The most common purpuras. Primary immune thrombocytopenia and IgA vasculitis (Henoch-Schönlein purpura)

https://doi.org/10.63149/j.pedint.161

 

Introduction

Purpura is a hemorrhagic lesion of the skin or mucous membranes secondary to extravasation of erythrocytes, resulting from alterations in vascular integrity or from disorders of hemostasis (platelet or coagulation).

Purpura is an elementary dermatologic lesion of hemorrhagic type, resulting from the extravasation of erythrocytes into the skin or mucous membranes. It manifests as red-violet lesions that, unlike erythematous lesions, do not blanch on diascopy (vitropressure). According to their size, they are classified as petechiae (< 2-5 mm) and ecchymoses (> 5 mm); a hematoma additionally involves swelling of the surrounding tissue. Although they often result from trivial causes such as trauma, their appearance may be the first manifestation of a serious disease, so they always require a systematic etiologic evaluation.

Primary hemostasis is the physiologic mechanism responsible for forming the initial platelet plug after vascular injury. It depends on the interaction of three components: the vascular wall (endothelium and subendothelium), the platelets, and von Willebrand factor (VWF), which acts as a bridge between platelets and the exposed subendothelial collagen. Alterations in any of these three elements give rise to the so-called purpuric diseases, whose characteristic clinical expression is mucocutaneous bleeding (petechiae, ecchymoses, epistaxis, gingival bleeding), in contrast to disorders of secondary hemostasis (coagulopathies), which tend to manifest as deep bleeding (hemarthrosis, muscle hematomas).

Among the most common causes of purpura in childhood, three major groups can be distinguished (see Algorithm 1 at the end of the article). First, the thrombocytopenias, which constitute the most common cause of purpura due to a disorder of primary hemostasis. Thrombocytopenia may be of central origin (impaired production) or peripheral origin (destruction, consumption, or sequestration), and congenital or acquired, with the acquired forms being the most common. It is important to remember that, although the normal platelet range is above 150,000/µL, spontaneous bleeding does not usually appear until counts fall below 30,000/µL; the presence of bleeding manifestations with relatively preserved counts should raise suspicion of a central component or an associated platelet function disorder, such as a thrombocytopathy. Second, von Willebrand disease, which, although it is the most prevalent inherited bleeding disorder, more often manifests as mucosal bleeding than as frank purpura. Finally, the vascular causes, in which the integrity or function of the vascular wall is compromised by infectious, inflammatory/immune (vasculitis), or structural mechanisms (connective tissue diseases, scurvy).

Of all these, the two entities that most frequently cause purpura in the pediatric age group are primary immune thrombocytopenia (ITP) and IgA vasculitis (IgAV), also known as Henoch-Schönlein purpura. This article reviews the pathophysiology, diagnosis, and management of both.

Immune thrombocytopenia

Introduction

Immune thrombocytopenia is an acquired autoimmune disorder characterized by accelerated platelet destruction and generally has a benign course.

Primary immune thrombocytopenia (ITP) is defined as isolated thrombocytopenia (<100,000/µL) in the absence of other causes that would account for it(1). It is the most common cause of acquired thrombocytopenia in childhood.

According to the terminology of the International Working Group(1), in effect since 2009, it is classified as: newly diagnosed ITP (up to 3 months’ duration), persistent ITP (3 to 12 months’ duration), and chronic ITP (more than 12 months’ duration). Severe ITP is defined as the presence of active bleeding that requires treatment or the addition of a new therapeutic agent.

Epidemiology

ITP has an incidence of 2-5 cases per 100,000 children/year(2), with a peak between 2 and 5 years of age.

The estimated incidence is 2-5 cases per 100,000 children/year. It occurs most frequently between 2 and 5 years of age. In younger children there is a slight male predominance that equalizes or reverses in adolescence, where cases tend to follow a more chronic course(3,4). A history of a viral infection or vaccination in the 2-4 weeks preceding onset is common.

Etiopathogenesis

The main mechanism is the production of autoantibodies directed against platelet membrane glycoproteins (GPIIb/IIIa and GPIb/IX), with an additional role for cellular immunity and inhibition of megakaryopoiesis.

The pathogenesis of ITP involves autoantibody-mediated platelet destruction (primarily IgG directed against the glycoproteins GPIIb/IIIa and GPIb/IX) and cytotoxic T lymphocytes through direct destruction of platelets and megakaryocytes(5,6). Regulatory T lymphocytes are decreased and there is a Th1/Th2 and Th17/Treg imbalance(5). In addition, in some cases there may be possible platelet destruction in the liver(7).

Likewise, it has been shown that autoantibodies, particularly anti-GPIb/IX, can inhibit platelet production in the bone marrow by interfering with megakaryocytic maturation. Thrombopoietin (TPO) levels are normal or slightly elevated but inappropriately low for the degree of thrombocytopenia, which supports the use of TPO receptor agonists as a therapeutic strategy(6).

Clinical features

The typical presentation is a previously healthy child between 2 and 5 years of age(8) with the abrupt onset of petechiae and ecchymoses without other symptoms.

The most common presentation is a previously healthy child aged 2-5 years(8) who abruptly develops diffuse cutaneous petechiae and ecchymoses. The child is in good general condition, without hepatosplenomegaly or significant lymphadenopathy, and the physical examination is normal except for the purpuric lesions.

Mucosal bleeding (epistaxis, gingival bleeding, hematuria) is less common and generally mild. Severe bleeding (intracranial hemorrhage, massive gastrointestinal bleeding) is rare, with an estimated incidence of 0.1-0.5% in pediatric ITP(9). Intracranial hemorrhage, the most feared complication, occurs with very low platelet counts (<10,000-20,000/µL) and generally when other risk factors coexist. It is extremely uncommon for it to occur spontaneously, without trauma.

Fatigue has been recognized as a relevant symptom in pediatric ITP, present even with relatively normal platelet counts. Recent studies have shown that fatigue significantly affects the quality of life of children and adolescents with ITP and should be taken into account in therapeutic decision-making, especially in chronic ITP(10).

Diagnosis

The diagnosis of ITP is one of exclusion. There is no confirmatory diagnostic test.

The diagnosis is based on the presence of isolated thrombocytopenia (<100,000/µL) in a child with a normal physical examination (except for the hemorrhagic manifestations) and on the exclusion of other causes. It is very important to obtain a thorough personal and family history, with emphasis on inherited thrombocytopenias and autoimmune diseases.

The 2019 American Society of Hematology guidelines (ASH 2019)(4) and their 2022 update(11) recommend: a complete blood count with peripheral blood smear as the fundamental test; a direct Coombs test; basic chemistry, coagulation study, and urinalysis; quantification of immunoglobulins to rule out underlying immunodeficiency; and viral serologies. Bone marrow aspiration is not necessary at diagnosis in the typical presentation(12).

Antiplatelet antibodies have relatively high specificity but low sensitivity (50-60%), so their determination is not recommended routinely.

Differential diagnosis

The differential diagnosis includes other causes of thrombocytopenia, and special attention should be paid to warning signs that suggest a more serious etiology.

It is essential to differentiate ITP from other causes of thrombocytopenia (Table I). The main warning signs are: impaired general condition, persistent fever, or systemic symptoms; hepatosplenomegaly or significant lymphadenopathy; involvement of other hematologic cell lines; a family history of thrombocytopenia; macro- or microthrombocytopenia suggestive of a congenital disorder; association with microangiopathic hemolytic anemia (HUS, TTP); and purpura with an atypical distribution that might suggest child abuse.

In adolescent patients, especially females, it is important to rule out autoimmune diseases such as systemic lupus erythematosus (SLE). In patients under one year of age, we should consider congenital thrombocytopenias or immunodeficiencies.

The mean platelet volume (MPV), the immunoglobulin values, or the presence of symptoms or a family history of autoimmune diseases can help in the differential diagnosis(13,14). Thus, for example, a very small MPV in a male patient with a history of dermatitis makes it necessary to rule out Wiskott-Aldrich syndrome.

Treatment

According to the ASH 2019 guidelines and the 2018 guidelines of the Spanish Society of Pediatric Hematology and Oncology (SEHOP ITP 2018), observation is recommended as initial management in children with newly diagnosed ITP who have no bleeding or bleeding limited to the skin.

Newly diagnosed ITP

The initial management of pediatric ITP has undergone a paradigm shift toward a more conservative approach. The ASH 2019 guidelines(4), confirmed in their 2022 update(11), and the SEHOP ITP-2018 protocol(15) recommend observation without treatment as first-line management in children with exclusively cutaneous bleeding, without mucosal bleeding or hemorrhagic risk factors, regardless of the platelet count.

This recommendation is based on the fact that most episodes of childhood ITP are self-limited and resolve within a few weeks or months, without the need for treatment. Evidence accumulated since the ASH 2019 guidelines has shown that this strategy significantly reduces hospitalizations and the use of IVIG without increasing serious adverse events(11).

When a decision is made to treat (mucosal bleeding, risk factors, active bleeding with platelets <30,000/µL), the first-line options are: corticosteroids (oral prednisone/prednisolone 2 mg/kg/day for 5-7 days) and IVIG (0.8-1 g/kg as a single dose). In life-threatening bleeding, one must act urgently, combining IVIG, IV corticosteroids, platelet transfusion (which is not recommended routinely except in this situation), and hemostatic measures.

Persistent and chronic ITP

Thrombopoietin receptor agonists (eltrombopag and romiplostim) have become established as second-line treatment in pediatric patients ≥ 1 year of age with ITP of more than 6 months’ duration, ahead of rituximab and splenectomy.

Approximately 20-30% of children with ITP develop a persistent or chronic form. Management should be individualized, considering the bleeding manifestations, quality of life (including fatigue), and the preferences of the patient and family(4,16).

Thrombopoietin receptor agonists (TPO-RAs) are the preferred second-line option in children. Eltrombopag (oral, dose of 25-50 mg/day, response rates of 62-80%) and romiplostim (subcutaneous, dose 1-10 µg/kg/week, 89% response) show sustained responses of around 50%(17,18) and can delay the use of rituximab and splenectomy(15,19). In addition, gradual tapering and discontinuation of TPO-RAs can be carried out safely in pediatric patients with chronic ITP once they have achieved a sustained complete response(20).

TPO-RAs are recommended before rituximab because they are non-immunosuppressive, have a good safety profile, and have potentially reversible effects.

Rituximab, as off-label use, has an initial response rate of 60-70% but only 20-30% in the long term. It is reserved for patients who do not respond to TPO-RAs. In combination with dexamethasone, some studies have observed durable remissions in specific subgroups (adolescent females with ITP of <24 months’ duration)(21).

Splenectomy has been shifted to later lines in the treatment algorithm and is reserved for severe refractory chronic ITP, preferably after >12 months of evolution and >5 years of age (because of the risk of sepsis and thrombosis)(15,22). Sustained responses of 70-80%.

Other investigational agents: rilzabrutinib (a BTK inhibitor, phase 2 in adults)(23), efgartigimod and rozanolixizumab (FcRn inhibitors). Fostamatinib(24) (a Syk inhibitor), approved in refractory adults, should not be used in the pediatric population because of growth-related adverse reactions (growth plate dysplasia).

The available treatments are detailed in table II (see Algorithm 2 at the end of the article).

It is advisable to refer complicated refractory chronic patients to specialized centers.

Course and prognosis

Most children with ITP recover spontaneously. Between 20% and 30% develop chronic ITP, with a higher risk in adolescents and in those with an insidious onset.

Pediatric ITP generally has a favorable prognosis. Between 60% and 70% of children recover within the first 6 months. Factors associated with progression to chronicity include, depending on the series: age >4 or 10 years, female sex, insidious onset, platelet count at diagnosis >20,000/µL, and ANA positivity(3,25,26). The risk of severe bleeding is low (0.1-0.5%), with an incidence of intracranial hemorrhage of 0.1-0.2%(9).

IgA vasculitis (Henoch-Schönlein purpura)

Introduction

IgA vasculitis is the most common vasculitis in childhood. It is a leukocytoclastic small-vessel vasculitis mediated by deposits of immune complexes containing IgA.

IgA vasculitis (IgAV), formerly called Henoch-Schönlein purpura (HSP), is a systemic small-vessel vasculitis characterized by the deposition of immune complexes containing predominantly IgA1 in the vascular wall. It typically affects the skin, joints, gastrointestinal tract, and kidney.

Epidemiology

The incidence is 3-27 cases per 100,000 children/year, with a peak between 3 and 10 years of age, a male predominance (1.5:1), and a seasonal pattern (autumn-winter).

It is the most common vasculitis in the pediatric age group, with an estimated incidence of 3-27 cases per 100,000 children per year. The peak incidence occurs between 3 and 10 years of age, with a slight male predominance (ratio 1.2-1.8:1) and an autumn-winter seasonal pattern(27).

Etiopathogenesis

The pathogenesis involves the deposition of galactose-deficient IgA1 (Gd-IgA1) in the small vessels, frequently triggered by upper respiratory tract infections.

In most cases there is a preceding infectious history. Group A Streptococcus pyogenes is the most frequently implicated agent, along with Mycoplasma pneumoniae, EBV, adenovirus, parvovirus B19 and, more recently, SARS-CoV-2(28). The occurrence of IgAV after vaccinations, including the SARS-CoV-2 vaccine, has also been documented.

The centerpiece of the pathogenesis is galactose-deficient IgA1 (Gd-IgA1), which can form immune complexes with anti-Gd-IgA1 antibodies (IgG or IgA), is deposited in the vascular walls, activates complement (the alternative and lectin pathways), and recruits neutrophils, producing a leukocytoclastic vasculitis(27,29). Genetic susceptibility (polymorphisms in HLA, among others) and the infectious trigger converge to initiate the abnormal immune response, mediated by inflammatory cytokines (IL-6, IL-8, TNF-α) and endothelial damage. Gd-IgA1 levels are increased in most patients and tend to be higher in those with renal involvement(30).

Clinical manifestations

The cardinal manifestations are: palpable purpura (100%), arthritis/arthralgia (60-80%), abdominal pain (50-75%), and renal involvement (20-60%).

Cutaneous manifestations

Cutaneous purpura is the manifestation required for diagnosis (see Algorithm 1 at the end of the article). It is a palpable, symmetric purpura, predominantly on the lower extremities. The lesions appear in successive crops, last 3-10 days, and recur over the following 4-6 weeks. They worsen with standing. They may be accompanied by subcutaneous edema of the scalp, face, dorsum of the hands and feet, perineum, and scrotum.

Joint manifestations

Arthritis or arthralgia occurs in 15-20% as the first symptom and in up to 80% during the course of the disease. It predominates in the large joints of the lower extremities (ankles, knees), is transient, and is neither erosive nor deforming.

Gastrointestinal manifestations

Diffuse colicky abdominal pain occurs in 50-75%. Gastrointestinal bleeding occurs in 20-30%. Intussusception (1-5%) is the most serious complication. Abdominal pain may precede the purpura in 10-20% of cases(31).

Renal manifestations

Renal involvement is the main determinant of the long-term prognosis. It occurs in 20-60% of patients, generally within the first 4-6 weeks.

IgAV nephritis determines the long-term prognosis(27). It occurs in 20-60% of patients, with greater frequency and severity in those >8 years of age. Proteinuria is the most important prognostic marker. The SHARE (Single Hub and Access point for pediatric Rheumatology in Europe)(32), IPNA 2024 (International Pediatric Nephrology Association)(33), and Kidney Disease: Improving Global Outcomes (KDIGO) 2025(34) recommendations emphasize that all patients with IgA vasculitis should be proactively evaluated for renal involvement, both at the time of diagnosis and throughout follow-up (Table III, Fig. 1).

 

Other manifestations

Orchitis (2-35%), central nervous system involvement (headache, seizures), pulmonary involvement (alveolar hemorrhage, exceptional but severe), and uveitis(35).

Diagnosis

The diagnosis is clinical and is based on the criteria of the 2008 Ankara Consensus (EULAR/PRINTO/PRES).

The diagnosis is based on the EULAR/PRINTO/PRES criteria(36) (Table IV). The mandatory criterion is the presence of purpura without thrombocytopenia together with at least one additional criterion: abdominal pain, compatible histopathology, arthritis/arthralgia, or renal involvement.

The initial workup includes: complete blood count, coagulation study, ESR, CRP, renal and hepatic profiles, urinalysis, and fecal occult blood. If proteinuria is present, the urine protein/creatinine ratio should be determined on a first-morning specimen. In more equivocal cases, the autoimmune panel may be expanded (ANA, ANCA, immunoglobulins, C3, C4).

Common findings include leukocytosis with neutrophilia, elevation of acute-phase reactants, and elevated IgA in half of patients. The basic coagulation study will be normal. Thrombocytopenia should prompt reconsideration of the diagnosis.

Skin biopsy, in an atypical presentation, shows leukocytoclastic vasculitis with predominant IgA deposition. Renal biopsy is indicated in severe renal involvement(33). Abdominal ultrasound is useful for assessing bowel wall thickening and ruling out intussusception.

Differential diagnosis

It should be differentiated from other vasculitis, abdominal processes, or renal diseases in cases of atypical presentation.

In an atypical cutaneous presentation, rule out other vasculitis’s, acute hemorrhagic edema of infancy (Finkelstein-Seidlmayer), and meningococcemia. When abdominal symptoms predominate, rule out appendicitis, unrelated intussusception, and inflammatory bowel disease. If renal involvement predominates, also consider poststreptococcal glomerulonephritis, lupus nephritis, primary IgA nephropathy, and hemolytic uremic syndrome (HUS).

Treatment

Treatment is primarily supportive. Nephritis requires a specific, severity-stratified approach according to the SHARE and IPNA recommendations.

General treatment: relative rest, hydration, and acetaminophen as the first analgesic option. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with caution if there is active renal or gastrointestinal involvement. The cutaneous lesions resolve spontaneously. Corticosteroids (prednisone 1-2 mg/kg/day for 1-2 weeks) are useful for severe abdominal or joint pain but do not prevent recurrences or nephritis(32).

Gastrointestinal treatment: oral prednisone (or IV methylprednisolone) for severe pain or significant bleeding. Intussusception: hydrostatic/pneumatic reduction, with surgery if this fails.

Treatment of nephritis (SHARE(32), IPNA 2024(33)): stratified by severity (Table III, Fig. 2). Isolated hematuria: follow-up. Mild nephritis: oral prednisone. Moderate nephritis: prednisone ± methylprednisolone pulses; second line: azathioprine, mycophenolate mofetil, or IV cyclophosphamide. Severe nephritis: IV cyclophosphamide with methylprednisolone pulses and prednisone. In patients with persistent proteinuria (>3 months’ duration): angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs).

Prognosis

In most cases, the disease resolves within a few weeks. One third have recurrences and, if there is moderate renal involvement at onset, up to 15% may develop hypertension or long-term renal impairment.

IgAV is generally self-limited, resolving in 2-6 weeks, with recurrences in up to 33% of children. The prognosis depends on renal involvement: >95% recover normal renal function, but 1-5% may progress to chronic kidney disease. Renal follow-up should continue for at least 6-12 months, and longer in those with nephritis(33).

Role of the Primary Care Pediatrician

The primary care pediatrician plays an essential role in diagnostic suspicion, initial evaluation, and long-term follow-up of both entities.

In ITP: suspect the diagnosis in a child with the abrupt onset of petechiae/ecchymoses and good general condition; order an urgent complete blood count; know the warning signs for urgent referral; collaborate in the follow-up of chronic ITP; and convey to families that observation is safe and recommended when there is no bleeding or only cutaneous bleeding and no risk factors. In addition, suspect inherited thrombocytopenia in the presence of extreme MPV values.

In IgAV: recognize the typical presentation; perform the initial evaluation and refer for severe abdominal pain, gastrointestinal bleeding, acute scrotum, or proteinuria/hematuria; ensure renal follow-up for ≥6 months; refer to nephrology for persistent proteinuria >4 weeks, gross hematuria >5 days, deterioration of renal function, hypertension, or nephrotic/nephritic syndrome (Fig. 1); and provide information about the generally benign and self-limited nature of the disease.

Conflict of interest

The authors declare that they have no conflicts of interest.

Funding

This work did not receive any specific funding.

References

The asterisks indicate the significance of the article in the authors’ judgment.

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36. Ruperto N, Ozen S, Pistorio A, Dolezalova P, Brogan P, Cabral DA, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010; 69: 798-806. Available at: https://doi.org/10.1136/ard.2009.116657.

37. Cervera Bravo A, Muñoz Bermudo F. Púrpuras más frecuentes. Trombocitopenia inmune primaria y vasculitis por IgA (púrpura de Schönlein-Henoch). Primary immune thrombocytopenia and IgA vasculitis (Schönlein-Henoch purpura). Pediatr Integral. 2021; 5: 254-64. Available at: https://www.pediatriaintegral.es/publicacion-2021-07/purpuras-mas-frecuentes-trombocitopenia-inmune-primaria-y-vasculitis-por-iga-purpura-de-schonlein-henoch/.

Recommended bibliography

– Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019; 3: 3829-66. Available at: https://doi.org/10.1182/bloodadvances.2019000966.

International reference guideline for the management of ITP, with specific recommendations for the pediatric population.

– Neunert CE, Arnold DM, Grace RF, Kuhne T, McCrae KR, Terrell DR. The 2022 review of the 2019 American Society of Hematology guidelines on immune thrombocytopenia. Blood Adv. 2024; 8: 3578-82. Available at: https://doi.org/10.1182/bloodadvances.2023012541.

Update that consolidates observation as first-line management and TPO receptor agonists as the preferred second-line therapy in children.

– Monteagudo E, Astigarraga I, Cervera Á, Dasí MA, Sastre A, Berrueco R, et al. Protocol for the study and treatment of primary immune thrombocytopenia: PTI-2018. An Pediatr (Barc). 2019; 91: 127.e1-e10. Available at: https://doi.org/10.1016/j.anpedi.2019.04.014.

National reference protocol for the study and treatment of pediatric ITP in Spain.

– Ozen S, Marks SD, Brogan P, Groot N, de Graeff N, Avcin T, et al. European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative. Rheumatology (Oxford). 2019; 58: 1607-16. Available at: https://doi.org/10.1093/rheumatology/kez041.

European consensus with 26 recommendations for the diagnosis and treatment of IgAV, based on evidence and expert consensus.

– Vivarelli M, Samuel S, Coppo R, Barratt J, Bonilla-Felix M, Haffner D, et al. IPNA clinical practice recommendations for the diagnosis and management of children with IgA nephropathy and IgA vasculitis nephritis. Pediatr Nephrol. 2025; 40: 533-69. Available at: https://doi.org/10.1007/s00467-024-06502-6.

Most recent international guideline for the management of IgAV nephritis in the pediatric age group.

– Kidney Disease: Improving Global Outcomes (KDIGO) IgAN and IgAV Work Group; Rovin BH, Barratt J, Cook HT, Noronha IL, Reich HN, Suzuki Y, et al. KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV). Kidney Int. 2025; 108: S1-S71. Available at: https://doi.org/10.1016/j.kint.2025.04.004.

Global clinical practice guideline that integrates IgA nephropathy and IgAV nephritis with updated recommendations.