Fatigue & Cognitive Impacts of ITP

Immune thrombocytopenia (ITP), a condition primarily characterised by marked thrombocytopenia, can also present with additional manifestations such as increased fatigue and cognitive difficulties.^1-5 In ITP patients who experience severe fatigue, it often remains prevalent and debilitating throughout the course of the disease, significantly affecting patients’ quality of life.³

Historically, care for ITP has focused on preventing severe bleeding—yet fatigue is frequently the top symptom that patients want resolved.³ As a result, fatigue in ITP has become a key focus for clinicians and researchers, with the emerging hypothesis that holistic management can help address the multi-factorial drivers of fatigue in individual patients.³ This article will explore fatigue, as well as other impacts of ITP, as an under-recognised facet of the disease that has a significant impact on patients’ daily lives.^1-5

ITP and fatigue

Fatigue in ITP is a pervasive issue, with nearly 50% of ITP patients identifying it as the single symptom they most wish to see resolved³ and two-thirds of physicians (66%) reporting fatigue as significantly impacting their patients’ health-related quality of life (HRQoL).⁶

Data from the ITP World Impact Survey (I-WISh) illustrate the scale of the problem⁶:

• 85% of patients report reduced energy levels due to their condition
• 75% of patients report a limited ability to complete daily tasks
• 73% of patients report difficulties with concentration

Severe fatigue is observed in 22-58% of the patient population; it frequently persists throughout the disease course and substantially disrupts patients’ lives.³ The severity of this symptom can lead to significant social and economic consequences, including patients missing work or school.²

While physicians recognise fatigue as a symptom of the disease, it has classically not been a focus of treatment, and physicians may not always attribute fatigue to ITP.^1,3 This under-recognition might extend to the patients themselves, who may adjust to a chronically reduced quality of life, perceiving their exhaustion as their “new normal” rather than a treatable symptom.^7,8
 

Cognitive symptoms of ITP

While ITP is classically defined by a low platelet count and bleeding risk, cognitive symptoms—including memory and concentration deficits—are frequently reported by patients, often alongside autonomic dysfunction.^4,5

Together, these lesser-acknowledged impacts of ITP significantly impair the daily lives of patients and may impact neuropsychological functioning, as established for other chronic autoimmune conditions like systemic lupus erythematosus.^5,9 In fact, the degree of cognitive impairment in ITP may be comparable with traumatic brain injury.⁵ Accordingly, a significant facet of the pathophysiology of ITP may be dysregulation of the autonomic nervous system.^4,10

Consequently, the mechanisms of cognitive decline in ITP are likely to be multifaceted, and are hypothesised to arise from acute neural inflammation, thrombotic occlusions of small blood vessels in the brain, and cerebral microbleeds.⁵

Cerebral microbleeds

Neuroimaging in patients with ITP has revealed that some patients experience silent (“occult”) cerebral microbleeds (CMBs); these events were detected in 43% of patients with ITP and nadir platelet counts less than 30x10⁹/L in a study by Cooper et al.^11,12

The mechanism of CMBs means that their distinct signs can be seen via imaging techniques. The small breaches in the endothelial lining of capillaries or postcapillary venules seen in CMBs allow erythrocytes to extravasate into the surrounding brain tissue. Macrophages subsequently phagocytise these escaped blood cells and degrade the haemoglobin into haemosiderin to prevent iron-mediated neurotoxicity. These haemosiderin-laden macrophages can then persist within the tissue, detectable via MRI techniques as distinct, small black dots.¹²

In addition to their potentially high prevalence, the study by Cooper et al. also suggests the risks of CMBs should not be overlooked, as they may be predictive of higher disease severity or refractory disease, significant bleeding, and high organ bleeding.¹¹ Accordingly, current approaches to ITP treatment based on clinical symptomatology alone may not appropriately protect patients from occult CNS bleeds.¹¹

Further exacerbating the complexity of management, it is known that platelet count alone does not reliably predict the risk of bleeding events, including CMBs. The quality of the platelets (function), the health of the vessel walls (endothelial integrity), and systemic inflammation are examples of significant contributing factors likely to also play a role in defining an individual patient’s bleeding risk.¹²

How does ITP cause fatigue?

Despite its prevalence, the precise biological mechanisms driving fatigue in ITP are not fully understood. It is likely driven by a complex array of several factors²: 

• Comorbidities: Patients with ITP may have underlying conditions like lupus that are associated with fatigue, or other comorbidities like hypothyroidism, that contribute to fatigue.²
• Thrombocytopenia: Thrombocytopenia can impact multiple factors that may indirectly influence mood and energy levels, including social engagement.²
• Pathophysiology and inflammation-driven “sickness behaviour”: Researchers suggest a role for pro-inflammatory cytokines in ITP, potentially leading to lethargy and other mental disturbances, akin to the effects of immune responses to viral infections.²
• Bruising and bleeding: Can lead to iron deficiency, known to cause fatigue in pre-menopausal women. Visible bruising can cause social embarrassment, which has also been linked to fatigue.²
• Medication side effects:
  • Corticosteroids have multiple side effects that could contribute to fatigue, including sleep disturbance, a range of psychiatric reactions, fluid retention, acne, muscle weakness, proximal myopathy, and susceptibility to infection.²
  • Side effects of immunosuppressive therapy, such as infection and anaemia, may also lead to fatigue.²
  • Thrombopoietin receptor agonists are a relatively targeted therapy and appear to be less likely than corticosteroids and immunosuppressive therapy to cause fatigue.² 

Adapted from Hill QA, Newland AC. Br J Haematol. 2015;170(2):141-149. © British Society for Haematology (BSH).²

Intracranial haemorrhage (ICH) in ITP

ICH is a rare but life-threatening neurological complication of ITP affecting both paediatric and adult patients.^13,14 In patients with immune thrombocytopenia, symptoms of ICH can include headaches, dizziness, persistent vomiting, altered mental status, and seizures.^15,16 

Carrying substantial morbidity and mortality, ICH necessitates aggressive decision-making in clinical practice—though optimal management, especially proactive management, remains highly debated and complex.^13,14 Some researchers argue that individual patients with ITP should be stratified according to their risk of developing ICH, acknowledging the balancing act that must be performed to meet a satisfactory trade-off between the benefit of treatment and potential toxicities.¹⁴ 

Further exacerbating management challenges, ITP is known to raise the risk of thromboembolic events. While paradoxical, biological rationale for the underlying pathophysiology has been proposed, and the risk is known to be associated with several factors—including patient-related factors (eg, comorbidities, age, and history of thrombosis), disease-related factors (eg, a greater proportion of younger, more reactive platelets, and the presence of microparticles and pro-inflammatory cytokines) and treatment-related factors (eg, splenectomy, thrombopoietin receptor agonists, and intravenous immunoglobulin [IVIg]).^17-19 

Taken together, management of ITP and the risk of ICH is complex and necessitates careful personalisation and balancing of treatment risks and benefits.^13,14,18

Recognising and addressing the full impact of ITP

The impacts of ITP go beyond low platelet counts and bleeding risk. Neurological manifestations of the disease, including debilitating fatigue, are often a top concern and burden for patients, extending to their caregivers and families.^3,20

The shift to a more holistic, personalised view of ITP management is now widely accepted with patient characteristics and preferences considered alongside an individual’s bleeding risk, thromboembolic risk, and potentially the risk of ICH.^14,18

Learn more about current treatment approaches in ITP or explore a potential second-line treatment↗.

CNS, central nervous system; IFN, interferon; MP, microparticles; MRI, magnetic resonance imaging; TNF, tumour necrosis factor; Th1, type 1 helper T [cell].