Case Report: Coexisting Hereditary Spherocytosis, Limited Cutaneous Systemic Sclerosis, and Antiphospholipid Syndrome: A Rare Autoimmune–Hemolytic Association

Abbreviations

ACL

anticardiolipin antibody

aPL

antiphospholipid antibodies

APS

antiphospholipid syndrome

CT

computed tomography

DAMPs

damage‐associated molecular patterns

DAT

direct antiglobulin test

DVT

deep vein thrombosis

Hb

hemoglobin

HS

hereditary spherocytosis

IIF

indirect immunofluorescence

LcSSc

limited cutaneous systemic sclerosis

MMF

mycophenolate mofetil

NO

nitric oxide

PAH

pulmonary arterial hypertension

SLC4A1

solute carrier family 4 member 1

SSc

systemic sclerosis

WES

whole‐exome sequencing

β₂GP1

beta‐2 glycoprotein I

Dear Editor,

Hereditary spherocytosis (HS) is an inherited, red‐cell membrane disorder characterized by chronic hemolysis and heterogeneity in clinical presentation [1]. Limited cutaneous systemic sclerosis (LcSSc) is an autoimmune connective‐tissue disorder characterized by vasculopathy, endothelial dysfunction, and fibrosis [2]. Antiphospholipid syndrome (APS) is a thromboinflammatory condition associated with persistent antiphospholipid antibodies and vascular thrombosis [3]. The coexistence of HS, LcSSc, and APS in a patient represents a previously unreported clinical association.

A 55‐year‐old woman with type 2 diabetes mellitus presented with progressive fatigue, exertional breathlessness, intermittent jaundice, limited mouth opening, dysphagia, and skin thickening limited to the wrists. She also had a history of Raynaud phenomenon and previous left lower‐limb deep‐vein thrombosis treated several years earlier. Family history revealed recurrent jaundice in two children, one of whom had undergone splenectomy for hemolytic anemia.

Clinical examination revealed pallor, icterus, sclerodactyly (Figure 1A), limited mouth opening, hepatosplenomegaly, and loud P₂. No digital ulcers were present. Laboratory investigations showed normocytic anemia with elevated mean corpuscular hemoglobin concentration and reticulocytosis. Liver biochemistry demonstrated isolated indirect hyperbilirubinemia with normal transaminases and alkaline phosphatase levels (Table 1). Direct antiglobulin test was negative. Peripheral smear showed numerous spherocytes (Figure 1B). Viral serologies were negative.

FIGURE 1.

(A) Skin thickening limited to wrists. (B) Peripheral Smear demonstrating the presence of spherocytes. (C) Nail fold capillaroscopy demonstrating Late systemic sclerosis pattern.

TABLE 1.

Serial hematological, biochemical parameters, inflammatory markers during hospitalization, treatment and follow‐up.

Parameters	Day (0)	Day (90)	Day (180)
Hb (g/dL)	10.5	10.8	11.8
WBC (×103/μL)	7.4	7.6	7.5
N/L	80/17	74/18	73/20
Platelets (×105/μL)	3.1	2.3	3.6
HCT (%)	24	21	26
MCV (fL)	84	86	84
MCH (pg)	31	28	31
MCHC (g/dL)	38	36	36
Urea (mg/dL)	40	11	25
Creatinine (mg/dL)	0.8	0.4	0.5
Sodium (mEq/L)	135	133	137
Potassium (mEq/L)	4.6	4.5	4.5
AST/SGOT (IU/L)	19	16	18
ALT/SGPT (IU/L)	18	17	18
Total Bilirubin (mg/dL)	4.3	2.4	2.0
Direct/Indirect Bilirubin (mg/dL)	0.9/3.4	0.9/1.5	0.8/1.2
TP/Albumin (g/dL)	6.2/3.6	6.3/3.7	6.2/3.6
ALP (IU/L)	46	56	60
ESR (mm/h)	20	30	28
CRP (mg/L)	Negative	Negative	Negative

Antinuclear antibody by indirect immunofluorescence demonstrated a centromere pattern, and ANA immunoblot revealed CENP‐B positivity. In view of her previous thrombotic episode, antiphospholipid antibody testing was performed and showed persistently elevated IgG and IgM anticardiolipin and β₂‐glycoprotein‐I antibodies in high titres on two occasions 12 weeks apart, confirming APS. Computed tomography of the chest showed no interstitial lung disease, while abdominal imaging demonstrated hepatosplenomegaly. Echocardiography revealed moderate pulmonary arterial hypertension. Nailfold capillaroscopy demonstrated a late systemic sclerosis pattern (Figure 1C).

Whole‐exome sequencing identified a heterozygous pathogenic stop‐gain mutation in the SLC4A1 gene, confirming autosomal‐dominant hereditary spherocytosis type 4. The same pathogenic variant was identified in her son, supporting familial inheritance.

A diagnosis of hereditary spherocytosis type 4 associated with limited cutaneous systemic sclerosis and antiphospholipid syndrome overlap was made and she was treated with a combination of nifedipine, tadalafil, and acenocoumarol for secondary thromboprophylaxis. Supportive care and nutritional counseling were provided. The patient is currently under follow‐up and at the 6 month follow‐up, hemoglobin has improved, bilirubin levels decreased, and exercise tolerance improved with better NYHA functional status.

While the possible explanations for this coexistence remain elusive, we postulate a potential relationship between chronic hemolysis, endothelial injury, and immune dysregulation. However, the proposed mechanisms should be regarded as biologically plausible hypotheses rather than evidence of a direct pathogenic association. Chronic hemolysis in HS may contribute to endothelial dysfunction and a prothrombotic state through the release of free hemoglobin, heme, and erythrocyte‐derived microparticles [1, 4, 5, 6]. Exposure of phosphatidylserine on circulating microparticles may further enhance coagulation activation [7, 8]. These mechanisms could potentially amplify thrombotic risk in patients with concomitant APS.

Systemic sclerosis (SSc) and APS share endothelial dysfunction as a central pathogenic mechanism. In SSc, immune‐mediated endothelial injury leads to vasculopathy, vascular remodeling, and fibrosis, whereas in APS, antiphospholipid antibodies activate endothelial cells, platelets, and the complement system, thereby promoting thrombosis. Although APS is not a typical manifestation of SSc, antiphospholipid antibodies are detected more frequently in patients with systemic sclerosis than in the general population [9].

Alternatively, chronic hemolysis may contribute to platelet activation and inflammation, thereby promoting a prothrombotic milieu [4, 6, 8, 10]. Chronic release of free heme and iron may reduce nitric oxide bioavailability, resulting in vasoconstriction and endothelial dysfunction [7]. Chronic hemolysis has been proposed to promote immune activation through release of heme and damage‐associated molecular patterns; however, whether this contributes to the development of systemic autoimmune diseases remains uncertain [6].

This case also posed a diagnostic challenge in identifying hereditary spherocytosis in the presence of systemic sclerosis (SSc) and antiphospholipid syndrome (APS). In our patient, a negative direct antiglobulin test (DAT), elevated mean corpuscular hemoglobin concentration (MCHC), and numerous spherocytes on the peripheral blood smear raised the suspicion of an underlying red‐cell membrane disorder, which was subsequently confirmed by whole‐exome sequencing.

This patient also presented significant management challenges. It is conceivable that the reduced deformability of spherocytes in hereditary spherocytosis may be further compromised within the fibrovasculopathic microcirculation of systemic sclerosis, thereby potentially exacerbating hemolysis, although direct evidence for this mechanism is currently lacking [10]. Furthermore, chronic hemolysis, endothelial injury, and the presence of antiphospholipid antibodies may collectively increase the risk of thrombotic events [7, 8, 10]. Pulmonary hypertension in this patient may have resulted from the combined effects of systemic sclerosis‐associated vasculopathy and hemolysis‐related nitric oxide depletion [10] Persistent antiphospholipid antibodies may further augment thrombotic risk through endothelial activation and complement‐mediated injury [4]. In addition, splenectomy, an established treatment option for hereditary spherocytosis, may result in reactive thrombocytosis and could further increase the risk of thrombosis in patients with concomitant APS [11].

This case describes the first reported coexistence of genetically confirmed hereditary spherocytosis, limited cutaneous systemic sclerosis, and antiphospholipid syndrome. Although a causal relationship cannot be inferred from a single case, this unique overlap highlights potential intersections between chronic hemolysis, endothelial dysfunction, and immune‐mediated vascular injury. Recognition of hereditary spherocytosis in patients with autoimmune rheumatic diseases presenting with chronic hemolysis is important, particularly when clinical and laboratory findings are atypical. Further case reports and mechanistic studies are required to determine whether this association represents more than a coincidental occurrence and to clarify whether shared pathogenic pathways contribute to this unique overlap.

Author Contributions

Devaraj Ashwant Kumar contributed to patient evaluation, conceptualization of the manuscript, literature review, drafting, and final revision of the manuscript. P. S. Arul Rajamurugan contributed to clinical supervision, manuscript review, and intellectual guidance. S. Ramesh contributed to clinical management, interpretation of investigations, and manuscript editing. Sabarinath Mahadevan contributed to literature review, interpretation of autoimmune and vascular aspects of the case, and critical revision of the manuscript. Dhiliprajan Kannan contributed to data collection, follow‐up assessment, and preparation of the final manuscript. All authors reviewed and approved the final version of the manuscript and fulfill the International Committee of Medical Journal Editors (ICMJE) authorship criteria.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for the publication of clinical details and images.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.