Thrombotic thrombocytopenic purpura

The underlying cause might involve the production of unusually large von Willebrand factor (vWF) multimers. In his report of the first patient with diagnosed TTP, Moschcowitz described hyaline thrombi in the terminal arterioles of the kidney and heart muscle.[20] These hyaline thrombi were later found to be platelet aggregates rich in vWF (not fibrin), thought to be stimulated by the presence of unusually large vWF multimers. These multimers are thought to remain in the circulation owing to a lack of von Willebrand factor cleaving enzyme (ADAMTS-13), which normally cleaves them.[21][22][23][24] In acquired (idiopathic) TTP, the lack of ADAMTS-13 is thought to be secondary to an autoimmune process. For this reason, treatment is aimed at suppressing the immune system (with corticosteroids or immunotherapy with rituximab), interrupting platelet aggregation (with aspirin), and replacing ADAMTS-13 (with plasma exchange).

Von Willebrand factor (vWF) has a twofold role in hemostasis. It acts as a carrier protein for factor VIII, thereby protecting factor VIII from rapid degradation, and as a bridge connecting platelets to damaged endothelium. ADAMTS-13 (an acronym for a disintegrin and metalloprotease with thrombospondin-1-like domains) is an enzyme that normally cleaves large multimers of vWF into various sizes as they are released from endothelial cells; these fragments circulate in plasma and participate in normal hemostasis. When ADAMTS-13 is deficient or inactive, unusually large vWF multimers are released into the circulation and interact with platelet membranes. This interaction triggers aggregation of circulating platelets at sites of high intravascular shear stress, which in turn results in thrombi in the microvasculature system. These microvascular thrombi result in the classic pentad of TTP symptoms: microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic symptoms (e.g., headache, confusion, blurred vision, tinnitus, lethargy, and seizures), fever, and renal disease.

An additional stressor (such as infection, pregnancy) may need to be placed on the patient before TTP manifests. This is supported by studies of transgenic knockout mice that have no ADAMTS-13 and no manifestations of TTP until an additional stress, such as Shiga toxin from Escherichia coli O157, is applied.[25] It is also supported by the observation that some patients with acquired (idiopathic) TTP go into remission despite having persistent anti-ADAMTS13 autoantibodies and a severe absence of ADAMTS13 activity.[26]

The Japanese TTP registry study revealed that patients with acquired thrombotic microangiopathy (TMA) could be largely grouped into three categories: idiopathic TTP, idiopathic hemolytic uremic syndrome (HUS), and secondary TMAs. The secondary TMAs were observed in heterogeneous patient groups and were associated with drugs, connective tissue diseases, malignancies, transplantation, pregnancy, E coli O157: H7 infection, and other factors. All of the patients with acquired severe ADAMTS-13 deficiency were positive for ADAMTS-13 inhibitor.[27] There have been reports of TMA associated with the use of targeted cancer agents (e.g., immunotoxins, monoclonal antibodies, tyrosine kinase inhibitors).[28]

TTP and hemolytic uremic syndrome

There is no strict classification system for TTP. Classically, TTP and hemolytic uremic syndrome have been thought of as a clinical spectrum of the same syndrome. There has been debate over whether they should instead be considered separate entities.

A consensus statement on the standardization of terminology used in TTP describes the term thrombotic microangiopathies to include both occlusive microvascular or macrovascular disease, but the term is also defined clinically by microangiopathic hemolytic anemia and thrombocytopenia.[1] Further investigations are necessary to identify the underlying cause for the presentation of a thrombotic microangiopathy. Causes include disseminated intravascular coagulation, TTP and hemolytic uremic syndrome.[1]

TTP is a clinical syndrome characterized by microangiopathic hemolytic anemia and thrombocytopenic purpura.[1]

Hemolytic uremic syndrome may be the result of an infection with the Escherichia coli strain O157:H7. Atypical hemolytic uremic syndrome (aHUS), which at times may be clinically indistinguishable from TTP, is an ultra-orphan disease (that is, it occurs in the range of 10-15 per 100,000 population or less), and is due to genetic defects in regulators of complement such as complement factor H and factor I.[7][8] This entity is a chronic condition that requires special assessment and exclusion of TTP and HUS for diagnosis.

Thrombotic microangiopathy has been described with COVID-19 infection, arising due to activation of the alternative complement pathway.[5][6][9][10]

British Committee for Standards in Haematology: subgroups of TTP[4]

The British Committee for Standards in Haematology has proposed the following subgroups of TTP:

Acute idiopathic TTP (the most common type of TTP, and the focus of this topic)

Congenital TTP

HIV-associated TTP

Pregnancy-associated TTP

Drug-associated TTP

Pancreatitis-associated TTP.

Pathophysiology

Classification

TTP and hemolytic uremic syndrome

British Committee for Standards in Haematology: subgroups of TTP[4]