(See also Overview of Platelet Disorders Overview of Platelet Disorders Platelets are circulating cell fragments that function in the clotting system. Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes... read more .)
Pathophysiology of TTP
Thrombotic thrombocytopenic purpura (similar to hemolytic-uremic syndrome Hemolytic-Uremic Syndrome (HUS) Hemolytic-uremic syndrome (HUS) is an acute, fulminant disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS usually occurs in children... read more [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 Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more is rare, unlike in HUS. The microthrombi do not include RBCs or fibrin (unlike thrombi in disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more ) and do not manifest the vessel wall granulocytic infiltration characteristic of vasculitis Overview of Vasculitis Vasculitis is inflammation of blood vessels, often with ischemia, necrosis, and organ inflammation. Vasculitis can affect any blood vessel—arteries, arterioles, veins, venules, or capillaries... read more ). Large-vessel thrombi are uncommon.
Etiology of TTP
Thrombotic thrombocytopenic purpura (TTP) is caused by
Congenital or acquired deficient activity of the plasma enzyme ADAMTS13
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 Preeclampsia and Eclampsia Preeclampsia is new-onset or worsening of existing hypertension with proteinuria after 20 weeks gestation. Eclampsia is unexplained generalized seizures in patients with preeclampsia. Diagnosis... read more )
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.
Symptoms and Signs of TTP
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 Symptoms and Signs Hemolytic-uremic syndrome (HUS) is an acute, fulminant disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS usually occurs in children... read more (HUS) are indistinguishable, except that neurologic symptoms are less common with HUS.
Diagnosis of TTP
Complete blood count (CBC) with platelets, peripheral blood smear, reticulocyte count, direct antiglobulin (Coombs) test, lactate dehydrogenase (LDH), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, haptoglobin, and serum bilirubin (direct and indirect)
Urinalysis and renal function tests
ADAMTS 13 activity and autoantibody levels
Exclusion of other thrombocytopenic disorders
Thrombotic thrombocytopenic purpura is suspected in patients with suggestive symptoms, thrombocytopenia, and anemia. If the disorder is suspected, urinalysis and renal function tests, CBC, peripheral blood smear, reticulocyte count, serum LDH, haptoglobin, 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, are unlikely to respond to such therapies, and should be assessed for other causes of anemia and thrombocytopenia, including disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more , sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more , occult cancer with hypercoagulability and migratory thrombophlebitis (Trousseau syndrome), preeclampsia Preeclampsia and Eclampsia Preeclampsia is new-onset or worsening of existing hypertension with proteinuria after 20 weeks gestation. Eclampsia is unexplained generalized seizures in patients with preeclampsia. Diagnosis... read more , systemic sclerosis Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more , systemic lupus erythematosus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , accelerated hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more , and acute renal allograft rejection. Rare patients may have low ADAMTS13 levels but no autoantibody; such patients should undergo ADAMTS13 genetic testing to confirm congenital Upshaw-Schulman syndrome 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 Microangiopathic Hemolytic Anemia Microangiopathic hemolytic anemia is intravascular hemolysis caused by excessive shear or turbulence in the circulation. (See also Overview of Hemolytic Anemia.) Excessive shear or turbulence... read more are sufficient evidence for a presumptive diagnosis.
Treatment of TTP
Corticosteroids and rituximab
Untreated thrombotic thrombocytopenic purpura is almost always fatal. With plasma exchange Therapeutic Apheresis Apheresis refers to the process of separating the cellular and soluble components of blood using a machine. Apheresis is often done on donors where whole blood is centrifuged to obtain individual... read more , however, > 85% of patients recover completely. Plasma exchange is started urgently and continued daily for several days or many weeks until there is evidence that disease activity has subsided, as indicated by a normal platelet count and LDH level. 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 the subject of much debate but remains 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 red blood cells are destroyed nonimmunologically by microvascular thrombi, leading to thrombocytopenia, anemia, and organ ischemia.
The 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.