Thrombotic Thrombocytopenic Purpura (TTP) is a critical microangiopathic hemolytic anemia, classically recognized by a pentad of clinical features: fever, hemolytic anemia, thrombocytopenia, renal dysfunction, and neurological abnormalities. At its core, TTP arises from a deficiency or absence of the ADAMTS13 protease (a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13), an enzyme crucial for cleaving von Willebrand factor. This deficiency, whether congenital or acquired, leads to the formation of microthrombi throughout the vasculature, causing ischemia and damage to vital organs. The central nervous system (CNS) and kidneys are particularly vulnerable. Prompt and accurate Diagnosis Ttp is paramount, as untreated TTP carries a staggering mortality rate of approximately 90%, underscoring its status as a medical emergency. However, with timely intervention, the response rate to initial treatment is around 80%, significantly reducing mortality to 10% to 15%.
Etiology of Thrombotic Thrombocytopenic Purpura
The fundamental cause of TTP is a marked reduction or absence of ADAMTS13 enzyme activity. This deficiency can stem from two primary origins: congenital or acquired. Acquired TTP is the more prevalent form, typically resulting from the development of autoantibodies that target and inhibit ADAMTS13. Several factors have been implicated in triggering the formation of these ADAMTS13 autoantibodies, including antiplatelet medications, immunosuppressive drugs, HIV infection, estrogen-containing contraceptives, and pregnancy. Congenital TTP, a less common variant, is attributed to genetic mutations within the ADAMTS13 gene itself.
It’s important to note that ADAMTS13 deficiency alone may not always manifest as clinical TTP. Individuals with hereditary ADAMTS13 deficiency can remain asymptomatic until a triggering event, such as an infection or pregnancy, occurs. The specific risk factors that predispose individuals to develop inhibitory autoantibodies against ADAMTS13 in acquired TTP are still not fully understood and are areas of ongoing research.
Epidemiology of Thrombotic Thrombocytopenic Purpura
Thrombotic Thrombocytopenic Purpura is considered a rare disease, and precise prevalence figures are still being established. Studies indicate an incidence ranging from 1 to 13 cases per million individuals, varying across different geographical regions. While TTP can occur at any age, it is most frequently diagnosed in adults over 40 years old. Congenital forms, however, can present in childhood. There is a notable gender disparity, with TTP being more common in women, exhibiting a female-to-male ratio of approximately 2:1.
The natural course of untreated TTP is severe, with a 90% mortality rate. However, with appropriate and timely treatment, this mortality rate dramatically decreases to 10% to 15%. TTP is exceptionally rare in pediatric populations. Additional factors associated with an increased risk of developing TTP include female gender, individuals of African American descent, and pregnancy, highlighting the need for heightened clinical awareness in these groups.
Pathophysiology of Thrombotic Thrombocytopenic Purpura
The cornerstone of TTP pathophysiology is a profound deficiency in ADAMTS13 activity, whether due to genetic mutations or acquired autoantibodies. Diagnosis TTP is often confirmed by demonstrating severely deficient ADAMTS13 protease activity, typically below 10% of normal levels. ADAMTS13 is a plasma protease responsible for cleaving von Willebrand factor (VWF), specifically breaking down ultra-large VWF multimers into smaller, manageable sizes.
When ADAMTS13 activity is compromised, ultra-large VWF multimers accumulate on the endothelial surface of blood vessels. These abnormally large VWF multimers are highly prothrombotic, readily binding to platelets and initiating platelet aggregation and subsequent microthrombi formation. These microthrombi obstruct small blood vessels, leading to ischemia and end-organ damage, particularly affecting the CNS and kidneys.
Thrombocytopenia, a hallmark of TTP, arises from the consumption of platelets as they are incorporated into the developing microthrombi. Hemolytic anemia develops due to the mechanical destruction of red blood cells (RBCs) as they are forced to traverse the partially occluded small vessels. This mechanical shearing of erythrocytes results in fragmented red cells, known as schistocytes, a characteristic finding in TTP.
Histopathology of Thrombotic Thrombocytopenic Purpura
The histopathological features of TTP and other thrombotic microangiopathies (TMAs) share common characteristics, primarily involving changes in small blood vessels. These changes include swelling of endothelial cells and the subendothelial space. There is also evidence of vessel wall thickening. Critically, platelet-rich microthrombi are observed within small arterioles and capillaries, often obliterating the vessel lumen. Importantly, large-vessel thrombosis is not a feature of TTP.
Autopsy studies of patients who succumbed to acute TTP episodes have revealed the widespread presence of microvascular thrombi, characteristic of TTP, in nearly all organs examined. Bone marrow evaluation, if performed, typically reveals normal maturation of all blood cell lineages (trilineage maturation). However, increased thrombopoiesis (platelet production) and erythropoiesis (red blood cell production) may be observed as a compensatory response to the increased consumption of platelets and RBCs in the peripheral circulation. The white blood cell (WBC) count is usually within the normal range in TTP, and significant coagulation abnormalities are also uncommon, helping to differentiate TTP from disseminated intravascular coagulation (DIC).
History and Physical Examination in Thrombotic Thrombocytopenic Purpura
In contrast to other primary TMAs, renal involvement is less prominent in TTP. Neurological symptoms are frequently the dominant clinical feature of TTP. These neurological manifestations can include headache, focal neurological deficits, seizures, confusion, and vertigo. The initial presentation of TTP may be nonspecific, with symptoms such as fatigue, dyspnea, petechiae (small pinpoint hemorrhages), or bleeding.
Studies analyzing the presenting symptoms of idiopathic TTP have shown that neurological complaints are the most common (reported in 44% of patients), followed by abdominal pain (23.5%). Interestingly, bleeding due to thrombocytopenia is a less frequent presenting symptom, reported in less than 10% of patients. As mentioned earlier, significant kidney involvement is uncommon clinically and is often only detected through biopsy. Pulmonary involvement is also relatively rare in TTP.
Cardiac involvement can occur in TTP, and the presence of elevated serum troponin levels in patients presenting with TTP is considered a poor prognostic indicator. Elevated troponin has been identified as an independent factor associated with a threefold increase in the risk of death or treatment refractoriness in TTP patients. The clinical presentation of TTP is highly variable, with a wide spectrum of signs and symptoms of varying severity, making diagnosis TTP challenging. A high index of clinical suspicion is crucial for timely and accurate diagnosis. Epidemiological studies, particularly the Oklahoma Registry, are frequently referenced to define the presenting signs and symptoms associated with TTP.
Clinical Presentation According to the Oklahoma Registry:
- Gastrointestinal symptoms: 69%
- Weakness: 63%
- Bleeding or purpura: 54%
- Major neurological findings (coma, stroke, seizure, transient focal abnormalities): 41%
- Minor neurological findings (headache, confusion): 26%
- Fever and chills: 10%
- Classical pentad (hemolytic anemia, thrombocytopenia, fever, acute kidney injury, and severe neurological findings): less than 5%
Evaluation and Diagnosis of Thrombotic Thrombocytopenic Purpura
Laboratory evaluation is indispensable in diagnosis TTP, given the variability in clinical signs and symptoms and the potential for delayed end-organ damage. The essential laboratory findings for diagnosis TTP are anemia and thrombocytopenia, coupled with evidence of active hemolysis. Indicators of hemolysis include the presence of schistocytes on peripheral blood smear, elevated unconjugated bilirubin, increased reticulocyte count, and elevated lactate dehydrogenase (LDH). As with any hemolytic process, serum haptoglobin levels are typically decreased as haptoglobin binds to free hemoglobin released from destroyed erythrocytes.
PLASMIC Score for TTP Diagnosis
The PLASMIC score is a valuable clinical tool that utilizes readily available presenting clinical and laboratory findings to predict the likelihood of severely reduced ADAMTS13 activity (less than or equal to 10%). This score aids in making a presumptive diagnosis TTP in the appropriate clinical context. The presence of peripheral schistocytes is a prerequisite for applying the PLASMIC score. One point is assigned for each of the following criteria:
- Platelet count less than 30,000/microL
- Evidence 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 active cancer
- Absence of solid organ or stem cell transplant
A higher PLASMIC score correlates with a greater probability of TTP. A score greater than 5 suggests a high likelihood of TTP, while a score below 5 indicates a lower probability. The PLASMIC score has demonstrated high sensitivity (99%) and specificity (57%) in validation studies. Due to its strong negative predictive value, it is particularly useful as a screening tool to identify patients who are unlikely to have TTP, helping to prioritize further diagnostic testing and interventions.
ADAMTS13 Activity Assay
The definitive diagnostic test for TTP is the ADAMTS13 activity assay. This assay quantifies the activity of the ADAMTS13 protease, expressed as a percentage of normal activity. An ADAMTS13 activity level of less than 10% in a patient with thrombocytopenia and evidence of hemolysis definitively confirms the diagnosis TTP. However, it is important to recognize that this assay is not entirely specific for TTP; ADAMTS13 activity levels below 10% have been reported in severe sepsis and systemic cancer. Furthermore, a decrease in ADAMTS13 activity to below 20% after initial recovery from an acute TTP episode is considered indicative of relapse, even in the absence of thrombocytopenia and hemolysis.
Evaluation of end-organ damage in TTP often includes measuring serum troponin levels to assess for cardiac involvement and obtaining brain magnetic resonance imaging (MRI) to evaluate for neurological complications.
Treatment and Management of Thrombotic Thrombocytopenic Purpura
The cornerstone of TTP treatment is plasma exchange (PEX) combined with high-dose corticosteroid therapy. Corticosteroids exert their therapeutic effect by reducing the activity of the reticuloendothelial system and suppressing autoantibody production. In patients with suspected TTP, characterized by unexplained hemolytic anemia and thrombocytopenia with a normal coagulation profile, PEX and corticosteroids should be initiated promptly as a medical emergency.
Plasma exchange effectively removes both the ultra-large VWF multimers and the ADAMTS13 autoantibodies from the patient’s circulation. The recommended volume for each PEX treatment is typically one estimated plasma volume (approximately 40 mL/kg of body weight), administered daily. Plasma is the preferred replacement fluid during PEX as it provides exogenous ADAMTS13. Once remission is achieved, PEX can usually be discontinued abruptly without the need for tapering.
The standard corticosteroid regimen is prednisone at a dose of 1 mg/kg per day for neurologically stable patients. In severely ill patients, intravenous methylprednisolone at higher doses (e.g., 1000 mg daily for three days or 125 mg two to four times daily) may be more appropriate. Corticosteroids are typically continued throughout the duration of PEX therapy and then gradually tapered based on the patient’s clinical response.
Other treatment modalities used in TTP management include splenectomy, cyclosporine, cyclophosphamide, vincristine, and rituximab. These agents are generally considered adjunctive therapies, employed when first-line treatment (PEX and corticosteroids) fails or in refractory cases. The addition of glucocorticoids and rituximab to PEX has been shown to potentially reduce the duration of therapeutic plasma exchange required. Splenectomy, by removing a major site of antibody production, has been used, but its efficacy is considered variable.
Rituximab, an anti-CD20 monoclonal antibody, has emerged as a valuable treatment option, particularly for TTP refractory to PEX. It targets B-lymphocytes, reducing autoantibody production, and has demonstrated good response rates in refractory and relapsed TTP. Rituximab is often favored over other non-specific immunosuppressive agents. Vincristine, cyclophosphamide, and cyclosporine are immunosuppressive agents with less robust efficacy and are usually reserved for refractory cases or when first-line therapy has failed, often used in conjunction with other secondary therapies.
Caplacizumab, a newer agent, holds significant promise in TTP treatment. It is a humanized monoclonal antibody fragment that targets the A1 domain of VWF, preventing platelet adhesion and microthrombi formation. Clinical studies have shown caplacizumab to have a rapid onset of action compared to other agents. Its use has been associated with a significant reduction in mortality, and some experts advocate for its use as a frontline therapy. While caplacizumab effectively inhibits microthrombi formation, it does not directly reduce the production of ADAMTS13 autoantibodies. Caplacizumab is administered as an initial intravenous dose followed by subcutaneous injections for 30 days after PEX is discontinued, ideally coinciding with an increase in ADAMTS13 activity to above 20%. A potential side effect of caplacizumab is an increased risk of bleeding, and clinically significant bleeding attributable to caplacizumab may necessitate discontinuation of therapy and/or VWF concentrate infusion.
Plasma infusion alone, without exchange, is not considered adequate primary treatment for TTP. However, it can serve as a temporizing measure in patients when PEX cannot be initiated immediately. Data suggests that plasma infusion can have similar efficacy to PEX if equivalent plasma volumes are administered, but this is often impractical due to the large volumes required.
Packed red blood cell (PRBC) transfusions can be administered if clinically indicated to address anemia. Platelet transfusions, however, are generally contraindicated in TTP unless major bleeding is present, as they may paradoxically exacerbate microthrombosis. Monitoring the patient’s response to treatment is crucial for determining the duration of plasma exchange. Hemolysis markers are typically monitored daily. PEX is usually discontinued once platelet levels stabilize above 150,000/microL for more than 48 hours.
2020 Treatment Guidelines by the International Society on Thrombosis and Hemostasis (ISTH)
- For initial TTP treatment, ISTH strongly recommends adding corticosteroids to therapeutic plasma exchange (PEX) over PEX alone, without specifying a preferred dosage or type of corticosteroid.
- For patients experiencing their first acute TTP event, ISTH suggests adding rituximab to corticosteroids and PEX. Rituximab’s primary documented benefit is preventing relapses, although its true benefit in acute management may be underestimated due to its use primarily in severe cases. This recommendation is conditional, based on practitioner judgment, especially if comorbid autoimmune disorders are present.
- For patients with relapsing TTP, ISTH recommends PEX, corticosteroids, and rituximab, as in initial treatment, with the addition of caplacizumab.
- For patients in TTP remission but with persistently low ADAMTS13 activity without clinical signs/symptoms, ISTH recommends prophylactic rituximab.
- For pregnant patients with decreased ADAMTS13 activity but no clinical TTP signs/symptoms, ISTH recommends prophylactic treatment with plasma infusion products.
Differential Diagnosis of Thrombotic Thrombocytopenic Purpura
The differential diagnosis of TTP includes several conditions that can present with similar clinical and laboratory features. The most important condition to differentiate from TTP is Hemolytic Uremic Syndrome (HUS). While both are thrombotic microangiopathies, key distinctions exist. In typical HUS, acute kidney injury is more prominent, whereas neurological symptoms tend to be more pronounced in TTP. Furthermore, TTP is primarily caused by ADAMTS13 deficiency, while HUS is often complement-mediated, particularly in atypical HUS. Shiga toxin-producing E. coli infection is a common cause of typical HUS, especially in children, often preceded by bloody diarrhea.
Other conditions in the differential diagnosis include:
- Disseminated Intravascular Coagulation (DIC): DIC is characterized by widespread activation of the coagulation cascade, leading to both thrombosis and bleeding. Coagulation tests (PT/INR, aPTT, fibrinogen) are typically abnormal in DIC, unlike in TTP.
- HELLP Syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets): HELLP syndrome occurs in pregnancy and postpartum and is characterized by hemolysis, liver enzyme elevation, and thrombocytopenia. Clinical context and liver function tests help differentiate HELLP from TTP.
- Other Thrombotic Microangiopathies: Conditions like atypical HUS, drug-induced TMA, and hematopoietic stem cell transplant-associated TMA should be considered.
- Systemic Infections: Severe infections can sometimes mimic TMA.
- Cancer-Associated Thrombotic Microangiopathy: Certain malignancies can be associated with TMA.
Prognosis of Thrombotic Thrombocytopenic Purpura
Without treatment, the prognosis of thrombotic thrombocytopenic purpura is dire, with a mortality rate reaching 90%. However, early and appropriate treatment, primarily with plasma exchange and corticosteroids, dramatically improves survival, reducing mortality to approximately 15%. The promptness of treatment initiation is a critical determinant of outcome; delays in diagnosis and treatment significantly increase the risk of adverse outcomes. A major cause of mortality in TTP is coronary thrombosis leading to acute myocardial infarction, congestive heart failure, and sudden death.
Complications of Thrombotic Thrombocytopenic Purpura and its Treatment
If plasma exchange is not immediately available, plasma infusion can be used as a temporizing measure. However, aggressive plasma infusion can lead to fluid overload and congestive heart failure. Once plasma exchange is initiated, this issue can be managed and reversed.
Complications associated with PEX primarily relate to central venous catheter placement and exposure to donor plasma. Transfusion-related acute lung injury (TRALI) is a potential, though rare, complication. Studies have reported mortality due to PEX complications in TTP patients to be around 4.4%, with complications including pulmonary hemorrhage and central venous catheter-associated bloodstream infections. Other non-lethal PEX complications include bacteremia, catheter-related venous thrombosis requiring anticoagulation, and anaphylaxis. However, advancements in adjunctive therapies, which reduce the required frequency and duration of PEX, have led to a significant decline in PEX-related complications over time.
Consultations for Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura is a medical and hematologic emergency requiring immediate and specialized care. All patients with suspected TTP should be admitted to an intensive care unit (ICU) setting for close monitoring and management. While an internist can serve as the primary coordinating physician, the involvement of an intensivist for tactical-level management is highly recommended, if available. Given the potential for organ ischemia and failure, consultations with other specialists, such as nephrologists and neurologists, may be necessary depending on the specific organ involvement.
Deterrence and Patient Education for Thrombotic Thrombocytopenic Purpura
Recovery from TTP can be prolonged, and the extent of rehabilitation needed depends on the severity of organ ischemia and any residual deficits. Patients who have recovered from TTP should be educated to remain vigilant for the recurrence of TTP signs and symptoms. Close monitoring of laboratory parameters is essential after plasma exchange and corticosteroids are tapered. Relapse can occur rapidly. For select patients at high risk of relapse, rituximab may be considered for secondary prevention, and caplacizumab is also available as a prophylactic agent in certain situations.
Pearls and Other Issues in Thrombotic Thrombocytopenic Purpura
Hemolytic uremic syndrome (HUS) and TTP are both subsets within the broader category of microangiopathic hemolytic anemia (MHA). While they share overlapping clinical features, including schistocytosis, fever, thrombocytopenia, hemolysis, renal injury, and neurological symptoms, their primary difference lies in their underlying causes. Acute kidney injury is more frequent in HUS compared to TTP, whereas neurological involvement is more prominent in TTP. TTP is caused by a deficiency in ADAMTS13, while HUS is typically complement-mediated. Hereditary HUS requires complement mutation studies for diagnosis, while acquired HUS often involves stool culture and PCR analysis for Shiga toxin, produced by Shigella bacteria and entero-toxin producing E. Coli O157:H7. Typical HUS often presents in children with colitis and bloody diarrhea. Treatment for HUS is primarily supportive, with volume expansion being crucial. Antibiotics are generally not helpful in typical HUS.
In clinical practice, differentiating between TTP and HUS can be challenging due to overlapping initial presentations. In situations where the diagnosis is unclear, and both TTP and HUS are possibilities, it is prudent to initiate plasma exchange (PEX) promptly. PEX is highly beneficial in TTP and may provide some relief in HUS. If a patient suspected of HUS does not respond to PEX, eculizumab, a monoclonal antibody against complement component C5, should be considered. Eculizumab inhibits complement-mediated TMA and can improve renal function in HUS.
Enhancing Healthcare Team Outcomes in Thrombotic Thrombocytopenic Purpura Management
TTP is a severe, life-threatening disorder that necessitates a coordinated interprofessional team approach for optimal patient management. This team typically includes nurses, hematologists, emergency department physicians, nephrologists, neurologists, and internists. Given that diagnostic test results, such as ADAMTS13 assays, may be delayed, the clinical acumen of the healthcare team is paramount in determining patient survival. Failure to promptly suspect diagnosis TTP can lead to delayed treatment and increased mortality.
Initial admission to the intensive care setting is recommended for TTP patients, allowing for close monitoring by critical care nursing staff and management by an intensivist, ideally in collaboration with a hematologist. Beyond corticosteroids, plasmapheresis (PEX) is the primary treatment. If PEX cannot be initiated immediately, plasma infusion should be performed as a bridge. The expertise of nurses and the apheresis team is essential in delivering PEX effectively. Monitoring for treatment response, typically through daily hemolysis markers, is crucial for guiding PEX duration. PEX is usually discontinued when platelet levels stabilize above 150,000/microL for over 48 hours.
The prognosis of TTP patients is influenced by factors such as age, neurological deficits, renal dysfunction, treatment response, and comorbidities. Most patients require prolonged hospitalization for gradual recovery. The apheresis team and clinical nurses play a vital role in monitoring patients during PEX to prevent fluid overload and cardiac arrhythmias. Clinical pharmacists contribute by monitoring for treatment side effects and reconciling medications to prevent adverse drug events. A well-coordinated interprofessional team significantly improves outcomes for patients with this potentially lethal disease. For patients with residual organ damage, rehabilitation may be necessary.
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