Upshaw-Schulman Syndrome

from Wikipedia, the free encyclopedia
Classification according to ICD-10
M31.1 Moschcowitz syndrome
ICD-10 online (WHO version 2019)
Blood smear of a TTP under the microscope with schistocytes (fragmentocytes) marked blue

The Upshaw-Schulman syndrome ( USS ) is a rare blood clotting disease and corresponds to the inherited form of thrombotic thrombocytopenic purpura (TTP). Patients with USS have too little ADAMTS13 protease , so the multimers of the ultra - long Von Willebrand factor (ULVWF) remain in the blood , which triggers a thrombotic microangiopathy with vascular occlusions in the small blood vessels. These vascular occlusions prevent sufficient blood flow in the underlying tissue, which is damaged as a result. The symptoms of acute USS are very variable, usually there is a thrombocytopenic microangiopathic hemolytic anemia (MAHA) with schistocytes in the blood smear , fever and ischemic organ damage in the brain, kidney and heart.

Epidemiology

The incidence of TTP is 1.7 to 4.5 million per year. Most TTP cases can be attributed to autoimmune TTP and are caused by autoantibodies that block the ADAMTS13 protease . Only about 5% of TTP cases are caused by the USS. The exact prevalence of the USS could not yet be calculated due to its rarity.

Upshaw Schulman syndrome is inherited as an autosomal recessive trait. It is more often caused by compound heterozygous mutations than by homozygous mutations. The age of onset is variable and ranges from newborn to advanced adulthood. The probability of a recurring course is very individual. The severity of the disease can be reduced with early diagnosis and, if necessary, prophylactic therapy.

etiology

Genetic mutations

The ADAMTS13 ( a disintegrin and metalloprotease with thrombospondin type 1 motif 13 ) gene is encoded on chromosome 9q34 and contains 29 exons . The ADAMTS13 protease consists of 1427 amino acids that form the following domains:

  • The “ signal peptide region ” is said to have an influence on the secretion, folding and stability of the ADAMTS13 protease. It acts on phospholipids of the cell membrane and proteins of the secretion complexes in the ADAMTS13 producing cells.
  • The “ metalloprotease domain ” is the active part of ADAMTS13, which cleaves the VWF at its A2 domain between the amino acids tyrosine 1605 and methionine 1606.
  • The “ disintegrin domain ” together with the “ Thrombospondin-1 repeat ” (TSP-1 repeat) and the subsequent “ cysteine-rich domain ” and “ spacer domain ” are required for substrate recognition and cleavage of the VWF A2 domain. First of all, the “Spacer Domain” recognizes the VWF and increases the affinity of ADAMTS13 to VWF. Then the “disintegrin-like domain” reacts with a low-affinity bond. Finally, the “metalloprotease domain” binds to the VWF like a three-part zip.
  • The " TSP-1 repeats " influence interactions between proteins and the extracellular matrix .
  • The “ cysteine-rich domain ” is important for docking with cells, for example with integrins from certain cell membranes.
  • The “ CUB domains ” form connections between proteins of the VWF that are accessible under high shear forces. You are responsible for both binding and splitting VWF. In addition, they are involved in ADAMTS13 secretion from the cells.

Mutations that cause USS occur in all domains. In the case of USS, the secretion of ADAMTS13 in particular is disturbed, and ADAMTS13 activity can additionally be reduced or lost. At the moment more than 120 mutations causing USS and numerous single nucleotide polymorphisms (SNP) are known. The various SNPs can, depending on the combination, increase and decrease the ADAMTS13 protease activity. Patients with residual activity of the ADAMTS13 protease tend to have a later onset of the disease.

The role of ADAMTS13 and Pathogenes of USS

The family of ADAMTS proteases includes enzymes for collagen processing , splitting of the intercellular matrix , inhibition of angiogenesis and for anticoagulation . ADAMTS13 is a zinc metalloprotease . It is mainly made in liver cells and endothelial cells , but has also been found in other cells such as platelets , kidney cells, and brain cells. The only known function of ADAMTS13 is the cleavage of VWF multimers.The measurable plasma half-life in blood of ADAMTS13 is approx. 2 to 4 days, whereby the protective effect seems to last longer.

A patient with USS usually has a severe decrease in ADAMTS13 activity of less than 10% of normal activity. Depending on the mutations present, a residual function can be retained in this area.

A deep ADAMTS13 activity is often not enough to trigger a (first) TTP episode. An acute TTP flare-up in USS patients is often initiated by an environmental trigger. Known triggersinclude infections (including mild upper respiratory infections), pregnancy , increased alcohol consumption, and medications. In these situations VWF is released from the storage organelles (for example the Palade-Weibel bodies , platelet granules ). This increases the VWF content of the blood and more ADAMTS13 is needed to prevent the blood from clotting spontaneously in the small blood vessels. The lack of ADAMTS13 activity in USS patients results in a TTP episode.

pathology

After its release, ADAMTS13 is either bound to the vessel wall ( endothelium ) or free in the plasma . The strong shear forces in small blood vessels pull the contracted spherical VWF into its linear shape. In this form, the active binding domain of the linear VWF lies freely on the surface and can initiate blood clotting . These binding domains connect platelets to lesions on blood vessels and link VWF to one another so that a blood clot can be formed. The ULVWF multimers have increased reactivity and binding capacities, which leads to spontaneous vascular occlusions. If there is enough ADAMTS13, it can split the linear ULVWF into its normal size. Normally large VWF is less willing to bind and only necessary blood clots are formed.

Symptoms

The clinical picture of a TTP is very different. The patient often seeks a doctor with symptoms that occur as a result of the often low platelet count, such as purpura (approx. 90% of patients), ecchymoses and hematomas . In addition, other symptoms that are present as a result of microangiopathic haemolytic anemia , such as dark urine, (mild) jaundice , tiredness and paleness can occur. Many patients have also variably pronounced neurological symptoms, such as headaches, movement disorders , speech disorders , stroke , comatose until comatose states. The symptoms can also temporarily disappear and reappear during an attack. Other unspecific findings are malaise and joint or muscle pain. Serious impairment of the heart or lungs are rare, although changes in the organ systems are often measurable (e.g. EKG abnormalities)

diagnosis

The diagnosis of TTP is based on the clinical signs and symptoms in the presence of thrombocytopenia (platelet count less than 100 × 10 9 / l, often less than 20 × 10 9 / l), microangiopathic haemolytic anemia with schistocytes in the blood smear , a negative direct antiglobulin test ( Coombs Test ) and elevated hemolysis markers (e.g. total bilirubin , LDH , free hemoglobin , deep haptoglobin ) after excluding other possible causes.

The following diagnoses, which resemble USS, are usually excluded: fulminant infection , disseminated intravascular coagulopathy (DIC), autoimmune hemolytic anemia , Evans syndrome , autoimmune atypical or post- infectious form of hemolytic uremic syndrome (HUS) , HELLP syndrome (hemolysis, elevated liveres , low platelets syndrome), preeclampsia and eclampsia , heparin-induced thrombocytopenia (HIT), (metastatic) cancer, kidney damage, antiphospholipid antibody syndrome , and side effects of a bone marrow transplant .

The pregnancy-associated clinical pictures such as preeclampsia , eclampsia and the HELLP syndrome can overlap with that of a TTP episode, as they themselves can trigger a TTP flare-up and require special attention.

Patients with fulminant infections, disseminated intravascular coagulation (DIC) , HELLP syndrome , pancreatitis , liver disease, or other inflammations may have decreased ADAMTS13 activity. Under these circumstances, they very rarely trigger a severe, disease-relevant reduction in ADAMTS13 activity below 10%.

A severe ADAMTS13 deficiency <5% or <10% (depending on the definition) is evidence of a TTP. The ADAMTS13 tests measure the VWF fission products directly or indirectly. The ADAMTS13 activity should be measured from a blood sample before the start of therapy in order to rule out an incorrectly high ADAMTS13 activity.

In severe ADAMTS13 deficiency , a distinction must be made between the autoimmune form and the congenital form of TTP, the USS. The antibodies are searched for either directly with a so-called ELISA test or indirectly, by testing for a functional inhibitor. With autoimmune TTP, the amount of antibodies in the blood can fluctuate, so if the test result is negative, second confirmatory measurements are carried out during a TTP episode-free phase. The confirmation of a severe ADAMTS13 deficiency in the absence of antibodies during this time is usually the indication for a genetic analysis to prove a mutation causing USS.

In unclear cases, a so-called plasma infusion trial can be carried out. Here, the dose-dependent ADAMTS13 activity can be confirmed in the half-life of 2 to 4 days typical for USS . Partial or severe ADAMTS13 deficiency in a first degree relative is also a strong indicator of USS.

therapy

A TTP episode requires immediate treatment. Standard therapy consists of daily replacement of the ADAMTS13 protease by plasma infusion or, in severe cases, by plasma exchange therapy (PEX). With PEX, the patient's own plasma is almost completely replaced by donor plasma. In both cases, the most common platelet-poor FFP (Fresh Frozen Plasma) is used, although other plasma products containing ADAMTS13 can also be used. The advantage of PEX therapy over plasma infusions is attributed to the removal of the excess ULVWF multimers. Some, mostly mild side effects have been observed. The number of infusions or PEX required for recovery vary, with the USS therapy usually lasting less than a week. Plasma therapy can be stopped when the platelet count normalizes and is stable for several days.

Preventive Therapy

Not all USS affected patients require regular preventative plasma infusions. However, those with frequent TTP flare-ups need such treatment. Therapy with plasma infusions every two to three weeks can prevent such relapses, although this can be individually adjusted. Mild disease courses without frequent recurrence of TTP attacks only require plasma infusions in special risk situations (as mentioned above) .

outlook

New developments in TTP research have been observed in recent years. A recombinant ADAMTS13 protease has been successfully tested in mice and first tests in USS patients have been announced. In addition, another drug was presented that reduces the (UL) VWF interactions with blood platelets and thereby inhibits excessive coagulation in a TTP episode. In addition to various multinational databases, a global research project was started at USS, which collects information about patients and their family members in order to derive new findings on diagnosis and therapy optimization.

history

TTP as such was first described in 1947 and named after its pathophysiology . In 1960, Schulman described the first USS patient. Upshaw reported a recurrent TTP in 1978 that he had followed for 11 years. Upshaw described the parallels between the two cases and also suspected the lack of a plasma factor as the cause. A year later the syndrome was first called Upshaw-Schulman syndrome. In 1996 the lack of the VWF-cleaving enzyme was recognized as the cause of USS. In 2001 ADAMTS13 was named, localized on chromosome 9q34 and the first disease-causing mutations were determined.

Web links

Individual evidence

  1. ↑ a b c d e f g h i j k l m n o p q r s t J. Evan Sadler: Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura . In: Blood . tape 112 , no. 1 , July 1, 2008, p. 11-18 , doi : 10.1182 / blood-2008-02-078170 , PMID 18574040 .
  2. ↑ a b c d e f g h i j k l Ravi Sarode, Nick Bandarenko, Mark E. Brecher, Joseph E. Kiss, Marisa B. Marques, Zbigniew M. Szczepiorkowski, Jeffrey L. Winters: Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research . In: Journal of Clinical Apheresis . tape 29 , no. 3 , June 1, 2014, p. 148–167 , doi : 10.1002 / jca.21302 .
  3. ↑ a b c d e f Joel L. Moake: Thrombotic Microangiopathies . In: New England Journal of Medicine . tape 347 , no. 8 , August 22, 2002, p. 589-600 , doi : 10.1056 / NEJMra020528 , PMID 12192020 .
  4. ^ DR Terrell, LA Williams, SK Vesely, B. Lämmle, J. a. K. Hovinga, JN George: The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency . In: Journal of Thrombosis and Haemostasis . tape 3 , no. 7 , July 1, 2005, p. 1432-1436 , doi : 10.1111 / j.1538-7836.2005.01436.x .
  5. ↑ Jessica A. Reese, Darrshini S. Muthurajah, Johanna A. Kremer Hovinga, Sara K. Vesely, Deirdra R. Terrell, James N. George: Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence , demographic and clinical features . In: Pediatric Blood & Cancer . tape 60 , no. 10 , October 2013, p. 1676-1682 , doi : 10.1002 / pbc.24612 , PMID 23729372 .
  6. ↑ a b c d e f g J. TB Crawley, MA Scully: Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies . In: Hematology . tape 2013 , no. 1 , December 1, 2013, p. 292–299 , doi : 10.1182 / asheducation-2013.1.292 .
  7. ↑ a b Reinhard Schneppenheim u. a .: A common origin of the 4143 insA ADAMTS13 mutation . In: Thrombosis and Haemostasis . tape 96 , no. 1 , June 14, 2006, p. 3-6 , doi : 10.1160 / TH05-12-0817 .
  8. ↑ a b c d e R. S. Camilleri, H. Cohen, IJ Mackie, M. Scully, RD Starke, JTB Crawley, DA Lane, SJ Machin: Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura . In: Journal of Thrombosis and Haemostasis . tape 6 , no. 2 , February 1, 2008, p. 331–338 , doi : 10.1111 / j.1538-7836.2008.02846.x .
  9. ↑ a b c d e f g Barbara Plaimauer u. a .: Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation . In: Blood . tape 107 , no. 1 , January 1, 2006, p. 118-125 , doi : 10.1182 / blood-2005-06-2482 , PMID 16160007 .
  10. ↑ a b c d e f g h i Stefano Lancellotti, Maria Basso, Raimondo De Cristofaro: Proteolytic Processing of Von Willebrand Factor by Adamts13 and Leukocyte Proteases . In: Mediterranean Journal of Hematology and Infectious Diseases . tape 5 , no. 1 , September 2, 2013, ISSN  2035-3006 , doi : 10.4084 / MJHID.2013.058 , PMID 24106608 .
  11. ↑ a b c d e Miriam Biol, Marina Noris, Giuseppe Remuzzi: Thrombotic Thrombocytopenic Purpura-Then and Now . In: Seminars in Thrombosis and Hemostasis . tape 32 , no. 2 , March 2006, p. 81-89 , doi : 10.1055 / s-2006-939763 .
  12. ↑ Zhou Zhou, Hui-Chun Yeh, Hua Jing, Christina Wang, Zhenyin Tao, Huiwan Choi, Khatira Aboulfatova, Renhai Li, Jing-Fei Dong: Cysteine ​​residues in CUB-1 domain are critical for ADAMTS13 secretion and stability . In: Thrombosis and Haemostasis . tape 105 , no. 1 , January 2011, p. 21-30 , doi : 10.1160 / TH10-07-0446 , PMID 20886194 .
  13. ↑ a b c Luca A. Lotta u. a .: Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura . In: Blood . tape 120 , no. 2 , July 12, 2012, p. 440-448 , doi : 10.1182 / blood-2012-01-403113 , PMID 22529288 .
  14. ↑ Luca A. Lotta, Isabella Garagiola, Roberta Palla, Andrea Cairo, Flora Peyvandi: ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura . In: Human Mutation . tape 31 , no. 1 , January 2010, p. 11-19 , doi : 10.1002 / humu.21143 , PMID 19847791 .
  15. ↑ Minola Manea, AnnCharlotte Kristoffersson, Reinhard Schneppenheim, Moin A. Saleem, Peter W. Mathieson, Matthias Mörgelin, Peter Björk, Lars Holmberg, Diana Karpman: Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura . In: British Journal of Hematology . tape 138 , no. 5 , September 1, 2007, pp. 651-662 , doi : 10.1111 / j.1365-2141.2007.06694.x .
  16. ↑ Ryoji Tauchi, Shiro Imagama, Tomohiro Ohgomori, Takamitsu Natori, Ryuichi Shinjo, Naoki Ishiguro, Kenji Kadomatsu: ADAMTS-13 is produced by glial cells and upregulated after spinal cord injury . In: Neuroscience Letters . tape 517 , no. 1 , May 23, 2012, p. 1–6 , doi : 10.1016 / j.neulet.2012.03.002 .
  17. ↑ a b M. Furlan, R. Robles, B. Lamie: Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis . In: Blood . tape 87 , no. 10 , May 15, 1996, pp. 4223-4234 , PMID 8639781 .
  18. ↑ a b c d e Johanna A. Kremer Hovinga, Bernhard Lämmle: Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura . In: ASH Education Program Book . tape 2012 , no. 1 , August 12, 2012, p. 610-616 , PMID 23233642 .
  19. ↑ a b Miha Furlan, Rodolfo Robles, Beat Morselli, Pierre Sandoz, Bernhard Lämmle: Recovery and Half-Life of von Willebrand Factor-Cleaving Protease after Plasma Therapy in Patients with Thrombotic Thrombocytopenic Purpura . In: Thromb Haemost . tape 81 , no. 1 , 1999, p. 8-13 .
  20. ↑ Y. Jiang et al. a .: Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura . In: Blood . tape 123 , no. 11 , March 13, 2014, p. 1674-1680 , doi : 10.1182 / blood-2013-11-538900 .
  21. ↑ James N. George, Qiaofang Chen, Cassie C. Deford, Zayd Al-Nouri: Ten patient stories illustrating the extraordinarily diverse clinical features of patients with thrombotic thrombocytopenic purpura and severe ADAMTS13 deficiency . In: Journal of Clinical Apheresis . tape 27 , no. 6 , January 1, 2012, p. 302-311 , doi : 10.1002 / jca.21248 .
  22. ↑ James N. George, Qiaofang Chen, Cassie C. Deford, Zayd Al-Nouri: Ten patient stories illustrating the extraordinarily diverse clinical features of patients with thrombotic thrombocytopenic purpura and severe ADAMTS13 deficiency . In: Journal of Clinical Apheresis . tape 27 , no. 6 , January 1, 2012, p. 302-311 , doi : 10.1002 / jca.21248 .
  23. ↑ Masahito Uemura, Yoshihiro Fujimura, Saiho Ko, Masanori Matsumoto, Yoshiyuki Nakajima, Hiroshi Fukui: Determination of ADAMTS13 and Its Clinical Significance for ADAMTS13 Supplementation Therapy to Improve the Survival of Patients with Decompensated Liver Cirrhosis . In: International Journal of Hepatology . tape 2011 , July 18, 2011, p. e759047 , doi : 10.4061 / 2011/759047 .
  24. ↑ James N. George, Zayd L. Al-Nouri: Diagnostic and therapeutic challenges in the thrombotic thrombocytopenic purpura and hemolytic uremic syndromes . In: Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program . tape 2012 , 2012, p. 604-609 , PMID 23233641 .
  25. ↑ A. Tripodi et al. a .: Second international collaborative study evaluating performance characteristics of methods measuring the von Willebrand factor cleaving protease (ADAMTS-13) . In: Journal of thrombosis and haemostasis: JTH . tape 6 , no. 9 , September 2008, p. 1534-1541 , doi : 10.1111 / j.1538-7836.2008.03099.x , PMID 18662260 .
  26. ^ A b Gail A. Rock, Kenneth H. Shumak, Noel A. Buskard, Victor S. Blanchette, John G. Kelton, Rama C. Nair, Robert A. Spasoff: Comparison of Plasma Exchange with Plasma Infusion in the Treatment of Thrombotic Thrombocytopenic purpura . In: New England Journal of Medicine . tape 325 , no. 6 , August 8, 1991, pp. 393-397 , doi : 10.1056 / NEJM199108083250604 , PMID 2062330 .
  27. ↑ a b Paul Knöbl: Inherited and acquired thrombotic thrombocytopenic purpura (TTP) in adults . In: Seminars in Thrombosis and Hemostasis . tape 40 , no. 4 , June 2014, p. 493-502 , doi : 10.1055 / s-0034-1376883 , PMID 24802084 .
  28. ↑ Alexandra Schiviz, Kuno Wuersch, Christina Piskernik, Barbara Dietrich, Werner Hoellriegl, Hanspeter Rottensteiner, Friedrich Scheiflinger, Hans Peter Schwarz, Eva-Maria Muchitsch: A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13 . In: Blood . tape 119 , no. 25 , June 21, 2012, p. 6128-6135 , doi : 10.1182 / blood-2011-09-380535 , PMID 22529289 .
  29. ↑ Josefin-Beate Holz: The TITAN trial - Assessing the efficacy and safety of an anti-von Willebrand factor Nanobody in patients with acquired thrombotic thrombocytopenic purpura . In: Transfusion and Apheresis Science . tape 46 , no. 3 , June 2012, p. 343-346 , doi : 10.1016 / j.transci.2012.03.027 .
  30. ↑ M. Mansouri Taleghani et al. A .: Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry: . In: Hemostaseology . tape 33 , no. 2 , 2013, p. 138-143 , doi : 10.5482 / HAMO-13-04-0026 .
  31. ^ A b Jefferson D. Upshaw: Congenital Deficiency of a Factor in Normal Plasma That Reverses Microangiopathic Hemolysis and Thrombocytopenia . In: New England Journal of Medicine . tape 298 , no. 24 , June 15, 1978, pp. 1350-1352 , doi : 10.1056 / NEJM197806152982407 , PMID 651994 .
  32. ^ S. Rennard, S. Abe: Decreased cold-insoluble globulin in congenital thrombocytopenia (Upshaw-Schulman syndrome) . In: The New England Journal of Medicine . tape 300 , no. 7 , February 15, 1979, p. 368 , doi : 10.1056 / NEJM197902153000718 , PMID 759902 .
  33. ↑ HM Tsai: Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion . In: Blood . tape 87 , no. 10 , May 15, 1996, pp. 4235-4244 , PMID 8639782 .
  34. ↑ M. Furlan, R. Robles, M. Solenthaler, M. Wassmer, P. Sandoz, B. Lämmle: Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura . In: Blood . tape 89 , no. 9 , May 1, 1997, pp. 3097-3103 , PMID 9129011 .