Continuing Education Activity

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia classically characterized by the pentad of fever, hemolytic anemia, thrombocytopenia, and renal and neurologic dysfunction. TTP results from either a congenital or acquired absence/decrease of the von Willebrand factor-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13). Low levels of ADAMTS13 activity result in microthrombi formation, which leads to end-organ ischemia and damage. The central nervous system and kidneys are the two most common organ systems affected by TTP. This activity reviews the evaluation and management of patients with thrombotic thrombocytopenic purpura and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Outline the characteristic pentad associated with thrombotic thrombocytopenic purpura.
• Describe the evaluation of thrombotic thrombocytopenic purpura.
• Summarize management strategies for thrombotic thrombocytopenic purpura.
• Explain the importance of enhancing care coordination amongst the interprofessional team to ensure proper evaluation and management of thrombotic thrombocytopenic purpura.

Introduction

Thrombotic thrombocytopenic purpura (TTP) is a type of microangiopathic hemolytic anemia that classically has been characterized by the pentad of fever, thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction. TTP results from either a congenital or acquired decrease/absence of the von Willebrand factor-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13). Low levels of ADAMTS13 result in microthrombi formation, which leads to end-organ ischemia and damage.[1][2][3] This is due to the inability of the ADAMTS13 to inactivate the large multimer von Willebrand factor (VWF) that is necessary to prevent spontaneous coagulation. Unchecked, the large multimers have a tremendous avidity to bind platelets and initiate thrombi formation. The central nervous system (CNS) and kidneys are the two most common organ systems affected by TTP. Timely diagnosis is very important because TTP is a medical emergency which, without treatment, has a mortality of about 90%.[4] About 80% of patients respond to initial treatment, and the post-treatment mortality is 10 to 15%.[5]

Etiology

TTP results from a decrease or absence of the enzyme ADAMTS13 activity. TTP can be either congenital or acquired. Acquired TTP is more common than the congenital type and is caused by autoantibodies targeting ADAMTS13. Antiplatelet drugs, immunosuppressive agents, HIV, estrogen-containing birth control, and pregnancy are the most commonly listed triggers for ADAMTS13 autoantibody formation causing acquired TTP. The less common congenital form of TTP results from mutations to ADAMTS13.[6][7] The deficiency of ADAMTS13 activity alone does not cause clinically apparent TTP. Individuals with hereditary ADAMTS13 deficiency remain asymptomatic until a triggering event such as an infection or pregnancy occurs.[8] Risk factors for the development of inhibitory autoantibodies to ADAMTS13 are not clearly defined.

Epidemiology

TTP is a rare disease; the exact prevalence is not clear. Studies cite incidences between 1 and 13 cases per million people depending on geographic location. TTP most often occurs after 40 years of age, but congenital forms can occur in children. TTP is more common in women with a 2:1 female to male predominance.[9]The mortality in TTP without treatment is 90%,[4] but this drops to a mortality of 10% to 15%[5] with proper treatment. TTP is very rare in children. Other factors associated with a higher risk of TTP include female sex, African American descent, and pregnancy.[10]

Pathophysiology

A deficiency of ADAMTS13 that is caused by gene mutations or acquired autoantibodies is central to the pathophysiology of TTP. TTP is defined by severely deficient activity of the ADAMTS13 protease to less than 10%.[10] ADAMTS13 is a plasma von Willebrand factor (VWF)-cleaving protease. It cleaves the ultra-large VWF multimer to a smaller-sized multimer. When ADAMTS13 activity is reduced, VWF multimers accumulate on the endothelial surface, causing platelet aggregation and eventual thrombi formation.[11] ADAMTS13 is synthesized in hepatic stellate cells and by endothelial cells and megakaryocytes.[11][12] The microthrombi cause ischemia, leading to end-organ damage, with the most commonly involved systems being the central nervous system (CNS) and kidneys. Thrombocytopenia results from platelet consumption during thrombus formation. Anemia results from hemolytic destruction of red blood cells as they pass through small vessels partially occluded by thrombi. The destruction of the erythrocytes causes a disruption of their morphology, best described as a structural shattering leading to the term "schistocytes."[13][14]

Histopathology

The histopathology of TTP and other thrombotic microangiopathies (TMAs) is characterized by small vessel changes with swelling of endothelial cells and the subendothelial space. There is vessel wall thickening, and platelet microthrombi are noted in small arterioles and capillaries obliterating the vessel lumen. Large-vessel thrombosis is not seen in TTP.[15] A 2006 study looking at autopsies of patients who had died secondary to an acute episode of TTP reported the presence of microvascular thrombi characteristic of TTP in almost all organs.[16] Bone marrow evaluation, if performed, typically reveals normal trilineage maturation. Increased thrombopoiesis and erythropoiesis may be noted secondary to increased consumption of platelets and red blood cells (RBCs) in the peripheral circulation.[17] The white blood cell (WBC) count is typically normal in TTP, and coagulation abnormalities are also uncommon.

History and Physical

In TTP, renal involvement is relatively rare when compared with other primary TMAs. Neurologic symptoms dominate the clinical picture of TTP[18] and include headache, focal neurologic deficits, seizures, confusion, and vertigo. The initial presentation includes fatigue, dyspnea, petechiae, or bleeding.[19] In patients with idiopathic TTP, neurologic complaints were noted to be the most common (44%), and the most common symptom was reported to be abdominal pain (23.5%). Less than 10% of patients reported bleeding secondary to thrombocytopenia as a presenting symptom.[19] As stated above, kidney involvement is uncommon and usually only seen on biopsy. Pulmonary involvement is also rare.[20] Patients with TTP can also have cardiac involvement, and an elevation of serum troponin in patients presenting with TTP is considered a bad prognostic sign. It was shown to be an independent factor associated with a three-fold increase in the risk of death or refractoriness to treatment in patients presenting with TTP.[21] Patients with TTP present with a myriad of signs and symptoms of varying severity, and there appears to be little uniformity in patients presenting with the disease. High clinical suspicion is required to adequately diagnose the patients. Multiple epidemiologic studies are used to define presenting signs and symptoms for TTP, with the Oklahoma Registry being the most frequently cited study.

Clinical Presentation According to the Oklahoma Registry[22]

• Gastrointestinal symptoms 69%
• Weakness 63%
• Bleeding or purpura 54%
• Major neurologic findings (coma, stroke, seizure, transient focal abnormalities) 41%
• Minor neurologic findings (headache, confusion) 26%
• Fever and chills 10%
• Classical pentad comprising of hemolytic anemia, thrombocytopenia, fever, acute kidney injury, and severe neurologic findings less than 5%

Evaluation

Laboratory evaluation plays a critically important role in diagnosing TTP because signs and symptoms are variable, and end-organ damage can be delayed. For diagnosis, the laboratory data must show anemia and thrombocytopenia along with an indication of active hemolysis, such as the presence of schistocytes, increased unconjugated bilirubin, increased reticulocyte count and increased lactate dehydrogenase.[23][24][25] As with any hemolysis in general, the serum haptoglobin decreases as it combines with the free hemoglobin released from the destroyed erythrocytes.

PLASMIC Score

The PLASMIC score is calculated using findings on presentation and predicts the likelihood of ADAMTS13 activity being less than or equal to 10% to help make a presumptive diagnosis of TTP in the appropriate clinical setting.[26] The presence of peripheral schistocytes is required to apply this score. One point is given for each of the following features:

• Platelet count less than 30,000/microL
• Presence of hemolysis (reticulocyte count greater than 2.5%, undetectable haptoglobin, or indirect bilirubin greater than 2 mg/dL)
• Mean corpuscular volume (MCV) less than 90 fL
• International normalized ratio (INR) of less than 1.5
• Creatinine less than 2.0 mg/dL
• Absence of cancer
• Absence of solid organ or stem cell transplant

The higher the score, the greater the likelihood of TTP, with a score of greater than 5 suggesting a high probability of TTP and a score lower than 5 suggesting a low probability of TTP. This score has been validated with a reported sensitivity of 99% and a specificity of 57%. Due to its high negative predictive value, it is recommended as a screening tool for patients who are unlikely to have TTP.[27] 

ADAMTS13 activity assays report the activity of the protease as a percentage of normal. An activity level of less than 10% confirms the diagnosis of TTP in patients with evidence of hemolysis and thrombocytopenia. However, this assay is not specific for TTP, and levels less than 10% have been reported in cases of severe sepsis and systemic cancer.[28] A decrease of the ADAMTS13 activity to less than 20% after initial recovery from an acute episode is considered a relapse, even if thrombocytopenia and hemolysis are absent.

Evaluation of end-organ damage is completed by measuring serum troponin levels and obtaining a brain magnetic resonance imaging study. 

Treatment / Management

The mainstay of treatment in TTP is plasma exchange (PEX) with high-dose corticosteroid therapy.[29] Corticosteroids operate by decreasing the activity of the reticuloendothelial system as well as decreasing autoantibody production. This should be initiated as soon as possible in all patients with unexplained hemolytic anemia and thrombocytopenia with a normal coagulation profile. Both the ultra-large VWF multimers and the ADAMTS13 autoantibodies are effectively removed from circulation by plasma exchange therapy. The recommended volume of exchange is one estimated plasma volume (usually 40 mL/kg of body weight) with each treatment. Plasma is used as the preferred fluid replacement during the treatment because it repletes ADAMTS13. The treatment should be provided once daily.[30] When remission is achieved, PEX can be stopped abruptly without any need for tapering. The generally recommended dose for corticosteroids is 1 mg/kg per day of prednisone in neurologically intact patients. In severely ill patients, intravenous methylprednisolone 1000 mg as a single daily dose for three days or 125 mg two to four times daily may be more appropriate.[29] Corticosteroids are continued as long as PEX is continued and subsequently tapered off based on clinical response. 

Other treatments used include splenectomy, cyclosporine, cyclophosphamide, vincristine, and rituximab.[31][32][33] These are typically adjunctive agents given when first-line therapy (PEX and corticosteroids) fail. The addition of glucocorticoids and rituximab to PEX has been shown to decrease the required duration of therapeutic plasma exchange.[34] Splenectomy removes a major site of antibody production and complex assimilation. It is a major intervention with results that have been quoted as "variable" in terms of efficacy. Rituximab is an anti-CD20 monoclonal antibody found to help treat TTP refractory to PEX. It targets B-lymphocytes and has a good response rate in refractory and relapsed TTP. It has gained more favor than other nonspecific immunosuppressive agents. Vincristine, cyclophosphamide, and cyclosporine are immunosuppressive agents with less than exemplary efficacy. For this reason, they are usually given concurrently with other secondary therapies in refractory cases or when first-line therapy has failed.

A newer agent, caplacizumab, has a high potential for the treatment of TTP. It is a humanized monoclonal antibody fragment (a bivalent, variable-domain-only fragment) that attacks the A1 section of VWF and prevents platelet adhesion.[35] In recent clinical studies, caplacizumab has been shown to have a more rapid onset of action compared to most agents. With the use of this agent, deaths have been significantly decreased, and some experts do advocate its use as a frontline modality. It rapidly halts the formation of microthrombi in TTP. However, it does not reduce the production of the autoantibody against ADAMTS13. Caplacizumab is given as an initial intravenous dose followed by subcutaneous injections for 30 days after PEX has been stopped. This should coincide with an increase in ADAMTS13 activity to above 20%. Caplacizumab can increase the risk of bleeding, and clinically significant bleeding attributable to caplacizumab should warrant discontinuation of therapy and/or VWF concentrate infusion.[36]

Plasma infusion without exchange is not an adequate treatment for TTP. It can be used as a temporizing measure in patients who are unable to receive PEX immediately. This is supported by the data that plasma infusion has similar efficacy to PEX if equivalent volumes of plasma are administered.[37] However, this is not feasible in most cases, given the high volume of infusion required.

A packed red blood cell (PRBC) transfusion can be given if there is a clinical indication. Platelet transfusion is controversial but is considered to be contraindicated unless major bleeding is present.[38] Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150,000/microL for more than 48 hours.[39]

2020 Treatment Guidelines by the International Society on Thrombosis and Hemostasis[29]

• For initial treatment of TTP, they gave a strong recommendation for the addition of corticosteroids to therapeutic plasma exchange (PEX) over PEX alone; however, they did not make any specific recommendation regarding a preferred dosage or type of corticosteroids.
• For patients with the first acute event, the panel suggested the addition of rituximab to corticosteroids and PEX. The primary documented effect of rituximab in patients with TTP is to prevent relapses, although they noted that the true benefit of rituximab might be masked by the fact that it has only been used in severe cases. They make a conditional recommendation for the use of this therapy based on practitioner judgment, especially if comorbid autoimmune disorders exist.
• For patients with relapsing TTP, the panel recommended PEX, corticosteroids, and rituximab as recommended for initial treatment, with the addition of caplacizumab.
• For patients with TTP who are in remission but still have low plasma ADAMTS13 activity without any evidence of clinical signs/symptoms, they recommended using rituximab for prophylaxis.
• For patients who are pregnant and have decreased plasma ADAMTS13 activity but have no clinical signs/symptoms of TTP, the panel recommended prophylactic treatment with plasma infusion products.

Differential Diagnosis

• Cancer-associated TMA; the majority are due to adenocarcinomas, particularly gastric, breast and prostate.[40]
• Disseminated intravascular coagulation; schistocytes are relatively uncommon, there are abnormal coagulation studies, and fibrinolysis is more common in DIC than TTP.[41][42]
• Haemopoietic transplant-associated TMA; can be due to the transplant regimen (e.g., TBI, tacrolimus), graft versus host disease, and infections.[43]
• Common ailments have also been known rarely to cause TTP.[44] Hypertension (malignant), pregnancy (HEELP), autoimmune disease (e.g., SLE), and vasculitis (e.g., scleroderma).
• Immune thrombocytopenia
• Infections; CMV, Streptococcus pneumonia, and HIV.[45]
• Drug-induced TMA.[46] This covers a wide field of drugs, including chemotherapy (e.g., mitomycin C, interferon, gemcitabine), antibiotics (e.g., trimethoprim, penicillin, rifampin), and cardiovascular medications, particularly clopidogrel.[47][48][49] The exact mechanism of clopidogrel-acquired TTP is unknown. Clinical data has shown that as many as 75% of patients with clopidogrel-TTP have normal ADAMTS13 levels. This finding lends some credence to the belief that there is a direct endothelial injury, followed by TMA, as the possible etiology. It is relatively uncommon, with 1 case per 20,000 patients treated with this medication. Clopidogrel is utilized for its antiplatelet effect in dealing with myocardial infarction with post-catheterization. It acts by disrupting the ADP binding sites (P2Y12 components) on platelets, thereby interfering with the binding of the large multimers with the platelet IIb/IIIa receptors. TTP occurs within the first two weeks of therapy, and skin reactions may be the only harbinger of this reaction. Discontinuation of the medication alone is insufficient to stop the process, and patients must be given plasma exchange (PEX) with concurrent steroids as the primary treatment with rituximab as second-line. The survival rate is upwards of 100% with PEX; however, the rate falls to 27% with a delay of diagnosis.

Prognosis

Without treatment, the mortality of thrombotic thrombocytopenic purpura is 90%.[4] Early treatment (with plasma exchange and corticosteroids) decreases the mortality to 15%.[5] The longer the patient waits for treatment, the more likely they are to have adverse outcomes. Early suspicion of the disease followed by administrations of plasma exchange/corticosteroids significantly reduces mortality. The primary cause of demise can occur with coronary thrombosis leading to an acute myocardial infarction, congestive heart failure, and sudden death.[50] 

Complications

Plasma infusion should be used if plasma exchange is not readily available. Rigorous infusion of plasma can lead to congestive heart failure but, once plasma exchange is established, this issue can be addressed and reversed.[50]

Complications of PEX may be related to the central venous catheter placements and exposure to donor plasma. Transfusion-related acute lung injury (TRALI) can occur.[51] According to one study, mortality in patients with TTP due to complications of PEX was reported at 4.4%. These complications included pulmonary hemorrhage and central venous catheter-associated bloodstream infections.[22] Other nonlethal complications of PEX reported in the study included bacteremia, catheter-related venous thrombosis requiring systemic anticoagulation, and anaphylaxis. However, a significant decline in complications associated with PEX has been observed over a 15-year period of observation.[34] This is thought to be due to the use of multimodal adjunctive therapies that decrease the required frequency and duration of PEX.

Consultations

Thrombotic thrombocytopenic purpura (TTP) is a medical/hematologic emergency, and all TTP patients should be placed in an intensive care unit (ICU) setting. An internist can act as the operational hub, but if an intensivist is available, they should be used for tactical level management. Organ ischemia may develop into failure, and other specialties (e.g., renal) may need to be involved.[50] 

Deterrence and Patient Education

An extended rehabilitation is likely dependent on the severity of the patient's organ ischemia and residual deficits. Patients should remain alert to the return of their thrombotic thrombocytopenic purpura signs and symptoms. Laboratory data should be monitored closely once the plasma exchange and corticosteroids have been tapered. Relapse, if it occurs, may resume quickly. Rituximab is available for secondary prevention in a select group of patients (as outlined above), and caplacizumab is also available as a prophylactic agent.[50]

Pearls and Other Issues

HUS and TTP are subsets within the general category of microangiopathic hemolytic anemia (MHA).[52] TTP and HUS do overlap in terms of their clinical manifestations. This 'overlap' extends to their manifestation of schistocytosis. Their primary difference is causation. Both diseases can manifest fever, thrombocytopenia, hemolysis, renal injury, and neurologic symptoms. Acute kidney injury in TTP is less frequent as compared to HUS. Whereas TTP is due to the paucity of ADAMTS13, HUS is a complement-mediated illness. The hereditary form requires complement mutation studies to diagnose, while the acquired form requires stool culture and PCR analysis for the Shiga toxin. This toxin is produced by Shigella bacteria and entero-toxin producing E. Coli 0157H7. The patient, usually a child, presents with colitis manifesting bloody diarrhea. The toxin binds to the endothelial walls of blood vessels leading to uncontrolled complement activation, vessel damage, and thrombosis with fibrosis. Blood cells are fractionated as they travel through these vessels leading to their formation as schistocytes. Treatment is supportive, with volume expansion as the mainstay of successful intervention. Antibiotics are of little help.

A difficult situation occurs where the patient presentation may initially overlap between TTP and HUS to such an extent that the clinician may be unclear as to the true problem. In this circumstance, since TTP carries the more immediate and higher mortality, it is better to place the patient initially on plasma exchange (PEX). If the patient has TTP, this would be most beneficial. PEX has been known to provide at least a modicum of relief in HUS, but if a response is not forthcoming, then the administration of eculizumab is recommended. This drug is a monoclonal antibody against the C5 of the C5-9 complement complex. It thereby obstructs complement-mediated MHA, and it can improve renal function.

Enhancing Healthcare Team Outcomes

TTP is a serious life-threatening disorder that is best managed by an interprofessional team that includes a nurse, hematologist, emergency department physician, nephrologist, neurologist, and internist. Recall that the results of diagnostic testing, like ADAMTS13, may be delayed, and therefore it is the clinical acumen of the healthcare team that can determine a patient's survival or demise. Failure to suspect TTP makes for delayed treatment and a moribund patient. It is recommended that TTP patients be admitted initially to the intensive care setting where close monitoring by critical care nursing and management by an intensivist and co-management by a hematologist would be ideal. Besides corticosteroids, these patients benefit primarily from plasmapheresis (PEX).

If PEX cannot be initiated in a timely manner, then plasma infusion should be performed. Hence, the role of the nurse as well as the apheresis team cannot be understated. Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150,000/microL for more than 48 hours. The prognosis of patients with TTP depends on age, neurological deficits, renal dysfunction, response to treatment, and other co-morbidities. Most patients will require a prolonged stay in the hospital as recovery is gradual.[53][54] 

The apheresis team and clinical nurse are essential in monitoring the patient during treatment to ensure fluid overload and cardiac arrhythmias do not occur. Clinical pharmacists play the crucial role of monitoring patients for treatment side-effects and reconciling medications to prevent adverse outcomes. A well-coordinated interprofessional team can significantly improve outcomes for patients affected with this potentially lethal disease.[Level 5] For those patients with residual organ damage from the thrombogenesis, a stay at a rehabilitation center is in order.