Thrombocytopenia, defined as low platelet count in the blood, is a disorder with different possible causes that increases bleeding risk in affected individuals. Immune thrombocytopenia (ITP), previously known as idiopathic thrombocytopenic purpura, is one such type of thrombocytopenia now known to be caused by complex immune dysregulation.1,2
Autoantibodies against platelet antigens in ITP contribute to low platelet counts, impaired production, and reduced platelet survival rates.2 While platelet counts are used to diagnose and grade the severity of the condition, management of immune thrombocytopenia goes beyond increasing platelet levels. Other factors such as the patient’s quality of life and potential treatment toxicities also need to be taken into account.1,3

<h2>How does ITP affect platelet function?</h2>
Currently, ITP remains a diagnosis of exclusion of other possible causes of thrombocytopenia. The <a href="https://pro.campus.sanofi/itp/articles/mechanism-of-disease-and-pathophysiology-of-itp">pathophysiology of ITP</a> involves complex immune dysregulation that is heterogeneous and varies from patient to patient.3 Studies show that the bodies of people with ITP produce antibodies against platelet glycoproteins. This leads to platelet destruction and impaired platelet production.2&nbsp;
The low platelet levels in ITP patients are associated with <a href="${link:{uuid:{8da50df0-f8f2-4d50-94cc-e30ab2e6b6cf},repository:{articles},path:{/Global/indications/itp/defining-itp-signs-and-symptoms}}}">symptoms</a> such as petechiae, purpura, and an increased risk of bleeding events.2 Immune thrombocytopenia is also associated with enlarged platelets.4,5 
 &nbsp;

<h2>Platelet count and ITP severity</h2>
ITP is typically diagnosed at platelet levels of less than 100x109 platelets per litre of blood, when all other causes of thrombocytopenia have been excluded as part of a differential diagnosis.2,3
<h3>Platelet count range for immune thrombocytopenia6-8</h3>

While platelet thresholds are used to guide management decisions, they are not the sole measure to determine the management strategy for immune thrombocytopenia. Other factors, such as symptoms and prior response to treatment, are also taken into account.1,3
Platelet levels are often used to evaluate risk of bleeding1:
<ul>
 <li>Platelet count above 50x109 per litre of blood: generally asymptomatic</li>
 <li>Platelet counts between 20 and 50x109 per litre of blood: mild skin manifestations such as petechiae, purpura, or ecchymosis</li>
 <li>Platelet counts of less than 10x109 per litre of blood: high risk of serious bleeding</li>
</ul>

<h3>Platelet count vs platelet function in ITP</h3>
Platelet levels are used to assess bleeding risk and severity; however, they do not define the risk of bleeding in isolation.1,3 It is possible for two people with similar low platelet counts to have differing bleeding symptoms.9
A study recently showed that platelet biomarkers are associated with bleeding severity, independent of platelet counts. Platelet activation and function are being researched as factors that can affect predisposition to bleeding in ITP.9

<h2>ITP management: thinking beyond low platelet count</h2>
Maintaining platelet counts at levels high enough to minimise chances of bleeding is a primary goal of <a href="https://pro.campus.sanofi/itp/articles/treating-itp">ITP management</a>, but it is not the only goal.10
Factors such as the patient’s quality of life and balancing treatment toxicity with risk of bleeding are also involved in selecting an effective management strategy. For instance, <a href="https://ashpublications.org/bloodadvances/article/3/23/3829/429213/American-Society-of-Hematology-2019-guidelines-for" target="_blank">guidelines</a> recommend keeping asymptomatic patients under observation, even if they have low platelet counts.10
Due to the heterogeneity of immune thrombocytopenia, it is important to develop individualised treatment plans for patients depending on their particular risk factors. Platelets are only one factor in this decision-making process.11

ITP and Platelet Counts

IMMUNE-THROMBOCYTOPENIC-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

<h2>ITP and fatigue</h2>
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:
<ul>
 <li>85% of patients report reduced energy levels due to their condition</li>
 <li>75% of patients report a limited ability to complete daily tasks</li>
 <li>73% of patients report difficulties with concentration</li>
</ul>
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 
 &nbsp;

<h2>Cognitive symptoms of ITP</h2>
While ITP is classically defined by a low <a href="https://pro.campus.sanofi/itp/articles/itp-platelet-counts">platelet count</a> 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 <a href="https://pro.campus.sanofi/itp/articles/mechanism-of-disease-and-pathophysiology-of-itp" target="_blank">pathophysiology of ITP</a> 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

<h3>Cerebral microbleeds</h3>
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 <a href="https://pro.campus.sanofi/itp/articles/treating-itp">ITP treatment</a> 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

<h3>How does ITP cause fatigue?</h3>
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:&nbsp;
<ul>
 <li>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</li>
 <li>Thrombocytopenia: Thrombocytopenia can impact multiple factors that may indirectly influence mood and energy levels, including social engagement.2</li>
 <li>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</li>
 <li>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</li>
 <li>Medication side effects:
 <ul>
 <li>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</li>
 <li>Side effects of immunosuppressive therapy, such as infection and anaemia, may also lead to fatigue.2</li>
 <li>Thrombopoietin receptor agonists are a relatively targeted therapy and appear to be less likely than corticosteroids and immunosuppressive therapy to cause fatigue.2&nbsp;</li>
 </ul></li>
</ul>

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

<h2>Intracranial haemorrhage (ICH) in ITP</h2>
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&nbsp; 
 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&nbsp;
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&nbsp;
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

<h2>Recognising and addressing the full impact of ITP</h2>
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 <a href="${link:{uuid:{5951058e-a726-4620-a2dc-66df25bdf733},repository:{articles},path:{/Global/indications/itp/treating-itp}}}">current treatment approaches in ITP</a> or <a href="https://pro.campus.sanofi/us/products/wayrilz" target="_blank">explore a potential second-line treatment↗</a>.

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

Fatigue & Cognitive Impacts of ITP

Immune thrombocytopenia (ITP), previously known as idiopathic thrombocytopenic purpura, is a type of thrombocytopenia involving immune-mediated reduction in platelet counts leading to defects in blood clotting.1 The resulting elevated bleeding risk has a direct impact on morbidity, mortality, and quality of life for people affected.2-5 This article will explore the causes, risk factors, symptoms, and management of bleeding in ITP, and discuss the wider impacts of ITP on affected individuals.

<h2>Mechanisms of thrombocytopenia</h2>
One of the central features of ITP is the production of IgG autoantibodies directed against platelet surface antigens (GP IIb/IIIa, Ib/IIa, and VI), which develop in the absence of another underlying disorder (“primary” ITP) or after exposure to an inciting event (“secondary” ITP)—including other autoimmune conditions, drugs or infections (including HIV, hepatitis C, cytomegalovirus, or varicella zoster).1,6
Antibody binding to platelet glycoproteins triggers platelet destruction through multiple pathways, involving both innate and adaptive responses as well as immunosuppressive cell defects. Today, it is now understood that abnormal T cell responses are also involved, promoting autoimmune activity against platelets and megakaryocytes.6 Learn more about the <a href="${link:{uuid:{c74a8bbe-8c42-444b-b7ca-84850a1d0137},repository:{articles},path:{/Global/indications/itp/mechanism-of-disease-and-pathophysiology-of-itp}}}">pathophysiology of ITP</a>.
The destruction of platelets by autoimmune processes leads to impaired blood clotting and a heightened risk of bleeding, a hallmark of ITP.7 Bleeding, present in around two-thirds of adults with ITP, ranges in severity from mild petechiae and epistaxis to potentially life-threatening gastrointestinal, intracranial, or urinary tract haemorrhage.1
Beyond bleeding, ITP can increase risk of thrombosis and has numerous effects on patients’ lives that can be easily overlooked, including <a href="${link:{uuid:{dabe656b-e431-4f27-a8dc-9c11b365f5c0},repository:{articles},path:{/Global/indications/itp/fatigue-and-cognitive-impacts-of-itp}}}">fatigue</a>, anxiety, depression, and headaches.5 Patients with chronic ITP may become so accustomed to a life with reduced health-related quality of life (HRQoL) that they believe it is their “normal.” 5 Uncover the <a href="${link:{uuid:{dabe656b-e431-4f27-a8dc-9c11b365f5c0},repository:{articles},path:{/Global/indications/itp/fatigue-and-cognitive-impacts-of-itp}}}">hidden impact of ITP</a> on patient’s lives. 
 &nbsp;

<h2>Risk factors for bleeding in ITP</h2>
Bleeding in ITP is highly variable and unpredictable, and—because of the heterogenous nature of ITP—there is no clear evidence of a direct correlation between platelet counts and bleeding symptoms, especially at lower platelet counts. This means that bleeding in patients with ITP, even with the same platelet levels, can present in bleeding that ranges in severity from mild to severe.8-10
Despite this heterogeneity, certain risk factors have been identified that can contribute to an increased risk of severe bleeding in ITP. These include8:
<ul>
 <li>The presence of severe thrombocytopenia (platelet count &lt;10,000–20,000/μL)</li>
 <li>Previous minor bleeding</li>
 <li>Older age (older than 60 years)</li>
 <li>Concomitant medication use that predisposes patients to bleeding</li>
 <li>Male sex</li>
</ul>
While platelet levels remain an&nbsp;important aspect of treatment decisions in <a href="${link:{uuid:{0cff5303-250f-4b3c-82ed-45f9cbfdf110},repository:{articles},path:{/Global/indications/itp/treatment-guidelines}}}">treatment guidelines</a>,11 because of the complex combination of risk factors in ITP, some researchers argue that treatment decisions should not be dictated solely by <a href="${link:{uuid:{2fdef590-19eb-4dc3-878d-b75293243f60},repository:{articles},path:{/Global/indications/itp/itp-platelet-counts}}}">platelet count</a> alone. Various&nbsp;additional factors may help to define individual treatment needs, such as bleeding phenotype, lifestyle, comorbidities, medication, patient preferences and lifestyle of each individual—including activity level, pregnancy planning, disease anxiety, and adherence to treatment.8

<h2>Bleeding-related symptoms in ITP</h2>
Bleeding in ITP may broadly be defined by its severity, ranging from minor bleeding to severe and critical bleeding, which can impact the skin, oral cavity, or internal organs.1,12
Bleeding-relating symptoms in those affected by ITP can include1,5,12,13:

<h3>Intracranial haemorrhage (ICH) and cerebral microbleeds (CMBs)</h3>
Intracranial haemorrhage refers to bleeding within the skull and is a severe bleeding event that can occur in 0.1 to 1% of patients with ITP, with most cases seen when platelet levels &lt;10,000/μL.1,13,14
Unlike other types of bleeding events in ITP, ICH appears to be more common in adults than children, with its associated mortality being highest for patients over 60 years old.15-17 It also tends to occur during chronic ITP (longer than 12 months) while other critical bleeds are frequently seen at all stages of the disease.17,18
Cerebral microbleeds are small bleeds from blood vessels in the brain. Over time, the accumulation of the haemosiderin deposits can be associated with cognitive impairment in a range of conditions (eg, cerebral amyloid angiopathy). In a 2020 study, the incidence of CMBs was found to be higher in patients with ITP (43%) than in the control group (0%), demonstrating that CMBs are common in moderate to severe ITP and suggesting a potential cause for cognitive impairment observed in some ITP patients.19

<h3>Skin bleeding symptoms</h3>
<ul>
 <li>Petechiae: Petechiae are red or purple patches on the skin (“dry”) or mucous membranes (“wet”) that measure less than 2 mm in size. They are caused by bleeding into the dermis20,21</li>
 <li>Ecchymosis: Ecchymosis is defined as red or purple patches on the skin that have a size of more than 1 cm. They occur due to leakage of blood into subcutaneous tissue20,22,23</li>
 <li>Haematoma: Haematoma is a large bruise on the skin, caused by local accumulation of blood24</li>
</ul>

Ecchymosis 
 Large extravasation of blood into the skin.23

Purpura 
 Non-blanching violaceous haemorrhagic lesions that can be flat or raised.25

Petechiae 
 1-2 mm non-blanching reddish vascular macules (“tiny flat form of purpura”).25

<h3>Epistaxis and bleeding in mucous membranes</h3>
<ul>
 <li>Epistaxis: Epistaxis is a bleeding of the nose from blood vessels of the anterior nasal septum (most common) or the posterior nasal cavity (less common but often severe). They can be unilateral or bilateral, and can be due to local, systemic, environmental, or medication-induced causes26</li>
 <li>Gingival bleeding: Gingival bleeding refers to the bleeding of the gingival tissue (gums) caused by the inflammation of the gingiva. The inflammation usually results from gingivitis or other conditions associated with poor oral health. In patients with ITP, it can also be due to minor trauma (eg, toothbrushing) 27-29</li>
 <li>Subconjunctival haemorrhage: Subconjunctival haemorrhage manifests as redness beneath the conjunctiva resulting from an extravasation of blood in the area. It does not cause pain or impair vision and is usually caused by trauma, but may also be caused by systemic comorbidities (eg, hypertension) or medications30</li>
</ul>

<h3>Internal bleeding in organs</h3>
Gastrointestinal (GI) bleeding can be a serious complication encountered in patients with ITP, and may be especially common in patients on chronic anticoagulation and/or antiplatelet agents—emphasising the need for careful management of polypharmacy.31 The risk of severe gastrointestinal bleeding is less than 1% in ITP.32
Other forms of internal bleeding that can be observed during ITP include1,33,34:
<ul>
 <li>Pulmonary or tracheobronchial bleeding</li>
 <li>Intraocular bleeding</li>
 <li>Intraspinal bleeding</li>
 <li>Retroperitoneal bleeding</li>
 <li>Pericardial bleeding</li>
 <li>Intramuscular bleeding</li>
 <li>Bleed causing haemodynamic instability</li>
 <li>Genitourinary tract bleeding</li>
</ul>

<h3>Thrombosis and thromboembolic events (TEs)</h3>
Thrombosis is defined as a blood clot within an arterial (arterial thromboembolism or ATE) or venous (venous thromboembolism or VTE) blood vessel.35 Patients with ITP have a higher risk of thrombosis than the general population, including VTE such as deep-vein thrombosis (DVT) and pulmonary embolism (PE)36,37; epidemiologic studies suggest the risk of VTE may be elevated up to 2-fold.38
The increase in risk could be due to high rates of platelet activation with increased thrombin generation, ITP treatment, and comorbidities. As a result, the group most at risk to experience thrombosis with ITP are older patients who possibly have more comorbidities and have undergone several lines of secondary ITP treatment and received thrombopoietin receptor agonists (TPO-RAs).37
Thromboembolic events can refer to blood clots that have travelled to a distant site from where it was formed.39 The rate of TEs in patients with ITP is, for similar reasons as for thrombosis, three to four times higher than in the general population.40

<h3>Menstrual bleeding</h3>
In menstruating people of reproductive age, ITP can cause significant menstrual problems such as heavy menstrual bleeding (HMB), also known as menorrhagia. HMB is defined as abnormally heavy bleeding and/or prolonged bleeding for more than 7 days.41
Beyond its effects on patients’ quality of life (including impairment on physical, social, and general health), HMB can lead to iron deficiency and anaemia, further impacting quality of life, as well as impacting cognitive and physical functions. A 2022 study on premenopausal people with a uterus found that while 39% of patients in the sample experienced HMB, 78% had experienced clinical menstrual problems.41

<h2>The ITP Bleeding Scale (IBLS)</h2>
Historically, treatment decisions in ITP were driven primarily by platelet counts. However, it is now acknowledged that platelet counts alone do not adequately define bleeding, nor capture the comprehensive disease burden experienced by patients.20
The ITP Bleeding Scale (IBLS) is a disease-specific bleeding assessment tool that uses 11 site-specific grades ranging from 0 (none) to 2 (marked bleeding). It evaluates bleeding at 9 sites on the body based on patient history over the previous week, with skin and oral bleeding also assessed by physical examination. In addition, the most severe bleeding ever experienced at each site is graded using the same system, providing a structured framework for characterising bleeding severity in patients with ITP.42 
 &nbsp;

<figure class="table" style="width:100%;">
 <table>
 <thead>
 <tr>
 <th style="background-color:#f5f5f5;">
 &nbsp;</th>
 <th colspan="3">
 Bleeding Grade</th>
 </tr>
 <tr>
 <th style="background-color:#f5f5f5;">
 Site</th>
 <th>
 0</th>
 <th>
 1</th>
 <th>
 2</th>
 </tr>
 </thead>
 <tbody>
 <tr>
 <td style="background-color:#f5f5f5;">
 Skin [physical examination (PE)]</td>
 <td>
 None</td>
 <td>
 1-5 bruises and/or scattered petechiae</td>
 <td>
 &gt;5 bruises with size &gt;2 cm and/or diffuse petechiae</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Oral (PE)</td>
 <td>
 None</td>
 <td>
 1 blood blister or &gt;5 petechiae or gum bleeding that clears easily with rinsing</td>
 <td>
 Multiple blood blisters and/or gum bleeding</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Skin (Hx)</td>
 <td>
 None</td>
 <td>
 1-5 bruises and/or scattered petechiae</td>
 <td>
 &gt;5 bruises with size &gt;2 cm and/or diffuse petechiae</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Oral (Hx)</td>
 <td>
 None</td>
 <td>
 1 blood blister or &gt;5 petechiae and/or gum bleeding &lt;5 min</td>
 <td>
 Multiple blood blisters and/or gum bleeding &gt;5 min</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Epistaxis</td>
 <td>
 None</td>
 <td>
 Blood when blowing nose and/or 
 epistaxis &lt;5 min (per episode)</td>
 <td>
 Bleeding &gt;5 min (per episode)</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Gastrointestinal (GI)</td>
 <td>
 None</td>
 <td>
 Occult blood</td>
 <td>
 Gross blood</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Urinary (U)</td>
 <td>
 None</td>
 <td>
 Microscopic (+ve dipstick)</td>
 <td>
 Macroscopic</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Gynecological (GYN)</td>
 <td>
 None (normal period)</td>
 <td>
 Spotting not at time of normal period</td>
 <td>
 Bleeding &gt;spotting not at time of period or very heavy period</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Pulmonary</td>
 <td>
 None</td>
 <td>
 N/A</td>
 <td>
 Yes</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Intracranial haemorrhage</td>
 <td>
 None</td>
 <td>
 N/A</td>
 <td>
 Yes</td>
 </tr>
 <tr>
 <td style="background-color:#f5f5f5;">
 Subconjunctival haemorrhage</td>
 <td>
 None</td>
 <td>
 Yes</td>
 <td>
 N/A</td>
 </tr>
 </tbody>
 </table>
</figure>

Adapted from Page LK, et al. Br J Haematol. 2007;138(2):245-248.42

<h2>Managing bleeding in ITP</h2>
ITP is a complex disorder, driven by underlying autoimmune pathophysiology that leads to reduced platelet levels and functioning in affected individuals, resulting in elevated bleeding risk.43
However, the impacts of ITP go beyond bleeding risk alone, with the disease having significant impacts on quality of life.43 It is now advised that treatment is highly personalised, taking into account the multiple individual characteristics, symptoms, experiences, and preferences of the patient.2,40
While current treatments are primarily focused on stopping or preventing bleeding, response rates for currently available ITP treatments vary widely from 18% to 80%, as measured by improved platelet counts.44,45 Furthermore, existing treatments may also be associated with unfavourable side effect profiles, dosing regimens, routes of administration, and dietary restrictions.44,46-48
There remains an <a href="https://pro.campus.sanofi/itp/articles/unmet-needs">unmet need for newer treatment options in ITP</a> that address its underlying complex immune dysregulation, induce durable platelet responses, are well tolerated, and improve fatigue and overall quality of life for affected patients.43

GP, platelet glycoprotein; HIV, human immunodeficiency virus; Hx, history; IgG, immunoglobulin G.

Bleeding in ITP

Immune thrombocytopenia (ITP) is an autoimmune disorder caused by complex immune dysregulation, leading to a reduction in platelet count. It is difficult to diagnose because there is no conclusive test for the condition.1,2 This article covers the diagnostic criteria for immune thrombocytopenia, differential diagnoses, and lab tests that may be involved in a typical ITP workup.

<h2>ITP diagnosis: from idiopathic thrombocytopenic purpura to immune thrombocytopenia</h2>
Previously, the abbreviation “ITP” referred to idiopathic thrombocytopenic purpura. However, as the understanding of the condition grew, it was found that the <a href="https://pro.campus.sanofi/itp/articles/mechanism-of-disease-and-pathophysiology-of-itp">pathogenesis of ITP</a> involved the production of autoantibodies against platelet glycoproteins. In addition, not all patients presented with purpura at the time of diagnosis. Therefore, the abbreviation ITP now stands for immune thrombocytopenia to more accurately reflect the disease.1
Currently, there is no “gold standard” test that can diagnose immune thrombocytopenia. ITP diagnosis is often made by excluding other causes of isolated thrombocytopenia using methods such as evaluation of patient history, blood count, and evaluation of peripheral blood film.2

<h2>Diagnostic criteria for ITP</h2>
Primary ITP is typically defined as a <a href="https://pro.campus.sanofi/itp/articles/itp-platelet-counts">platelet count</a> of less than 100x109/L (100,000/μL) with no evidence of leucopenia or anaemia, and when all other causes of thrombocytopenia—such as certain drugs, liver diseases, or pseudothrombocytopenia—have been ruled out.1,2 Patients with ITP can be asymptomatic despite low platelet counts, but the risk of bleeding appears to increase when platelets drop below 20 x 109/L.1,2

<h3>Diagnosing primary vs secondary ITP</h3>
Immune thrombocytopenia can be categorised into primary and secondary ITP depending on the cause of the condition3:&nbsp;
<ul>
 <li>Secondary ITP: This form of immune thrombocytopenia occurs due to an inciting factor. This can be a drug, an infection such as H. pylori, or other malignancies. The ITP differential diagnosis process often involves testing for these causes.4</li>
 <li>Primary ITP: When all possible causes of secondary immune thrombocytopenia are ruled out, the patient is diagnosed with primary ITP. The cause here can be idiopathic or autoimmune-system mediated.4</li>
</ul>

<h3>Differential diagnosis</h3>
The differential diagnosis workup for immune thrombocytopenia involves testing for conditions with symptoms&nbsp;that may overlap with ITP. 3
<figure class="table">
 <table style="border:2px solid #932c87;">
 <tbody>
 <tr>
 <td>
 Differential diagnoses of thrombocytopenia include3:
 <ul>
 <li>Drugs including chemotherapy, heparin, PD-1 inhibitors, and alcohol abuse</li>
 <li>Bone marrow disorders including myelodysplastic syndromes, leukemias, and aplastic anaemia</li>
 <li>Recent transfusions or vaccinations</li>
 <li>Inherited thrombocytopenias including TAR syndrome, congenital amegakaryocytic thrombocytopenia, and Type IIB or platelet-type von Willebrand disease</li>
 <li>Infections like HIV, hepatitis B, or hepatitis C</li>
 <li>Autoimmune/immunodeficiency disorders like CVID or lupus erythematosus</li>
 <li>Malignancies</li>
 <li>Other thrombocytopenic disorders like TTP, DIC, or HUS</li>
 </ul></td>
 </tr>
 </tbody>
 </table>
</figure>

Adapted from Kashiwagi H, et al. Int J Hematol. 2024;119(1):1-13.5

<h3>Diagnosing acute, chronic, and persistent ITP</h3>
Immune thrombocytopenia can be further categorised into acute, chronic, and persistent forms depending on the duration of disease. Some classifications and guidelines also consider newly diagnosed ITP and severe ITP as distinct forms.6,7&nbsp;
<ul>
 <li>Acute ITP: Also known as short-term ITP, this refers to ITP where symptoms resolve in 12 months or less.6,7 </li>
 <li>Newly diagnosed ITP: Patients with ITP diagnosed in the past 3 months are said to have newly diagnosed ITP.6,7 </li>
 <li>Persistent ITP: Patients diagnosed with ITP in the past 3-to-12 months, who have not reached spontaneous remission, or are not maintaining a complete response off-therapy, are said to have persistent ITP.6,7 </li>
 <li>Chronic ITP: ITP is termed as chronic when the disease persists for 12 months or more.6,7 </li>
 <li>Severe ITP: Severe ITP is characterised by bleeding at presentation at levels sufficient to mandate treatment. Severe ITP may also necessitate the use of a new platelet-enhancing therapy or an increased dose of current treatment to control symptoms.6,7&nbsp;&nbsp;</li>
</ul>

<h2>Tests used in an immune thrombocytopenia workup</h2>
As ITP is diagnosed based on medical history and a process of exclusion, every diagnosis journey looks different.4
Typical factors used to inform an immune thrombocytopenia diagnosis include1,4:&nbsp;
<ul>
 <li>Medical history: Analysis of personal history with a focus on drugs and medical conditions that have the potential to cause thrombocytopenia.</li>
 <li>Family history: ITP is generally not an inherited disorder, so a family history of thrombocytopenia or other bleeding disorders can indicate another, possibly inherited cause of thrombocytopenia.</li>
 <li>Physical exam: Presence of conditions like lymphadenopathy or hepatosplenomegaly may suggest other underlying causes of thrombocytopenia. Children with ITP are usually well-appearing except for bruising symptoms associated with thrombocytopenia, while two-thirds of adults show a wide range of bleeding symptoms.</li>
</ul>
The exact lab workup varies due to the individualised nature of ITP differential diagnosis; however, some of the lab tests that can be used are listed below.1,4

<h3>Blood tests</h3>
The first step in ITP diagnosis is the determination of isolated thrombocytopenia. The defining feature of thrombocytopenia is a low platelet count (below 150,000/μL), which can be determined through a complete blood count, and a blood smear.8
<ul>
 <li>Complete Blood Count (CBC): CBC is used to measure the level of platelets in the blood.8</li>
 <li>Blood smear: The presence of giant platelets in a blood smear, caused by increased platelet turnover and release of immature forms into circulation can indicate immune thrombocytopenia.8</li>
</ul>

<h3>Ultrasound</h3>
Ultrasound can be used to assess the size of the spleen, to exclude splenomegaly as the cause of thrombocytopenia. The presence of fatty liver and splenomegaly may indicate a diagnosis other than immune thrombocytopenia.9

<h3>Coombs test and quantitative immunoglobulin analysis</h3>
A direct antiglobulin test (DAT), or direct Coombs Test, is used to analyse the presence of antibodies circulating around red blood cells (RBCs) that can induce haemolysis. It can also be used to determine the safety of immunoglobulin therapy and other immune-modifying treatments. Studies show that a positive DAT has a known association with chronic ITP.10,11

<h3>Screening for thrombocytopenia-associated infections</h3>
Some bacterial and viral infections can induce thrombocytopenia or secondary immune thrombocytopenia. Screening for these infections can help rule out primary immune thrombocytopenia. Some of these infections include4:&nbsp;
<ul>
 <li>HIV</li>
 <li>Hepatitis C</li>
 <li>Helicobacter pylori</li>
 <li>Epstein-Barr virus&nbsp;</li>
</ul>

<h3>Bone marrow biopsy</h3>
Bone marrow biopsies can be used to distinguish between immune thrombocytopenia and other haematological malignancies. However, they are not commonly used in children and adults unless clinical examination suggests the presence of conditions such as neutropenia, leucocytosis, or bone marrow failure. Bone marrow analysis is also recommended if the patient is unresponsive to immunotherapy.4

<h3>Thrombopoietin (TPO) tests</h3>
In people with ITP, thrombopoietin levels are normal or slightly elevated. In some cases, measuring thrombopoietin levels can be helpful to distinguish between immune thrombocytopenia and hypoplastic thrombocytopenia.5

<h2>Considering ITP treatment options</h2>
While platelet levels are useful in diagnosing ITP, they are not the only factor governing bleeding symptoms and management. Studies show that people with similar platelet levels do not necessarily show the same incidence of bleeding symptoms.12,13
As such,&nbsp;<a href="https://pro.campus.sanofi/itp/articles/treating-itp">ITP treatment</a> decisions should consider more than just platelet levels. Beyond bleeding, ITP can increase risk of thrombosis and has numerous effects on patients’ lives, including fatigue, anxiety, depression, and headaches. Patients with chronic ITP may become so accustomed to a life with reduced quality of life, that they believe it is their “normal.”14
A holistic understanding of the disease and the patient is required for their treatment. Options that act on the immune dysregulation in ITP can potentially benefit patients.15

APS, antiphospholipid syndrome; CVID, common variable immune deficiency; DIC, disseminated intravascular coagulation; GP, platelet glycoprotein; HIV, human immunodeficiency virus; HUS, hemolytic-euremic syndrome; IPF, immature platelet fraction; MDS, myelodysplastic syndrome; PD-1, programmed cell death 1; &nbsp;RP, reticulated platelets; SLE, systemic lupus erythematosus; TAR, thrombocytopenia-absent radius; TPO, thrombopoietin; TTP, thrombotic thrombocytopenia purpura; ULN, upper limit of normal.

Understanding an ITP Diagnosis

The complex immune dysregulation of ITP can impact platelet counts, bleeding, and HRQoL.1,3-6
In ITP, dysregulation of immune pathways results in increased platelet destruction and decreased platelet production.7

<h2>Bleeding occurs in around 60% of patients. Bleeding symptoms vary and can include8:</h2>

Petechiae and purpura, usually on the extremities1,9

black

Heavy menstrual bleeding1

Bleeding blisters and epistaxis1,9

Intracranial haemorrhage8

Learn more about how ITP can affect patients’ quality of life

Some ITP patients may experience systemic symptoms, including fatigue, fever, tachycardia, and cognitive effects, such as headaches and memory impairment.1,12-14

<h3>Severe bleeding occurs in 7% to 10% of adult patients and is typically correlated with lower platelet counts.10,11</h3>

<a href="${link:{uuid:{5951058e-a726-4620-a2dc-66df25bdf733},repository:{articles},path:{/Global/indications/itp/treating-itp}}}">Treatment of ITP</a> typically focuses on managing primary symptoms such as petechiae, purpura, and bleeding. However, patients with ITP often experience other symptoms such as fatigue and difficulties with memory and concentration that can profoundly affect their quality of life. That is why it is important to use treatment strategies that help improve HRQoL in ITP patients.1,12-14

<h2>Purpura and petechiae in ITP</h2>
ITP is an autoimmune disorder where easy bruising, petechiae and purpura often appear as common symptoms—typically in lower extremities. Petechiae and purpura occur due to bleeding under the skin or mucous membranes.15,16
<h3>Petechiae in thrombocytopenia</h3>
Petechiae are small, non-blanching red or purple pinpoint lesions, usually less than 2 mm, that appear on the skin and mucous membranes. Petechial rashes result from bleeding into the skin’s dermal layer.15,17
<h3>Purpura in thrombocytopenia</h3>
Purpura refers to larger areas of cutaneous bleeding, which appear as purple or red patches on the skin that measure greater than 2 mm in size.15,17
In patients with ITP, purpura can appear due to even minor trauma or spontaneously due to low platelet levels. Purpura can also appear in mucosal membranes such as the hard palate, nasal septum, or gums, which can lead to bleeding gums.15,16,18

<h2>Other ITP bleeding symptoms and complications of thrombocytopenia</h2>
A low platelet count can lead to certain types of bleeding symptoms in ITP patients, including nose bleeds (epistaxis), gum bleeds (gingival), mouth blood blisters, blood in urine or stools, and heavy menstrual bleeding.9,19
Platelet levels &lt;10,000/μL could be associated with spontaneous widespread haematomas, and severe bleeding in ITP usually occurs when the platelet count is &lt;10 (x109/L). Severe bleeding can manifest as intracranial haemorrhages, gastrointestinal tract bleeds, and macroscopic haematuria. In some studies, severe bleeding occurred in approximately 7% to 10% of adult patients and typically correlated with lower platelet counts.10-12,16,20,21
<h3>ITP and intracranial haemorrhaging (brain bleed)</h3>
Intracranial haemorrhaging (ICH) is a rare and serious complication of ITP. The incidence of ICH in ITP patients is 1.54% in all ages.19,20,22,23
ICH symptoms that are a cause for concern include headache, persistent vomiting, altered mental status, and seizures. Risk factors for ICH include extremely low platelet counts of &lt;10,000/μL, head trauma, antiplatelet medication use, and severe bleeding.19,20,22,23

<h3>The symptoms of ITP go beyond bleeding</h3>
Learn more about the less visible symptoms of ITP and <a href="${link:{uuid:{9d762c77-664a-467f-a4f0-78211ab9453e},repository:{articles},path:{/Global/indications/itp/living-with-itp}}}">how they impact ITP patients’ quality of life</a>.&nbsp;

<h2>Primary ITP is a <a href="https://pro.campus.sanofi/itp/articles/diagnosing-itp">diagnosis</a> of exclusion7,24,25</h2>
<ul>
 <li>Platelet counts &lt;100,000/μL can indicate ITP</li>
 <li>Platelet counts &lt;50,000/μL can indicate severe thrombocytopenia</li>
</ul>
<h3>But the lack of a specific test means other potential causes of thrombocytopenia must be ruled out7,24,26,27</h3>
Causes of secondary ITP include7,24,26,27:
<ul>
 <li>Chronic lymphocytic leukaemia (CLL)</li>
 <li>Helicobacter pylori infection</li>
 <li>COVID-19 infection</li>
</ul>
<h3>ITP is further classified as either newly diagnosed, persistent, or chronic27:</h3>

Low platelet counts are one facet of ITP, but when we look at it from another angle, we see the multiple dimensions of ITP. Immune thrombocytopenia (ITP) is a condition of complex immune dysregulation that reduces platelet counts—causing bleeding, bruising, fatigue, and other health-related quality-of-life (HRQoL) issues—while increasing inflammation and the risk of thromboembolic events (TEs).1-5

Defining ITP: Signs and Symptoms

<h2>Living with ITP beyond platelets: fatigue, quality of life, and impact measures</h2>
In a study, patients living with ITP rated their health-related quality of life (HRQoL) significantly worse than the general US population. They also reported worse HRQoL than patients living with hypertension, arthritis, or cancer, and similar to that of patients living with diabetes.1*
<h3>ITP can impact patient HRQoL in multiple ways, including:&nbsp;</h3>

<h3>Fatigue</h3>
Reported as severe by patients with ITP, often regardless of platelet counts2

<h3>Heavy menstrual bleeding</h3>
Rated by patients and doctors as one of the most severe ITP symptoms2

<h3>Thromboembolic events (TEs)</h3>
Compared to patients without ITP, there is up to a 2x higher risk of TEs3

<h3>Cerebral microbleeds (CMBs)</h3>
Associated with lower platelet count and longer disease duration4

*The study used the Short-Form 36 questionnaire to evaluate the HRQoL of 73 adult ITP patients compared with that of the general US population and of patients with 6 other relatively common chronic disorders.1

<h2>Fatigue is common and can be severe in patients with ITP2</h2>
In the Immune Thrombocytopenia World Impact Survey (I-WISh)† of 1507 patients and 472 physicians, patients rated functional, psychological, and emotional aspects of their condition. In I-WISh2:

58% of patients reported fatigue at diagnosis (n=870/1507),2&nbsp;

and 73% of those patients rated fatigue as severe (n=637/870)2

<h4>Even in patients with low disease activity, prevalence of severe fatigue exists, and fatigue persists even after platelet counts have increased. Disease activity alone does not explain variance in ITP.2,5</h4>
<h3>Factors that may play a role in fatigue5,6:</h3>
<ul>
 <li>Inflammation</li>
 <li>Physical and functional well-being</li>
 <li>Physical activity</li>
</ul>
Research shows that ITP is also linked to reduced activity and a notable increase in general, mental, and physical fatigue.7,8&nbsp;
The exact causes of fatigue and the underlying pathophysiology are not fully understood. However, ITP-related excessive and prolonged bleeding leads to iron deficiency and anaemia, which can be contributors to fatigue. Learn more about the <a href="${link:{uuid:{c74a8bbe-8c42-444b-b7ca-84850a1d0137},repository:{articles},path:{/Global/indications/itp/mechanism-of-disease-and-pathophysiology-of-itp}}}">causes and pathophysiology of ITP</a>.6,9,10
Furthermore, ITP-related activity restrictions can result in frustration, social withdrawal, and mood decline.7,11

—Male living with ITP, Germany

†I-WISh was an online, cross-sectional survey of patients with ITP and haematologists or haemato-oncologists who treat patients with ITP in 13 countries. The patient questionnaire collected information on demographics and diagnosis, symptoms of ITP, HRQoL and emotion associated with ITP, impact of ITP on work, finances, and support, treatment received, and patient and physician relationship. The physician survey comprised 6 sections that collected information on demographics, diagnosis of ITP and patient caseload, symptoms of ITP, impact of ITP on aspects of patients’ physical, emotional, HRQoL, social health, treatment patterns, and patient and physician relationship. There were 2 questions about the emotional impact of ITP, and the responses were based on a 7-point Likert scale (1 = never, 7 = a great deal). There was 1 additional question on the need for professional support.7

<h2>Heavy menstrual bleeding can have a major negative impact on patient HRQoL2</h2>

45% of women with ITP reported heavy menstrual bleeding at diagnosis,2

and 83% of those said it was one of their most severe symptoms2

<h2>Thromboembolic events (TEs) are also more common among patients with ITP3</h2>

Patients with ITP face up to a 2x higher risk of TEs compared to patients without ITP3‡
<h3>Risk factors for TEs in ITP12:</h3>
<ul>
 <li>Mechanisms of ITP itself</li>
 <li>Patient comorbidities and past history</li>
 <li>Current ITP treatments patient may be taking</li>
</ul>
‡Adjusted risk ratio of 1.7 in a retrospective cohort study of 1140 patients with ITP and 5657 patients without ITP.3

<h2>Patients with ITP might also suffer from cerebral microbleeds4</h2>

CMBs were associated with lower platelet count and longer disease duration. The strong association between CMBs and ITP duration could indicate that CMBs may accumulate over time.4

In a 2020 study published in Blood,§ 43% of patients with ITP had CMBs (n=21/49)4

§A cross-sectional prospective study of 49 patients with ITP and nadir platelet counts &lt;30,000/μL and 18 age-matched healthy controls that used susceptibility-weighted magnetic resonance imaging (MRI) to detect CMBs as a marker of occult haemorrhage.4

<h3>Neurological symptoms and cognitive effects of immune thrombocytopenia</h3>

Neurological manifestations in ITP without clinically significant bleeding are rare.14
However, patients with ITP might also suffer from cognitive impairment.14

50% of patients with ITP experience some level of cognitive impairment (N=69)13

<h3>Can ITP cause headaches?</h3>
Individuals&nbsp;with ITP can suffer from headaches and migraines. A sudden headache in ITP patients can also be an indication of the rare but severe complication of intracranial haemorrhage (ICH), which can cause other neurological symptoms.2,15-17

Assessing fatigue in ITP patients

Patients reported significant quality of life (QoL) challenges related to their immune thrombocytopenia (ITP).1

Living With ITP

<h3>ITP Patient-Reported Outcomes Assessment Questionnaire (ITP-PAQ)5,6</h3>
ITP-PAQ is a validated tool that was designed to measure the health-related quality of life (HRQoL) and treatment impact specifically for patients diagnosed with ITP.
The questionnaire typically evaluates various aspects of life affected by ITP, such as emotional well-being, and physical and social functioning. Additionally, the survey aids in assessing symptoms and their severity, including bruising and bleeding.&nbsp;
The ITP-PAQ facilitates a better overall understanding of how ITP affects individuals beyond clinical measures alone and their HRQoL.
<h3>ITP Life Quality Index (ILQI)1,6</h3>
The ILQI is a validated 10-item questionnaire that was developed to aid clinical discussions between patients and physicians about patients’ disease experiences, facilitating a patient-centric approach toward treatment decision-making. The ILQI typically involves surveys or questionnaires that patients complete, detailing their experiences, symptoms, and how these affect their quality of life.

<h3>Modified Fatigue Impact Scale (MFIS)2,7</h3>
The MFIS measures the impacts of fatigue on physical, cognitive, and psychosocial functioning.&nbsp;
This validated scale consists of a series of statements related to fatigue and its impact over a longer time, usually 4 weeks. The respondents rate their experiences over this period. The total scoring can then help healthcare providers understand the severity of fatigue and its effects on daily functioning. &nbsp;
In contrast to the MFIS, the daily fatigue impact scale (D-FIS) is a scoring tool to measure the short-term impact of fatigue in everyday life.
<h3>The Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F)4,8</h3>
The FACIT-F is a validated scale that provides a 13-item tool to determine self-reported fatigue and its impact on daily activities and function.&nbsp;
The questionnaire includes questions regarding the intensity and frequency of fatigue, its effects on social and personal activities, and overall energy level.&nbsp;
<h3>The Daytime Sleepiness Scale3</h3>
The daytime sleepiness scale is often represented by the validated Epworth Sleepiness Scale (ESS), a scale used to evaluate patients for excessive daytime sleepiness. The questionnaire measures how likely someone falls asleep in various situations.

For immune thrombocytopenia (ITP) patients, several scales are available to measure and track fatigue and its impact on quality of life. These tools can help patients and healthcare providers gauge symptoms and adjust their ITP treatment accordingly.1-4

Assessing Fatigue in ITP Patients

In immune thrombocytopenia (ITP), immune dysregulation lowers platelet counts through multiple pathways. Autoreactive B cells produce autoantibodies that target platelets for destruction by macrophages and impair megakaryocyte maturation, reducing platelet production. Autoantibodies may also destroy platelets through other mechanisms.1-6
Immune system activity can also lead to elevated levels of inflammatory markers.1-6

Adapted from Kashiwagi H, et al. Int J Hematol. 2013;98(1):24-33. © Japanese Society of Hematology (JSH).1

Treatments designed to achieve multi-immune modulation aim to better address the multiple dimension of ITP7,8

<h3>Watch the mechanism of disease (MOD) video to learn more about the multiple dimensions of ITP</h3>

Complex immune dysregulation can lead to autoimmunity and inflammation.1-6

Mechanism of Disease & Pathophysiology of ITP

Video Transcript

<h2>Bruton’s tyrosine kinase (BTK) plays a pivotal role in complex immune dysregulation9,10</h2>
B cells are responsible for the production of autoantibodies; macrophages are essential for phagocytosis; and the NLRP3 inflammasome plays a key role in systemic inflammation. All of these processes are regulated by BTK.9,10
<ul>
 <li>In B cells: The BTK pathway is crucial for proliferation, differentiation, and autoantibody production9,10</li>
 <li>In macrophages: Various signalling pathways dependent on BTK drive phagocytosis, degranulation, and the production of inflammatory cytokines9,10</li>
 <li>Systemically: BTK drives the production of mediators of inflammation like NLRP3 inflammasome, which can contribute to platelet destruction and systemic inflammation9,10</li>
</ul>

Patients living with ITP have elevated inflammatory markers, including10:
<ul>
 <li>TNF-α and IFN-γ</li>
 <li>IL-2 and IL-6</li>
 <li>NLRP3 inflammasome cytokines IL-1β and IL-18</li>
</ul>
BTK is implicated in the production or activation of these inflammatory markers and is a critical driver of inflammation.10
<h3>Other signalling pathways involved in the pathogenesis of ITP8</h3>
With incremental understanding of molecular mechanisms driving ITP pathology, it is becoming increasingly clear that multiple signalling pathways are involved in the pathogenesis and manifestation of the disease.8

ITP is about more than platelets

BCR, B-cell receptor; Fc, fragment crystallisable; IFN, interferon; IL, interleukin; NLRP3, nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF, tumour necrosis factor.

<h2>Causes and pathophysiology of ITP1-4,8,11,12</h2>
ITP has an estimated prevalence of up to 9.5 per 100,000 people. The causes and pathophysiology of ITP, historically called idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura, are multifactorial and trigger a wide range of symptoms.
The pathophysiology of ITP is complex, involving various immune cells and different organs. Platelet destruction and inhibition of thrombopoiesis (platelet production) are key drivers of the disease. Current treatments for ITP aim to target these mechanisms of immune thrombocytopenia.
Our understanding of the pathophysiology of ITP is expanding and opening up new treatment possibilities for more targeted therapies and overall disease control.
<h3>What are the causes of ITP12-14</h3>
The cause of ITP in adults can be differentiated by whether the disease is primary or secondary ITP.&nbsp;
In primary ITP, the underlying causes remain unidentified—this is why it was previously known as idiopathic thrombocytopenic purpura. This is the most common cause of ITP, with approximately 80% of ITP patients diagnosed with primary ITP.&nbsp;
In contrast, secondary ITP is caused by known factors such as certain medications, infections, or cancers.&nbsp;
It is often associated with persistent autoimmunity and underlying autoimmune diseases including systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS).&nbsp;
Chronic ITP is characterised by the persistence of symptoms for more than 12 months after the initial diagnosis. Chronic ITP is more common in adults than in children. Recent studies suggest genetic factors, including polymorphisms in cytokine receptor genes and genes regulating T cell activity, may influence the susceptibility for chronic ITP. However, more research is needed to fully understand the causes of chronic ITP.

Treating ITP

Complex immune dysregulation can lead to autoimmunity and inflammation.1-6

<h2>ITP treatment and management1,2</h2>
Many ITP patients without severe bleeding could be managed by observation and may only require pharmacological interventions when their platelet count falls below 20-30 (x109/L).1,2
More information on how healthcare providers can create an individualised ITP treatment plan can be found in the <a href="https://pro.campus.sanofi/global/itp/articles/treatment-guidelines">ITP diagnosis and treatment guidelines</a>.

<h3>Treating ITP with pharmacological interventions3-10</h3>
Current ITP therapies aim to address thrombocytopenia only by preventing bleeding and increasing low platelet counts. Whilst ITP-related bleeding is common, only in rare cases is it life-threatening.&nbsp;
There remains an unmet need for therapies that address multiple targets contributing to <a href="${link:{uuid:{c74a8bbe-8c42-444b-b7ca-84850a1d0137},repository:{articles},path:{/Global/indications/itp/mechanism-of-disease-and-pathophysiology-of-itp}}}">the underlying immune dysregulation driving ITP</a> instead of just the primary symptoms.

<h4>Corticosteroids for ITP1,2,11</h4>
For many patients, corticosteroids are the recommended first-line treatment for ITP. The therapy may be initiated in newly diagnosed adult patients without severe bleeding when their platelet count falls below a threshold between 30 (x109/L) to 20 (x109/L).
Corticosteroids may ameliorate platelet counts by broadly suppressing the activity of the autoreactive immune system, thereby reducing the generation of autoantibodies against platelets.&nbsp;
The medication starts to exert its function within 2-14 days and has a response rate of 60-80%. However, only 30-50% of patients show a durable response when the medication is discontinued, and permanent remissions are uncommon.&nbsp;
Corticosteroids may cause side effects in most patients, including negative impact on mental health, hypertension, muscular atrophy, and glaucoma.
<h4>Thrombopoietin receptor agonists (TPO-RA) for ITP</h4>
TPO-RA are usually indicated for second-line treatment in treatment-resistant patients with new, persistent, and chronic ITP. They can also be used as an emergency treatment.1,2,11,12&nbsp;
TPO-RA stimulate thrombocytopoiesis in megakaryocytes. Effects are seen after 3-14 days depending on the specific drug used, with response rates varying between 65-80% and only 8-32% of patients experiencing a durable response after stopping the medication.2,11,12
TPO-RA cause various side effects such as thrombosis, transaminitis skin reactions, and gastrointestinal problems.2,11,12

<h4>Targeted immunotherapy for ITP1,2,11,12</h4>
Targeted immunotherapy is used as a second- or third-line treatment. These drugs might be a suitable option for patients who want to avoid long-term medication and surgery.&nbsp;
Targeted immunotherapy uses antibodies to target the autoantibody-producing B cells, leading to the destruction of the cells.&nbsp;
This therapy starts to exert its function after 7-56 days. 60% of patients initially respond to the treatment, with the effect sustained in 10-40% after the drug is discontinued.&nbsp;
Side effects are usually mild; however, treatment could make patients more susceptible to infections.&nbsp;
<h4>Intravenous immunoglobulin (IVIg) for ITP1,2,13,14</h4>
IVIg quickly elevates platelet levels and could therefore be used as an emergency treatment for ITP. As a first-line treatment, IVIg could also be combined with corticosteroids. However, IVIg treatment for ITP alone has not been reported to provide a durable response.&nbsp;
The detailed mechanism of action of IVIg is currently unknown. It is thought to inhibit phagocytosis of platelets.&nbsp;
Clinically relevant side effects of IVIg can include low blood pressure, arrhythmia, skin reactions, and flu-like symptoms.
<h4>Anti-D immunoglobulin (anti-D) for ITP1,2</h4>
Anti-D immunoglobulin is only available in some countries for the treatment of ITP. It could be used as a first-line treatment. However, the potential side effects could render it unsuitable for most patients without severe bleeding.&nbsp;
Anti-D is an antibody that attaches selectively to rhesus-positive erythrocytes. The interaction leads to the degradation of the erythrocytes by the spleen. The process is thought to interfere with the destruction of platelets and consequently cause an increased platelet count in patients with immune thrombocytopenia.&nbsp;
Serious side effects of anti-D treatment for ITP include intravascular haemolysis.&nbsp;

<h3>Non-pharmacological treatments of ITP</h3>
In addition to medications, non-drug-based interventions are available.

<h4>Splenectomy for ITP1-3,11,12,15</h4>
Splenectomy can be a useful second-line treatment for chronic patients who prefer to avoid long-term medication and aim for a durable response—the success rate of splenectomy for ITP is approximately 80%. A splenectomy should be avoided in the first 12 months of the initial diagnosis since ITP can go spontaneously into remission during the first year. Furthermore, ITP relapse or refractory ITP after a splenectomy affects 30-50% of patients.&nbsp;
A splenectomy can also be used as an emergency treatment.&nbsp;
The spleen plays a dual role in ITP. Splenic macrophages clear platelets covered in autoantibodies while splenic plasma cells are the main producers of autoantibodies against platelets. Therefore, removing the spleen interrupts these processes.
Side effects for ITP patients post-splenectomy include an increased risk of infection with encapsulated bacteria, which requires repeated vaccinations. A large registry-based study showed a higher risk of both early and late sepsis among patients with ITP who had undergone splenectomy than among those who did not. A higher incidence of other vascular complications, such as coronary artery disease, stroke, and chronic thromboembolic pulmonary hypertension, has also been reported among patients who have undergone splenectomy.
<h4>Platelet transfusion for ITP2,11,12,16,17</h4>
Platelet transfusion in combination with IVIg and corticosteroids can be used as an emergency treatment.&nbsp;
The effect of platelet transfusions wanes quickly. In addition, the treatment appears to fail in reducing mortality, and there are only limited studies on the benefits of platelet transfusions in ITP.&nbsp;
It’s important to note that platelet transfusions can induce severe immune responses such as anaphylactic and febrile non-haemolytic transfusion reactions.&nbsp;

<h4>Medication-induced ITP18,19</h4>
Some drugs can trigger ITP. Medications that can induce ITP include quinine, penicillin, heparin, gold salts, sulfonamide antibiotics, and non-steroidal anti-inflammatory drugs. In these cases, stopping the medication should be considered for the management of ITP.
<h4>Lifestyle2</h4>
Some ITP patients may have to adopt lifestyle changes to prevent bleeding. This could include avoiding activities that are associated with an increased risk of bleeding, such as combat and contact sports.

<h3>Emerging treatments for ITP</h3>
Bleeding is only one consequence of ITP, but there is a wide range of <a href="${link:{uuid:{8da50df0-f8f2-4d50-94cc-e30ab2e6b6cf},repository:{articles},path:{/Global/indications/itp/defining-itp-signs-and-symptoms}}}">ITP symptoms</a>&nbsp;that impact the health-related quality of life (HRQoL) of patients.3,20-23
Treatment goals in ITP have shifted from targeting only platelet counts to comprehensive disease control.2
An improved understanding of ITP disease pathophysiology is enabling researchers to develop innovative treatments that target the underlying mechanisms of ITP. Among these are Bruton’s tyrosine kinase (BTK) inhibitors, neonatal Fc receptor (FcRn) blockers, recombinant immunoglobulin multimers, complement inhibitors, plasma-cell–depleting therapies, and B cell activating factor (BAFF) inhibitors.7,11
Learn more about:

Immune thrombocytopenia, or immune thrombocytopenic purpura (ITP), treatment in adults needs to be individualised for each patient based on various factors such as the duration of the disease, age, general health, and importantly, patient preference.1,2

Treating ITP

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