(See also Overview of Platelet Disorders.)
Thrombotic thrombocytopenic purpura (similar to hemolytic-uremic syndrome [HUS]) involves nonimmunologic platelet destruction. Endothelial damage is common. Loose strands of platelets and fibrin are deposited in multiple small vessels and damage passing platelets and red blood cells (RBCs), causing significant thrombocytopenia and anemia (microangiopathic hemolytic anemia). Platelets are also consumed within multiple small thrombi, contributing to the thrombocytopenia.
Multiple organs develop bland platelet–von Willebrand factor (VWF) thrombi localized primarily to arteriocapillary junctions, described as thrombotic microangiopathy. The brain, gastrointestinal tract, and kidneys are particularly likely to be affected. Although kidney involvement is often present on biopsy (if done), severe acute kidney injury is rare, unlike in HUS. The microthrombi do not include RBCs or fibrin (unlike thrombi in disseminated intravascular coagulation) and do not manifest the vessel wall granulocytic infiltration characteristic of vasculitis). Large-vessel thrombi are uncommon.
Thrombotic thrombocytopenic purpura (TTP) is caused by
The ADAMTS13 enzyme is a plasma protease that cleaves von Willebrand factor into smaller sizes and thereby eliminates unusually large von Willebrand factor (VWF) multimers that would otherwise accumulate on endothelial cells where they can cause platelet thrombi. ADAMTS13 activity usually has to be < 10% of normal for disease to manifest. Other prothrombotic factors may also need to be present.
Most cases are acquired and involve development of an autoantibody against ADAMTS13. Rare cases are hereditary (Upshaw-Schulman syndrome), involving an autosomal recessive mutation of the ADAMTS13 gene.
In many acquired cases, the cause of the autoantibody is unknown. Known causes and associations include
Use of desmopressin
Pregnancy (TTP is often indistinguishable from severe preeclampsia or eclampsia)
Thrombotic microangiopathy similar to that of TTP can be triggered by a number of drugs, including quinine, cyclosporine, tacrolimus, and cancer chemotherapy drugs (eg, mitomycin C, gemcitabine). In most cases, the drugs are thought to damage small vessels and cause microthrombi. Unlike with TTP, such patients invariably have normal levels of ADAMTS 13 and do not respond to plasma exchange, corticosteroids or complement inhibition.
Hereditary cases often manifest in infancy and early childhood. Acquired cases typically occur among adults. Initial symptoms range from mild and gradual to acute and severe. Without treatment, the disease progresses and is often fatal.
Anemia typically causes weakness and fatigue.
Thrombocytopenia often causes purpura or bleeding.
Manifestations of ischemia develop with varying severity in multiple organs. These manifestations include weakness, confusion, seizures, and/or coma, abdominal pain, nausea, vomiting, diarrhea, and arrhythmias caused by myocardial damage. Fever does not usually occur. The symptoms and signs of thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome (HUS) are indistinguishable, except that neurologic symptoms are less common with HUS.
Thrombotic thrombocytopenic purpura is suspected in patients with suggestive symptoms, thrombocytopenia, and anemia. If the disorder is suspected, urinalysis, peripheral blood smear, reticulocyte count, serum LDH, haptoglobin, renal function tests, ADAMTS13 activity and autoantibody (inhibitor) assays, serum bilirubin (direct and indirect), and direct antiglobulin test are done. Early recognition is important in order to initiate treatment as quickly as possible. Therapy may need to be initiated in suspected cases before the confirmatory ADAMTS13 testing is completed if other manifestations of thrombotic thrombocytopenic purpura (TTP, clinical symptoms, thrombocytopenia, elevated LDH, peripheral blood smear examination) are consistent with this diagnosis.
The diagnosis of TTP is suggested by
Thrombocytopenia and anemia
Fragmented red blood cells on the blood smear indicative of microangiopathic hemolysis (schistocytes: helmet cells, triangular RBCs, distorted-appearing RBCs)
Evidence of hemolysis (falling hemoglobin level, polychromasia, elevated reticulocyte count, elevated serum LDH and bilirubin, reduced haptoglobin)
Negative direct antiglobulin test
Normal coagulation profile
Testing for ADAMTS13 activity and autoantibody is appropriate in all patients with suspected TTP. Although initial treatment should not be delayed to await the results of ADAMTS13 testing, results are important to guide subsequent treatment. ADAMTS13 levels < 10% with the presence of antibody against ADAMTS13 is characteristic of most adults with TTP, and these patients respond to plasma exchange and immunosuppression (corticosteroids and rituximab). Patients with levels of ADAMTS13 ≥ 10% and no antibody against ADAMTS13 S, are unlikely to respond to such therapies, and should be assessed for other causes of anemia and thrombocytopenia, including disseminated intravascular coagulation, sepsis, occult cancer, preeclampsia, systemic sclerosis, systemic lupus erythematosus, accelerated hypertension, and acute renal allograft rejection. Rare patients may have low ADAMTS13 levels and no autoantibody; such patients should undergo ADAMTS13 genetic testing since they will require only plasma infusion without need for immunosuppression. Genetic testing is also indicated in patients with onset during childhood or pregnancy, recurrent episodes, a positive family history, or other clinical suspicion.
Otherwise unexplained thrombocytopenia and microangiopathic hemolytic anemia are sufficient evidence for a presumptive diagnosis.
Untreated thrombotic thrombocytopenic purpura is almost always fatal. With plasma exchange, however, > 85% of patients recover completely. Plasma exchange is started urgently and continued daily until evidence of disease activity has subsided, as indicated by a normal platelet count, which may require several days to many weeks. Adults with thrombotic thrombocytopenic purpura (TTP) are also often given corticosteroids and rituximab.
Caplacizumab, an anti–von Willebrand factor humanized single-variable-domain immunoglobulin (nanobody), inhibits the interaction between unusually large von Willebrand factor multimers and platelets. Caplacizumab appears to hasten resolution of thrombocytopenia, but it may increase bleeding tendency. While it may reduce the need for plasma exchange, it alone rarely produces disease remission; its role in the treatment of TTP is unclear.
Most patients experience only a single episode of TTP. However, relapses occur in about 40% of patients who have a severe deficiency of ADAMTS13 activity caused by an autoantibody inhibitor of ADAMTS13. In patients with recurrence when plasma exchange is stopped or in patients with relapses, more intensive immunosuppression with rituximab may be effective. Patients must be evaluated quickly if symptoms suggestive of a relapse develop.
Platelets and RBCs are destroyed nonimmunologically by microvascular thrombi, leading to thrombocytopenia, anemia, and organ ischemia.
Cause is deficient activity of the ADAMTS13 protease, which is usually due to an acquired autoantibody but rarely by an inherited gene mutation.
Untreated thrombotic thrombocytopenic purpura is usually fatal
Timely treatment with plasma exchange along with corticosteroids and rituximab results in > 85% survival rates.