Thrombotic microangiopathy M31.1

E. Moschcowitz, 1925 (1924)

Etiologically distinct group of diseases with representatives:

TPP (Thrombotic thrombocytopenic purpura - also called Moschcowitz syndrome)

and

HUS (Hemolytic Uremic Syndrome - also called Gasser's Syndrome).

Although it is controversial whether these are separate entities or a spectrum of disease with different organ manifestations, both result in the clinical picture of thrombocytopenia, hemolytic anemia, and varying degrees of endothelial damage in different organs (Webster K et al. 2014) . The following triad is characteristic:

• Coombs-negative hyemolytic anemia with evidence of -fragmentocytes in the blood.
• Thrombocytopenia (microangiopathic-hemolytic anemia).
• ischemic endothelial damage in various organs

The acute systemic coagulation disorder with intravascular haemolysis and thrombotic microangiopathy (+anaemia) leads to various organ damage depending on the vascular system affected: central nervous and nephrogenic deficits up to acute renal failure (=haemolytic-uraemic syndrome HUS), cardiac complications, respiratory failure, visual disturbances, pancreatitis, intestinal ischaemia. Skin changes are rather rare.

Untreated, the lethality is high and lies at 72-94% (Rock GA et al. 1991).

The following syndromes are subsumed under the term "thrombotic microangiopathy":

Hemolytic uremic syndrome (HUS also called Gasser syndrome)

• Typical HUS (Shiga toxin-associated HUS after EHEG infection)
• Atypical HUS (A-HUS, 5% of all cases, increased activation of the complement system due to various mutations). mutations)

Thrombotic thrombocytopenic purpura (TPP also called Moschcowitz syndrome)

• Congenital (familial form, Upshaw-Schulmann syndrome)
• Acquired sporadic form (antibody formation against ADAMTS13)

Rare disease with an incidence of 0.5/100,000 people/year

TPP (thrombotic thrombocytic pupura)

TPP (congenital familial form also called Upshaw-Schulman syndrome ):

• Congenital deficiency of vWF-cleaving (cleaving) protease, also called ADAMTS 13 (ADAMTS = acronym for "a disintegrin and metallprotease with thrombospondin-1-like domains"), a metalloprotease. ADAMTS 13 cleaves the large von Willebrand factor multimers that are 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 extracorpuscular hemolytic anemia and ultimately ischemia in the capillary end-stream regions of the organs. Described are >100 mutations. Depending on the underlying mutation, patients are symptomatic in early childhood (about 50-60% of cases) or become ill only in the 3rd-4th decade of life.

TPP (acquired sporadic form):

• Antibody formation to ADAMTS13; ADAMTS13 levels are decreased. Protease activity during acute TPP <10% or undetectable.

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HUS (Hemolytic Uremic Syndrome).

Thrombotic microangiopathy with renal failure as a leading finding is called hemolytic uremic syndrome (HUS ). HUS can be subdivided into:

Typical HUS:

• The most common form of HUS is after infection with Shiga toxin producing Escherichia coli (STEC). This form is known as EHEC-HUS (enterohemorrhagic Escherichia coli, EHEC) or STEC-HUS. Rarely, this symptomatology occurs after a respiratory infection with Streptococcus pneumoniae (SP-HUS). Triggering factors may be pregnancy, infections (e.g. infections with Escherichia coli, Mycoplasma pneumoniae, etc.), drugs (sulfonamides, estrogens, tacrolimus, gemcitabine, clopedigrel), collagenoses.

Atpic HUS (5% of all HUS cases):

• triggered by various mutations with activation of the complement system. Mutations with activation of the complement system

Varies; TPP predominantly in young adults; HUS in infants and young children

Uncharacteristic preliminary stage. Sudden onset of fever, multiple thromboses, disorientation, stupor. Stroke or sudden cardiac death is possible. According to Amarosi (Amarosi El et al. 1966), the following symptoms are found in different frequencies (Page EE et al. 2017):

• Neurological symptoms (up to 80%): headache, confusion, neurological deficits, seizures
• Haemolytic anaemia (100%)
• thrombocytopenia (100%)
• fever (10%)
• Renal insufficiency (=/>degree 3) (9%)
• Purpura on skin and mucous membranes: petechiae and ecchymoses (incidences are not confirmed)

For therapy, plasmapheresis is in the foreground; possibly immunosuppression with prednisone in high doses. but also rituximab, cyclophosphamide and others.

1. Anarosi EL et al (1966) Thrombotic thrombopenic purpura: report of 16 cases and review of the literature. Medicine 45: 139-160
2. Kremer Hovinga JA et al (2017) Thrombotic thrombocytopenic purpura.
   Nat Rev Dis Primers 6:437-454.
3. Kuhne T et al (2001) Intercontinental Childhood ITP Study Group. Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study. Lancet 358: 2122-2155
4. Moschcowitz E (1925) An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries. Arch Intern Med 36: 89-93
5. Nzerue CM (2002) Thrombotic microangiopathies. N Engl J Med 347: 2171-2773.
6. Page EE et al. (2017) Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, andlong-term
   outcomes from 1995 through 2015. Blood Adv 1:590-600.

7. Webster K et al (2014) Hemolytic uremic syndrome. Handb Clin Neurol 120:1113-1123.

8. Zheng X et al (2003) Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab. Ann Intern Med 138: 105-108