Standard of Care

From Standard of Care

Life-threatening, multisystem disease manifested by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic changes and renal abnormalities.

Hemolytic uremic syndrome (HUS) considered as the same entity i.e. TTP-HUS.

Many patients have only thrombocytopenia and microangiopathic hemolysis.

Approximately 2-7 cases per million person years, with more frequency and in females, with nearly 2 to 1 female to male ratio.

Most patients are 20-60 years of age.

Viral infections, pregnancy, obesity, African-American race and certain drugs are risk factors.

Microvascular thrombi the hallmark of pathologic diagnosis.

Von Willebrand factor-cleaving protease (ADAMS-13) deficient in patients with TTP resulting in abnormally large von Willebrand factor multimers to circulate.

The largest multimers promote platelet adhesion by binding to the platelet glycoprotein Ibalpha- IX-V surface receptors.

ADAMTS13 cleaves ultra large multimers , preventing inappropriate platelet adhesion and thrombosis.

Ultra large von Willebrand secretion from endothelial cells is stimulated by inflammatory cytokines TNF-alpha, IL-8,, IL-6, Shiga toxin, estrogen and other agonists.

It is caused by a deficiency of A Disintegrin-like And Metalloprotease with a ThromnoSpondin type 1 motif 13 (ADAMTS13), which may be an inherited disorder, but more commonly it is an acquired disease due to autoantibodies directed against ADAMTS13.

Low ADAMTS13 levels result in increased ultra large von Willebrand factor multimers, which induced platelet adhesion and thrombosis.

Patients may have characteristic clinical features without severe ADAMS-13 deficiency.

Large von Willebrand factor multimers cause disseminated platelet clumping in the microcirculation.

Ultra large von Willebrand factor multimers are no longer cleaves by the protease and accumulate within the microcirculation causing shear stress dependent platelet aggregation, and red blood cell damage.

Damage caused by ultra large von Willebrand factor multimers resulted in a thrombi formation, thrombocytopenia, microangiopathic hemolysis and neurologic symptoms.

90% mortality rate when left untreated.

Plasma exchange standard treatment with survival rates of 75-92%.

Responds to plasma exchange secondary to the removal of inhibitory antibodies and restoration of ADAMS-13 activity from infused donor plasma.

Nearly all cases with severe ADAMS-13 deficiency are secondary to an autoantibody inhibitor.

Congenital deficiency of ADAMS13 causing TTP is also known associated Upshaw Schulman syndrome.

Patients with ADAMS-13 inhibitors and severely deficient in functional activity are predisposed to relapse after plasma exchange treatment.

Inverse relationship exists between severe ADAMS-13 deficiency and TTP relapses or exacerbations.

A small fraction of patients are refractory to plasma exchange or unable to be independent from plasma exchange or plasma infusions and require immunosuppressive therapy.

Platelet transfusions may be dangerous precipitating deterioration and exacerbation of thromboses.

Chronic renal failure occurs in 25% of patients within 1 year of the diagnosis.

Red blood cell fragmentation occurs as blood circulates though abnormal microcirculation.

Most cases are idiopathic.

3.7 cases per million persons.

May result from infection with E.Coli strain 0157:H7, ticlopidine, clopidrogrel, bone marrow transplantation, cancer chemotherapy, HIV infection and pregnancy.

Fever and hemolytic anemia are the most common symptoms.

Cogulation studies and bone marrow biopsy are typically normal or mildly so.

Microagioathic hemolytic anemia resolves in an elevated LDH and indirect bilirubin values, and schistoctes are seen on peripheral blood smear.

Hyaline thrombi are present in terminal arterioles and capillaries is most commonly in the brain, spleen, heart, kidneys, pancreas, and adrenal glands.

No specific criteria set for diagnosis.

Remains a clinical diagnosis.

Kidneys are not usually affected, as is present in hemolytic uremic syndrome.

Only 51% of patients have the classic presentation of the pentad of fever, hemolytic anemia, thrombocytopenia, renal failure, and neurologic symptoms.

68% of patients have hemolytic anemia, thrombocytopenia, and neurologic deficits, and the differential diagnoses of patients with these three signs and symptoms must include TTP.

Immunosuppressive treatments such as rituximab, cyclosporine vincristine, cyclophosphamide and intravenous immunoglobulin reported to induce remissions in patients with relapsing or refractory forms of disease.

No efficacy of corticosteroids in treatment of TTP or for prevention of relapses has been found although a rare patient reportedly responds.