Thrombotic thrombocytopenic purpura

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Thrombotic thrombocytopenic purpura
Other namesMoschcowitz syndrome, [1] idiopathic thrombotic thrombocytopenic purpura [2]
Echymosis.jpg
Spontaneous bruising in a woman with critically low platelets
Specialty Hematology
Symptoms Large bruises, fever, weakness, shortness of breath, confusion, headache [3] [2]
Usual onsetAdulthood [3]
CausesUnknown, bacterial infections, certain medications, autoimmune diseases, pregnancy [3]
Diagnostic method Based on symptoms and blood tests [2]
Differential diagnosis Hemolytic-uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS) [4]
Treatment Plasma exchange, immunosuppressants [1]
Prognosis < 20% risk of death [1]
Frequency1 in 100,000 people [3]

Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in blood clots forming in small blood vessels throughout the body. [2] This results in a low platelet count, low red blood cells due to their breakdown, and often kidney, heart, and brain dysfunction. [1] Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache. [2] [3] Repeated episodes may occur. [3]

Contents

In about half of cases a trigger is identified, while in the remainder the cause remains unknown. [3] Known triggers include bacterial infections, certain medications, autoimmune diseases such as lupus, and pregnancy. [3] The underlying mechanism typically involves antibodies inhibiting the enzyme ADAMTS13. [1] This results in decreased break down of large multimers of von Willebrand factor (vWF) into smaller units. [1] Less commonly TTP is inherited, known as Upshaw–Schulman syndrome, such that ADAMTS13 dysfunction is present from birth. [5] Diagnosis is typically based on symptoms and blood tests. [2] It may be supported by measuring activity of or antibodies against ADAMTS13. [2]

With plasma exchange the risk of death has decreased from more than 90% to less than 20%. [1] Immunosuppressants, such as glucocorticoids, and rituximab may also be used. [3] Platelet transfusions are generally not recommended. [6]

About 1 per 100,000 people are affected. [3] Onset is typically in adulthood and women are more often affected. [3] About 10% of cases begin in childhood. [3] The condition was first described by Eli Moschcowitz in 1924. [3] The underlying mechanism was determined in the 1980s and 1990s. [3]

Signs and symptoms

The signs and symptoms of TTP may at first be subtle and nonspecific. Many people experience an influenza-like or diarrheal illness before developing TTP. [7] Neurological symptoms are very common and vary greatly in severity. Frequently reported symptoms include feeling very tired, confusion, and headaches. [7] Seizures and symptoms similar to those of a stroke can also be seen. [7] Other symptoms include, but are not limited to jaundice or paleness of the skin, a fast heart rate or shortness of breath, [8] or dots on the skin known as petechiae. [9] High blood pressure has also been observed as a symptom. [10]

As TTP progresses, blood clots form within small blood vessels (microvasculature), and platelets (clotting cells) are consumed. As a result, bruising, and rarely bleeding can occur. The bruising often takes the form of purpura, while the most common site of bleeding, if it occurs, is from the nose or gums. Larger bruises (ecchymoses) may also develop. [11] The classic presentation of TTP, which occurs in less than 10% of people, includes five medical signs. These are: [3]

Causes

TTP, as with other microangiopathic hemolytic anemias (MAHAs), is caused by spontaneous aggregation of platelets and activation of coagulation in the small blood vessels. Platelets are consumed in the aggregation process and bind vWF. These platelet-vWF complexes form small blood clots which circulate in the blood vessels and cause shearing of red blood cells, resulting in their rupture and formation of schistocytes. [12] The two best understood causes of TTP are due to autoimmunity (acquired TTP), caused by autoantibodies targeting ADAMTS13, [13] or congenital TTP: an inherited deficiency of ADAMTS13 (known as the Upshaw–Schulman syndrome). [12]

Autoimmune

In 1998, the majority of cases were shown to be caused by the inhibition of the enzyme ADAMTS13 by antibodies. Knowledge of this relationship between reduced ADAMTS13 and the pathogenesis of TTP is credited to two independent groups of researchers (Furlan and Tsai) who published their research in the same issue of the New England Journal of Medicine . [14]

ADAMTS13 is a metalloproteinase responsible for the breakdown of von Willebrand factor (vWF), a protein that links platelets, blood clots, and the blood vessel wall in the process of blood coagulation. Very large vWF multimers are more prone to lead to coagulation. Hence, without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the microvasculature, part of the blood vessel system where vWF is most active due to high shear stress. [5]

Genetic

Thrombotic thrombocytopenic purpura is inherited in an autosomal recessive manner. Autosomal recessive - en.svg
Thrombotic thrombocytopenic purpura is inherited in an autosomal recessive manner.

TTP may also be congenital. Such cases may be caused by mutations in the ADAMTS13 gene. [17] [18] This hereditary form of TTP is called Upshaw–Schulman syndrome (also spelled Upshaw–Schülman). [19] [20] People with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased von Willebrand factor levels (e.g. infection). Reportedly, less than 5% of all TTP cases are due to Upshaw–Schulman syndrome. [21] People with this syndrome generally have 5–10% of normal ADAMTS-13 activity. [22] [23]

A 2024 study suggested that hereditary TTP is underdiagnosed and should be considered in cases of unexplained stroke, neonatal jaundice, and severe pre-eclampsia. [24] The study estimated the global prevalence of hereditary TTP at 40 per million, in contrast to previously reported estimates of 0.5 to 2.0 per million. [19]

Secondary

Secondary TTP is diagnosed when the person's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are: [12]

The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage, [26] although the formation of thrombi resulting in vessel occlusion may not be essential in the pathogenesis of secondary TTP. [27] These factors may also be considered a form of secondary aHUS; people presenting with these features are, therefore, potential candidates for anticomplement therapy.

Pathophysiology

The underlying mechanism typically involves autoantibody-mediated inhibition of the enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) into smaller units. The increase in circulating multimers of vWF increases platelet adhesion to areas of endothelial injury, particularly where arterioles and capillaries meet, which in turn results in the formation of small platelet clots called thrombi. [28] As platelets are used up in the formation of thrombi, this then leads to a decrease in the number of overall circulating platelets, which may then cause life-threatening bleeds. Red blood cells passing the microscopic clots are subjected to shear stress, which damages their membranes, leading to rupture of red blood cells within blood vessels, [9] which in turn leads to microangiopathic hemolytic anemia and schistocyte formation. The presence of the thrombi reduces blood flow to organs resulting in cellular injury and end organ damage. [13]

Recovery

Depression is common in those recovering from TTP; 59% of recovered TTP patients screened positive for depression within 11 years after recovery. [29]

Diagnosis

Thrombotic thrombocytopenic purpura (TTP) initially presents with a range of symptoms that may include severe thrombocytopenia (platelet count usually < 30,000/mm³), microangiopathic hemolytic anemia (evidenced by schistocytes in the blood smear), and various clinical signs such as petechiae, purpura, neurologic symptoms, myocardial ischemia, mesenteric ischemia, and renal abnormalities. Notably, the complete classic pentad of TTP symptoms—microangiopathic hemolytic anemia, thrombocytopenia, renal abnormalities, fever, and neurologic abnormalities—is only seen in about 10% of acute cases at initial presentation. [30] Clinical suspicion of TTP is often established with an initial emergent presentation of one or more classic symptoms and a complete blood count revealing severe thrombocytopenia. [31]

The PLASMIC score, [32] Bentley score, [33] and French TMA score [34] have been used to assess clinical probability of TTP. [35]

A definitive diagnosis of TTP may be established when a laboratory assay of ADAMTS13 identifies under 10% of normal enzyme function. Borderline or normal ADAMTS13 activity suggests a different diagnosis is more likely. [31]

The ISTH guidelines suggested diagnostic and early management strategy. [36] Suggestions included 1) for high pretest probability based on PLASMIC score or French score, start TPE and corticosteroids, and collect plasma samples for ADAMTS13 testing before therapy. Consider caplacizumab if ADAMTS13 test results are expected within 72 hours. If ADAMTS13 <10 IU/dL, continue caplacizumab and rituximab. If ADAMTS13 is ≥20 IU/dL, consider to stop caplacizumab and seek other diagnoses. If ADAMTS13 activity is borderline, use clinical judgment; 2) for low or intermediate pretest probability, still consider TPE and corticosteroids, but withhold caplacizumab until plasma ADAMTS13 test results are available; if ADAMTS13 activity is <10 IU/dL, consider adding caplacizumab and rituximab; if ADAMTS13 activity is ≥20 IU/dL, no caplacizumab should be used and other diagnoses should be sought; if ADAMTS13 activity falls borderline, consider other diagnoses.

Differential diagnosis

TTP is a form of thrombotic microangiopathy (TMA), [37] the formation of blood clots in small blood vessels throughout the body, which can lead to microangiopathic hemolytic anemia and thrombocytopenia. [37] This characteristic is shared by two related syndromes, hemolytic-uremic syndrome (HUS) and atypical hemolytic uremic syndrome (aHUS). [4] Consequently, differential diagnosis of these TMA diseases is essential. Both TTP and HUS are characterized by fever, anemia, thrombocytopenia, renal failure, and neurological symptoms. Generally, TTP has higher rates of neurological symptoms (≤80%) and lower rates of renal symptoms (9%) than HUS (10–20% and 90%, respectively). [38]

Unlike HUS and aHUS, [39] [40] TTP is known to be caused by a defect in the ADAMTS13 protein, [41] so a lab test showing ≤5% of normal ADAMTS13 levels is indicative of TTP. [28] ADAMTS13 levels above 5%, coupled with a positive test for shiga-toxin/enterohemorrhagic E. coli (EHEC), are more likely indicative of HUS, [42] whereas absence of shiga-toxin/EHEC can confirm a diagnosis of aHUS. [28]

Treatment

Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only microangiopathic hemolytic anemia and thrombocytopenia are seen, and therapy is started. Transfusion is contraindicated in thrombotic TTP, as it fuels the coagulopathy. Since the early 1990s, plasmapheresis has become the treatment of choice for TTP. [43] [44] This is an exchange transfusion involving removal of the person's blood plasma through apheresis and replacement with donor plasma (fresh frozen plasma or cryosupernatant); the procedure must be repeated daily to eliminate the inhibitor and abate the symptoms. If apheresis is not available, fresh frozen plasma can be infused, but the volume that can be given safely is limited due to the danger of fluid overload. [45] Plasma infusion alone is not as beneficial as plasma exchange. [43] Corticosteroids (prednisone or prednisolone) are usually given. [44] Rituximab, a monoclonal antibody aimed at the CD20 molecule on B lymphocytes, may be used on diagnosis; this is thought to kill the B cells and thereby reduce the production of the inhibitor. [44] A stronger recommendation for rituximab exists where TTP does not respond to corticosteroids and plasmapheresis. [44]

Caplacizumab is an adjunct option in treating TTP as it has been shown that it induces a faster disease resolution compared with those people who were on placebo. [46] However, the use of caplacizumab was associated with increase bleeding tendencies in some studied subjects. [47] Its cost-effectiveness has also been questioned. [48] Use of caplacizumab without plasmapheresis has been reported in select patients. [49] The MAYARI study was designed to evaluate the effectiveness of this option. [50]

The ISTH guidelines [51] recommended for first acute episode and relapses of immune-mediated TTP (iTTP), add corticosteroids to therapeutic plasma exchange (TPE) and consider adding rituximab and caplacizumab. For asymptomatic iTTP with low plasma ADAMTS13 activity, consider rituximab outside of pregnancy, but prophylactic TPE during pregnancy. For asymptomatic congenital TTP, offer prophylactic plasma infusion during pregnancy, and consider plasma infusion or a wait and watch approach outside of pregnancy.

People with refractory or relapsing TTP may receive additional immunosuppressive therapy, e.g. vincristine, cyclophosphamide, cyclosporine A, or splenectomy. [3] [45]

Children with Upshaw-Schulman syndrome receive prophylactic plasma every two to three weeks; this maintains adequate levels of functioning ADAMTS13. Some tolerate longer intervals between plasma infusions. Additional plasma infusions may be necessary for triggering events, such as surgery; alternatively, the platelet count may be monitored closely around these events with plasma being administered if the count drops. [52]

Measurements of blood levels of lactate dehydrogenase, platelets, and schistocytes are used to monitor disease progression or remission. [13] [53] ADAMTS13 activity and inhibitor levels may be measured during follow-up, but in those without symptoms the use of rituximab is not recommended. [44]

Apadamtase alfa (Adzynma) was approved for medical use in the United States in November 2023. [54] [55] The use of ADAMTS13 is well established for the treatment of congenital TTP. [56]

Prognosis

The mortality rate is around 95% for untreated cases, but the prognosis is reasonably favorable (80–90% survival) for people with idiopathic TTP diagnosed and treated early with plasmapheresis. [57]

Epidemiology

The incidence of TTP is about 4–5 cases per million people per year. [58] Idiopathic TTP occurs more often in women as well as people of African descent, and TTP secondary to autoimmune disorders such as systemic lupus erythematosus occurs more frequently in people of African descent, although other secondary forms do not show this distribution. [59] Although Black people are at an increased risk for TTP, its presentation in Black people does not have any distinguishable features compared to those of other races. [60] Pregnant women and women in the post partum period accounted for a notable portion (12–31%) of the cases in some studies; TTP affects about one in 25,000 pregnancies. [61]

History

TTP was initially described by Eli Moschcowitz at the Beth Israel Hospital in New York City in 1924. [53] [62] Moschcowitz ascribed the disease (incorrectly, as now known) to a toxic cause. Moschcowitz noted his patient, a 16-year-old girl, had anemia, small and large bruises, microscopic hematuria, and, at autopsy, disseminated microvascular thrombi. [63] In 1966, a review of 16 new cases and 255 previously reported cases led to the formulation of the classical pentad of symptoms and findings (i.e., thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, kidney failure, fever); in this series, mortality rates were found to be very high (90%). [64]

While a response to blood transfusion had been noted before, a 1978 report and subsequent studies showed blood plasma was highly effective in improving the disease process. [65] In 1991, plasma exchange was reported to provide better response rates compared to plasma infusion. [66] In 1982, the disease had been linked with abnormally large von Willebrand factor multimers. The identification of a deficient protease in people with TTP was made in 1998. The location of ADAMTS13 within the human genome was identified in 2001. [65]

Related Research Articles

<span class="mw-page-title-main">Hemolysis</span> Rupturing of red blood cells and release of their contents

Hemolysis or haemolysis, also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid. Hemolysis may occur in vivo or in vitro.

<span class="mw-page-title-main">Immune thrombocytopenic purpura</span> Medical condition with rash and bleeding risk

Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is an autoimmune primary disorder of hemostasis characterized by a low platelet count in the absence of other causes. ITP often results in an increased risk of bleeding from mucosal surfaces or the skin. Depending on which age group is affected, ITP causes two distinct clinical syndromes: an acute form observed in children and a chronic form in adults. Acute ITP often follows a viral infection and is typically self-limited, while the more chronic form does not yet have a specific identified cause. Nevertheless, the pathogenesis of ITP is similar in both syndromes involving antibodies against various platelet surface antigens such as glycoproteins.

Microangiopathic hemolytic anemia (MAHA) is a microangiopathic subgroup of hemolytic anemia caused by factors in the small blood vessels. It is identified by the finding of anemia and schistocytes on microscopy of the blood film.

<span class="mw-page-title-main">Thrombocytopenia</span> Abnormally low levels of platelets in the blood

In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients and a third of surgical patients.

<span class="mw-page-title-main">Hemolytic–uremic syndrome</span> Group of blood disorders related to bacterial infection

Hemolytic–uremic syndrome (HUS) is a group of blood disorders characterized by low red blood cells, acute kidney injury, and low platelets. Initial symptoms typically include bloody diarrhea, fever, vomiting, and weakness. Kidney problems and low platelets then occur as the diarrhea progresses. Children are more commonly affected, but most children recover without permanent damage to their health, although some children may have serious and sometimes life-threatening complications. Adults, especially the elderly, may present a more complicated presentation. Complications may include neurological problems and heart failure.

von Willebrand factor Mammalian protein involved in blood clotting

Von Willebrand factor (VWF) is a blood glycoprotein that promotes hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic–uremic syndrome. Increased plasma levels in many cardiovascular, neoplastic, metabolic, and connective tissue diseases are presumed to arise from adverse changes to the endothelium, and may predict an increased risk of thrombosis.

Evans syndrome is an autoimmune disease in which an individual's immune system attacks their own red blood cells and platelets, the syndrome can include immune neutropenia. These immune cytopenias may occur simultaneously or sequentially.

<span class="mw-page-title-main">Schistocyte</span> Fragmented portion of a red blood cell

A schistocyte or schizocyte is a fragmented part of a red blood cell. Schistocytes are typically irregularly shaped, jagged, and have two pointed ends.

<span class="mw-page-title-main">ADAMTS13</span> Metalloprotease enzyme

ADAMTS13 —also known as von Willebrand factor-cleaving protease (VWFCP)—is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting. It is secreted into the blood and degrades large vWf multimers, decreasing their activity, hence ADAMTS13 acts to reduce thrombus formation.

<span class="mw-page-title-main">Thrombotic microangiopathy</span> Medical condition

Thrombotic microangiopathy (TMA) is a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury. It may be seen in association with thrombocytopenia, anemia, purpura and kidney failure.

John W. Semple is a Canadian Scientist formally at St. Michael's Hospital and a Professor of Pharmacology at the University of Toronto. He is currently a Professor of Transfusion Medicine at Lund University in Sweden. He was born in Windsor, Ontario in 1959 and received his PhD in Immunology at Queen's University at Kingston, Ontario. In 1991, Semple, along with John Freedman, discovered a T helper cell defect in patients with the bleeding disorder called immune thrombocytopenia (ITP). ITP is a condition of having a low platelet count (thrombocytopenia) and most causes appear to be related to antibodies and T cells against platelets. Very low platelet counts can lead to a bleeding diathesis and purpura. The T cell defect was initially shown to be an exaggerated interleukin-2 response when T cells were cultured with platelets in vitro. Subsequently, this cytokine abnormality was shown by others to be responsible for many of the autoimmune mechanisms causing the disorder.). The importance of understanding the T cell defects in ITP is that novel therapies aimed at these cells may significantly benefit patients with ITP.

Venom-induced consumption coagulopathy (VICC) is a medical condition caused by the effects of some snake and caterpillar venoms on the blood. Important coagulation factors are activated by the specific serine proteases in the venom and as they become exhausted, coagulopathy develops. Symptoms are consistent with uncontrolled bleeding. Diagnosis is made using blood tests that assess clotting ability along with recent history of envenomation. Treatment generally involves pressure dressing, confirmatory blood testing, and antivenom administration.

Hematologic diseases are disorders which primarily affect the blood and blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease and complications from chemotherapy or transfusions.

The term cryosupernatant refers to plasma from which the cryoprecipitate has been removed. It is used to treat thrombocytopenic purpura.

Caplacizumab is a bivalent single-domain antibody (VHH) designed for the treatment of thrombotic thrombocytopenic purpura (TTP) and thrombosis.

Atypical hemolytic uremic syndrome (aHUS), also known as complement-mediated hemolytic uremic syndrome, is an extremely rare, life-threatening, progressive disease that frequently has a genetic component. In most cases, it can be effectively controlled by interruption of the complement cascade. Particular monoclonal antibodies, discussed later in the article, have proven efficacy in many cases.

<span class="mw-page-title-main">Upshaw–Schulman syndrome</span> Medical condition

Upshaw–Schulman syndrome (USS) is the recessively inherited form of thrombotic thrombocytopenic purpura (TTP), a rare and complex blood coagulation disease. USS is caused by the absence of the ADAMTS13 protease resulting in the persistence of ultra large von Willebrand factor multimers (ULvWF), causing episodes of acute thrombotic microangiopathy with disseminated multiple small vessel obstructions. These obstructions deprive downstream tissues from blood and oxygen, which can result in tissue damage and death. The presentation of an acute USS episode is variable but usually associated with thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytes on the peripheral blood smear, fever and signs of ischemic organ damage in the brain, kidney and heart.

Eli Moschcowitz was an American doctor best known for his role in discovering thrombotic thrombocytopenic purpura (TTP), which was originally called "Moschcowitz syndrome". He is also known for having an early role in the development of psychosomatic medicine.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia accompanied by variable neurological dysfunction, kidney failure, and fever. It is caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. Hereditary TTP, caused by ADAMTS13 gene mutations, is much less common.

Hemolytic jaundice, also known as prehepatic jaundice, is a type of jaundice arising from hemolysis or excessive destruction of red blood cells, when the byproduct bilirubin is not excreted by the hepatic cells quickly enough. Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice.

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