductions in retinopathy, stroke, renal disease, and ulcers. The prevalence of alpha-thalassemia is high in Jamaica (gene frequency ~0.2) (J Clin Invest), where our patient is originally from.

An alternative hypothesis to concurrent hemoglobinopathy in our patient is the presence of a mutation leading to dampened sensitivity to cellular volume changes in RBCs. Gardos is a calcium-activated cation channel that mediates RBC volume status and is overactive in SCD. Cellular hydration prevents hemoglobin interaction and crystallization. Thus, hydration through volume repletion is the first line of defense against occlusive crises in the blood vessels of SCD patients (Blood). Prior studies identified gain-of-function mutations in the Gardos channel-induced RBC dehydration and scalloping (Blood). It is possible that a loss-in-function mutation of the gene encoding Gardos would improve RBC volume, decrease fragility, and lead to fewer irreversibly sickled cells. Further investigations should assess if mutations in this channel may reveal clinically significant explanations.

We next considered how sickled cells interact with their environment. Occlusion of the blood vessels results from sickled RBCs attaching to endothelial cells, circulating WBCs, and platelets, creating thrombosis and subsequent vascular ischemia. Previous studies in SCD patients revealed that WBCs had increased rolling, adhesion, and interaction with platelets, while sickled RBCs interact more with WBCs and the endothelium when compared to normal RBCs (Proc Natl Acad Sci U S A). While multiple adhesive molecules (i.e., cadherins, adhesions, selectins, integrins) are implicated in thrombosis and immune cell adhesion, P-selectin is ubiquitous across all cell types involved in thromboses. Experimental models have demonstrated therapeutic potential in targeting P-selectin in SCD (Arterioscler Thromb Vasc Biol) (Blood Adv). Excitingly, a P-selectin antibody, Crizanlizumab, is currently under investigation for treatment in SCD. Crizanlizumab treatments in a phase 2 trial led to fewer vaso-occlusive crises and prolonged time between vaso-occlusive events with mild side effects. Further investigations are warranted to determine if these treatments are effective long-term. Reflecting on our patient, we hypothesize that she has aberrant P-selectin activity that attenuates her SCD and prevents vaso-occlusive crises. Considering her mild SCD course, joint pain and swelling, and eczema, our patient may have an underlying rheumatologic illness associated with P-selectin autoantibodies, leading to her recent hospital admission.

Summary and Future Steps

Together, we believe our patient's dramatic SCD progression is a combination of genetic contribution and potential P-selectin activity. We recommend genetic testing to determine if our patient inherited thalassemia or functional mutation resulting in loss-of-function of the Gardos channel, thus explaining her relatively mild clinical course prior to this first episode at age 28. Furthermore, we could investigate RBC plasticity using Fluo-4 confocal microscopy to assess calcium activity (Cell Calcium) or osmotic gradient ektacytometry (measures RBC deformation) (Clin Hemorheol Microcirc) in our patient compared to individuals with more severe SCD. Lastly, further investigations into P-selectin activity should be assessed to explain why she suddenly had this dramatic presentation. Lines of inquiry include (1) vascular biopsy for endothelial P-selectin immunohistochemistry, (2) skin biopsy to assess for neutrophil extravasation, (3) platelets isolated from peripheral blood to assess P-selectin activity via aggregometry, (4) neutrophils isolated from peripheral blood to assess for the presence of P-selectin and platelet co-binding via flow cytometry, and (5) isolation of neutrophils and RBCs for microfluidic analysis. Understanding the role of P-selectin and its potential contribution to disease in our patient would enable better treatment strategies in the future for many patients with SCD.

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