Upshaw–Schulman Syndrome

Overview

Upshaw–Schulman syndrome is a rare, inherited form of thrombotic thrombocytopenic purpura (TTP), a life-threatening blood disorder characterized by the formation of microvascular blood clots. Unlike acquired TTP, which is caused by autoantibodies, Upshaw–Schulman syndrome is congenital and results from mutations in the ADAMTS13 gene. This gene encodes an enzyme responsible for cleaving von Willebrand factor (vWF), a protein involved in blood clotting. Deficiency of this enzyme leads to the accumulation of unusually large vWF multimers, causing widespread clot formation in small blood vessels.

Causes

Upshaw–Schulman syndrome is caused by biallelic (homozygous or compound heterozygous) mutations in the ADAMTS13 gene, located on chromosome 9q34. These mutations result in a severe deficiency or complete absence of ADAMTS13 enzyme activity. As a result, the body cannot properly regulate von Willebrand factor, leading to the spontaneous formation of microthrombi that consume platelets and damage red blood cells.

The disorder is inherited in an autosomal recessive pattern, meaning both parents must carry a defective copy of the gene for their child to be affected.

Symptoms

Symptoms of Upshaw–Schulman syndrome typically manifest in infancy or early childhood but can also appear later in life, especially during periods of physiological stress. Common symptoms include:

• Thrombocytopenia (low platelet count)

• Microangiopathic hemolytic anemia (destruction of red blood cells)

• Neurological symptoms (confusion, headaches, seizures, or stroke-like episodes)

• Fatigue and pallor

• Jaundice (yellowing of the skin and eyes)

• Fever

• Kidney dysfunction

Episodes may be recurrent and triggered by infections, surgery, pregnancy, or other stressors. Without treatment, acute episodes can be fatal.

Diagnosis

Diagnosis of Upshaw–Schulman syndrome involves a combination of clinical evaluation and laboratory testing. Key diagnostic steps include:

• Blood tests – revealing anemia, schistocytes on blood smear, low platelet count, elevated lactate dehydrogenase (LDH), and indirect hyperbilirubinemia

• ADAMTS13 activity assay – showing severe deficiency (<10% activity)

• ADAMTS13 inhibitor test – negative in Upshaw–Schulman syndrome, helping distinguish it from acquired TTP

• Genetic testing – confirming mutations in the ADAMTS13 gene

Early diagnosis is crucial for prompt initiation of appropriate therapy to prevent complications.

Treatment

Treatment of Upshaw–Schulman syndrome aims to replace the deficient ADAMTS13 enzyme and manage acute episodes. Options include:

• Plasma infusion – provides functional ADAMTS13 enzyme; used prophylactically or during acute episodes

• Plasma exchange (plasmapheresis) – may be used in severe cases, similar to acquired TTP

• Recombinant ADAMTS13 therapy – under development and may provide targeted treatment in the future

• Supportive care – includes hydration, blood transfusions, and management of complications

Prophylactic plasma infusions are often required every few weeks to prevent relapses, especially during high-risk situations like surgery or childbirth.

Prognosis

With timely and appropriate treatment, the prognosis of Upshaw–Schulman syndrome has improved significantly. Lifelong management with regular plasma infusions can prevent episodes and complications. However, without treatment, the condition can be fatal due to organ damage from widespread clotting. Advances in genetic testing and enzyme replacement therapies offer hope for better disease monitoring and individualized care in the future.