International Journal for Doctor of Medicine and  Medical Students (IJDMMS)

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and widespread microvascular thrombosis. The condition is primarily associated with severe deficiency of the ADAMTS13 enzyme, which normally cleaves ultra-large von Willebrand factor multimers.

Pediatric TTP may occur as congenital TTP or immune-mediated TTP. Early diagnosis and treatment with plasma exchange, immunosuppressive therapy, and targeted agents have significantly improved patient survival and clinical outcomes [1].

Introduction

Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA) first described in 1924 by Dr. Eli Moschcowitz when he reported the case of a teenage girl presenting with fever, weakness, anemia, and petechial rash [1]. Two days after the initial symptoms, the patient developed neurological signs and died two weeks later. Autopsy findings revealed disseminated hyaline thrombi in the small vessels of multiple organs including the kidney, spleen, liver, and heart while medium-sized vessels were spared [1].

Although this case represented the first description of TTP, it remained unclear whether the disease was congenital or immune-mediated. In later years, advances in hematology research

demonstrated that TTP results primarily from severe deficiency of the ADAMTS13 enzyme, which plays a crucial role in regulating von Willebrand factor (vWF) multimers responsible for platelet aggregation [2,3].

Pathophysiology

The central mechanism in TTP involves deficiency or inhibition of ADAMTS13 protease. Under normal conditions, ADAMTS13 cleaves ultra-large vWF multimers into smaller fragments, preventing excessive platelet adhesion. When ADAMTS13 activity is severely reduced, unusually large vWF multimers accumulate in circulation and promote platelet aggregation within small blood vessels [2].

This process leads to formation of platelet-rich microthrombi in the microvasculature. These thrombi obstruct blood flow and cause mechanical destruction of red blood cells, producing microangiopathic hemolytic anemia. Fragmented red blood cells known as schistocytes can be observed on peripheral blood smear and serve as an important diagnostic indicator [3].

Types of Pediatric TTP

Pediatric TTP is broadly classified into two forms: congenital TTP and immune-mediated TTP. Congenital TTP

Congenital TTP, also known as Upshaw–Schulman syndrome, is caused by mutations in the ADAMTS13 gene. It is inherited in an autosomal recessive pattern and results in severe deficiency of ADAMTS13 enzyme from birth. Patients may present with neonatal jaundice, thrombocytopenia, and recurrent hemolytic episodes triggered by infections, pregnancy, or surgery [3].

Immune-mediated TTP

Immune-mediated TTP occurs when autoantibodies develop against ADAMTS13 enzyme. These antibodies either inhibit enzyme activity or accelerate its clearance from circulation. As a result, ultra-large vWF multimers accumulate and lead to abnormal platelet aggregation and microvascular thrombosis [2,4].

Clinical Manifestations

The classical clinical presentation of TTP has traditionally been described as a pentad consisting of:

1.               Thrombocytopenia

2.               Microangiopathic hemolytic anemia

3.               Neurological abnormalities

4.               Renal dysfunction

5.               Fever

However, the complete pentad is rarely observed in clinical practice. Most patients present primarily with thrombocytopenia and hemolytic anemia. Neurological manifestations such as headache, confusion, seizures, or stroke-like symptoms may also occur due to microvascular thrombosis affecting the brain [4].

Additional symptoms may include fatigue, weakness, jaundice, and petechiae caused by low platelet counts.

Diagnosis

Diagnosis of TTP involves clinical evaluation combined with laboratory investigations. Key laboratory findings include thrombocytopenia, elevated lactate dehydrogenase (LDH), increased indirect bilirubin, and reduced hemoglobin levels. Peripheral blood smear often reveals schistocytes resulting from red blood cell fragmentation [2].

A definitive diagnosis is confirmed by demonstrating severe deficiency of ADAMTS13 activity, usually less than 10%. Detection of anti-ADAMTS13 antibodies helps differentiate

immune-mediated TTP from congenital TTP [3]. Treatment

TTP is considered a medical emergency and requires immediate treatment.

The standard therapy for immune-mediated TTP is therapeutic plasma exchange (TPE), which removes circulating autoantibodies and replenishes ADAMTS13 enzyme [4]. Corticosteroids are commonly administered to suppress immune activity, and rituximab may be used in refractory cases.

A newer therapeutic agent, caplacizumab, targets the interaction between von Willebrand factor and platelets, thereby preventing further clot formation [4].

Patients with congenital TTP are usually treated with periodic plasma infusions to replace the deficient ADAMTS13 enzyme.

7. Conclusion

Thrombotic thrombocytopenic purpura is a rare but potentially fatal disorder caused by severe deficiency of the ADAMTS13 enzyme. Pediatric TTP may occur in congenital or

immune-mediated forms, both of which can lead to widespread microvascular thrombosis and organ damage. Early diagnosis and prompt treatment with plasma exchange and immunosuppressive therapy are essential for improving survival and preventing complications.

References

[1]  Moschcowitz E.

Hyaline Thrombosis of the Terminal Arterioles and Capillaries: A Hitherto Undescribed Disease. Proceedings of the New York Pathological Society, 1924.

Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12108744/

[2]  Shrestha N, Okpako EO, Maitta RW.

Thrombotic Thrombocytopenic Purpura in Pediatric Patients. National Center for Biotechnology Information (NCBI), 2025. Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12108744/

[3]  Zheng XL.

ADAMTS13 and von Willebrand Factor in Thrombotic Thrombocytopenic Purpura. Annual Review of Medicine.

Link: https://pubmed.ncbi.nlm.nih.gov/23146723/

[4]  Moake JL.

Thrombotic Microangiopathies. New England Journal of Medicine. Link:

https://resolve.cambridge.org/core/services/aop-cambridge-core/content/view/FC36938202DFB 8CA394DFEF2EAD9D14E/9781107147447c45_347-355.pdf

[5]  Steele M, et al.

Pediatric Thrombotic Thrombocytopenic Purpura. Pediatric Blood and Cancer Journal.

Link: https://pubmed.ncbi.nlm.nih.gov/23146723/

[6]  Rodasa MA, et al.

Thrombotic Thrombocytopenic Purpura in Pediatrics – A Case Report.

Archives of Argentine Pediatrics.

Link: https://www.sap.org.ar/docs/publicaciones/archivosarg/2023/v121n5a02e.pdf