General Neurology
Brain death/death by neurologic criteria
Nov. 09, 2024
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Thrombotic thrombocytopenic purpura: neurologic complications …
- Updated 01.06.2024
- Released 08.30.2019
- Expires For CME 01.06.2027
Thrombotic thrombocytopenic purpura: neurologic complications
Introduction
Overview
Thrombotic thrombocytopenic purpura is a serious condition that belongs to a group of disorders known as thrombotic microangiopathies. The disease is caused by the congenital or acquired deficiency of the metalloproteinase ADAMTS13, which is responsible for the cleavage of von Willebrand factor multimers. The decreased activity of ADAMTS13 leads to the accumulation of ultra-large von Willebrand factor multimers that enhance platelet agglutination and induce thrombosis of small arterioles and capillaries in most organs in the body, including the brain, kidney, and heart. Thrombotic thrombocytopenic purpura patients commonly have neurologic manifestations, and these may represent the initial symptoms for which patients seek medical attention. Left untreated, thrombotic thrombocytopenic purpura has a mortality rate of 85% to 90%. However, early recognition of the disease and proper management reduces the mortality rate to 10% to 20%.
Key points
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• Thrombotic thrombocytopenic purpura belongs to a group of disorders known as thrombotic microangiopathies. | |
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• It can affect previously healthy individuals of patients with autoimmune disorders. | |
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• Thrombotic thrombocytopenic is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ damage. | |
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• It is caused by the severe deficiency of ADAMTS13, which leads to the accumulation of ultra-large von Willebrand factor multimers that induce thrombosis. | |
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• Ischemic stroke is one of the neurologic manifestations in thrombotic thrombocytopenic purpura. | |
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• Plasma exchange is the mainstay treatment for thrombotic thrombocytopenic purpura. | |
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• Caplacizumab has been approved by the U.S. Food and Drug Administration as adjunctive therapy for the treatment of thrombotic thrombocytopenic purpura. |
Historical note and terminology
Thrombotic thrombocytopenic purpura and other microangiopathies, such as those associated with hematopoietic progenitor cell transplantation, pregnancy, drugs, and disseminated malignancy as well as hemolytic uremic syndrome belong to a class of disorders called thrombotic microangiopathies (37). As a group, thrombotic microangiopathies are characterized by microangiopathic hemolytic anemia with red blood cell fragmentation, thrombocytopenia, and end organ injury secondary to microvascular thrombosis. In particular, thrombotic thrombocytopenic purpura is associated with ADAMTS13 deficiency and elevated levels of ultra-large von Willebrand factor multimers in the plasma. Thrombotic thrombocytopenic purpura, which is also known as Moschcowitz disease, was first described by Eli Moschcowitz in 1924. He reported a 16-year-old girl who died after having an acute presentation of hemolytic anemia, thrombocytopenia, purpura, fever, and neurologic dysfunction (28). In 1982, Moake and colleagues reported four patients with chronic relapsing thrombotic thrombocytopenic purpura who had elevated plasma levels of von Willebrand factor multimers that caused spontaneous platelet agglutination. The authors hypothesized that thrombotic thrombocytopenic purpura was the result of a deficiency of a plasma von Willebrand factor–cleaving protease (27). In 1998, a similar presentation was described in different cohorts of patients with acquired thrombotic thrombocytopenic purpura (42). In this case, the formation of von Willebrand factor multimers was associated with antibodies against the von Willebrand factor–cleaving protease. At this point, it became clear that thrombotic thrombocytopenic purpura could be hereditary or acquired (idiopathic). In 1996, the von Willebrand factor–cleaving protease was isolated from human plasma (13). Because the activity of this enzyme was dependent on the presence of divalent metal ions, it was concluded that the von Willebrand factor–cleaving protease was a metalloproteinase. Based on partial protein sequencing in 2001, it was determined that the von Willebrand factor–cleaving protease was a novel member of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) family of metalloproteinases. The gene encoding for ADAMTS is located on chromosome 9q34, and, according to the HUGO Gene Nomenclature Committee, it was designated as ADAMTS13 (45).
Clinical manifestations
Presentation and course
Historically, thrombotic thrombocytopenic purpura was defined by the clinical pentad of fever, thrombocytopenia, hemolytic anemia, neurologic abnormalities, and kidney dysfunction. However, the complete pentad is seen in only 40% of the cases and many patients present with nonspecific complaints, including dyspnea, fatigue, dizziness, and bleeding disorders. Patients not necessarily are critically ill.
Approximately 60% of the patients present with involvement of the central nervous system (14). The neurologic deficits can be fleeting and nonspecific, ranging from headaches, altered mental status, and agitation to seizures, cerebral ischemia, and coma. On physical examination, patients may present with confusion, aphasia, amaurosis, dysarthria, hemiplegia, papilledema, or ataxia depending on the area of the brain affected by the disease (31; 04). The clinical manifestations are secondary to brain hypoperfusion caused by microvascular thrombosis. In a small series of 17 cases of thrombotic thrombocytopenic purpura admitted to Indiana University Medical Center between 1985 to 1994, mental status changes and seizures were the most common neurologic manifestations (31).
Cerebral ischemia in thrombotic thrombocytopenic purpura is common. Patients typically present with punctate infarcts that result from the obliteration of arterioles and capillaries. However, cases with large vessel occlusion and cryptogenic stroke have also been reported (39; 41). Cerebral microbleeds can be seen in thrombotic thrombocytopenic purpura. It was suggested that microthrombi formation and the consequent hypoperfusion cause endothelial injury and loss of blood-brain barrier function (30; 29). The microhemorrhages observed on brain MR would occur due to the synergistic effect of increased vascular permeability and severe thrombocytopenia.
Endothelial dysfunction and blood-brain barrier dysregulation can also predispose to posterior reversal leukoencephalopathy syndrome (PRES). PRES is a condition characterized by headache, confusion, seizures, and visual changes in the context of vasogenic edema evidenced on brain MR. The occurrence of PRES in thrombotic thrombocytopenic purpura patients has been described under the form of case reports (11). However, it remains uncertain whether PRES is caused by thrombotic thrombocytopenic purpura or by other conditions that typically coexist with both diseases, including pregnancy, transfusion, connective tissue disorders, and certain drugs such as immunosuppressant agents.
Several electrographic abnormalities, including generalized spike-and-wave discharges, sporadic polyspike-and-wave discharges, and electrographic seizures have been described in a case series of 17 patients with thrombotic thrombocytopenic purpura (26). Both convulsive and nonconvulsive status epilepticus, even in the setting of treatment with plasmapheresis, have also been reported. Based on autopsy studies, it was suggested that status epilepticus may be secondary to cortical ischemia (14). In comparison, lateralizing slowing has been associated with luxury perfusion that may resolve after treatment of thrombotic thrombocytopenic purpura (44). This suggests that some electrographic abnormalities can occur in the absence of cerebral ischemia. Resolution of EEG changes is common after treatment of thrombotic thrombocytopenic purpura (04). However, the prognostic value of EEG and the long-term risk of epilepsy have not been investigated.
Psychiatric disorders, including depression, posttraumatic stress disorder, and neurocognitive decline, are common in thrombotic thrombocytopenic purpura (18; 07). Falter and colleagues reported that the rate of depression in this condition might be as high as 68% (12). In addition, compared to healthy controls, thrombotic thrombocytopenic purpura patients had lower scores in memory, attention, and executive function testing. Interestingly, depression severity had a strong correlation with cognitive dysfunction, raising the question of whether the poor performance in psychometric studies is due to depression or parenchymal injury. Cognitive function was studied in 24 patients with thrombotic thrombocytopenic purpura who were enrolled in the Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome Registry; those patients had complete recovery of their symptoms (21). All the patients performed significantly worse than the general U.S. population on 4 of the 11 cognitive domains investigated. Importantly, many of the participants had normal Mini-Mental State Examinations, suggesting that this screening tool lacks the sensitivity to detect cognitive decline in thrombotic thrombocytopenic purpura. Also, the pattern of cognitive deficits seen in thrombotic thrombocytopenic purpura patients resembles what is observed in individuals with diffuse subcortical microvascular infarcts. Based on this observation, it was proposed that thrombotic thrombocytopenic purpura–associated diffuse cerebral microvascular thrombosis may be a contributor to persistent cognitive dysfunction (21).
Nonneurologic findings in thrombotic thrombocytopenic purpura patients include fever, though this is not a prominent feature (Table 1). Renal dysfunction consists, most commonly, of hematuria or proteinuria. Elevation of serum creatinine is typically mild and below 2 mg/dL, but severe cases of acute renal failure have been described in patients with severe thrombotic thrombocytopenic purpura.
Gastrointestinal symptoms are reported by 35% of the patients with thrombotic thrombocytopenic purpura. These may be related to mesenteric ischemia, which can manifest with nonspecific symptoms, including abdominal pain, vomiting, and diarrhea (20). Cardiac ischemia occurs in 25% of the cases. Patients present with chest pain and elevated troponin and CK-MB levels that are indicators of cardiac hypoperfusion. However, myocardial infarction is uncommon. Other findings include arrhythmia and cardiac failure, which, albeit uncommon, anticipate a high mortality risk.
Hematological findings include thrombocytopenia, which is believed to result from the deposition of platelet-rich microthrombi in the microvasculature. Platelet counts usually range from 10,000 to 30,000 per microlL, and these are associated with epistaxis, gingival bleeding, and petechiae. There are, in addition, findings consistent with hemolytic anemia, which include decreased levels of hemoglobin (typically 8-10 mg/dL) and haptoglobin (may be undetectable), increased reticulocyte counts (> 120 per microL), and the presence of fragmented red blood cells (schistocytes), which are typically more than 1% in peripheral blood smear (32). Table 1 summarizes clinical and laboratory findings commonly found in thrombotic thrombocytopenic purpura patients (37).
Atypical presentations of thrombotic thrombocytopenic purpura have been described but are rare. These refer to patients with transient neurologic manifestations who may develop the typical thrombotic thrombocytopenic purpura features days or weeks after presentation (16).
Table 1. Clinical and Laboratory Findings Commonly Found in Thrombotic Thrombocytopenic Purpura
Organ | Manifestations |
Hematologic thrombocytopenia | Mucosal bleeding, petechiae, hematuria, menorrhagia, gastrointestinal bleeding, retinal hemorrhage, hemoptysis |
Hemolytic anemia | Low hemoglobin, elevated reticulocyte count, decreased haptoglobin, schistocytes, increased bilirubin (particularly indirect), increased lactic dehydrogenase, jaundice, pallor, fatigue |
Neurologic | Headache, confusion, hemiparesis, aphasia, dysarthria, visual changes, seizures, coma |
Renal | Proteinuria, microhematuria, elevated creatinine, acute renal failure |
Cardiac | Chest pain, heart failure, cardiac arrhythmia, elevated troponin and CK-MB levels |
Gastrointestinal | Abdominal pain, nausea, vomiting, diarrhea |
Nonspecific | Fever, malaise, arthralgia/myalgia, increased levels of markers of tissue hypoperfusion (lactate and lactic dehydrogenase) |
Prognosis and complications
With early initiation of treatment, the survival rate of thrombotic thrombocytopenic purpura is 80% to 90%. In comparison, this condition has a survival rate of less than 20% when left untreated (23). Advanced age, elevated lactic dehydrogenase (> 10 times the upper normal level), coma, and increased cardiac troponin levels at onset are associated with death and treatment refractoriness (10). Oberlander and colleagues showed that neurologic symptoms at admission are not good predictors of survival or responsiveness to treatment (31). Focal neurologic symptoms can be mistaken with symptomatic atherosclerotic disease, especially in patients who have vascular risk factors (03). Some of these patients have been treated with recombinant tissue plasminogen activator (05). However, caution should be exercised when using thrombolytics as the thrombocytopenia associated with this condition can increase the risk of hemorrhagic complications. Sugarman and colleagues reviewed 10 cases of thrombotic thrombocytopenic purpura with large cerebral vessel occlusion; only one patient had full neurologic recovery (39). Despite the normalization of laboratory parameters and the resolution of clinical findings, a large proportion of the thrombotic thrombocytopenic purpura patients report incomplete resolution. Depression and neurocognitive decline constitute some of the most common sequelae, and both have a direct impact on quality of life. Thus, longitudinal screening for these conditions and aggressive treatment are warranted.
Relapses are a major concern in thrombotic thrombocytopenic purpura and occur in as many as 40% of the patients who survive the first episode. These are typically observed within 7 to 10 years of follow-up, highlighting the importance of long-term follow-up (24). In addition, up to 50% of the patients experience exacerbations of the acute events.
Clinical vignette
A 36-year-old female presented to the emergency department after having two transient events of confusion and new onset of headache. Her vital signs were within normal limits, and her general and neurologic exams were unrevealing. Her initial laboratory analysis showed severe thrombocytopenia (38,000/microL), anemia (Hb=8.6 g/dL), and mildly increased bilirubin to 2.2 mg/dL (reference < 1.2 mg/dL). Brain MR and CT angiography of the head and neck were unrevealing. An electroencephalogram showed mild-to-moderate slowing of the left hemisphere, but no evidence of epileptic or epileptiform activity. Additional laboratory studies showed lactic dehydrogenase of 650 units/L (reference 100 to 190 units/L), reticulocyte counts of 4% (reference 0.5% to 1.5%), and schistocytes on peripheral smear (2%). Haptoglobin was 25 mg/dL (reference 50 to 150 mg/dL), and fibrinogen was normal 220 mg/dL (reference 150 to 350 mg/dL). Plasmapheresis and high-dose corticosteroids were initiated given the high suspicion for thrombotic thrombocytopenic purpura. The following day, the patient became increasingly confused and unable to follow commands. A new HCT showed diffuse subarachnoid hemorrhage. Shortly after, the patient experienced a cardiac arrest and ultimately expired.
Biological basis
Von Willebrand factor has a critical role in thrombus formation and growth. It is produced primarily in endothelial cells and stored in the Weibel-Palade bodies. Megakaryocytes and platelets produce approximately 10% to 20% of the von Willebrand factor and store it in alpha granules. Von Willebrand factor is released as ultra-large multimers that are cleaved by ADAMTS13 into smaller multimers. These smaller multimers circulate in an inactive coiled confirmation. After vascular damage and exposure to the subendothelium, these multimers uncoil and expose their GP1b-binding sites, promoting platelet adhesion and rolling. In addition, they enhance the engagement of platelet receptors, such as GPIIbIIIa, which bind to fibrinogen and von Willebrand factor promoting thrombus growth. Ultra-large von Willebrand factor strings interact with adhesion molecules such as P-selectin to facilitate platelet clumping. In addition, they enhance platelet-induced leukocyte recruitment, which further potentiates inflammation and plays a major role in atherothrombosis and ischemic stroke (06).
Etiology and pathogenesis
Thrombotic thrombocytopenic purpura is caused by a severe deficiency of ADAMTS13 (typically < 10% activity), and it can be either congenital or, most commonly, acquired due to the production of autoantibodies, usually IgG, directed against ADAMTS13. Deficiency in this protein results in the production of ultra-large von Willebrand factor multimers, which activate platelets and lead to thrombosis of small arterioles and capillaries. In addition, they cause thrombocytopenia due to scavenging of platelets as the thrombi disseminate and hemolytic anemia due to the mechanical destruction of red blood cells in the microcirculation. Diffuse microthrombi deposits are observed within the small vessels of different organs including the kidneys and brain.
Acquired thrombotic thrombocytopenic purpura can also be seen in association with several other conditions, which are summarized in Table 2 (37).
Table 2. Conditions Associated with Thrombotic Thrombocytopenic Purpura
|
Condition |
Notes |
|
Pregnancy |
• It can result in placental thrombosis, which leads to fetal growth restriction and intrauterine fetal death. • Relapse during subsequent pregnancies is possible. |
|
HIV |
• Thrombotic thrombocytopenic purpura may be the presenting manifestation of HIV. • Remission is associated with enhanced immune function. |
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Drugs |
• Thrombotic thrombocytopenic purpura has been associated with quinine, clopidogrel, ticlopidine, simvastatin, trimethoprim, immunosuppressants (mitomycin C and cyclosporine), and pegylated interferon. |
|
Transplant |
• Thrombotic thrombocytopenic purpura has been described in association with bone marrow transplantation. • ADAMTS13 activity may not be significantly reduced. |
|
Pancreatitis |
• Thrombotic thrombocytopenic purpura may be seen days after resolution of pancreatitis. • ADAMTS13 activity doesn’t correlate with disease severity. |
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Malignancies |
• Thrombotic thrombocytopenic purpura is associated with different malignancies, particularly with adenocarcinomas. • Thrombotic thrombocytopenic purpura may be seen in early or advanced stages of the cancer. • ADAMTS13 activity may not be significantly reduced. |
|
Inflammatory and hypercoagulable conditions |
• Systemic lupus erythematous, Sjögren syndrome, antiphospholipid syndrome |
Epidemiology
The incidence of thrombotic thrombocytopenic purpura in the United States is approximately two to three per million adults per year, and the prevalence 10 cases per million. Acquired thrombotic thrombocytopenic purpura is mainly seen in adults (9:1, adult to child), mostly in the third to fifth decades of life in the United States and Europe and seventh decade of life in Japan. Women tend to be affected by the disease more than men, with a female to male ratio between 2.5:1 and 3.5:1 (23). The incidence of the disorder is also higher in African Americans than in non-African Americans. This difference is not completely understood. However, the low frequency of the protective allele DRB1*04 observed in African Americans suggests a genetic modulatory effect (25).
The prevalence of congenital thrombotic thrombocytopenic purpura is unknown, and it affects men and women equally. Congenital thrombotic thrombocytopenic purpura accounts for less than 5% of all acute cases of thrombotic thrombocytopenic purpura. Inheritance is autosomal recessive. In cases of congenital thrombotic thrombocytopenic purpura, individuals are often found to belong to families with parental consanguinity. Different mutations that can account for congenital thrombotic thrombocytopenic purpura cases in families of unrelated individuals have been reported in Scandinavian, British, and French patients as well as in central Europe, Italy, and Turkey (23).
Prevention
Relapses are more common in the first year after having the first episode of thrombotic thrombocytopenic purpura. It has been estimated that 41% of thrombotic thrombocytopenic purpura patients will have a relapse during the follow-up period of 7.5 years after the first attack. The risk of relapse increases when the levels of ADAMTS13 are persistently below 10% or when the levels continue to decrease during remission. Rituximab is often used in these situations (10). Splenectomy was also reported to significantly decrease the likelihood of relapse (20).
Differential diagnosis
The differential diagnosis in young patients who lack atherosclerotic risk factors and present with focal neurologic symptoms and thrombocytopenia includes vasculitis, antiphospholipid syndrome, infections, disseminated intravascular coagulation, toxic drugs, and thrombophilia. Also, multiple conditions can be associated with thrombotic microangiopathies; these are summarized in Table 3 (37). From a practical standpoint, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and disseminated intravascular coagulation may represent a diagnostic challenge. The typical findings for these conditions are summarized in Table 4 (43).
Table 3. Differential Diagnosis in Patients Presenting with Thrombotic Microangiopathy
|
Condition |
Notes |
|
Autoimmune hemolysis |
• Coombs test (+) |
|
Pregnancy |
• Differential diagnosis includes preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and hemolytic uremic syndrome |
|
Severe infections |
• Viral: cytomegalovirus, adenovirus, herpes simplex virus • Bacterial: meningococcus, pneumococcus |
|
Disseminated intravascular coagulation |
• Fibrinogen levels are decreased and fibrin degradation products are increased |
|
Hemolytic uremic syndrome (diarrhea positive/negative) | |
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• Usually affects children • Associated with Shiga toxin-producing Escherichia coli or abnormalities of proteins of the alternative complement pathway (atypical hemolytic uremic syndrome) • Relative to thrombotic thrombocytopenic purpura, these patients have more severe renal dysfunction, milder cerebral deficits, and less severe thrombocytopenia. Also, fever is not commonly seen in hemolytic uremic syndrome. |
Table 4. Differentiation of Thrombotic Thrombocytopenic Purpura, Hemolytic Uremic Syndrome, and Disseminated Intravascular Coagulation
|
Findings |
Thrombotic thrombocytopenic purpura |
Hemolytic uremic syndrome |
Disseminated intravascular coagulation | |
|
Laboratory | ||||
|
Schistocytes |
+ |
+ |
+/- | |
|
Thrombocytopenia |
+++ |
++ |
++ | |
|
Coagulopathy* |
+/- |
+/- |
++ | |
|
Decreased fibrinogen |
- |
- |
+ | |
|
Neurologic deficits |
+++ |
+/- |
+/- | |
|
Renal involvement |
++ |
+++ |
+ | |
|
Hypertension |
+/- |
++ |
+/- | |
|
| ||||
Diagnostic workup
Historically, thrombotic thrombocytopenic purpura was diagnosed based on clinical and laboratory findings. With the establishment of plasma exchange therapy, a Canadian randomized clinical trial used only thrombocytopenia and microangiopathic hemolytic anemia without an identifiable cause as inclusion criteria for therapy between 1982 and 1988. In 1998, thrombotic thrombocytopenic purpura was defined by severe deficiency of ADAMTS13 activity, which provided better specificity for the diagnosis (32). However, the utility of using ADAMTS13 activity as an initial evaluation for the condition is confounded by the fact that reduced ADAMTS13 activity can occur with other conditions such uremia, pregnancy, or postoperative states (37; 32). Measurement of ADAMTS activity is recommended to confirm the diagnosis and to monitor for response to treatment. Therefore, the clinical presentation and initial laboratory findings constitute key elements to establish the diagnosis. Laboratory tests and diagnostic workup to be performed when thrombotic thrombocytopenic purpura is suspected are summarized in Table 5 (37; 22).
Table 5. Diagnostic Workup in Suspected Thrombotic Thrombocytopenic Purpura Patients
|
Category |
Laboratory finding |
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Hematologic |
• Hemoglobin, platelets, reticulocytes, peripheral smear (schistocytes), lactic dehydrogenase, haptoglobin, fibrinogen, coagulation studies, D-dimer |
|
Renal |
• Serum creatinine, glomerular filtration rate, urine output, urinalysis |
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Cardiac |
• Troponin/CK-MB, NT-proBNP, electrocardiogram |
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Brain |
• CT scan, MRI, electroencephalogram, neurocognitive testing |
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Other etiologies |
• Hepatitis panel and liver function test |
Management
Mortality related to thrombotic thrombocytopenic purpura is mostly a result of late diagnosis and delayed treatment. Plasma exchange is the mainstay treatment for thrombotic thrombocytopenic purpura, which has improved survival from 10% to between 80% and 90%. Plasma exchange (or plasmapheresis) needs to be started as soon as the diagnosis is established or suspected (22). It has been suggested that dual treatment with steroids and plasma exchange should be considered over steroids or plasma exchange alone. Clinical trials investigating the use of recombinant ADAMTS13 for the treatment of congenital thrombotic thrombocytopenic purpura are in progress (22). Caplacizumab (ALX-0081) is a bivalent nanobody that blocks GPIb-von Willebrand factor interaction (35; 22; 34). The phase III HERCULES study compared the efficacy of caplacizumab to placebo for the treatment of thrombotic thrombocytopenic purpura patients receiving daily plasma exchange (34). The addition of caplacizumab to plasma exchange resulted in a 74% reduction in the primary outcome of time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter (p=0.01). The most common adverse event observed with caplacizumab was bleeding. At three years, TTP-related events occurred in 8% of patients receiving caplacizumab and 38% of those receiving placebo (36). In 2019, the U.S. Food and Drug Administration approved the use of caplacizumab for adults with acquired thrombotic thrombocytopenic purpura to be used in combination with plasma exchange and immunosuppressive therapy (02).
Based on these observations, in 2020 the International Society on Thrombosis and Haemostasis released new guidelines for the treatment of thrombotic thrombocytopenic purpura (46; 47). It is recommended to base the treatment on (A) the timely access to ADAMTS13 activity and (B) clinical suspicion of severe ADAMTS13 deficiency. Different scoring algorithms can assist in the prediction of the likelihood of severe ADAMTS13 deficiency in patients with suspected thrombotic thrombocytopenic purpura (Table 6).
Table 6. Scores Predicting the Likelihood of Severe ADAMTS13 Deficiency in Thrombotic Thrombocytopenic Purpura*
|
Variable |
French Score¶ |
PLASMIC Score |
|
Platelet count (< 30 109/L) |
1 point |
1 point |
|
Creatinine levels (mg/dL)** |
1 point |
1 point |
|
Detectable ANA |
1 point |
n/a |
|
Presence of hemolysis*** |
n/a |
1 point |
|
No active cancer in the previous year |
n/a |
1 point |
|
No solid organ or stem cell transplantation |
n/a |
1 point |
|
INR <1.5 |
n/a |
1 point |
|
Mean corpuscular value <90 |
n/a |
1 point |
|
Likelihood of severe ADAMTS13 deficiency* |
0 points = 2% |
0 to 4 points = 0% to 4% |
|
| ||
The treatment strategy for acquired thrombotic thrombocytopenic purpura recommended by International Society on Thrombosis and Haemostasis includes:
|
1. High probability of thrombotic thrombocytopenic purpura and ADAMTS13 activity available within 72 hours | ||
|
a. Obtain levels before initiation of treatment | ||
|
b. Start plasma exchange and steroids without waiting for ADAMTS13 results | ||
|
c. Consider early addition of caplacizumab | ||
|
d. Based on ADAMTS13 levels | ||
|
i. <10%: consider adding rituximab | ||
|
ii.10%-20%: use clinical judgment | ||
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iii. >20%: stop caplacizumab and consider other diagnoses | ||
|
2. Intermediate or low probability of thrombotic thrombocytopenic purpura and ADAMTS13 activity available within 72 hours | ||
|
a. Obtain levels before initiation of treatment | ||
|
b. Consider plasma exchange and steroids depending on clinical judgment | ||
|
c. Do not start caplacizumab | ||
|
d. Based on ADAMTS13 levels | ||
|
i. <10%: consider adding rituximab and caplacizumab | ||
|
ii.10% to 20%: use clinical judgment | ||
|
iii. >20%: do not add caplacizumab and consider other diagnoses | ||
|
3. In cases when ADAMTS13 activity is not available and based on the anticipated risks and benefits, the recommendation is for not using caplacizumab due to the incremental bleeding risk and cost. | ||
ADAMTS13 levels are not necessarily required for the diagnosis of thrombotic thrombocytopenic purpura relapse. The treatment of these cases includes the use of plasma exchange, steroids, rituximab, and caplacizumab. Rituximab is also recommended for patients in clinical remission who have low ADAMTS13 levels.
Plasma infusion to replace the missing enzyme is used in congenital thrombotic thrombocytopenic purpura. Plasma infusion or watch and wait strategy should be considered for patients with congenital thrombotic thrombocytopenic purpura in remission. Clinical trials investigating the use of recombinant ADAMTS13 for the treatment of congenital thrombotic thrombocytopenic purpura are in progress (22).
The treatment of thrombotic thrombocytopenic purpura, in addition, should also concentrate on the identification and treatment of the precipitating factors, such as infections, or removal of offending agents (drugs), or both.
Thrombolytic therapy and endovascular recanalization have been used for the treatment of thrombotic thrombocytopenic purpura patients presenting with acute cerebral infarction. However, the beneficial effect of these therapeutic modalities in thrombotic thrombocytopenic purpura patients has not been investigated. There are no formal recommendations regarding the use of pharmacologic thrombolysis in patients with acute cerebral ischemia. The use of thrombolytics could be considered in selective cases where the benefits outweigh the risk of major hemorrhage. Persistent confusion despite the use of standard treatment should raise high suspicion for subclinical seizure activity. In these cases, the use of continuous EEG is recommended (14).
Outcomes
Mortality related to thrombotic thrombocytopenic purpura is mostly the result of late diagnosis and treatment. Risk factors for mortality include age older than 60 years, severe involvement of central nervous system, LDH levels greater than 10x the upper level of normal, and cardiac troponin levels greater than 0.25 μg/L at presentation. Plasma exchange is the mainstay treatment for thrombotic thrombocytopenic purpura and has been reported to improve survival; however, plasma exchange therapy is not free of complications. The incidence of severe, life-threatening complications is estimated at 0.025% to 4.75%. Septic complications can take place as a result of impaired immunity caused by the removal of antibodies during the procedure. Other complications include catheter-associated infections and infections related to transfusion of blood products. Moreover, cardiovascular adverse effects such as severe hypotension, cardiac arrhythmias, and water-electrolyte imbalance can occur. Other more common complications include urticaria, paresthesia, muscle contractions, dizziness, nausea, vomiting, transient fever, and diffuse pain. Altogether, the total incidence of complications is estimated to be between 25% and 40% (40). Advanced age, elevated lactic dehydrogenase (> 10 times the upper normal level), coma, and increased cardiac troponin levels at onset are associated with death and treatment refractoriness (10).
Special considerations
Pregnancy
Pregnancy is a known predisposing factor for thrombotic thrombocytopenic purpura. Pregnant and postpartum women make up 10% to 25% of thrombotic thrombocytopenic purpura patients. Before the use of plasma exchange, fetal mortality rate approached 80%. Once suspected, plasma exchange therapy should be initiated and continued for several days until normalization of platelet counts and improvement in clinical symptoms are achieved. Prophylactic treatment should be considered for patients with acquired thrombotic thrombocytopenic purpura who have decreased ADAMTS13 levels or those with congenital thrombotic thrombocytopenic purpura, even if no signs and symptoms develop (47). Prompt diagnosis and treatment before 20 weeks is associated with better outcomes as there is adequate placental function to avoid the development of severe intrauterine growth restriction (38).
Vaccine-induced immune thrombotic thrombocytopenia
Vaccines have emerged as an effective and safe strategy to contain the devastating consequences of the coronavirus-19 (COVID-19) pandemic. A prothrombotic syndrome has been described in association with the ChAdOx1 nCoV-19 and Ad26.COV2 adenoviral vector vaccines. This syndrome, called vaccine-induced immune thrombotic thrombocytopenia (VITT), begins 4 to 30 days after exposure to these vaccines and is characterized by:
|
• Thrombosis at uncommon sites (cerebral venous sinus, middle cerebral artery, splanchnic vein), | |
|
• Thrombocytopenia, which can be mild to severe and positive antibodies against PF4, which can be confirmed with a positive platelet factor-4 (PF4)-heparin enzyme-linked immunosorbent assay (01). |
The incidence of VITT ranges from 0.5 to 6.8 cases per 100,000 vaccines, and this may be higher for the ChAdOx1 nCoV19 vaccine than the Ad26.COV2 vaccine. The syndrome occurs more often in females and patients under 60 years of age (09).
The pathogenesis of VITT is similar to that of heparin-induced thrombocytopenia (HIT), namely that it is associated with platelet-activating antibodies against platelet factor 4 (PF4). However, these patients lack a previous exposure to heparin. In HIT, antibodies bind to a PF4-heparin complex, which then binds to a receptor on platelets called FCgammaRII, which results in cross-linking of the aforementioned receptors. This causes platelet activation and subsequent aggregation. It also activates coagulation pathways that result in thrombosis and thrombocytopenia. (08). In VITT, antibodies bind to PF4, causing PF4 tetramers to form clusters, which eventually leads to the formation of immune complexes, and subsequent platelet activation and aggregation. Thus, VITT antibodies mimic the effect of HIT antibodies, and their presence can be confirmed by a heparin antibody immunoassay (19). Similar to thrombotic thrombocytopenic purpura, VITT is associated with thrombosis and thrombocytopenia. Unlike VITT, however, thrombotic thrombocytopenic purpura is characterized by microvascular thrombosis, microangiopathic hemolytic anemia and ADAMTS13 deficiency.
The first line therapy for VITT, with or without associated thrombosis, is anticoagulation with nonheparin agents, given the similarity of VITT to HIT, and to avoid further platelet activation and worsening of thrombosis (17). High dose IVIG can inhibit platelet activation and aggregation by competitively inhibiting the binding of VITT antibodies with the FCgammaRIIa platelet receptor. IVIG therapy should be initiated as soon as VITT is diagnosed with the goal of preventing further platelet activation (33). Although steroids can prevent synthesis of autoantibodies, there are not enough data available to suggest their use as second line agents. Steroids have, however, successfully been used in combination with IVIG (15).
Platelet transfusion should be avoided, as it has been documented to increase mortality in patients with HIT and the overall risk of thrombosis in VITT patients. Additionally, platelet transfusion could worsen VITT induced platelet activation (33).
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Fernando Testai MD PhD
Dr. Testai of The University of Illinois College of Medicine has no relevant financial relationship to disclose.
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Aisha Ali MD
Dr. Ali of University of Illinois College of Medicine at Chicago has no relevant financial relationships to disclose.
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Editor
-
Amy A Pruitt MD
Dr. Pruitt of the University of Pennsylvania School of Medicine has no relevant financial relationships to disclose.
See Profile
Patient Profile
- Age range of presentation
-
- 19 to 44 years
- Sex preponderance
-
- female > male
- Heredity
-
- autosomal recessive
- Population groups selectively affected
-
- African American
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD
-
- Thrombotic thrombocytopenic purpura: M31.1
- OMIM
-
- Congenital thrombotic thrombocytopenic purpura: # 274150
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