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Congenital TTP (Upshaw-Schulman)
This condition, also known as Upshaw-Schulman syndrome, is typically present from birth and can lead to a range of symptoms due to reduced blood flow, affecting various organs. It primarily affects individuals who inherit altered copies of the ADAMTS13 gene.
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Overview
Congenital Thrombotic Thrombocytopenic Purpura (TTP), often called Upshaw-Schulman syndrome, is a very rare inherited blood disorder. It causes tiny blood clots to form in small blood vessels throughout the body. These clots can block blood flow to organs such as the brain, kidneys, and heart, potentially leading to serious health issues [PMID:33671239]. The condition often presents during infancy or childhood, but symptoms can sometimes appear later in life, particularly during times of stress like infection, pregnancy, or surgery.
Congenital TTP is distinct from acquired TTP, which is more common and usually develops later in life due to autoimmune factors. While both conditions share similar symptoms, their underlying causes and treatment approaches differ significantly. Understanding the specific type of TTP is crucial for appropriate management.
Symptoms & clinical features
The symptoms of congenital TTP can vary widely in severity and presentation. Common features often include anaemia (low red blood cell count) due to the destruction of red blood cells (haemolysis), a low platelet count (thrombocytopenia), and kidney problems [PMID:33671239]. Neurological symptoms, such as headaches, confusion, seizures, or even strokes, can occur if blood clots affect the brain.
Other potential symptoms include fatigue, yellowing of the skin or eyes (jaundice), abdominal pain, and purple or reddish spots on the skin (purpura or petechiae) caused by bleeding under the skin due to low platelets. Some individuals may experience recurrent episodes of these symptoms, while others might have a more continuous presentation. The specific combination and severity of symptoms depend on which organs are most affected by the tiny blood clots.
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Affected organs
Congenital TTP primarily affects organs that rely on small blood vessels for their function, as these are the sites where the mini-clots tend to form. Key organs that can be impacted include the brain, leading to neurological complications, and the kidneys, which can result in kidney dysfunction or failure. The heart may also be affected, potentially causing cardiac issues.
Additionally, the blood itself is profoundly affected, with red blood cells being damaged and platelets consumed in the clotting process. This ongoing destruction of red blood cells can also put a strain on the spleen and liver. The widespread nature of these micro-clots means that practically any organ system could, in theory, be compromised, though the brain and kidneys are most commonly and significantly affected.
Risks & severity
Congenital TTP is a rare condition, affecting approximately 1 in 1,000,000 people. The severity can range from mild, intermittent episodes to severe, life-threatening complications. Without appropriate treatment, severe episodes can be fatal. The typical age of onset varies; some individuals experience their first symptoms in infancy or childhood, while others may not develop symptoms until adulthood [PMID:24602283].
Episodes of congenital TTP can be triggered by events that place stress on the body, such as infections, pregnancy, surgery, or certain medications. The long-term risks include chronic kidney disease, neurological damage, and an increased risk of cardiovascular problems due to repeated episodes of clotting and inflammation. Regular monitoring and proactive management are essential to minimise these risks.
Genetic causes
Congenital TTP is caused by genetic changes (pathogenic variants) in the ADAMTS13 gene. This gene provides instructions for making an enzyme called ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin Type 1 Motif, 13). The ADAMTS13 enzyme plays a critical role in regulating blood clotting. Its main function is to cut very large protein molecules called von Willebrand factor (VWF) into smaller pieces [PMID:33671239].
Von Willebrand factor is essential for normal blood clotting, as it helps platelets stick to sites of injury and to each other. If the VWF molecules are too large due to a faulty ADAMTS13 enzyme, they become overactive, leading to spontaneous and widespread formation of tiny blood clots. Pathogenic variants in ADAMTS13 reduce or eliminate the enzyme's activity, which is the underlying cause of congenital TTP.
- ADAMTS13 ADAM metallopeptidase with thrombospondin type 1 motif 13The ADAMTS13 gene provides instructions for an enzyme crucial in regulating blood clotting by processing von Willebrand factor, preventing excessive clot formation.
Inheritance pattern
Congenital TTP is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the ADAMTS13 gene - one from each parent - to develop the condition. People who have only one altered copy of the gene are called carriers. Carriers typically do not have symptoms of congenital TTP because their one working copy of the gene produces enough functional ADAMTS13 enzyme.
If both parents are carriers of a pathogenic ADAMTS13 variant, there is a 25% chance with each pregnancy that their child will inherit two altered copies and develop congenital TTP. There is a 50% chance the child will be a carrier, and a 25% chance the child will inherit two normal copies of the gene and not be affected or a carrier. Family members of someone with congenital TTP may wish to discuss carrier testing and genetic counselling.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of congenital TTP typically involves a combination of clinical symptoms, blood tests, and genetic testing. Blood tests will often show the hallmark features of the condition: severely reduced ADAMTS13 enzyme activity (usually less than 10% of normal), a low platelet count, and evidence of haemolytic anaemia, which can be seen by examining a blood smear for fragmented red blood cells (schistocytes).
Genetic testing for pathogenic variants in the ADAMTS13 gene confirms the diagnosis. This testing is crucial to differentiate congenital TTP from acquired forms of TTP and other conditions that might have similar symptoms. Referrals for genetic testing and diagnosis are usually made by haematologists or clinical geneticists, often as part of the NHS Genomic Medicine Service (GMS) pathways. The relevant NHS Genomic Medicine Service 'R-code' for severe constitutional ADAMTS13 deficiency with TTP is R189 (Thrombotic Thrombocytopenic Purpura (TTP)).
Management & lifestyle
Management for congenital TTP focuses on replacing the deficient ADAMTS13 enzyme and managing acute episodes. This often involves regular infusions of fresh frozen plasma (FFP) or a specific plasma-derived ADAMTS13 concentrate. These infusions provide the missing enzyme, helping to break down excess von Willebrand factor and prevent clot formation [PMID:24602283]. The frequency and dose of these treatments are tailored to the individual's needs, depending on the severity and frequency of their symptoms.
During acute episodes, more intensive treatment with plasma exchange may be necessary. Ongoing monitoring of blood counts and ADAMTS13 activity is essential. Individuals with congenital TTP are typically managed by a multidisciplinary team, including haematologists, clinical geneticists, and specialist nurses, within the NHS. Genetic counselling is also an important part of care for affected individuals and their families.
UK care pathway
In the UK, individuals suspected of having congenital TTP would typically be referred to a haematologist. If a genetic cause is suspected, they would be further referred to NHS Clinical Genetics services. The NHS Genomic Medicine Service (GMS) provides diagnostic genetic testing under specific 'R-codes', such as R189 for Thrombotic Thrombocytopenic Purpura (TTP). A genetic counsellor can provide support and information regarding inheritance patterns, genetic testing for family members, and implications for family planning.
Frequently asked questions
What is the difference between congenital and acquired TTP?
Congenital TTP is a genetic condition present from birth due to inherited changes in the ADAMTS13 gene. Acquired TTP is usually an autoimmune condition that develops later in life, where the body's immune system attacks the ADAMTS13 enzyme.
Can congenital TTP be cured?
Currently, there is no cure for congenital TTP. However, it can be effectively managed with lifelong treatment, typically involving regular infusions of plasma or ADAMTS13 concentrate, to replace the missing enzyme and prevent symptoms.
Are my children at risk if I have congenital TTP?
Congenital TTP is autosomal recessive. If you have the condition, you will pass one altered ADAMTS13 gene to all your children. Whether they develop the condition or are carriers depends on the genetic status of your partner. Genetic counselling can provide personalised advice.
What triggers an episode of congenital TTP?
Episodes can be triggered by various factors that increase stress on the body. Common triggers include infections, surgery, pregnancy, and certain medications. Identifying and avoiding triggers where possible is part of managing the condition.
How often do I need treatment for congenital TTP?
The frequency of treatment, often plasma or ADAMTS13 concentrate infusions, varies for each individual. It depends on the severity of symptoms, how well you respond to treatment, and whether you are experiencing an acute episode or are in remission. Your haematologist will determine your specific treatment schedule.