TTP is a rare hematologic emergency in which various organs, mainly the brain and kidneys, are affected by ischemic damage due to platelet aggregation. Advances in our understanding of the molecular pathology led to the recognition of three different diseases: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypical HUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and TTP that results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor. TTP may be congenital or acquired as a result of HIV, connective tissue disorder, cancers, drugs like quinine, mitomycin C, cyclosporine, oral contraceptives, and ticlopidine or it may be idiopathic.
Clinical Manifestations (i.e. the PENTAD!)
It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, neurological abnormalities, and renal dysfunction; however, this pentad is not necessary for diagnosis. Only thrombocytopenia and MAHA without another clinically apparent etiology (e.g., disseminated intravascular coagulation, malignant hypertension, severe preeclampsia, sepsis, systemic malignancy, etc.) are required to suspect the diagnosis of TTP and to initiate therapy. MAHA is defined as nonimmune hemolysis (i.e., negative direct antiglobulin test) with prominent red cell fragmentation (schistocytes) observed on the peripheral blood smear.
The pathogenesis may be autoimmune in nature since autoantibodies against ADAMTS13 (acronym for a Disintegrin and a Metalloproteinase with Thrombospondin-1 Motifs, 13th member of the family), which cleaves von Willebrand Factor (vWF), are typically present in most cases of idiopathic TTP. These antibodies cause the absence of ADAMTS 13 protease activity and the persistence of vWF. Subsequently the procoagulation tendency dominates and causes the systemic abnormalities.
In STEC-HUS, the toxin triggers endothelial complement deposition through the upregulation of P-selectin and possibly interferes with the activity of complement regulatory molecules.
In aHUS, mutations in the genes coding for complement components predispose to hyperactivation of the alternative pathway of complement.
The mainstay of treatment for patients with TTP is plasma exchange (PE) in conjunction with steroids. The mortality rate of TTP prior to the use of PE was approximately 90 percent and is currently 20 percent or less in patients treated with PE. PE reverses the platelet consumption responsible for the thrombus formation and symptoms in TTP.
Rituximab is a monoclonal antibody directed against CD20 which is specific to B lymphocytes. It depletes the production of antibodies from these lymphocytes and thus has been used for antibodies-mediated diseases including TTP. Observational studies have suggested good outcomes in some settings. Rituximab should be considered in the management of TTP along with PE and well-designed prospective studies are needed to evaluate its role in TTP.
Importantly, evidence is emerging that pharmacological targeting of complement with the anti-C5 monoclonal antibody eculizumab can effectively treat not only aHUS for which it is indicated, but also STEC-HUS and TTP in some circumstances.
N. Abdel Karim, S. Haider, C. Siegrist, et al., “Approach to Management of Thrombotic Thrombocytopenic Purpura at University of Cincinnati,” Advances in Hematology, vol. 2013, Article ID 195746, 4 pages, 2013. doi:10.1155/2013/195746
Noris, M., Mescia, F., Remuzzi, G.
STEC-HUS, atypical HUS and TTP are all diseases of complement activation
(2012) Nature Reviews Nephrology, 8 (11), pp. 622-633.