Pathogenesis

For TTP patients, two main factors are of great importance:
1. the von-Willbrand factor (vWF)
2. the von-Willbrand factor (vWF) cleaving protein (vWF protease)

The von Willebrand factor (vWF) is a protein formed in the endothelium. It is produced there as the ultra large vWF-- multimer. In the case of vascular lesions, resulting for example from an infection, these ultra large vWF multimers are increasingly produced.

Usually, these ultra large vWF multimers are cleaved directly by the vWF protease (a zinc containing metalloproteas, also known as vWF-cleaving protease) directly at the endothelium.

The vWF protease itself is produced by a gene that is located on the 9th chromosome and bears the name "ADAMTS13 gene". The ADAMTS13 gene normally encodes the zinc metallo protease that cleaves the vWF multimers.

Also in TTP patients the vWF is formed in the endothelium. However, the ADAMTS13 gene producing the cleaving vWF protease is defective. According to Levy and Ginsburg, it exists in one of twelve different mutations that produce only ineffective vWF proteases.

If, for example, an increased development of ultra large vWF multimers occurs due to an inflammatory reaction of the vessels, these can only be inadequately or not cleaved at all in TTP patients due to the lack of vWF protease activity.

In contrast to the cleaved and by this harmless vWF in healthy people, the ultra large vWF multimers have essentially two negative properties in TTP patients:
1. They are "sticky" and lead to platelet aggregation.
2. Due to their great shear force, they cleave erythrocytes.

Through these negative characteristics the following problems arise in the body:

1.Thrombotic microangiopathy
Platelet aggregation and ultra large vWF multimers result in (partial) occlusion of the arterioles (thrombotic microangiopathy). The consequences are ischemia, organ infarctions, and neurological disorders.
2.Microangiopathic, haemolytic anemia
Due to the size of the vWF multimers, the erythrocytes are exposed to increased shear force. They are split.
This process is further reinforced by the following context:
Because of the platelet aggregation, clearing conditions in the vessels occur. The blood vessels become narrower, which leads to an increased flow rate of the erythrocytes (microangiopathic, haemolytic anemia). This leads to an even faster cleavage of the erythrocytes on the ultra large vWF multimers.
3.Thrombocytopenia
Since most platelets are consumed during thrombocyte aggregation, there is too little free platelets present, so that hematomas form quickly.
4. Vascular lesions
An increased secretion of ultra large vWF multimers occurs in the case of vascular lesions of the endothelium. If these multimers are not cleaved directly at the endothelium by the vWF protease, they destroy not only the erythrocytes, but can also interfere with the organ supply due to their size and microthrombus formation and also damage the organ itself.

Kn, reviewed by Prof. Dr. med. Scharrer