Thrombotic thrombozytopenic Purpura M31.1

E. Moschcowitz, 1925 (1924)

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.

The pathophysiology of TTP is based on severe ADAMTS13 deficiency, the specific von Willebrand factor (VWF)-cleaving protease. ADAMTS13 deficiency is:

• congenital (familial TPP)
• or
• 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.

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

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).

TPP (unlike HUS - infants and young children) occurs predominantly in young adults.

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)

Hemolytic uremic syndrome.

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).

Alternative: cyclophosphamide

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).

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).

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