TL;DR
Thrombotic thrombocytopenic purpura (TTP) is a type of thrombocytopenia due to deficiency of ADAMTS13 metalloprotease which leads to formation of platelet thrombi in microvessels.
Signs and symptoms (pentad) ▾
- Thrombocytopenia
- Microangiopathic hemolysis
- Neurologic dysfunction
- Renal impairment
- Fever
Causes ▾
- Inherited mutations
- Acquired: inhibitory IgG autoantibodies stimulated by infection, autoimmune/connective tissue disease, drugs, stem cell transplantation or cardiac surgery
Pathophysiology ▾
Thrombotic thrombocytopenic purpura (TTP) is primarily due to a deficiency or dysfunction of ADAMTS13, a metalloprotease enzyme responsible for cleaving von Willebrand factor (VWF). This deficiency leads to the formation of abnormally large VWF multimers, which can bind platelets excessively, triggering platelet aggregation and thrombus formation. These microthrombi can occlude small blood vessels, leading to tissue damage and the characteristic symptoms of thrombotic thrombocytopenic purpura (TTP), including thrombocytopenia, hemolytic anemia, fever, neurologic changes, and renal dysfunction.
Laboratory investigations ▾
- Full blood count: Thrombocytopenia
- Peripheral blood smear: Schistocytosis
- Bone marrow characteristics: Markedly hypercellular with erythroid hyperplasia
- ↑↑ serum LDH
- Coagulation tests normal
- Specific assay: ADAMTS-13 ↓↓ or absent
Treatment and management of TTP ▾
- Plasma exchange using FFP or cryosupernatant
- Rituximab
*Click ▾ for more information
Introduction
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening blood disorder. It is characterized by the formation of small blood clots (microthrombi) throughout the body. These microthrombi can block small blood vessels and damage organs, such as the brain, kidneys, and heart.
Thrombotic thrombocytopenic purpura (TTP) is caused by a deficiency of a protein called ADAMTS13. ADAMTS13 is responsible for cleaving a large protein called von Willebrand factor (VWF). VWF acts as a bridge between platelets and the walls of blood vessels at the site of an injury by binding to collagen and capturing platelets. VWF also stabilizes factor VIII, another essential clotting protein. When ADAMTS13 is deficient, VWF forms large multimers that can clump together to form microthrombi.
There are two main types of thrombotic thrombocytopenic purpura (TTP):
- Acquired: This is the most common type of thrombotic thrombocytopenic purpura (TTP) and is caused by an autoimmune disorder. In autoimmune disorders, the body’s immune system attacks its own tissues. In acquired thrombotic thrombocytopenic purpura (TTP), the immune system attacks ADAMTS13.
- Congenital: This is caused by a genetic mutation that affects the ADAMTS13 gene and is rare.
Related Clinical Signs and Symptoms
Thrombotic thrombocytopenic purpura (TTP) has traditionally been described as the pentad of thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal failure and fever. The microvascular thrombosis causes variable degrees of tissue ischemia and infarction and is responsible for the microangiopathic hemolytic anemia and thrombocytopenia.
The clinical manifestations of this disorder depend on the severity of the disease and the organs that are affected. The most common clinical manifestations include:
- Thrombocytopenia
- Microangiopathic hemolytic anemia (MAHA)
- Neurologic signs and symptoms, such as headache, confusion, seizures, and focal neurologic deficits
- Renal failure
- Fever
- Fatigue
- Pallor
.
Blood Vessels with Onion Skinning in TTP Kidney Biopsy
Onion skinning refers to a specific histological finding in kidney biopsies. It describes the appearance of blood vessel walls with concentric layers of fibrinoid material. This layering resembles the skin of an onion, hence the name.
In the context of thrombotic thrombocytopenic purpura (TTP), onion skinning is a significant finding and indicates vascular occlusive disease. Thrombotic thrombocytopenic purpura (TTP) is a rare but serious disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and neurological symptoms.
The mechanism behind onion skinning in thrombotic thrombocytopenic purpura (TTP) involves the deposition of platelet-fibrin thrombi within small blood vessels, particularly the arterioles. These thrombi consist of platelets, fibrin, and other blood components. As the thrombi accumulate, they cause the vessel walls to become thickened and layered, leading to the characteristic onion-skinning appearance.
Significance
- Diagnosis: The presence of onion skinning in a kidney biopsy is a strong indicator of thrombotic thrombocytopenic purpura (TTP) and can aid in diagnosis.
- Prognosis: The degree of onion skinning seen in the biopsy can also provide information about the severity of the disease and potentially help predict the patient’s prognosis.
- Treatment: Identifying onion skinning helps confirm the diagnosis of thrombotic thrombocytopenic purpura (TTP), allowing for swift initiation of appropriate treatment, such as plasma exchange therapy.
It’s important to note that while onion skinning is a significant finding in thrombotic thrombocytopenic purpura (TTP), it can also be seen in other conditions. Therefore, a comprehensive clinical evaluation is essential for accurate diagnosis.
Pathophysiology of Thrombotic Thrombocytopenic Purpura (TTP) & ADAMTS13
ADAMTS-13, an enzyme responsible for cleaving large von Willebrand factor (VWF) multimers, plays a pivotal role in maintaining the delicate balance of blood vessel integrity. In thrombotic thrombocytopenic purpura (TTP), the absence of ADAMTS-13 leads to an accumulation of these large VWF multimers, creating a sticky environment that promotes platelet aggregation.
This disorder occurs in familial or acquired forms.
There is a deficiency of ADAMTS13 metalloprotease which breaks down ultra large von Willebrand factor multimers. In the inherited forms, there are more than 50 ADAMTS13 mutations and the acquired forms follow the development of an inhibitory IgG autoantibody which may be stimulated by infection, autoimmune or connective tissue disease, certain drugs, stem cell transplantation or cardiac surgery.
Ultra large vWF multimeric strings secreted from Weibel-Palade bodies are anchored to the endothelial cells and passing platelets adhere via their GP1bɑ receptors. Increasing platelet aggregation onto the ULVWF multimeric strings has the potential to form large, occlusive, platelet thrombi. These strings are capable of embolising to microvessels downstream contributing to organ ischemia.
Under physiological circumstances a metalloprotease ADAMTS13 cleaves high molecular weight multimers at a Tyr-842-Met-843 bond, resulting in vWF with a molecular weight of 500 – 20000 kDA. In acquired thrombotic thrombocytopenic purpura (TTP), an antibody develops against the metalloprotease and impedes the cleavage of vWF multimers while in congenital thrombotic thrombocytopenic purpura (TTP), the protease is absent.
Laboratory Investigations of TTP
- Complete blood count (CBC): A CBC measures the levels of red blood cells, white blood cells, and platelets in the blood. In thrombotic thrombocytopenic purpura (TTP), the CBC will typically show thrombocytopenia (low platelet count) and microangiopathic hemolytic anemia (MAHA), a type of anemia characterized by the presence of fragmented red blood cells (schistocytes).
- Peripheral blood smear: A peripheral blood smear is a microscopic examination of the blood cells. In thrombotic thrombocytopenic purpura (TTP), the peripheral blood smear will typically show schistocytes.
- ADAMTS13 activity assay: The ADAMTS13 activity assay measures the level of ADAMTS13 in the blood. ADAMTS13 is a protein that cleaves von Willebrand factor (VWF), a large protein that plays a role in blood clotting. In thrombotic thrombocytopenic purpura (TTP), the ADAMTS13 activity level is typically low.
- ADAMTS13 inhibitor assay: The ADAMTS13 inhibitor assay detects the presence of autoantibodies that inhibit ADAMTS13 activity. Autoantibodies are antibodies that are produced by the body’s own immune system against its own tissues or cells. In acquired thrombotic thrombocytopenic purpura (TTP), the most common type of thrombotic thrombocytopenic purpura (TTP), autoantibodies against ADAMTS13 are present in the blood.
In current clinical practice, thrombocytopenia, schistocytosis and an impressively elevated serum LDH are sufficient to suggest the diagnosis. The bone marrow is hypercellular with erythroid hyperplasia. Coagulation tests are normal. ADAMTS13 is absent or severely reduced in plasma.
Treatment and management
The treatment and management of thrombotic thrombocytopenic purpura (TTP) is aimed at increasing the levels of ADAMTS13 in the blood and preventing the formation of microthrombi. The mainstay of treatment is plasma exchange, a procedure in which the plasma (liquid portion of the blood) is removed and replaced with fresh plasma from a donor. Plasma exchange provides a source of ADAMTS13 and also removes autoantibodies that may be inhibiting ADAMTS13 activity.
Other treatments that may be used include:
- Corticosteroids: Corticosteroids can suppress the immune system and reduce inflammation. Corticosteroids are often used in conjunction with plasma exchange in patients with acquired thrombotic thrombocytopenic purpura (TTP).
- Rituximab: Rituximab is a monoclonal antibody that targets and destroys B cells, which are the type of white blood cell that produces autoantibodies. Rituximab may be used in patients with acquired thrombotic thrombocytopenic purpura (TTP) who have a high risk of relapse, or in patients who do not respond to plasma exchange and corticosteroids.
- Caplacizumab: Caplacizumab is a monoclonal antibody that targets and blocks von Willebrand factor (VWF), preventing platelet aggregation and microthrombus formation. Caplacizumab is a newer treatment that has been shown to be effective in reducing the mortality rate of thrombotic thrombocytopenic purpura (TTP).
Frequently Asked Questions (FAQs)
Can you live a normal life with thrombotic thrombocytopenic purpura (TTP)?
Living with TTP can be challenging, but it is possible to lead a relatively normal life with proper management. The key is to work closely with a healthcare team that specializes in TTP. Treatment often involves plasma exchange therapy to remove harmful antibodies and replace deficient ADAMTS13. Additionally, corticosteroids may be used to suppress the immune system.
While there may be limitations, especially during acute flares, many individuals with TTP can maintain a good quality of life with consistent medical care and lifestyle adjustments.
What are the triggers of thrombotic thrombocytopenic purpura (TTP)?
Triggers of thrombotic thrombocytopenic purpura (TTP) can vary, but some common factors include:
- Infections: Viral or bacterial infections can sometimes trigger thrombotic thrombocytopenic purpura (TTP).
- Pregnancy: Thrombotic thrombocytopenic purpura (TTP) can occur during or after pregnancy.
- Medications: Certain medications, such as immunosuppressants, antiplatelet drugs, or antibiotics, may be associated with thrombotic thrombocytopenic purpura (TTP).
- Underlying medical conditions: Autoimmune disorders or other medical conditions can increase the risk of thrombotic thrombocytopenic purpura (TTP).
- Surgery: Major surgeries or trauma can sometimes lead to thrombotic thrombocytopenic purpura (TTP).
It’s important to note that not everyone with these factors will develop thrombotic thrombocytopenic purpura (TTP), and sometimes the cause remains unknown.
Can thrombotic thrombocytopenic purpura (TTP) be cured?
TTP is not typically curable. While treatment can effectively manage the condition and prevent life-threatening complications, it often requires lifelong monitoring and management. The goal of treatment is to control symptoms, prevent future flares, and improve overall quality of life.
What is the difference between TTP and immune thrombocytopenia (ITP)?
TTP (Thrombotic Thrombocytopenic Purpura) and ITP (Immune Thrombocytopenia) are both blood disorders that affect platelets, but they have different underlying causes and mechanisms.
ITP (Immune Thrombocytopenia) is an autoimmune disorder where the body’s immune system mistakenly attacks and destroys platelets. This results in a low platelet count (thrombocytopenia), leading to easy bruising and bleeding.
TTP (Thrombotic Thrombocytopenic Purpura) is a disorder caused by a deficiency or dysfunction of an enzyme called ADAMTS13. This enzyme is responsible for breaking down large von Willebrand factor (VWF) molecules. When ADAMTS13 is not working properly, these large VWF molecules can cause blood clots to form in small blood vessels throughout the body. This can lead to a variety of symptoms, including low platelet count, anemia, fever, neurologic problems, and kidney failure.
Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.
References
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- UpToDate – Diagnosis of Immune TTP.
- Nuñez Zuno JA, Khaddour K. Thrombotic Thrombocytopenic Purpura Evaluation and Management. [Updated 2023 Sep 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
- Inés Gómez-Seguí, Cristina Pascual Izquierdo, María Eva Mingot Castellano & Javier de la Rubia Comos (2023) An update on the pathogenesis and diagnosis of thrombotic thrombocytopenic purpura, Expert Review of Hematology, 16:1, 17-32, DOI: 10.1080/17474086.2023.2159803
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