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Year : 2022  |  Volume : 11  |  Issue : 4  |  Page : 224-226

Congenital thrombotic thrombocytopenic purpura simulating alloimmune thrombocytopenia

1 Department of Pediatrics, Almana General Hospital, Al Ahsa, Saudi Arabia
2 Department of Pathology, Maternity and Children Hospital, Al Ahsa, Saudi Arabia

Date of Submission04-Jun-2022
Date of Decision26-Jun-2022
Date of Acceptance01-Jul-2022
Date of Web Publication04-Oct-2022

Correspondence Address:
Muneer Hassan Albagshi
Department of Pediatrics, Almana General Hospital, Al Ahsa
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.jcn_63_22

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Congenital thrombotic thrombocytopenic purpura (cTTP) is a thrombotic microangiopathic caused by severely reduced activity of the von Willebrand factor-cleaving protease A Disintegrin And Metalloproteinase with a Thrombospondin type 1 Motif, member 13 (ADAMTS-13), which leads to small-vessel platelet-rich thrombi, thrombocytopenia, and microangiopathic hemolytic anemia (MHA) in the absence of neutralizing antibodies. We describe a case of cTTP in a female neonate presenting initially on the 1st day of life with asymptomatic thrombocytopenia thought to be alloimmune thrombocytopenia, then progressed to severe neonatal jaundice, pallor, and MHA, in whom ADAMTS-13 levels <5%, and the anti-ADAMTS-13 antibody titer was negative confirming the diagnosis of cTTP. The patient initially received intravenous immunoglobulin infusion before documenting MHA. She received fresh frozen plasma infusions which successfully reversed the MHA (by supplying ADAMTS-13) and prevented organ damage in this patient.

Keywords: A Disintegrin And Metalloproteinase with a Thrombospondin type 1 Motif, member 13, congenital thrombotic thrombocytopenic purpura, microangiopathic hemolytic anemia

How to cite this article:
Albagshi MH, Al Omran AM, Elhakeem HA. Congenital thrombotic thrombocytopenic purpura simulating alloimmune thrombocytopenia. J Clin Neonatol 2022;11:224-6

How to cite this URL:
Albagshi MH, Al Omran AM, Elhakeem HA. Congenital thrombotic thrombocytopenic purpura simulating alloimmune thrombocytopenia. J Clin Neonatol [serial online] 2022 [cited 2022 Dec 9];11:224-6. Available from: https://www.jcnonweb.com/text.asp?2022/11/4/224/357819

  Introduction Top

Thrombotic thrombocytopenic purpura (TTP) is a rare condition, which is either acquired (mainly in adults) or congenital in children (congenital TTP [cTTP]). The disease is characterized by episodes of microangiopathic hemolytic anemia (MHA), thrombocytopenia, and organ damage.[1] The initial disease manifests in the neonatal period, but it could pass into adulthood without prior symptoms or diagnosis.[2] If not treated promptly, the mortality rate is high, especially if the diagnosis is delayed due to a lack of an index of suspicion.[1],[3] TTP in the neonatal period is usually due to deficiency of A Disintegrin And Metalloproteinase with a Thrombospondin type 1 Motif, member 13 (ADAMTS-13) protein (a product of ADAMTS-13 gene located on the long arm of chromosome 9 q 34.2) in the absence of antibodies targeting ADAMTS-13. There are more than 150 mutations in the ADAMTS13 gene that have been reported in people with the familial form of TTP.[4] Individuals with cTTP require life-long infusions supply of the deficient protein and special attention during certain life stages, including the neonatal period and during pregnancy. The TTP registry indicates that the annual incidence of cTTP is 1–3/1,000,000.[2]

  Case Report Top

A 18-h female neonate was admitted to the neonatal intensive care unit because of thrombocytopenia without bleeding manifestations as part of routine neonatal care. She was a product of full-term uneventful gestation by consanguineous marriage. The mother's platelet count was normal. The initial examination showed icteric neonate with no dysmorphic features, organomegaly or skin bleeds. Intensive phototherapy was started as the indirect serum bilirubin was pathologic. The initial impression was alloimmune neonatal thrombocytopenia; therefore, a single dose of intravenous immunoglobulin (IVIG) was infused slowly. On the 2nd day of life, the hemoglobin (HB) started to decrease, and reached the lowest level on the 3rd day with a significant rise of lactate dehydrogenase (LDH) [Table 1]. Red blood cell transfusion was given as the HB dropped to 84 g/L. Pretransfusion red cell morphology revealed evidence of MHA. The diagnosis of cTTP was confirmed by low levels of ADAMTS-13 activity and antigen in the absence of antibodies [Table 2]. She was treated with daily infusions of fresh frozen plasma (FFP) for 3 days [Figure 1]. The hemolysis evidence, LDH, and platelet count quickly normalized. The patient was discharged healthy without neurological or renal sequela with a follow-up plan for prophylactic FFP infusion every 3 weeks.
Figure 1: Laboratory data and clinical management. IVIG - Intravenous immunoglobulin, Phot – Phototherapy, FFP - Fresh frozen plasma

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Table 1: Laboratory investigations during admission and follow-up

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Table 2: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 diagnostic tests

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  Discussion Top

Plasma protein metalloproteinase (ADAMTS-13) was discovered in 2001.[3],[5] It is responsible for downregulation of the ultra-large von Willebrand factor (vWf) multimers by cleaving it to prevent thrombosis,[4] as shown in [Figure 2].
Figure 2: ADAMTS-13 function. ADAMTS-13 - A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13

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Genetic mutation, absence of ADAMTS-13, as well as the presence of inhibitors lead to the accumulation of ultra-large vWf multimers in the blood, which in turn bind to platelets and form microthrombosis in the small blood vessels; hence, the name microangiopathy.[5],[6] These microthrombi cause mechanical hemolytic anemia with the end result of thrombocytopenia, hemolytic anemia, and neonatal jaundice.[6]

With the progression of the condition, these microthrombi involve the kidneys and the brain to cause renal impairment and seizures.[2],[5] Luckily, in our patient, we made the diagnosis of cTTP very early before it affects neither the kidney nor the brain; even though she was initially treated by IVIG in the assumption of neonatal alloimmune thrombocytopenia. IVIG was used as salvage therapy for refractory TTP with clinical improvement in a case series.[7]

In our patient, the clinical presentation was progressive thrombocytopenia together with severe neonatal jaundice and progressive direct antiglobulin test - negative hemolytic anemia. Therefore, she was initially treated with neonatal alloimmune thrombocytopenia with IVIG infusion before documenting MHA at the age of 36 h and triggered the diagnosis of cTTP. We speculate that IVIG added positively to quick the clinical improvement for a reason mentioned earlier.[7] The patient had extremely low levels of ADAMTS13 activity and antigen (<1% of the normal plasma) and undetectable ADAMTS-13 inhibitor.

She was treated early before the microvascular thrombi affect her vital organs (brain and kidneys) by FFP infusions, which provided super quantities of the deficient enzyme. In the absence of genetic cure nowadays, lifelong replacement of deficient ADAMTS-13 is the standard of care by regular infusions by FFP every 2–3 weeks to prevent organ damage which carries minimal risk for transfusion-associated complications with the current blood bank standard or the use of pharmaceutically manipulated plasma by solvent detergent method to eliminated viral transmission.[1] In the absence of other comorbidity and regular FFP infusion, the life span is equivalent to the general population. The diagnosis of cTTP needs an index of suspicion as the initial manifestation could be asymptomatic thrombocytopenia with normal maternal platelets, leading to the diagnosis of alloimmune thrombocytopenia mimicking the underlining cTTP. Close monitoring and laboratory follow-up will lead to early diagnosis and prompt intervention to prevent multiorgan damage. The confirmatory diagnosis was made by demonstrating low ADAMTS-13 antigen and activity levels in the absence of neutralizing antibodies. The initial IVIG infusion might have played a role in the fast recovery of this patient as it has been used in adult refractory TTP.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Loirat C, Girma JP, Desconclois C, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatr Nephrol (Berlin, Germany) 2009;24:19-29.  Back to cited text no. 1
Terrell DR, Williams LA, Vesely SK, Lämmle B, Hovinga JA, George JN. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: All patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J Thromb Haemost 2005;3:1432-6.  Back to cited text no. 2
Singer K, Bornstein FP, Wile SA. Thrombotic thrombocytopenic purpura; hemorrhagic diathesis with generalized platelet thromboses. Blood 1947;2:542-54.  Back to cited text no. 3
Wang J, Zhao L. Clinical features and gene mutation analysis of congenital thrombotic thrombocytopenic purpura in neonates. Front Pediatr 2020;8:546248.  Back to cited text no. 4
Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001;276:41059-63.  Back to cited text no. 5
Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001;413:488-94.  Back to cited text no. 6
Ding J, Baer MR, Hess JR, Zimrin AB. Intravenous immunoglobulin as salvage therapy for refractory thrombotic thrombocytopenic purpura. Am J Hematol 2018;93:E77-9.  Back to cited text no. 7


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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