Case of the week #403 (2025)

5 October 2016 - Case of the Week #403

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Thanks to Dr. Avinash Mane, Krishna Institute of Medical Sciences Deemed University (India), for contributing this case. To contribute a Case of the Week, follow the guidelines on our main Case of the Week page.

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Case of the Week #403

Clinical history:
A 3 kg boy was born at 38 weeks following spontaneous vaginal delivery. Themother was a healthy 30 year old G3P1 with O+ blood type. Maternal laboratoryfindings were within normal limits and included a negative antibody screen. There wasno significant family medical history, specifically no known history of jaundice, anemia orhematological disorders.

APGARS at birth were normal but within 3 hours of birth, the baby presented in acuterespiratory distress with a feeble pulse, marked jaundice, pallor and cyanosis, with awhole body purpuric rash.

Laboratory investigations revealed: Hb - 112 g/L; WBC - 22.7 x 10⁹/L; platelet count- 25 x 10⁹/; reticulocytes - 8.5%. The baby died on the first day of life due to acutebilirubin encephalopathy.

Hematology (blood smear) images:

What is your diagnosis?

Diagnosis:
Congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome)

Discussion:
Thrombotic thrombocytopenic purpura (TTP, congenital or acquired) is a rare form ofthrombotic microangiopathy (TMA) characterized by thrombocytopenia andmicroangiopathic hemolytic anemia (MAHA) associated with a range of clinical findingsrelated to end-organ damage. The underlying mechanism is a deficiency in ADAMTS13(Von Willebrand factor-cleaving protease) enzyme.

In congenital TTP (Upshaw-Schulman syndrome), a genetic defect in the ADAMTS13gene (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member13 gene) results in a severe deficiency of ADAMTS13 enzyme.

Acquired TTP is attributed to an auto-immune process (IgG auto-antibody) directedagainst ADAMTS13.

Clinical presentation:
As described in this case of the week, patients with congenital TTP (Upshaw-Schulmansyndrome) typically present shortly after birth or early in the neonatal period with arange of clinical findings, which may include hemolytic anemia with fragmentation oferythrocytes, thrombocytopenia, diffuse and non-focal neurologic findings, decreasedrenal function and fever.

Pathogenesis and tissue findings:
ADAMTS13 enzyme, also known as Von Willebrand factor-cleaving protease, degradeslarge Von Willebrand factor (vWF) multimers, decreasing their activity. Deficiency ofADAMTS13 enzyme (either congenital or acquired) results in the persistence of unusuallylarge von Willebrand factor (UL-vWF) multimers. These multimers induce vWF-richplatelet microthromboses. In tissue sections, these microthrombi are found in arteriolesand capillaries with little or no associated inflammatory changes (angiopathy).Microthrombi are only seen in small caliber vessels which have high shear stress(arterioles and capillaries) as UL-vWF multimers are elongated and binds platelets toform microthrombi. In vessels without high shear stress, vWF has a globoid form whichdoes not bind platelets in a similar manner.

Laboratory findings:
Findings consistent with TMA and MAHA: schistocytes on peripheral blood smears,low platelet count and reticulocytosis. Increased lactate dehydrogenase (LDH), increasedindirect bilirubin and low haptoglobin. Direct antiglobulin (Coombs) test (DAT) isnegative.

Diagnosis:
Thrombocytopenia and microangiopathic hemolytic anemia and a severe ADAMTS13deficiency (< 10% normal values), in the absence of anti-ADAMTS13 antibodies,suggest a diagnosis of congenital TTP. There may be a known family history of jaundiceor bleeding disorders, especially in neonates. Diagnosis is confirmed by molecularanalysis revealing a double heterozygous or homozygous mutation in the ADAMTS13gene.

Genetics:
Congenital TTP is transmitted in an autosomal recessive (AR) manner and geneticcounseling should be provided to affected families.

Treatment:
Therapeutic plasma exchange transfusion (TPE) using fresh frozen plasma (FFP) toreplace ADAMTS13 is the treatment of choice and has reduced mortality from > 90% toless than 20% if initiated in the acute phase (within 4-8 hours) of the suspected diagnosis.

In newborns, exchange transfusion is often required due to the associated anemia andhyperbilirubinemia which may develop in the acute phase. Subsequent acute episodesare treated by therapeutic plasma exchange transfusion and chronic relapsing disease mayrequire prophylactic plasma therapy every 2-3 weeks to maintain ADAMTS13 enzymelevels. There is some controversy regarding the role of platelet transfusions precedinginterventional procedures like intravascular catheter placement, which until recently hadbeen considered contraindicated due to significant mortality.

A bio-engineered wild-type recombinant human ADAMTS13 has been successfullyinvestigated in experimental models and human clinical trials are expected soon.

References:
1. Thromb Res 2014;134:1171
2. J Clin Apher 2014;29:148
3. Biorheology 2015;52:319
4. Blood 2012;119:6128
5. Vox Sang 2015;109:168
6. Orphanet
7. OMIM #274150

Discussion by: Dr. Belinda Lategan, St. Boniface Hospital (Canada)