Hereditary thrombotic thrombocytopenic purpura mimicking idiopathic thrombocytopenic purpura was revealed by miscarriage——Novel Compound Heterozygous Mutations in hTTP

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Hereditary thrombotic thrombocytopenic purpura mimicking idiopathic thrombocytopenic purpura was revealed by miscarriage——Novel Compound Heterozygous Mutations in hTTP

https://doi.org/10.21203/rs.3.rs-4283536/v1

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We report a case of early-onset hereditary thrombotic thrombocytopenic purpura in a 16-years old girl, who suffered from solely thrombocytopenia and was misdiagnosed as idiopathic thrombocytopenic purpura for years until two failed gestations finally revealed the underlying cause. Novel compound heterozygous mutations c.2865G>A:p.Trp955X and c.721delG:p.Gly241fs in ADAMTS13 gene were found and were predicted to be associated with the disease. She responded to plasma therapy but renal dysfunction may remain longstanding.

Hereditary thrombotic thrombocytopenic purpura

idiopathic thrombocytopenic purpura

ADAMTS13

mutation

plasma infusion

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare and life-threaten blood disorder caused by heterozygous or homozygous mutations in the gene ADAMTS13 (A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)^[1]. ADAMTS13 is a vital enzyme consisting of 1427 amino acids encoded by 29 exons on chromosome 9q34^[2]. In the absence of ADAMTS13, uncleaved ultra-large vWF (UL-VWF) multimers bind to platelets and microthrombus secondary arouses acute thrombotic microangiopathy (TMA) via shear force^[3]. Thus, hTTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, renal failure and neurologic deficits. Deficiency of ADAMTS13 activity solely is not sufficient to cause acute thrombotic microangiopathy. Pregnancy, infection or inflammation is necessary to induce an acute episode of TTP^{[1, 4, 5]}. Clinical features vary with mutation type, environment and disease course. An acute episode of TTP may present classic pentad of above-mentioned symptoms while in remission, they may present asymptomatic or solely thrombocytopenia, which make it difficult to diagnose early and accurately. Here we report a hTTP case which was misdiagnosed as idiopathic thrombocytopenic purpura (ITP) for years, and finally revealed by two failed gestations. Two novel mutations in ADAMTS13 were found in this patient.

A female patient presented spot ecchymosis on her extremities without any injury when she was 16, laboratory examinations revealed that her platelet count was 14×10⁹/L，and hemoglobin was 103g/L, bone marrow aspirate smear was executed successively at local hospital and in our center, both of which showed Megakaryocytes hyperplasia and decrease of thromocytogenic Megakaryocyte. According to above evidence, this patient was identified as ITP, and was treated with methylprednisolone. The platelet count returned to 50×10⁹/L, but deceased as the dosage of methylprednisolone reduced. In place of methylprednisolone, cyclosporin A (CsA) finally maintained the platelet count between 100-200×10⁹/L. However, the platelet count dropped off as she got pregnant 5 years later. She had to accept the abortion at the 8^thweek of gestation as the platelet count was too low to keep them save. After the abortion and drug treatment including corticosteroids and CsA, she achieved a normal blood examination most of the time until she got another pregnant, this time, she got through the second trimester, with the platelet ranging from 27 to 40×10⁹/L without medial intervention. Unfortunately, the fetus was found intrauterine death at 26th week of gestation. The placenta examination and fetus chromosome analysis were normal.

The failure of the 2 gestations inspired us to do a comprehensive assessment. Except thrombocytopenia and anemia, the percentage of reticulocytes was found especially high—7.1%, and the hapto-globin below detection limit, indicting hemolysis. Furthermore, schistocytes were seen, for the first time, in peripheral blood and bone marrow. The level of serum creatinine (Cr) and urinary protein were higher than normal. Besides, anticardiolipin antibody was negative and the level of lupus anticoagulant was normal. Autoimmune disease was excluded prudently. Thus, the hypothesis of TTP or HUS was considered. We detected the activity of ADAMTS13, which turned out to be lower than 0.1%, and ADAMTS13 inhibitor was negative. The level of VWF antigen was normal. Gene analysis of ADAMTS13 showed a nonsense mutation p. Trp955X in exon23, and frame shift mutation p. Gly241fs in exon7, both of the mutations are not included in Genome Aggregation database and ClinVar database and not ever reported before. According to ACMG guideline, these mutations are classified as Likely Pathogenic. Both of the novel mutations were predicted to be deleterious with Mutation Taster (http:// mutationtaster.org) software. Moreover, the prediction indicates that nonsense-mediated massage RNA decay (NMD) is likely to be triggered in these mutations. These results lead to a final diagnosis—hTTP. Fresh frozen plasma transfusion (FFP) (10ml/kg) and plasma exchange (PE)(40ml/kg) were applied^[6-9], and the platelet count and hemoglobin normalized, the Cr and urinary protein level declined (Fig.1-2). ADAMTS13 activity returned to baseline 2 weeks after 600ml plasma infusion while the platelet count remained normal, consequently, the patient is receiving FFP infusion every 2 weeks.

On family history, parental consanguineous marriage is denied. ADAMTS13 activity and gene analysis of the family were showed in figure 3. The proband inherited the mutation p.Trp955X in exon23 from her father, whose ADAMTS13 activity is 47.77% without clinical manifestation. Her mother gave birth to 4 kids, one of whom died from unknown reason within month after birth. Her mother once suffered from jaundice after fertilizing her brother and finally died in a car accident years ago. Whether anemia or neurologic deficit was involved in the tragedy as she was believed to carry a mutation of ADAMTS13 remains unknown. Her sister has born 2 kids without relative complications during pregnancy. ADAMTS13 activity is 56.46% and mutation p.Gly241fs in exon7 is verified. ADAMTS13 activity is intact in her brother and neither of the mutations was found in his blood sample.

The nonsense mutation c.2865G>A contributes to abnormal termination of the translation in 955th amino acid and results in deletion of TSP6-8 and CUB domains. Unfortunately, the Swiss Model tool fails to predict the mutated protein structure. The frame shift mutation c.721delG changes the amino acid and ends the translation at the 7nd amino acid after the mutation point, which means the synthesis simply includes signal peptide and pro-peptide (figure 4). Even if nonsense-mediated massage RNA decay (NMD) is not involved, both of the two novel mutations will alter the protein structure and the protein function is definitely impaired, promoting the occurrence of the disease.

Delay diagnosis may account for the high morbidity and mortality in hTTP^{[10, 11]}. There is no accurate definition about the remission and acute episode of hTTP as the severe deficiency of ADAMTS13 activity persists. Diagnostic algorithm does not work well in “remission” course. In our case, thrombocytopenia dominated the onset of the hTTP. Minor anemia without schistocytes in peripheral blood smear was consistent with hemorrhage events especially in woman. Bone marrow aspirate smear with Megakaryocytes hyperplasia and decrease of thromocytogenic Megakaryocyte led to the diagnose of ITP. We are not the only one misdiagnosing the TTP as ITP. Patients disturbed by discontinuous thrombocytopenia were usually treated as ITP with oral steroid and remained symptom-free until an acute episode indicating TTP^[12-14]. Although ITP is not in the list of differential diagnosis in guidelines of TTP^[6-9], ITP concurrent with intravascular hemolysis looks alike TTP^[15], and in verse, TTP in remission period showed a similar characteristic of ITP^{[16, 17]}. In this study, we put forward that ITP should be enrolled in the differential diagnosis list of TTP. Intense follow-up and further examinations should be carried out when anemia appears in suspected ITP. TTP should be taken into consideration when a patient with ITP history experiences miscarriage, hemolysis or organ dysfunction.

The relationship between genotype and phenotype remains intangible. Here, we reported two novel mutations in ADAMTS13, c.721delG and p.Trp955X, which contributed to early-onset hTTP with thrombocytopenia and miscarriage. Early age-onset hTTP was found to be inclined to carry truncating sequence variations and deleterious sequence variation in a French cohort ^[18]. Whilst in another large cohort, mutations earlier in the ADAMTS13 sequence especially pre-spacer domain, were potentially relevant to earlier onset and severer manifestation of the disease^[11]. The enzyme activity region of metalloprotease domain and recognition domain locate in front of spacer may account for the above discovery. Missense mutation R1060W behind spacer is well-known in adult onset hTTP^[19]. Compound heterozygous mutation usually makes it more complicated to elucidate the relationship between genotype and phenotype. As to the patient reported here, earlier onset at 16 years old may due to pre-spacer mutation c.721delG. Although the residual ADAMTS13 activity is pretty low, the disease seems modest. Various triggers like infection, pregnancy and alcohol together determine the final clinical features ^[20]. The residual ADAMTS13 activity is not always parallel to the severity of the disease. Different mutations lead to ADAMTS13 deficiency via diverse mechanism such as reduced synthesis, damaged proteolytic activity, or impaired secretion. Nonsense mutation and frameshift mutation sometimes activate NMD resulting reduced ADAMTS13^[21]. CUB and TSP domains were reported to be in charge of the secretion and conformation changing of ADAMTS13^{[18, 21, 22]}. Mutation p.Trp955X terminates the translation of CUB and TSP domains. We supposed that the proband in this case is going through NMD and impaired secretion of ADAMTS13, together resulting in an undetectable level of ADAMTS13 activity. It is the first time that mutations of c.721delG and p.Trp955X in ADAMTS13 are reported in hTTP, further experiments are required to confirm the exact pathological mechanisms inside.

Plasma infusion is the first choice for hTTP^[7-9]. FFP infusion at the volume of 10-15ml/Kg is recommended for prophylaxis once every 2–3 weeks^{[8, 9]}, as the ADAMTS13 half-life in plasma is 2-4 days^[23]. For therapeutic need, duration relies on the recovery of platelet count and cease of hemolysis, which usually takes 1-3 days^[24]. The exact volume of FFP and the duration of transfusion varies from clinical phenotypes. For the patient reported here, the ADAMTS13 activity declines to baseline 2 weeks after 600ml plasma infusion, but the platelet count remains normal level, which indicates the frequency is reasonable. There is no consensus on when should hTTP patients initiate prophylactic plasma infusion. Real-world study and reliable clinical trials are in urgent need to establish an evidence-based therapeutic program. Most reports prefer to start prophylactic plasma infusion for patients with overt symptoms or chronic organ damage^{[11, 25]}. Recently, prophylactic plasma infusion was considered insufficient to avoid acute episode and long-term organ damage^[26]. PE is not recommended as autoantibody is negative in hTTP, not to mention the unpredictable complications^[27]. Sever renal failure is reported to be associated with lower level of ADAMTS13 activity^{[28, 29]} mainly due to the deficiency expression of ADAMTS13 in podocytes ^[30]. We supposed that FFP infusion is inadequate to rescue the renal damage. PE was instituted in our patient and surprisingly, immediate decline creatine and proteinuria were seen. However, PE was disconnected as anaphylaxis with mild dyspnea, hypotension and allergic rash happened. Subsequent FFP infusions failed to further ameliorate the kidney function. Researchers noted that some cases may benefit from PE as it achieves a higher ADAMTS13 activity and removes the UL-VWF multimers directly at the same time^[23]. The amount and frequency of FFP infusions were suggested to increase to avoid persistent organ damage while the adverse effect of plasma infusion was reminded^[26]. Little information is available about the management of patient with chronic organ failure, but the approaches in managing pregnancy are sophisticated. High prevalence with pregnancy-onset hTTP was found in a cohort^[31]. At present, most physicians agree to commence prophylactic FFP infusions as soon as conception is confirmed and the dosage and frequency usually begin to increase in second trimester, a period when TTP boot and fetus death reach its peak^[32-34]. Daily FFP infusions or PE plays a great role in severe episode and during delivery^[35]. Novel therapies like recombinant ADAMTS13 is on the horizon and gene therapy is under exploration^{[2, 36]}. Chances are that hTTP sufferers are going to get rid of time-wasted and money consuming plasma therapy and to get better control of the disease.

Funding

This study was supported by Natural Science Foundation of China (No.81600147) and Guangdong Provincial Medical Science and Technology Research Fund Project（No. A2023314）.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate. No ethical approval required. This case report was performed in accordance with Declaration of Helsinki.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

RQZ and JHW were the contributors in writing the manuscript. RQZ and JHW collected and analyzed the patient data. WJM designed the work, interpreted the clinical data and revised it as the corresponding author. All authors read and approved the final manuscript.

Acknowledgements

We would like to thank hematologist professor Ying Feng for her help in diagnosis, laboratory technician Jianxi Lai for his help in coagulation test, and laboratory technician Ahui Wang for her help in bone marrow smear.

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No competing interests reported.

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Hereditary thrombotic thrombocytopenic purpura mimicking idiopathic thrombocytopenic purpura was revealed by miscarriage——Novel Compound Heterozygous Mutations in hTTP

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