Long Term Follow Up of Hereditary Thrombotic Thrombocytopenic Purpura on Plasma Therapy for 9 Years: A Case Report

ABSTRACT

A 7.6‐year‐old boy with hTTP had fever‐induced hemorrhagic rash, MAHA, cerebral infarction, and renal impairment. After plasma therapy, symptoms were partially relieved; 9‐year follow‐up showed regular plasma transfusion was needed, with CKD Stage 3. Early genetic diagnosis is crucial; plasma therapy prevents recurrence, and gene therapy offers new hope for hTTP.

Key Clinical Message

hTTP is a severe multiorgan disorder in children. On‐demand plasma therapy effectively treats acute episodes, with adherence critical to prognosis. Cutting‐edge gene therapy offers patients new hope to eliminate lifelong plasma dependence and achieve long‐term remission.

1. Introduction

Hereditary thrombotic thrombocytopenic purpura (hTTP) in children [1] is a rare hereditary thrombotic microangiopathy (TMA) caused by ADAMTS13 gene mutations, which leads to severe deficiency of von Willebrand factor (vWF)‐cleaving enzyme (a disintegrin‐like and metalloprotease with thrombospondin Type 1 motif, ADAMTS13) (activity < 10%). It is characterized by the classic pentad of TMA, namely microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, neurological symptoms, and renal impairment. The persistent and severe deficiency of ADAMTS13 cleavage function caused by ADAMTS13 gene abnormalities is the fundamental pathogenesis of hTTP. Severe deficiency of ADAMTS13 enzyme activity (often < 5%) leads to the accumulation of ultra‐large molecular weight von Willebrand factor (UL‐vWF) multimers, inducing abnormal platelet aggregation and thrombosis in microvessels. The clinical manifestations of this disease lack specificity, making it prone to misdiagnosis as immune thrombocytopenia (ITP) or Evans syndrome, which leads to incorrect treatment and high rates of disability and mortality [2, 3]. The key to treating hTTP is to increase the level of ADAMTS13 enzyme in patients. Currently, the main treatment method is replacement therapy with blood products containing ADAMTS13. This study reports the long‐term plasma therapy in a child with hTTP caused by ADAMTS13 gene mutations and systematically summarizes the potential directions and application prospects of gene therapy for this disease in combination with literature, aiming to provide references and ideas for clinicians to conduct in‐depth research on hTTP treatment.

2. Case History

A 7.6‐year‐old boy presenting with acute onset fever and altered sensorium was transferred from an external hospital to the Intensive Care Unit of the Children's Hospital of Soochow University in December 2017. The history of the present illness indicated a fever lasting 10 h with no obvious inciting event, reaching a maximum temperature of 38.6°C. The child had received ibuprofen for the fever, which was accompanied by nasal congestion and rhinorrhea, and was initially evaluated at a local hospital. During this period, he developed altered consciousness, sialorrhea, poor responsiveness, and dysarthria, accompanied by fatigue. There was no reported dizziness, headache, nausea, vomiting, or amaurosis prior to transfer to our institution. Examination at the external hospital showed: blood routine revealed hemoglobin 80 g/L (reference range 118–156 g/L) and platelet count 7.4 × 10⁹/L [reference range (167–453) × 10⁹/L]. The child was his mother's first child, born by cesarean section at 36 weeks due to placenta previa, with a birth weight of 3.26 kg. There was no history of asphyxia resuscitation, head trauma, or special drug use. Thrombocytopenia was incidentally detected during the routine well‐baby check‐up at 3 months of age, with no cutaneous purpura or other bleeding manifestations. The platelet count rose following treatment with intravenous immunoglobulin (IVIG) and corticosteroids. Relevant medical data including pre‐ and post‐treatment platelet counts and exact drug dosages were unavailable. Relapses took place at 6 months, 1 year and 8 months, and 7 years of age. Each episode was marked by fever preceding cutaneous rash and thrombocytopenia. The child sought care across multiple hospitals and received repeated diagnoses of isolated thrombocytopenia or Evans syndrome. Hematuria, proteinuria and renal dysfunction were absent in all recurrent flares. Hematologic remission was attained following treatment with platelet transfusions, IVIG, and/or corticosteroids. Similarly, detailed clinical information could not be obtained. The parents were not consanguineous and had no family history of genetic diseases.

3. Diagnosis, Investigations and Treatment

On admission, he was found to have hemorrhagic purpura with partial ecchymoses, positive neurological pathological signs, and elevated blood pressure (120/90 mmHg). Heart, lung, and abdomen examinations were normal. Auxiliary examinations results revealed decreased platelets (13 × 10⁹/L) and hemoglobin (60 g/L), hematuria (urine red blood cell count 47.6/μL), proteinuria (24‐h urine protein quantification was 2197 mg/24 h), elevated lactate dehydrogenase (1162 U/L), renal impairment (creatinine 125 μmol/L; urea nitrogen 14.7 mmol/L; uric acid 581 μmol/L), and cerebral infarction (Cranial CT showed increased density of the left frontal cortex with unclear gray‐white matter boundary and reduced volume of the left frontoparietal lobe, as shown in Figure 1A). Coagulation function, complement C3, and complement C4 results were normal. Autoantibodies and Coombs test were negative.

FIGURE 1.

Cranial CT of the Child with Hereditary Thrombotic Thrombocytopenic Purpura (hTTP). (A) The left frontal cortex demonstrates increased density with ill‐defined local gray‐white matter demarcation, accompanied by reduced volume of the left frontoparietal lobe (arrow). (B) The left cerebral hemisphere shows atrophy with the presence of multiple malacic foci (arrows).

After admission, the child was given oxygen inhalation, latamoxef for anti‐infection, methylprednisolone sodium succinate (2 mg/kg) for anti‐inflammation, and symptomatic and supportive treatments such as infusion of leukocyte‐reduced red blood cell suspension and leukocyte‐filtered apheresis platelets. The body temperature could be controlled. Re‐examination of blood routine showed that hemoglobin and platelets did not increase significantly. Considering that the child had the classic pentad of TMA, the treatment plan was adjusted to plasma exchange and fresh frozen plasma infusion (FFPI).

Subsequently, the whole‐exome sequencing (WES) report from his previous outpatient visit was available. The WES report showed that the child had two heterozygous variants in the ADAMTS13 gene (NM_139025): (1) Exon 3: c.330 + 1G>A, splicing (splice site mutation) heterozygous variant. Sanger sequencing indicated that this variant was inherited from the child's father, and the child's mother did not carry this heterozygous variant; (2) Exon 26: c.3616C>T, p.R1206X (nonsense mutation) heterozygous variant. Sanger sequencing indicated that this variant was inherited from the child's mother, and the child's father did not carry this heterozygous variant. According to the American College of Medical Genetics and Genomics (ACMG) variant classification guidelines, the two variants were classified as pathogenic variants. Pathogenic variants of the ADAMTS13 gene can lead to hTTP.

Combined with the pre‐plasma ADAMTS13 test results (ADAMTS13 activity of 1.21% and negative anti‐ADAMTS13 antibodies) and the typical clinical manifestations, the child was diagnosed with hereditary thrombotic thrombocytopenic purpura (hTTP). Upon confirmation of hTTP, the single course of plasma exchange was discontinued, and intermittent FFPI was retained. Corticosteroids were tapered and eventually ceased. Following treatment adjustment, the child's hemoglobin and platelet counts increased steadily and remained sustained. The therapeutic regimen was further optimized to scheduled prophylactic infusion of 400 mL fresh frozen plasma (FFP) administered every 3 weeks, and the child has received intermittent homologous FFP transfusions since diagnosis. Given persistent renal dysfunction, renal biopsy was conducted after clinical stabilization. Histopathological analysis demonstrated chronic renal sequelae secondary to prior resolved TMA, with an absence of acute intrarenal microthrombi (Figure 2).

FIGURE 2.

Renal Biopsy Pathology of the Child with hTTP. (A) Some glomeruli showed fibrotic and sclerotic changes. The glomerular capsule wall exhibited focal fibrous hyperplasia and thickening, with variable widening of the mesangial areas. Partial capillary loops were shrunken and atrophic, accompanied by expansion of the Bowman's space. Thickening of the small vessel walls was also noted. (PAS staining, ×400). (B) Glomerular fibrosis (Masson staining, ×400). (C) Thickening of the glomerular capillary basement membrane (PASM staining, ×400). (D) Basement membrane thickening, segmental mesangial interposition, focal endothelial cell proliferation, and partial foot process fusion. (Electron microscopy, ×6000).

4. Follow‐Up and Outcome

Due to economic, cross‐regional, and other factors, the child's treatment compliance was poor. He was hospitalized for plasma infusion mostly after the appearance of fatigue and skin hemorrhagic rash, with an interval of approximately 23–57 days. According to the change in body weight, the FFPI dose was adjusted to 800 mL per session, and the symptoms could be quickly relieved after blood transfusion. During 9 years of follow‐up, the child's neurological symptoms improved, with mild unclear articulation, and the right upper limb and fine coordination movements were poorer than the left. Re‐examination of cranial CT on May 23, 2021 showed cerebral atrophy of the left cerebral hemisphere with multiple softening foci, as shown in Figure 1B; blood pressure fluctuated at 120/90 mmHg; renal function did not progress further. Re‐examination of serum creatinine on December 22, 2025 was 122.9 μmol/L (reference range 37–93 μmol/L), urea nitrogen 16.44 mmol/L (reference range 2.7–7 mmol/L), urinalysis revealed mild proteinuria and an absence of urinary red blood cells. As shown in Figure 3A–D.

FIGURE 3.

Long‐term follow‐up trends of key hematological markers in the child with hTTP (2017–2025). Data points represent individual values; the trend line connects the median values.

5. Discussion

hTTP presents nonspecific manifestations, easily causing misdiagnosis, delayed treatment, disability or death, especially in early/neonatal‐onset children with extremely low ADAMTS13 activity (< 3%), frequent episodes and severe complications [2, 3]. This child developed post‐fever hemorrhagic rash, thrombocytopenia, MAHA, cerebral infarction, and renal injury, confirmed as hTTP via genetic testing; the case helps clarify pathogenesis and guide individualized therapy.

hTTP is an autosomal recessive disorder caused by homozygous or compound heterozygous ADAMTS13 variants. Located at 9q34 with 29 exons, the gene encodes a 1427‐amino‐acid protein; this child harbored two heterozygous variants altering nucleotides and amino acids. Over 200 pathogenic mutations have been reported globally [4], mostly missense mutations (59%). Long‐term complications include renal impairment, cerebral infarction, and multiorgan arterial thrombosis [2, 5, 6]. The kidney is highly susceptible due to microcirculatory high shear stress, presenting glomerular endothelial injury and platelet microthrombosis [3]. Though the child had no prior renal abnormalities, early proteinuria, hematuria, and elevated creatinine, plus renal pathology showing focal glomerulosclerosis and tubulointerstitial damage indicated chronic injury from subclinical microthrombosis. Delayed diagnosis correlates with severe complications, making early recognition critical for prognosis.

This case exhibited atypical hTTP phenotypes alongside several study limitations. Inter‐hospital transfers resulted in incomplete medical records missing pre‐diagnostic platelet counts, full steroid regimens, and quantitative platelet recovery data post‐IVIG, which complicates analysis of this atypical therapeutic response. IVIG merely induces temporary Fc receptor blockade and cannot restore ADAMTS13 activity, whereas plasma infusion supplies functional protease to achieve durable remission. The renal biopsy displayed chronic thrombotic sequelae rather than canonical acute TMA lesions [7]; this morphological difference stems from delayed biopsy during remission and recurrent vascular injury, distinguishing chronic residual damage from active acute microangiopathy [8, 9, 10].

hTTP treatment prioritizes early intervention and complication prevention. Acute episodes rely on on‐demand FFP infusion; prophylactic FFP (10–15 mL/kg, every 1–3 weeks) cannot fully prevent relapses and carries risks of iron overload, allergies, and transfusion‐transmitted infections. Recombinant ADAMTS13 (Adzynma, FDA‐approved in November 2023) offers a safer alternative with proven efficacy across Phases I–III trials, using 40 U/kg intravenously weekly or biweekly for prophylaxis [11]. Both regimens require lifelong adherence without curative potential. Frequent hospital visits, repeated venipuncture, drug adverse reactions, and dose adjustments during childhood growth may cause psychological stress and compromise treatment compliance.

Gene therapy provides a new treatment direction for hTTP. By integrating therapeutic genes into host cells, long‐term transgene expression corrects the phenotype of monogenic diseases to achieve therapeutic effects. Currently, researchers have attempted to use various vectors to deliver gene sequences encoding full‐length ADAMTS13 or carboxy‐terminal truncated bodies (MDTCS, truncated ADAMTS13 including M domain to S domain) in hTTP mouse models, including adenovirus [12], lentivirus [13, 14], adeno‐associated virus (AAV) [15], and mRNA lipid nanoparticles [16]. However, relevant studies on the efficacy of hTTP gene therapy are still limited.

Niiya et al. [13] first reported a gene therapy study for hTTP in 2008. This study adopted intrauterine gene transfer therapy, encoding full‐length recombinant ADAMTS13 or MDTCS through modified lentiviral vectors, which were delivered into Adamts13 knockout (Adamts13⁻/⁻) mice via intrauterine injection on the 8th and 14th days of the embryonic stage. The experimental results showed [13] that ADAMTS13 with varying degrees of activity (5–70 IU/dL) could be detected in the mice, and this activity could last for up to 24 weeks. The recombinantly expressed human ADAMTS13 and MDTCS were mainly expressed in hepatocytes and secreted into the circulating blood, then effectively degraded vWF multimers in plasma and inhibited carotid artery thrombosis induced by ferric chloride injury. Laje et al. [14] reported a second gene therapy method, which transduced hematopoietic progenitor cells (HPCs) in vitro to carry mouse full‐length recombinant ADAMTS13 gene fragments and transplanted them into Adamts13⁻/⁻ mice using lentiviral vectors. The results showed that the recombinant ADAMTS13 activity in plasma was 24.1 ± 13.7 IU/dL, 27.5 ± 14.3 IU/dL, and 26.3 ± 14.3 IU/dL at 1, 3, and 5 months after transplantation, respectively, which successfully corrected the severe ADAMTS13 deficiency and inhibited carotid artery thrombosis. However, lentiviral vector‐mediated gene transfer may have safety issues caused by the integration of vector sequences into the genome [17, 18], especially intrauterine administration, which increases the risk of abortion. Trionfini et al. [12] delivered the gene encoding human ADAMTS13 using adenoviral vectors. The study results showed that in Adamts13⁻/⁻ mice, ADAMTS13 activity reached its peak in the first week after injection (up to approximately 300 IU/dL), then decreased rapidly; by the 4th week, the activity had dropped to 5–10 IU/dL, accompanied by a significant immunogenic reaction. The adeno‐associated virus (AAV)‐based gene delivery system has made great progress in the treatment of human hereditary diseases such as hemophilia [19, 20]. Jin et al. [15] prepared TTP model mice by gene knockout. Mice in the experimental group were injected with recombinant adeno‐associated virus (rAAV) vectors to directly deliver the target gene ADAMTS13 to the specific target organ (liver) in TTP mice. Shiga toxin was used to induce TTP‐related symptoms in the mice. The results showed [15] that AAV8‐mediated ADAMTS13 variant maintained the plasma ADAMTS13 activity of TTP model mice at the therapeutic level without severe platelet decrease (decrease by 40%–60%), suggesting that AAV gene therapy is feasible for hTTP. There are also relevant preclinical studies on the delivery of target genes by nonviral vector systems. Verhenne et al. [21] used the Sleeping Beauty transposon system as a gene delivery vector to achieve supraphysiological stable expression of the ADAMTS13 transgene in Adamts13⁻/⁻ mice, which lasted for up to 25 weeks. In addition, the study showed [21] that administration of recombinant vWF approximately 20 weeks after gene therapy could effectively prevent the occurrence and progression of TTP‐related signs. However, the Sleeping Beauty transposon system is delivered to hepatocytes through tail vein hydrodynamic injection, which is invasive and currently difficult to translate into clinical application. Furthermore, Liu‐Chen et al. [16] encapsulated mRNA encoding human ADAMTS13 in lipid nanoparticles and used hepatic stellate cells as endogenous producer cells to generate ADAMTS13 in wild‐type and Adamts13⁻/⁻ mice. After a single intravenous injection of lipid nanoparticles containing mRNA, ADAMTS13 activity in the mice increased by 20% within 24 h and returned to baseline activity within 5 days. A concise summary of the aforementioned therapeutic strategies is provided in Table 1. In conclusion, any viral or nonviral vector system that uses liver‐specific promoters to target hepatocytes, stably expresses ADAMTS13 for a long time without producing related antibodies, and has no genotoxicity can be used as a potential delivery medium for hTTP gene therapy.

TABLE 1.

Established and investigational therapeutic modalities for hTTP.

Treatment	Mechanism	Core efficacy	Key limitations	Stage
Prophylactic FFP transfusion	Supply plasma‐derived ADAMTS13	First‐line for acute flares; 10–15 mL/kg q1–3 weeks prevents recurrence	Cannot fully avoid relapse; transfusion complications; lifelong non‐curative infusion	Standard clinical care
Recombinant ADAMTS13 (Adzynma) [7]	IV enzyme replacement	FDA‐approved 2023; 40 U/kg q1–2 week; Phase I–III verified efficacy; safer than FFP	Lifelong repeated injection; palliative only; pediatric dose adjustment burden	Clinically available
Lentiviral gene therapy [8, 10]	Deliver ADAMTS13/MDTCS to HPCs/hepatocytes	Sustained ADAMTS13 activity (5%–70% for 24 weeks; 24–27 IU/dL for 5 m); inhibits arterial thrombosis	Genomic integration risk; abortion risk (in utero delivery); no human safety data	Preclinical mouse studies
Adenoviral gene therapy [9]	Transient hepatic ADAMTS13 expression	Peak activity ~300 IU/dL at 1 week; detectable for 12 weeks; degrades VWF multimers	Rapid activity decay within 4 weeks; severe host immunogenicity	Preclinical mouse studies
AAV8 liver gene therapy [11]	Liver‐specific stable ADAMTS13 expression	Sustained therapeutic enzyme levels; prevents toxin‐induced thrombocytopenia	Long‐term human safety unproven	Preclinical validation
Sleeping Beauty transposon [17]	Nonviral hepatic ADAMTS13 overexpression	Durable supraphysiological activity for 25 weeks; prevents VWF‐induced TTP	Invasive hydrodynamic injection; poor clinical translatability	Preclinical mouse studies
LNP‐ADAMTS13 mRNA [12]	Transient hepatic ADAMTS13 synthesis	> 20% activity elevation within 24 h; returns to baseline in 5 days	Short therapeutic window; frequent re‐dosing required	Preclinical proof‐of‐concept

Abbreviations: AAV8, adeno‐associated virus serotype 8; FFP, fresh frozen plasma; HPCs, hematopoietic progenitor cells; LNP, lipid nanoparticle; MDTCS, truncated ADAMTS13; VWF, von Willebrand factor.

6. Conclusion

hTTP is a fatal rare disease requiring early genetic diagnosis and timely replacement therapy. Plasma treatment alleviates acute symptoms but cannot eliminate irreversible brain and renal complications, imposing substantial physical and psychological burdens on pediatric patients. Multidisciplinary collaboration is essential for long‐term management. Gene therapy holds unique curative potential to eliminate lifelong transfusion dependence. Current evidence remains limited to preclinical research; key challenges involve vector immunogenicity, expression stability, targeted delivery, and off‐target risks. Further clinical trials are needed to validate safety and efficacy. Optimized gene therapy is expected to become the definitive treatment for pediatric hTTP and greatly improve long‐term survival and quality of life.

Author Contributions

Dai Xiaomei: writing – review and editing, writing – original draft, formal analysis, data curation. Chen Ruyue: conceptualization, writing – review and editing, resources, funding acquisition. Wu Shuang: conceptualization, investigation, software, formal analysis. Tang Hanyun: methodology, validation, visualization, data curation, supervision. Lin Qiang: validation, formal analysis, data curation, supervision. Li Xiaozhong: conceptualization, investigation, methodology, validation, visualization, software, formal analysis, project administration, data curation, supervision, resources.

Funding

This work was supported by Suzhou Science and Technology Bureau (Suzhou Municipal Science and Technology Program). The project name is Suzhou Applied Basic Research (Medical and Health) Science and Technology Innovation Project (No. SYW2024102).

Ethics Statement

As a single‐case report with the patient's signed consent, no other ethical review was required.

Consent

Written informed consent was obtained from the patient for the publication of this case report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

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