Thrombotic Thrombocytopenic Purpura (TTP)

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 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 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 (VWF) into smaller sizes and thereby eliminates unusually large 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 TTP 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 gene.

In many acquired cases, the cause of the autoantibody is unknown. Known risk factors include (1)

• Female sex

• Pregnancy (TTP is often indistinguishable from severe preeclampsia or eclampsia)

Black people may also be at increased risk for TTP based on cohort data from the United States, which reported a 7-fold higher risk (1).

Hereditary cases often manifest in infancy and early childhood. Acquired cases typically occur among adults.

Initial symptoms may be mild and develop gradually or 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 and renal failure more common with HUS.

• 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

• ADAMTS13 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 tests 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 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—see photo Schistocytes)

• Evidence of hemolysis (falling hemoglobin level, polychromasia, elevated reticulocyte count, elevated serum LDH and bilirubin, reduced haptoglobin)

• Negative direct antiglobulin test

• Normal coagulation profile

The PLASMIC score cane help provide a pre-test probability of TTP and help guide treatment decisions (1).

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

Patients with levels of ADAMTS13≥ 10% and no antibody against ADAMTS13 are unlikely to respond to plasma exchange and immunosuppression and should be assessed for other causes of anemia and thrombocytopenia, including disseminated intravascular coagulation, sepsis, occult cancer with hypercoagulability and migratory thrombophlebitis (Trousseau syndrome), preeclampsia, systemic sclerosis, systemic lupus erythematosus, accelerated hypertension

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 are sufficient evidence for a presumptive diagnosis.

• Plasma exchange

Untreated thrombotic thrombocytopenic purpura is almost always fatal. With plasma exchange, however, > 91% of patients recover completely (1). 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 (2

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. The International Society on Thrombosis and Haemostasis (ISTH) conditionally recommends using caplacizumab (3). However, recent analyses present much disagreement with the use of caplicizumab based on the markedly elevated cost of this therapy and potential to enhance bleeding risk (4).

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