HistoryThis section has been translated automatically.
E. Moschcowitz, 1925 (1924)
DefinitionThis section has been translated automatically.
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, wasting thrombocytopenia, and organ damage (Joly BS et al. 2019).
It is caused by a severe functional deficiency of ADAMTS13, usually due to autoantibodies against ADAMTS13, hence also called acquired autoimmune TTP. ADAMTS13 specifically regulates the adhesive activity of von Willebrand factor (VWF) by cleavage of its high molecular weight multimers (HMWM). The skin lesions of this clinical picture appear as extensive purpura.
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ClassificationThis section has been translated automatically.
The pathophysiology of TTP is based on severe ADAMTS13 deficiency, the specific von Willebrand factor (VWF)-cleaving protease. ADAMTS13 deficiency is:
- congenital (familial TPP)
- acquired (autoimmunological TTP)
TPP (congenital familial form also called Upshaw-Schulman syndrome ): Congenital deficiency of vWF-cleaving protease, also called ADAMTS 13 (ADAMTS = acronym for "a disintegrin and metallprotease with thrombospondin-1-like domains"), a metalloprotease. Described are >100 mutations. Depending on the underlying mutation, patients are symptomatic in early childhood (about 50-60% of cases) or do not develop the disease until the 3rd-4th decade of life.
TPP (autoimmunological TPP, also called sporadic TPP): In the acquired sporadic form, antibodies are formed against ADAMTS 13. ADAMTS13 levels are reduced. Triggering factors can be: pregnancy, infectious diseases, drugs (sulfonamides, estrogens, tacrolimus, gemcitabine, clopedigrel), also occurring in the context of collagenoses.
Occurrence/EpidemiologyThis section has been translated automatically.
Rare disease with an incidence of 0.5/100,000 people/year
PathophysiologyThis section has been translated automatically.
The following symptomatology is characteristic:
- Coombs-negative hyemolytic anemia with evidence of fragmentocytes in the blood.
- Pronounced thrombocytopenia (microangiopathic-hemolytic anemia)
- Ischemic endothelial damage: Acute systemic coagulopathy with intravascular hemolysis and thrombotic microangiopathy (+anemia) leads to various organ damage depending on the vascular systems affected: central nervous and nephrogenic failure, cardiac complications, respiratory failure, visual disturbances, pancreatitis, intestinal ischemia.
- Plasma activity of ADAMST13: The diagnosis of TTP is confirmed by the detection of ADAMTS13 activity in plasma of < 10%. ADAMTS 13 cleaves the large von Willebrand factor multimers synthesized and secreted in the endothelia. Enzyme deficiency leads to the formation of overlong vWF multimers. This leads to endothelial damage in the capillaries and to extracorpuscular hemolytic anemia and ultimately to ischemia in the capillary endflow regions of the organs. Loss of VWF-HMWM is associated with anti-ADAMTS13 antibodies, severe neurological symptoms and thrombocytopenia. Recovery occurs during the convalescent phase (Béranger N et al. 2019).
- Serum creatinine <120μmol/l (<1.3mg/dl) - Note in HUS: serum creatinine >220 μmol/l.
- Anti-ADAMTS13 IgG antibodies do not always have an inhibitory effect.
- Note: All patients with the first confirmed diagnosis of TTP should be screened for mutations of the ADAMTS13 gene (see Upshaw-Schulman syndrome below).
ManifestationThis section has been translated automatically.
TPP (unlike HUS - infants and young children) occurs predominantly in young adults.
Clinical featuresThis section has been translated automatically.
Uncharacteristic precursor. Sudden onset with fever, multiple thromboses, disorientation, stupor. The following symptoms are found in varying frequencies (Page EE et al 2017):
- Neurological symptoms (up to 80%): headache, confusion, neurological deficits, seizures.
- Hemolytic anemia (100%).
- Thrombocytopenia (100%)
- fever (10%)
- Renal insufficiency (=/>grade 3) (9%)
- Purpura of skin and mucous membranes: petechiae and ecchymosis (incidences are not certain)
Differential diagnosisThis section has been translated automatically.
TherapyThis section has been translated automatically.
Plasmapheresis in combination with corticosteroids remains the first-line treatment of the acute phase of acquired TTP.
Alternative: Immunosuppression with prednisone in high doses.
In acquired TTP, rituximab is additionally used curatively and preemptively (Joly BS et al 2019).
Caplacizumab, an anti-von Willebrand factor may contribute to disease control and overall survival by preventing persistent thrombosis and acute end organ damage (Kubo M et al (2020).
Note(s)This section has been translated automatically.
Although it is controversial whether TPP (Thrombotic thrombocytopenic purpura - also called Moschcowitz syndrome) and HUS(Hemolytic uremic syndrome - also called Gasser syndrome) are separate entities or a spectrum of disease with different organ manifestations, both lead to microangiopathic hemolytic anemia with acute onset thrombocytopenia, and varying degrees of endothelial damage in different organs (Webster K et al. 2014). Extrinsic and intrinsic coagulation tests are unremarkable (INR, aPTT).
LiteratureThis section has been translated automatically.
- Béranger N et al. (2019) Loss of von Willebrand factor high-molecular-weight multimers at acute phase is associated with detectable anti-ADAMTS13 IgG and neurological symptoms in acquired thrombotic thrombocytopenic purpura. Thromb Res 181:29-35.
- Joly BS et al (2019) An update on pathogenesis and diagnosis of thrombotic thrombocytopenic purpura. Expert Rev Hematol 12:383-395.
- Kremer Hovinga JA et al (2017) Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers 6:437-454.
- Kubo M et al (2020) Diagnosis and treatment of thrombotic thrombocytopenic purpura. Rinsho Ketsueki 61:529-535.
- Kuhne T et al (2001) Intercontinental Childhood ITP Study Group. Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study. Lancet 358: 2122-2155
- Meissner T (2020) Cablivi® prevents organ ischemia: acquired thrombotic thrombocytopenic purpura. MMW Fortschr Med 162:64.
- Moschcowitz E (1925) An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries. Arch Intern Med 36: 89-93
- Nzerue CM (2002) Thrombotic microangiopathies. N Engl J Med 347: 2171-2773.
- Page EE et al. (2017) Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, andlong-term outcomes from 1995 through 2015. Blood Adv 1:590-600.
- Webster K et al (2014) Hemolytic uremic syndrome. Handb Clin Neurol 120:1113-1123.
- Zheng X et al (2003) Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab. Ann Intern Med 138: 105-108
Incoming links (5)Antiphospholipid antibodies; Disorders of the coagulation system (haemorrhagic diathesis); Moschcowitz-singer-symmers syndrome; Purpura moschcowitz; Upshaw-Schulman-Syndrom;
Outgoing links (4)Adamts13; Hemolytic uremic syndrome; Upshaw-Schulman-Syndrom; Von willebrand factor;
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