The following article has been written especially for this TTP Network newsletter, by Dr. Sarah Allford of University College Hospital, London(now moved on). 

Our greatest thanks go to Dr. Allford for the time and effort that it must have taken to put this together.

TTP Research

TTP is a relatively rare condition which is recognised clinically by the classical pentad of thrombocytopenia (low platelets), microangiopathic haemolytic anaemia (anaemia secondary to red cell destruction with red cell fragments), fluctuating neurological signs, renal impairment and fever. Formerly mortality rates approached 100% but the introduction of plasma exchange has had a huge impact on prognosis: survival rates are now in the region of 80 – 90%. Nevertheless it is still a matter of debate as to whether plasma exchange is efficacious secondary to the removal or to the replacement of a hitherto unidentified substance. Although mortality has fallen there is still further scope for improvement in treatment. However, effective therapeutic strategies depend on a thorough understanding of the disease pathogenesis which remains at present obscure.

It has been recognised for some time that the symptoms of TTP are secondary to occlusion of the blood vessels supplying tissues, in particular the kidney and brain. Histological examination shows that these thrombi are composed primarily of platelets with a relatively large amount of the protein von Willebrand factor (vWF).

 VWF is an integral component of the process resulting in platelet adhesion and aggregation which is vital for normal clotting of the blood. It is synthesised in the endothelium from single subunits  (monomers) which link together to form a large multimeric structure (ultra large vWF or ULvWF). However, ULvWF is not a normal constituent of plasma – instead circulating vWF is found to be composed of smaller multimers with certain sizes being a consistent finding. This suggests that once secreted from the endothelium, ULvWF is broken down into smaller multimers in a non-random fashion.

Research has concentrated on vWF in TTP since it was recognised that ultra large vWF (ULvWF) multimers may be found in the plasma of some TTP patients. It is has been demonstrated that ULvWF is more effective than the normal vWF at promoting platelet aggregation and hence it was suggested that ULvWF might be involved in the formation of thrombi which is seen in TTP. If the proposed vWF-cleaving mechanism were defective in TTP this might account for some of the laboratory and clinical findings found in this condition.

Recent work from two independent groups in America and Switzerland has shown that a novel vWF-cleaving protease activity is reduced in TTP. In adults who develop the disease it appears that the reduction in activity is secondary to an acquired inhibitor. In those cases studied to date this appears to be an antibody of IgG type.  Hence adult onset TTP may represent an auto-immune disorder. Other examples of auto-immune diseases include rheumatoid arthritis and myasthenia gravis. In addition to adult onset TTP there are cases of so-called congenital TTP which classically present in infancy or early childhood. In these patients there is no circulating inhibitor but vWF-cleaving activity appears to be absent per se.

These findings help to explain why adult onset TTP characteristically requires plasma exchange (which achieves both removal of the inhibitor and replacement of vWF-cleaving activity) whilst this is not necessary for effective treatment of congenital TTP. In congenital TTP only replacement of the deficient vWF-cleaving activity is required and can be achieved by simple FFP infusion.

Despite these advances there is still much we do not understand about TTP. The picture portrayed above is undoubtedly an oversimplification: an individual has been described who appears to lack vWF-cleaving activity but who has not, to date had an episode of TTP. In addition the inhibitory activity may persist in some individuals despite clinical resolution of the disease. Data clearly supporting correlation of disease severity with vWF-cleaving activity is still lacking. Furthermore the putative vWF-cleaving protease has yet to be purified – it may represent a single enzyme or be a complicated cascade of enzymes and cofactors which could be freely circulating, complexed to other proteins or be endothelial cell bound.

At University College Hospital we are actively researching this field. Initially work concentrated on the possibility that excessive platelet activity (or activation) might contribute to TTP. Platelets normally circulate in a quiescent form and only become activated in response to certain triggers such as endothelial damage. Once activation has been achieved the platelet surface becomes “stickier” and hence platelet adhesion either to each other or damaged tissue is promoted. If platelets should circulate in an activated state they are more likely to result in inappropriate clot formation. We have shown in TTP that although those few remaining platelets are activated this is only a subtle effect and that platelet function normalises with resolution of the disease.

Hence it is more likely that this is an effect of the disease process itself rather than contributing to its initiation.

Since the initial publications concerning vWF-cleaving protease activity and TTP we have developed our own vWF-cleaving protease assay. We are utilising this to study in detail the relationship between vWF-cleaving protease activity and the clinical features of the disease.

 One of the aspects of TTP which we do not understand at present is why some individuals continue to relapse at irregular intervals whilst in others the disease never recurs. It is possible that this might be secondary to persistence of vWF-cleaving protease inhibitory activity and this is one of our current fields of interest. Obviously if we could identify more accurately those individuals at high risk of relapse and in particular the reason(s) for this, potential treatment options could be chosen and assessed more rationally than is now possible. I am extremely hopeful that such studies will result in improved treatment strategies for TTP in the forthcoming years.

THE GROUP MEMBERS ARE NOT MEDICAL PROFESSIONALS. YOU MUST SEEK MEDICAL ADVICE IF YOU HAVE ANY CONCERNS REGARDING TTP.