Upshaw–Schulman syndrome (USS) is the recessively inherited form of thrombotic thrombocytopenic purpura (TTP), a rare and complex blood coagulation disease. USS is caused by the absence of the ADAMTS13 protease resulting in the persistence of ultra large von Willebrand factor multimers (ULvWF), causing episodes of acute thrombotic microangiopathy with disseminated multiple small vessel obstructions. These obstructions deprive downstream tissues from blood and oxygen, which can result in tissue damage and death. The presentation of an acute USS episode is variable but usually associated with thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytes on the peripheral blood smear, fever and signs of ischemic organ damage in the brain, kidney and heart.
Signs and symptoms The presentation of TTP is variable. The initial symptoms, which force the patient to medical care, are often the consequence of lower platelet counts like purpura (present in 90% of patients), ecchymosis and hematoma. Patients may also report signs and symptoms as a result of (microangiopathic) hemolytic anemia, such as (dark) beer-brown urine, (mild) jaundice, fatigue and pallor. Cerebral symptoms of various degree are present in many patients, including headache, paresis, speech disorder, visual problems, seizures and disturbance of consciousness up to coma. The symptoms can fluctuate so that they may only be temporarily present but may reappear again later in the TTP episode. Other unspecific symptoms are general malaise, abdominal, joint and muscle pain. Severe manifestations of heart or lung involvements are rare, although affections are not seldom measurable (such as ECG changes).
Cause
Genetics The ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13) gene is located on chromosome 9q34 and encoding 29 exons. The ADAMTS13 protease consists of 1427 amino acids and has several protein domains:
The signal peptide is thought to have a role in the secretion, folding and stability of the ADAMTS13 protein. It interacts with membrane phospholipids and protein components of the secretory machinery within the cells. The metalloprotease domain contains the active site, which cleaves the unfolded vWF within the A2 domain, between the amino acids Tyrosine 1605 and Methionine 1606. The disintegrin domain together with the TSP1 repeat, the following cysteine-rich and spacer domains are necessary for substrate recognition, binding and cleavage of the vWF-A2 domain. First, the spacer domain recognizes vWF, increasing the affinity of ADAMTS13 to vWF. Next the disintegrin-like domain engages in a low-affinity binding. Then the metalloprotease domain interacts with the vWF, similar to a three-step molecular zipper. The TSP1 repeats mediate extracellular matrix protein-protein interactions. The cystein-rich domain is responsible for attachment, for example, to integrins of different cell membranes. The CUB domains take part in protein-protein interactions with vWF domains, which become exposed under shear stress, and are also involved in the binding and cleavage of vWF. Additionally they are involved in the ADAMTS13 protein secretion Disease causing mutations in ADAMTS13, which can be found in all ADAMTS13 protease domains. result predominantly in impaired ADAMTS13 secretion with or without decreased ADAMTS13 protease activity. More than 120 disease causing mutations and numerous single-nucleotide polymorphisms (SNP) are known today. Residual ADAMTS13 activity has been observed with certain mutations and seems to be associated with a later disease-onset. It has been postulated that some SNPs interact with each other and may amplify or reduce overall ADAMTS13 activity.
ADAMTS13 function and pathogenesis The ADAMTS protease family contains enzymes that process collagen, cleave inter-cellular matrix, inhibit angiogenesis and blood coagulation. ADAMTS13 belongs to the zinc metalloproteases, and is mainly expressed in liver stellate cells and endothelial cells, but was also found in other cell types, such as platelets, podocytes in the kidney and several brain cells. The only known role of the ADAMTS13 protease is to cleave vWF multimers. The plasma half-life of administered ADAMTS13 in USS patients is around 2–4 days, whereas the protective effects seems to last longer. Usually USS patients have a severely deficient ADAMTS13 activity of <10% of the normal. In this low range there may be residual ADAMTS13 activity, depending on the underlying mutations. In USS severe ADAMTS13 deficiency is often not enough to induce a (first) acute TTP episode. It primarily occurs when an additional (environmental) trigger is present. Recognized triggers are infections (including mild flu-like upper airway infections), pregnancy, heavy alcohol intake or certain drugs. In these situations, vWF is released from its storage organelles, such as Weibel–Palade bodies and granules of platelets. Increased vWF levels in the circulation are leading to a higher demand of ADAMTS13, which is lacking in USS, and can bring forward a TTP episode.
Pathology After secretion, ADAMTS13 is either bound to the endothelial surface or free in the blood stream. The heightened shear stress in small- and microvessels alters the 3D-structure of vWF from the contracted globular form to its linear form. The linear vWF has now its active binding sites exposed, that are important to start blood coagulation. These sites bind platelets and blood vessel lesions by interlinking the stretched vWF with one another – a blood clot is formed. In its uncut form, (ultra large) vWF's heightened stickiness and interlinking causes spontaneous platelet binding and blood clotting. The linear vWF exposes the A2 domain, so that in the presence of enough ADAMTS13 activity it gets cut to its normal size. vWF in the normal length loses its heightened stickiness and spontaneous crosslinking activity to only form blood clots when needed.
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