# Characterization of autopsy findings including multivisceral glomeruloid vascular bodies in hereditary thrombotic thrombocytopenic purpura with two new variants in ADAMTS13 gene

Roberta Maragliano, Adélie Perrot, Philippe Loget, Claire Combescure, Nicolas Belhomme, Marie Faoucher, Christèle Dubourg, Mélanie Fradin, Sophie Collardeau Frachon

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Roberta Maragliano, Adélie Perrot, Philippe Loget, Claire Combescure, Nicolas Belhomme, et al. Characterization of autopsy findings including multivisceral glomeruloid vascular bodies in hereditary thrombotic thrombocytopenic purpura with two new variants in ADAMTS13 gene. Virchows Archiv, 2025, 10.1007/s00428-025-04200-8. hal-05235735

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# Characterization of autopsy findings including multivisceral glomeruloid vascular bodies in hereditary thrombotic thrombocytopenic purpura with two new variants in ADAMTS13 gene

Roberta Maragliano<fnref n="1" />,<fnref n="2" /> · Adélie Perrot<fnref n="2" />,<fnref n="3" /> · Philippe Loget<fnref n="2" />,<fnref n="3" /> · Claire Combescure<fnref n="4" /> · Nicolas Belhomme<fnref n="5" /> · Marie Faoucher<fnref n="6" /> · Christele Dubourg<fnref n="6" /> · Mélanie Fradin<fnref n="7" /> · Sophie Collardeau-Frachon<fnref n="2" />,<fnref n="8" />

Received: 26 May 2025 / Revised: 4 July 2025 / Accepted: 17 July 2025
© The Author(s) 2025

## Abstract

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare genetic disorder caused by a severe deficiency in ADAMTS13 enzyme activity, leading to potentially fatal perinatal outcomes and requiring urgent management. While the clinical and biological aspects of the disease are well-documented, pathological findings are less commonly described. We report two cases of cTTP within the same family, both resulting in perinatal death. Autopsies of the neonate and the subsequent fetal recurrence revealed a distinctive and prominent multivisceral glomeruloid vascular proliferation, an unreported feature in this syndrome. However, the presence of multiple thrombi along with ischemic and hemorrhagic changes suggested an underlying thrombotic microangiopathy. Whole genome sequencing confirmed cTTP, identifying two novel pathogenic variants in the *ADAMTS13* gene. Beyond expanding the phenotypic and genotypic spectrum of this disorder, the unusual vascular proliferation contributes to a deeper understanding of the underlying physiopathological mechanisms.

**Keywords** Angiomatosis · Autopsy · Fetus · Neonate · Pathology · Thrombotic microangiopathies · Purpura thrombotic thrombocytopenic · SARS-CoV-2

<figure><img src="image_2.png" /></figure>

## Introduction

Hereditary or congenital thrombotic thrombocytopenic purpura (cTTP), also known as Upshaw-Schulman syndrome (OMIM#274150), is due to a severe deficiency of the ADAMTS13 enzyme (A Disintegrin and Metalloprotease with a Thrombospondin type 1 motif, member 13). Congenital TTP usually starts in the neonatal period with hematological features and severe jaundice, requiring emergency management [1] as it can result in fetal or perinatal death [2–4]. While clinical and biological anomalies of cTTP are well documented, pathological findings are less commonly described compared to hemolytic uremic syndrome (HUS) where kidney biopsies are often performed. In fatal cases of cTTP, autopsies were rarely performed [5–13]. When described, microscopic findings often show vascular proliferation, thrombosis, and ischemic damage.

We present two cases of cTTP in siblings, both resulting in perinatal death. Post-mortem examinations revealed multivisceral vascular thrombi, accompanied by an unusual extensive multi-organ glomeruloid vascular proliferation, which had not been previously described in genetically

<footnote>Sophie Collardeau-Frachon
sophie.collardeau-frachon@chu-lyon.fr</footnote>

<footnote n="1">¹ Department of Pathology, ASST Sette Laghi, Varese, Italy</footnote>

<footnote n="2">² SOFFOET, Société française de foetopathologie, Paris, France</footnote>

<footnote n="3">³ Department of Pathology, Rennes University Hospital, Rennes, France</footnote>

<footnote n="4">⁴ Department of Obstetrics, St Brieuc Hospital, St Brieuc, France</footnote>

<footnote n="5">⁵ Department of Internal Medicine & Clinical Immunology, Rennes University Hospital, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), Environnement Et Travail) - UMR_S 1085, Rennes UMR_S 1085, France</footnote>

<footnote n="6">⁶ Department of Molecular Genetics and Genomics, FHU GenOMedS, CHU Rennes, Rennes, France, Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes), Rennes UMR 6290, France</footnote>

<footnote n="7">⁷ Department of Genetics, Rennes University Hospital, Rennes, France</footnote>

<footnote n="8">⁸ Department of Pathology, Lyon University Hospital, 59 bd Pinel, Bron Cedex 69677, France</footnote>
confirmed cTTP. Autopsy findings suggested thrombotic microangiopathy (TMA), and the diagnosis of cTTP was confirmed through whole genome sequencing (WGS), finding 2 new pathogenic variants in the *ADAMTS13* gene, never reported to date.

This report provides a comprehensive description of the autopsy findings, highlighting features indicative of TMA. We also explore the differential diagnoses of glomeruloid vascular proliferation and discuss potential mechanisms underlying these histopathological changes.

# Case report

## Maternal/family history

Parents were non-consanguineous without notable familial history. A first child was born three years before and was in good health.

Case 1 corresponded to the second pregnancy of this 30-year-old mother, without medical background. The mother received two doses of the SARS-CoV-2 vaccine (Comirnaty, BioNTech/Pfizer) during the 3rd trimester of pregnancy, with the second dose administered two weeks before the delivery.

Case 2 corresponded to the 3rd pregnancy, which occurred 1 year later. The mother received 1 dose of SARS-CoV-2 vaccine (Moderna) between the 2 pregnancies.

## History of pregnancies (Table 1)

Case 1: The course of the pregnancy was unremarkable. The mother gave birth to a female child born full term at 40+3 gestational weeks (GW). The newborn showed a poor adaptation to extra uterine life and exhibited petechiae and hematomas. The suction brought back large amounts of blood from the stomach. Full blood count revealed anemia (hemoglobin at 7.9 g/dl) and thrombocytopenia. The newborn died at 2 h of life during an episode of bradycardia not responding to resuscitation.

Case 2: Pregnancy was marked by SARS-CoV-2 infection at 25GW with positive nasal swab PCR test. Prenatal ultrasounds performed at 26+6 GW showed severe bilateral ventriculomegaly, associated with an edematous cerebellum, as well as cardiomegaly with pericardial effusion. Infectious work-up on amniocentesis was negative for TORCH and SARS-CoV-2. Due to the poor prognosis of the brain lesions, termination of pregnancy (TOP) was proposed and accepted by the parents. TOP

was performed at 28+5 GW along with cordocentesis which revealed severe anemia (hemoglobin 3.3 g/dl) and thrombocytopenia (5000/mm³).

Parents gave consent for autopsy of both cases, except for examination of the brain in case 1. Autopsies were performed the day after death in both cases.

## Autopsy findings (Table 1)

At autopsy, body and weight measurements were suggestive of mild intrauterine growth restriction (IUGR) in both cases (corresponding respectively to 38 GW and 27 GW).

On gross examination (Fig. 1), both cases presented with an enlarged abdomen, pale integuments, hypoplastic lungs and thymus, and non-specific facial dysmorphism, including thin lips, a pronounced nasal saddle, large ears, hypertelorism, a large forehead, and mild microretrognathia. In addition, case 1 exhibited hepatomegaly, multiple cutaneous petechiae on the limbs and hemorrhagic effusions in the subcutaneous tissue, thymus and lungs. Case 2 showed non-hypertrophic cardiomegaly, a hemorrhagic appearance of the kidneys' hilum and sinus, mild pericardial effusion, and ascites (mild fetal hydrops).

On microscopic examination, multiple nodular, small, millimetric glomeruloid formations were seen in most of the viscera of both cases. The glomeruloid bodies (GB) were particularly numerous in the thyroid (Fig. 2), the pancreas (within the endocrine islets), the myocardium and the lungs (Figs. 3, 4). Some were also present in the renal hilum and within the lymph nodes in case 1, and in sympathetic ganglia, the spleen (around the splenic arterioles), the pituitary gland and the peripheral adrenal cortex in case 2.

All GB developed in small vessels, mainly corresponding to capillaries or small arterioles. All GB were composed of small capillaries lined with slightly hobnail endothelial cells and surrounded by one layer of pericytes. Some lumen contained fibrinous microthrombi. There was no associated inflammatory component. On immunohistochemistry (Fig. 2), endothelial cells expressed CD31 (clone JC70, Ventana/Roche) and CD34 (clone QBEnd10, Dako) but no podoplanin (clone D2-40, Ventana/Roche) and Glut1 (polyclonal, Ventana/Roche). Smooth muscle actin (clone 1A4, Dako) underlined pericytes. There was no expression of HHV8 (clone 13B10, BIOSB).

In the pancreas, GB tended to destroy and replace the endocrine islets, as highlighted by insulin and glucagon immunostainings. In addition, some endocrine cells presented nucleomegaly. Similarly, the thyroid follicles were decreased in number.

In the lungs (Fig. 4), GB were often located near the vessels either in or next to the interlobular septa or broncho vascular pedicles in case 1. There was also significant lymphatic

<figure><img src="image_3.png" /></figure>
<table><caption>**Table 1** History of pregnancies and autopsy findings</caption><thead><tr><th></th><th>Case 1</th><th></th><th>Case 2</th><th></th></tr></thead><tbody><tr><td>Position in sibships</td><td>2<br>perinatal death at 40 GW + 3 days &amp; 2 h</td><td></td><td>3<br>TOP at 28 GW + 5 days</td><td></td></tr><tr><td>Pregnancy</td><td>unremarkable</td><td></td><td>SARSCov2 at 25GW</td><td></td></tr><tr><td>Prenatal US</td><td>unremarkable</td><td></td><td>ventriculomegaly at 26 GW along with cardiomegaly and pericardial effusion</td><td></td></tr><tr><td></td><td><strong>Biometry</strong></td><td><strong>Gross examination</strong></td><td><strong>Biometry</strong></td><td><strong>Gross examination</strong></td></tr><tr><td>Body weight</td><td>3152 g</td><td>pale</td><td>1008 g</td><td>pale</td></tr><tr><td>Crown heel length</td><td>50 cm</td><td>Non-specific traits of facial dysmorphism</td><td>35 cm</td><td>Non-specific traits of facial dysmorphism</td></tr><tr><td>Crown rump length</td><td>35.5 cm</td><td>multiple cutaneous petechiae on the limbs as well as hemorrhagic effusions in subcutaneous tissue, thymus and lungs</td><td>24.5 cm<br>25.5 cm<br>21 cm<br>22 cm/</td><td>hemorrhagic aspect of the kidneys 'hilum sinus mild pericardial effusion and ascites</td></tr><tr><td>Crown circumference</td><td>34 cm</td><td></td><td></td><td></td></tr><tr><td>Thoracic circumference</td><td>30 cm</td><td></td><td></td><td></td></tr><tr><td>Abdominal</td><td>29 cm/</td><td></td><td></td><td></td></tr><tr><td>Foot length</td><td>7.7 cm</td><td></td><td>0.5 cm</td><td></td></tr><tr><td><strong>Organ weights</strong></td><td></td><td><strong>Microscopic examination</strong></td><td><strong>Organ weights</strong></td><td><strong>Microscopic examination</strong></td></tr><tr><td>Liver</td><td>223.5 g/</td><td>increased hematopoiesis &amp; mild hemosiderosis</td><td>62 g</td><td>increased hematopoiesis &amp; mild hemosiderosis, lack of hepatic artery branches and ductal plate development retardation in some portal tracts, some fragmentation of the erythroblasts</td></tr><tr><td>Spleen</td><td>13 g</td><td>Extramedullary hematopoiesis &amp; lymphoid hypoplasia</td><td>2.7 g</td><td>GB, extrahepatic hematopoiesis, hemophagocytosis, lymphoid hypoplasia</td></tr><tr><td>Pancreas</td><td>NA</td><td>GB &amp; reduced endocrine component</td><td>NA</td><td>GB &amp; reduced endocrine component</td></tr><tr><td>Kidneys</td><td>32 g</td><td>GB (sinus), strong hemosiderosis</td><td>8.9 g</td><td>mild hemosiderosis</td></tr><tr><td>Adrenals</td><td>8 g</td><td></td><td>4.7 g</td><td>GB, microcalcifications, focal nucleomegaly</td></tr><tr><td>Lungs</td><td>47 g/</td><td>GB</td><td>16 g/</td><td>GB</td></tr><tr><td>Thymus</td><td>4 g/</td><td>Lymphoid hypoplasia</td><td>0.9 g/</td><td>Lymphoid hypoplasia</td></tr><tr><td>Thyroid</td><td>NA</td><td>GB &amp; reduced number of follicles</td><td>NA</td><td>GB &amp; reduced number of follicles</td></tr><tr><td>Heart</td><td>20.2 g</td><td>GB</td><td>10.4 g/</td><td>GB</td></tr><tr><td>Brain</td><td>NA</td><td></td><td>NA</td><td>ischemic and hemorragic changes</td></tr><tr><td>Lymph nodes</td><td></td><td>GB</td><td></td><td>hemophagocytosis</td></tr><tr><td>Sympathetic ganglia</td><td></td><td></td><td></td><td>GB</td></tr><tr><td>Pituitary gland</td><td></td><td></td><td></td><td>GB</td></tr></tbody></table>

GB glomeruloid bodies, NA non-available data

dilation, accentuation of lobulation and features suggestive of focal venous malalignment. However, no rarefaction of capillaries in the alveolar septa was seen on CD31 immunostaining. In case 2, the lesions were mainly located in the broncho vascular pedicles in contact with the distal branches of the pulmonary arteries, and sometimes associated with features suggestive of plexiform arteriopathy. Some GB were also adjacent to pleura.

In case 1, the liver was enlarged due to increased hematopoiesis along with mild hemosiderosis on Perls staining.

There was no fibrosis. Microthrombi were found in some liver sinusoids, as well as in adrenals. In case 2, the hepatic artery branches were not always present in the portal tracts, suggestive of possible obstruction of the hepatic artery. This was associated with ductal plate development retardation. The portal veins were often dilated, and the wall of the central veins was often thickened with a fibro-edematous appearance. Myofibroblast cells were found in the hepatic sinusoids on smooth muscle actin immunostaining.
<figure><img src="image_4.png" /><figcaption>**Fig. 1** Gross examination. **A:** case 1: female, pallor and abdominal distension. **B,C,** **D:** facial dysmorphism: thin lips, pronounced nasal saddle, large ears with small vertical notches at the middle of the upper edge of the helixes of both ears, hypertelorism, large forehead, and mild microretrognathia. **E:** case 2: female, abdominal distension.</figcaption></figure>

**F,G,** **H:** case 2: similar facial dysmorphism. **I,J,** **K,** **L:** case 1, petechia on limbs and extremities. **M,N:** case 1, hemorrhagic changes in the distal part of the pulmonary lobes (M left, N right) and the subcutaneous tissue (arrows). **O,P:** case 2: cardiomegaly with pericardial effusion

Hematopoiesis was slightly increased, with some fragmentation of the erythroblasts, suggesting hemolysis. There was also mild diffuse hemosiderosis on Perls staining.

Extrahepatic hemosiderosis was observed in the kidneys with diffuse Perls staining in the proximal convoluted tubules, associated with epithelium necrosis in both cases. Perls staining was strong in case 1 and mild in case 2 (Fig. 5). Perls was negative in the thyroid, pancreas and spleen in both cases. In case 1, some glomeruli presented an ischemic aspect. In case 2, the kidney's sinus exhibited severe hemorrhagic and ischemic changes. Rare microthrombi were found in glomerular arterioles (Fig. 5). GB were absent within the renal and liver parenchyma in both cases.

Extrahepatic hematopoiesis was noticed in several viscera, especially in the kidneys and spleen of both cases. Lymphoid hypoplasia of the splenic white pulp and the thymic cortex was seen in both cases. In addition, some

hemophagocytosis was visualized in the spleen (red pulp) and lymph nodes of case 2.

Ischemic changes were seen in the adrenals with microcalcifications in the fetal cortex of case 2. It was associated with rare nucleomegaly.

Brain examination of case 2 (Fig. 6) showed multiple fibrinous thromboses in vessels of the basilar trunk/polygon of Willys and in the choroid plexus. These thromboses were sometimes associated with a few GB in the meninges. Hemorrhage was present in the aqueduct of Sylvius and the ventricular cavities along with ependymal alterations and peri-ependymal rosettes. There were massive periventricular necrotic hemorrhagic changes with siderophages on Perls staining. No GB were seen in the cerebral and cerebellar parenchyma.

Placenta examination was unremarkable except for meconium membranes and a twisted cord without microscopic signs of fetal vascular malperfusion in case 1. In case 2, placenta examination showed an intervillous thrombus and

<figure><img src="image_5.png" /></figure>
<figure><img src="image_6.png" /><figcaption>**Fig. 2** Thyroid features. **A:** case 1, glomeruloid bodies (GB, stars) within thyroid parenchyma, many containing microthrombi (arrows), **H&EB:** case 1, focus on one GB: small vessels, arranged back-to-back, lined by plumped endothelium; narrow lumens, microthrom-</figcaption></figure>

bus in one lumen (arrow), H&EC: GB highlighted by CD31 immu-
nostaining which is diffusely expressed by endotheliumD: podoplanin
(D2-40) is not expressed by GBE: smooth muscle actin (SMA): one
GB surrounds one terminal arteriole (arrow)

vessel wall hypertrophy of the villous trunks. In addition,
the villous capillaries were many for the gestational age, but
without a congestive or dilated appearance.

Biological and genetic investigations

Maternal antiphospholipid syndrome (APS) and autoim-
mune disease assessment were negative, including the search
for unconventional antiphospholipid and anti-endothelial
cell antibodies.

The search for platelet incompatibility found incompat-
ibility in the HPA5 system, the mother being HPA5bb and
the father heterozygous in this system. Case 2 did not have
anti-HPA5 allo-antibodies.

Array-CGH performed on frozen tissue (case 1) and
amniocentesis (case 2) revealed no anomaly.

A NGS panel (Ion Torrent Next-Generation Sequencing, custom ampliseq library), including known genes involved in vascular tumor and malformation according to ISSVA classification was performed from FFPE tissues, on the pathological thyroid block and on a block without vascular lesion (gonads) from the 2nd case. No mosaic mutation suggestive of a vascular tumor or malformation was found.

WGS was performed at the SeqOIA platform (Plan France Médecine Génomique 2025, Paris, France). The first WGS in trio (DNA from parents and the first case) revealed no mutation including *FoxF1* and *FLVCR2*. A second WGS in quatuor (DNA from parents and both cases) was performed and revealed a compound heterozygous variant in *ADAMTS13* gene. One
<figure><img src="image_7.png" /><figcaption>**Fig. 3** Location of GB and microthrombi in other organs. **A:** GB (arrows) in pancreas, **H&EB:** GB (arrows) in spleen, **H&EC:** GB (arrows) in myocardium, **H&E D:** myocardium, microthrombi (arrows) within capillaries, **Masson trichrome E:** adrenals, microthrombi (arrows) within sinusoids, **H&EF:** lungs: GB in distal paren-</figcaption></figure>

chyma (stars) within acini, **H&EG:** lungs: thrombus (arrow) within distal pulmonary artery, **H&EH:** lungs: GB (stars) next to or in interlobular septa (arrow), **H&EI:** lungs: GB next to pleura (arrows) and one adjacent to a small arteriole (star), **H&E**

variant was inherited from the mother (a stop gain variant at position 732 in exon 18 of 29 (c.2167C>T p.(Gln723*)) and one inherited from the father (intragenic duplication in trans of the stop gain variant involving exons 9 to 11 seq[GRCh38] dup [9] (q34.2q34.2) NC_000009.12:g.133431780_133434514dup), respectively classified pathogenic (class 5) and likely pathogenic (class 4) according to the international recommendations of the American College of Medical Genetics [14]. These 2 alterations co-segregate in the 2 affected cases. The presence of the duplication variant was confirmed by digital droplet PCR in one of the 2 cases and in the father. The presence of the stop gain variant was confirmed by SANGER sequencing in the 2 cases and the mother. Neither of these 2 variants have been previously described in the literature or in databases.

## Discussion

Hereditary or congenital thrombotic thrombocytopenic purpura (cTTP), also known as Upshaw-Schulman syndrome, is a rare genetic disorder due to severe deficiency or absence

of ADAMTS13 enzyme activity. ADAMTS13 enzyme, which is synthesized by the liver hepatic stellate cells [15], is essential for cleaving ultra-large von Willebrand factor (ULvWF) multimers, secreted by vascular endothelial cells and megakaryocytes [16]. Without proper cleavage, these ULvWF multimers promote excessive platelet aggregation, leading to the formation of vWF-platelet-rich thrombi in blood vessels [17]. The disease follows an autosomal recessive inheritance pattern, predominantly affecting offspring of consanguineous parents, while those with simple heterozygous mutations usually show no symptoms [18].

The clinical presentation of cTTP is heterogeneous. Some patients experience severe symptoms from birth, while others may not manifest the disease until adulthood. The disease usually starts in the neonatal period with hematological features and severe jaundice, requiring emergency management [1] as it can result in fetal or perinatal death [2–4]. In newborns, cTTP should be suspected when severe jaundice, thrombocytopenia and hemolytic anemia are present. A peripheral blood smear showing schistocytes and a negative Coombs test (indicating non-immune hemolysis)

<figure><img src="image_8.png" /></figure>
<figure><img src="image_9.png" /><figcaption>**Fig. 4** Lungs, other microscopical findings. **A (H&E)** and **B (SMA):** case 1, GB (stars) in broncho vascular pedicles: some (stars) looked appended to the pulmonary artery (a) (arrows) **C (H&E)** and **D (Weigert elastin staining):** same broncho vascular pedicle: features of venous malalignment (v) in broncho vascular pedicle (a: pulmonary</figcaption></figure>

artery); b: bronchus with cartilage, stars: GB, cross: thrombi **E:** proximal pulmonary artery with several elastic fibers in its wall (control of elastin staining) **F (H&E)** and **G (SMA):** aspects that mimic plexiform arteriopathy of pulmonary artery in 2 different broncho vascular pedicles: narrow lumen and tortuous aspect
<figure><img src="image_10.png" /><figcaption>**Fig. 5** Kidneys features. A.B: case 2, hemorrhagic changes in renal sinus (arrow) on gross examination after cut transverse section (A) and on microscopic examination (B)C.D: Perls staining, case 1: dif-</figcaption></figure>

fuse renal hemosiderosis on low power field (C), involving renal tubules (D)E: case 2, microthrombus within a capillary in the cortical area (arrow). Star: glomerulus

is diagnostic. Laboratory tests typically reveal increased unconjugated bilirubin, elevated reticulocyte count, high lactate dehydrogenase, and decreased haptoglobin, as in general hemolysis. The white blood cell count is typically normal, and coagulation anomalies are uncommon. Diagnosis is confirmed by ADAMTS13 activity levels below 10% and genetic testing showing mutations in the *ADAMTS13* gene. In older children, immune causes should be ruled out by the absence of inhibitory antibodies [19]. For cTTP, emergency treatment involves plasma infusion with fresh frozen plasma to restore ADAMTS13 levels [2, 20]. Neonatal onset cTTP presents the highest risk of frequent relapses and requires more intensive treatment. Long-term prophylactic plasma

infusions are recommended for these patients to prevent relapses [21].

However, the diagnosis of cTTP is often delayed. In a study of 226 patients reported by Borogovac, 83 presented with severe jaundice at birth, but only 3 were accurately diagnosed and treated for cTTP [7]. Symptoms are often mistaken for hemolytic disease of the fetus and newborn, which is caused by anti-red cell antibodies but does not result in severe thrombocytopenia. cTTP can also be confused with disseminated intravascular coagulation [22], and its presentation may overlap with hemolytic uremic syndrome (HUS). While HUS is typically associated with acute kidney injury, cTTP more commonly involves neurological symptoms [23]. Children under

<figure><img src="image_11.png" /></figure>
<figure><img src="image_12.png" /><figcaption>**Fig. 6** Case 2, brain examination. **A:** necrotic and hemorrhagic changes of the right hemisphere **B:** necrotic and hemorrhagic changes of the left hemisphere **C:** extensive necrotic and hemorrhagic changes</figcaption></figure>

of both cerebral hemispheres on coronal cut section after formalin fixation **D:** thrombi within vessels in meninges (arrows), H&E

2 years old are often misdiagnosed with idiopathic thrombocytopenic purpura, HUS, hemophagocytic syndrome, or paroxysmal nocturnal hemoglobinuria [24]. In some cases, patients may die without receiving a correct diagnosis, making the estimated prevalence of 0.5 to 2 cases per million likely underestimated [17, 25]. Accurate diagnosis is crucial to ensure proper treatment and avoid ineffective or harmful medications. Rapid assays for ADAMTS13 activity and complement genotyping are essential in facilitating prompt and accurate diagnosis.

In fatal cases, autopsies were rarely performed [5–9, 11–13, 26]. When described, microscopic findings often indicate ischemic changes along with platelet-rich thrombi involving small arterioles and capillaries in various organs such as the myocardium, kidneys, adrenal glands, skin, lungs, pancreas, gingiva and brain [6, 8, 11]. In our cases, thrombi were also found in small vessels, such as the adrenals and liver sinusoids, as well as inside the capillaries of GB. Thrombus formation

with platelet consumption result in thrombocytopenia, hemorrhage and ischemic damage. Ischemic and hemorrhagic changes were especially present in subcutaneous tissue with petechial hemorrhages and ecchymoses in case 1. In case 2, hemorrhagic obstruction of the aqueduct of Sylvius resulted in hydrocephaly with extensive necrosis of brain parenchyma. Cerebral ischemic changes explain neurological signs commonly reported in cTTP such as focal seizures, visual disturbance, confusion, aphasia, hemiparesis and coma [2]. Ischemic and hemorrhagic changes were also present and severe in the kidneys of both cases affecting both glomeruli and tubules. Renal involvement in cTTP is less frequent but can include hematuria, tubular necrosis and acute renal failure [2, 27]. Bleeding manifestation can affect all organ. Epistasis, rectal bleeding and menorrhagia have also been reported in cTTP [2, 4]. Chronic ischemia and tissue anoxia likely contributed to IUGR present in both cases as also noted in the literature [4]. Lymphoid depletion of the
thymus and splenic white pulp is also typically seen in chronic fetal hypoxia. The ductal plate developmental delay with ductopenia in case 2 is also probably related to chronic ischemia due to hepatic artery thrombosis, as bile duct development and maintain depend on the hepatic artery [28].

Anemia results from hemolytic destruction of red blood cells as they pass through small vessels partially occluded by thrombi, leading to schistocytes [19]. Hemolytic anemia can manifest as pallor and lead to cardiomegaly and fetal hydrops as seen in case 2. Anemia also contributes to tissue hypoxemia. Both thrombocytopenia and anemia explain increased liver hematopoiesis and multivisceral extrahepatic hematopoiesis. Both increased hematopoiesis and hemorrhagic changes can explain hepatosplenomegaly. Liver hemosiderosis and focal adrenal nucleomegaly are also secondary to anemia [29, 30]. Hemophagocytosis observed in case 2 is a feature of hemolytic anemia [31]. Jaundice is also related to hemolytic anemia with increased unconjugated bilirubin [32, 33].

Hemosiderosis was also present and massive in the kidneys in both cases. Renal hemosiderosis is reported in contexts of intravascular hemolysis, such as paroxysmal nocturnal hemoglobinuria and sickle cell anemia [34–37]. Except for the liver and kidneys, we did not observe hemosiderosis in other organs such as reported by Singer et al. [10].

The lungs were also significantly affected in both cases. Pulmonary vein malalignment (MPV) such as seen in case 1 may suggest alveolar capillary dysplasia (ACD). Kitano et al. reported autopsy findings in 2 siblings with genetically confirmed ACD/MPV. *FoxF1* mutations were associated in both cases with GB [38]. They did not observe GB in other organs. *FoxF1* mutations were specifically assessed in our cases, but none were found. In case 2, features suggestive of plexiform arteriopathy were noted. Some cases of cTTP have been reported with pulmonary hypertension [39]. Pulmonary hypertension can lead to the formation of shunt or arteriovenous fistulas between the pulmonary and the systemic vascularization which can mimic MPV [40], [41]. Lung hypoplasia was present in both cases and can be explained by fetal hydrops or hepatomegaly or chronic hypoxia.

The placenta can also be involved with placental arteriolar thrombosis, infarction and maternal vascular malperfusion [42]. Miscarriage is therefore a common complication of pregnancy in mother with cTTP [2, 21, 43, 44]. In the 3 stillbirth cases reported by Yang et al., placentas were normal [4]. We did not see signs of vascular malperfusion in our cases. However, in case 2, the villi contained many vessels in addition to wall vessels hypertrophy to the villous trunks, changes possibly linked to chronic fetal hypoxia.

The prominent feature in our 2 cases was the glomeruloid vascular proliferation in many organs. To our knowledge, such multiorgan involvement has not been previously documented in genetically confirmed cTTP. GB have been described in rare autopsy cases involving only the kidneys [12, 13, 45] and brain

[13]. GB are typically seen in aggressive tumors such high-grade glial neoplasms, reflecting abnormal angiogenesis and vascular proliferation. Ultrastructural studies of GB showed tufted collections of newly formed vascular channels lined by hyperplastic endothelial cells and surrounded by basal lamina and an incomplete layer of pericytes [41]. GB have also been reported in kaposiform hemangioendothelioma [46, 47]. However, the microscopic, immunohistochemical and molecular findings were inconsistent with vascular proliferation that can be encountered at birth such as congenital hemangioma, infantile hemangioma, tufted angioma/kaposiform hemangioendothelioma which can be accompanied by thrombocytopenia in the settings of Kasabach-Merritt phenomenon, and multifocal lymphangioendotheliomatosis with thrombocytopenia [48–50]. GB could also have suggested multiple glomeruloid hemangiomas which are classically reported in antiphospholipid syndrome (APS) [51], POEMS syndrome [52–54] and reactive angioendotheliomatosis [55]. APS was ruled out in the mother including tests for unconventional antibodies [56]. POEMS syndrome, a paraneoplastic disorder due to plasma cell dyscrasia, is extremely rare in children, with the youngest reported cases around 10 years of age [57]. GB are also a feature of Fowler syndrome, but this syndrome only affects the brain and no mutation of *FLVCR2* was detected in our 2 cases.

The pathogenesis of GB is still unknown, but endothelial activation is believed to play a key role in cTTP [58]. Vascular occlusion and tissue hypoxia may trigger the production of VEGF, an angiogenic factor that promotes new blood vessel formation, contributing to the formation of GB [59].

The severity of cTTP presentation is linked to the type of *ADAMTS13* gene mutation. Since the initial discovery of *ADAMTS13* sequence variations on chromosome 9q34 [60], more than 200 mutations have been identified to date [61]. The impact of these mutations varies depending on the affected domains and can influence either the activity or secretion of the enzyme [4]. Mutations affecting the highly conserved N-terminal domains are associated with lower residual *ADAMTS13* activity and a more severe clinical phenotype, with earlier disease onset in an allelic dose-dependent manner [4, 24]. An *ADAMTS13* activity threshold below 2% appears to be a clinically relevant severity marker [62]. The mutations found in our cases have not been previously reported. The in-phase deletion of exons 9 to 11, downstream of the N-terminal domain, likely resulted in a non-functional protein. The stop variant might either lead to a truncated protein or trigger a nonsense-mediated decay mechanism, causing degradation of unstable mRNA. Given the severity of the phenotype, the residual level of functional *ADAMTS13* protein was likely extremely low or even absent.

cTTP symptoms typically require additional triggers, as *ADAMTS13* deficiency alone does not cause clinically apparent TTP. Common triggers include infections, vaccinations, surgery, and pregnancy, explaining why symptoms may first

<figure><img src="image_13.png" /></figure>
appear in adulthood [58, 63–65]. cTTP is an arterial endothe-
liopathy-associated vascular micro thrombotic disease [66].
Endothelial dysfunction is triggered by complement system
activation in response to factors such as pathogens, toxins,
hormones, hypertension, or hyperglycemia. This promotes
microthrombosis by inducing excessive release of ULvWF
and factor VIII from endothelial cells. In individuals with
ADAMTS13 mutations, impaired cleavage of ULvWF multim-
ers leads to platelet aggregation and microthrombi formation.
Unlike cTTP, SarsCov2 primarily causes venous endotheli-
opathy with widespread inflammation [66].

Several factors contribute to cTTP severity, including infec-
tions (via cytokine release), pregnancy (through hormonal
changes and increased vWF levels), aging (as vWF levels rise
over time), non-O blood groups, and female gender (as women
have lower baseline ADAMTS13 levels than men) [67]. These
genetic and environmental factors likely interact, explaining
the phenotypic heterogeneity of cTTP within and between
families. According to some authors, exacerbation of cTTP in
newborn infants is caused by the occurrence of high-velocity,
turbulent blood flow through the patent ductus arteriosus [68].

In our cases, the mother was vaccinated against SARS-CoV-2 during her first pregnancy and between the two pregnancies and developed a confirmed SARS-CoV-2 infection during her second pregnancy. SARS-CoV-2 infection is known to worsen ADAMTS13 deficiency due to direct endothelial damage and inflammatory cytokine storms, which increase vWF release and further reduce ADAMTS13 activity [67, 69]. However, the SARS-CoV-2 infection was not documented in our cases. Vaccination against SARS-CoV-2 has also been associated with onset or relapse of TTP, including congenital forms, possibly through immune activation or endothelial stress [70–72]. Although direct causality cannot be established, maternal immune activation from vaccination or infection may have contributed to disease expression in genetically predisposed fetuses.

Conclusion

Diagnosing cTTP can be challenging, as vascular prolifera-
tion with a glomeruloid aspect may be a prominent feature.
Multivisceral involvement of small arterioles and capillaries
along with thrombi and hemorrhagic signs should prompt the
diagnosis. The peculiar aspect of vascular proliferation and
the two new genetic variants of ADAMTS13 gene expanded
both the phenotypic and genotypic spectrum of cTTP. Patho-
logical endothelial proliferation may play a significant role in
the disease process. Our findings reinforce the hypothesis of
an artery endotheliopathy with vascular injury and prolifera-
tion occurring first. Autopsy findings are critical for correlat-
ing clinical manifestations with underlying pathology and can
help suggest the diagnosis when unclear.

**Author contribution** A Perrot Adélie and P Loget Philippe performed the autopsy of the 2 cases.

C Combescure: obstetrician involved in the pregnancies and deliver-
ies of the 2 cases.

N Belhomme: prescribed and analyzed maternal biological investigations.

M Faoucher Marie and C Dubourg performed the genetic study (WGS).

M Fradin: geneticist involved in the family consultation and follow-up.

R Maragliano Roberta and S Collardeau-Frachon: reviewed all the slides from autopsy samples, suggested the diagnosis and wrote the manuscript.

Funding Open access funding provided by Hospices Civils de Lyon.

**Data Availability** The datasets generated during and/or analysed dur-
ing the current study are available from the corresponding author on
reasonable request.

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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