Background

Thrombocytopenic purpura refers to a group of disorders characterized by a low platelet count, leading to an increased risk of bleeding and the development of purpura, which are small purple or red spots on the skin and mucous membranes due to bleeding beneath the surface.

Two main types include immune thrombocytopenic purpura (ITP), and thrombotic thrombocytopenic purpura (TTP), a rare and life-threatening disorder caused by the formation of abnormal blood clots. The condition can result from various underlying causes, and symptoms may include easy bruising, petechiae, and, in severe cases, internal bleeding.

Diagnosis involves blood tests to assess platelet levels and identify the underlying cause. Treatment strategies aim to raise platelet counts, manage symptoms, and address the specific cause of thrombocytopenic purpura. 

Epidemiology

Immune Thrombocytopenic Purpura (ITP): 

• ITP is more common in children & young adults, with a peak incidence between ages of 2 and 10 years. In adults, the incidence increases again after the age of 60. ITP affects females more frequently than males. It is estimated that approximately 3.3 per 100,000 children and 3.9 per 100,000 adults are diagnosed with ITP annually. 

Thrombotic Thrombocytopenic Purpura (TTP): 

• It is a rare disorder, with an annual incidence of about 3 cases per million people. It can affect individuals of any age, but it is more commonly diagnosed in adults. Women are more frequently affected than men. TTP can be associated with various underlying conditions, including pregnancy, infections, and certain medications. 

Hemolytic-Uremic Syndrome (HUS): 

• HUS is another condition that can cause thrombocytopenia, and it shares some similarities with TTP. It is most seen in children and is often associated with gastrointestinal infections, particularly those caused by Escherichia coli (E. coli). The incidence of HUS is estimated to be around 2 per 100,000 children. 

Drug-Induced Thrombocytopenic Purpura: 

• Thrombocytopenia induced by medications is uncommon. It can occur as adverse reaction to certain drugs, including heparin, quinine, and some antibiotics. The prevalence of drug-induced thrombocytopenia is not well-defined, as it depends on the specific drugs used and patient populations. 

Anatomy

Pathophysiology

Immune Thrombocytopenic Purpura (ITP): 

• ITP is primarily an autoimmune disorder where the immune system mistakenly recognizes platelets as foreign and targets them for destruction. Antibodies, particularly anti-platelet antibodies, are produced, leading to increased clearance of platelets by macrophages in the spleen and liver. This immune-mediated destruction reduces the circulating platelet count, resulting in thrombocytopenia. 

Thrombotic Thrombocytopenic Purpura (TTP): 

• TTP is characterized by the formation of abnormal blood clots within small blood vessels, leading to platelet consumption and thrombocytopenia. This abnormal clotting is primarily due to a deficiency or dysfunction of a protein called ADAMTS13, which normally cleaves large multimers of von Willebrand factor (vWF). Reduced ADAMTS13 activity results in the accumulation of ultra-large vWF multimers, leading to platelet adhesion and microthrombi formation. 

Hemolytic-Uremic Syndrome (HUS): 

• HUS can cause thrombocytopenia as part of a triad of symptoms that also includes microangiopathic hemolytic anemia and acute kidney injury. In many cases, HUS is associated with infections, particularly those caused by certain strains of Escherichia coli (E. coli). The infection triggers the release of toxins that damage endothelial cells, leading to platelet adhesion and aggregation in small blood vessels. 

Drug-Induced Thrombocytopenic Purpura: 

• Thrombocytopenia induced by medications can result from various mechanisms, including direct toxicity to megakaryocytes (cells that produce platelets), immune-mediated destruction of platelets, or interference with platelet function. For example, heparin-induced thrombocytopenia (HIT) is an immune-mediated reaction to heparin that leads to platelet activation and consumption. 

Etiology

Immune Thrombocytopenic Purpura (ITP): 

• Primary ITP: The exact cause is often unknown, but it is considered an autoimmune disorder. The immune system mistakenly targets platelets, leading to their destruction by macrophages, particularly in the spleen. Genetic predisposition and viral infections, such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), may contribute. 
• Secondary ITP: It can be associated with autoimmune conditions, infections, or underlying malignancies. 

Thrombotic Thrombocytopenic Purpura (TTP): 

• Deficiency of ADAMTS13: TTP is primarily caused by a deficiency or dysfunction of ADAMTS13, a von Willebrand factor-cleaving protease. Reduced ADAMTS13 activity leads to the accumulation of ultra-large von Willebrand factor multimers, causing microvascular thrombosis and platelet consumption. 
• Acquired TTP: Can be triggered by various factors, including infections, certain medications, pregnancy, and autoimmune conditions. 

Hemolytic-Uremic Syndrome (HUS): 

• Infections: The most common cause of HUS is infection with Shiga toxin-producing Escherichia coli (STEC), particularly serotype O157:H7. Other infections, such as Shigella and Salmonella, can also lead to HUS. 
• Other Factors: HUS can also be triggered by medications, systemic illnesses, and conditions affecting the complement system. 

Drug-Induced Thrombocytopenic Purpura: 

• Heparin-Induced Thrombocytopenia (HIT): Heparin, an anticoagulant medication, can induce an immune response leading to formation of antibodies against platelet factor 4 (PF4). This immune reaction causes platelet activation and consumption, leading to thrombocytopenia. 
• Other Medications: Thrombocytopenia can also result from direct toxicity to bone marrow, immune-mediated destruction, or interference with platelet function by various medications. 

Genetics

Prognostic Factors

Immune Thrombocytopenic Purpura (ITP): 

• Duration of Symptoms: Acute ITP in children often resolves spontaneously, with a favorable prognosis. Chronic ITP in adults may persist for months or years, requiring ongoing management. Spontaneous remission is more likely in children than in adults. 
• Response to Treatment: The response to initial treatments, such as corticosteroids, intravenous immunoglobulin (IVIG), or splenectomy, can impact prognosis. Some patients may achieve long-term remission, while others may experience relapses. 

Thrombotic Thrombocytopenic Purpura (TTP): 

• Timely Diagnosis and Treatment: Prompt recognition and initiation of therapeutic plasma exchange (TPE) are crucial for a positive outcome. Delayed treatment can result in a more severe course and poorer prognosis. 
• ADAMTS13 Activity Levels: Patients with severe ADAMTS13 deficiency (<10% activity) may have a higher risk of relapse. Monitoring ADAMTS13 activity is essential for managing the condition. 

Hemolytic-Uremic Syndrome (HUS): 

• Underlying Cause: HUS associated with Shiga toxin-producing Escherichia coli (STEC) infections often has a better prognosis than non-infectious forms. The severity of kidney involvement and complications such as neurological symptoms can influence outcomes. 
• Age: Pediatric cases of HUS may have a better prognosis than adult-onset cases. 

Drug-Induced Thrombocytopenic Purpura: 

• Early Recognition and Withdrawal of Causative Drug: Prompt identification of the offending drug and discontinuation can lead to rapid improvement in thrombocytopenia. Delayed recognition or continued exposure to the causative drug may worsen the prognosis. 

General Prognostic Factors: 

• Age: In general, pediatric patients may have more favorable outcomes compared to adults, particularly in ITP and certain types of HUS. 
• Overall, Health Status: Patients with underlying health conditions, comorbidities, or compromised immune systems may have a more challenging prognosis. 
• Complications: The presence of severe complications, such as major bleeding or organ dysfunction, can impact the prognosis negatively. 
• Response to Treatment: A positive response to initial therapies may indicate a more favorable prognosis, while refractory cases may require more aggressive interventions. 

Clinical History

Immune Thrombocytopenic Purpura (ITP): 

• Age: ITP can affect individuals of any age but is more commonly diagnosed in children and young adults. 
• Acuity of Presentation: The onset of ITP can be sudden, and patients may present with petechiae, purpura, easy bruising, and, in severe cases, mucosal bleeding. In children, it often follows a viral illness. 

Thrombotic Thrombocytopenic Purpura (TTP): 

• Age: TTP can occur in adults of any age but is most diagnosed in individuals in their 30s to 40s. 
• Acuity of Presentation: TTP typically presents acutely with a pentad of symptoms, including thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological symptoms, and renal dysfunction. The onset can be rapid and life-threatening. 

Hemolytic-Uremic Syndrome (HUS): 

• Age: HUS often occurs in children, especially after an episode of gastroenteritis caused by Shiga toxin-producing Escherichia coli (STEC). However, it can also affect adults. 
• Acuity of Presentation: The presentation includes microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In children, a prodrome of bloody diarrhea may precede the onset. 

Drug-Induced Thrombocytopenic Purpura: 

• Age: Drug-induced TP can occur at any age, and the age range depends on the medication and patient population. 
• Acuity of Presentation: The onset of drug-induced TP can be variable and is often related to the timing of medication exposure. Patients may present with bleeding, purpura, or other symptoms of thrombocytopenia. 

Physical Examination

Immune Thrombocytopenic Purpura (ITP): 

• Skin Examination: Look for petechiae, purpura, and ecchymosis. Examine the oral mucosa, conjunctiva, and other mucous membranes for signs of bleeding. 
• Lymph Nodes and Spleen: Palpate lymph nodes for enlargement and assess the spleen size, which is usually not significantly enlarged in ITP. 

Thrombotic Thrombocytopenic Purpura (TTP): 

• Skin Examination: Check for petechiae, purpura, and ecchymosis. Pay attention to the distribution, which may be more widespread than in ITP. 
• Neurological Examination: Evaluate for neurological symptoms, including confusion, headache, and focal deficits. Neurological involvement is a key feature of TTP. 
• Renal Examination: Assess for signs of acute kidney injury, which can occur in TTP. 

Hemolytic-Uremic Syndrome (HUS): 

• Skin Examination: Look for petechiae, purpura, and ecchymosis. Pay attention to the distribution of skin lesions. 
• Abdominal Examination: Assess for abdominal tenderness, especially in the setting of gastrointestinal symptoms. Evaluate for signs of peritonitis, which may indicate complications. 

Drug-Induced Thrombocytopenic Purpura: 

• Skin Examination: Like ITP, check for petechiae, purpura, and ecchymosis. 
• Medication-Related Findings: Consider signs of drug reactions, such as rash or other cutaneous manifestations. 

Age group

Associated comorbidity

• Underlying Conditions: Comorbidities may vary based on the specific subtype of TP. In ITP, there may not be underlying conditions, while TTP and HUS can be associated with autoimmune conditions, infections, or genetic predispositions. 
• Medication History: For drug-induced TP, a detailed medication history is crucial to identify the causative drug. 

Associated activity

Acuity of presentation

Differential Diagnoses

Other Causes of Thrombocytopenia: 

• Drug-Induced Thrombocytopenia: Some medications can cause immune-mediated destruction of platelets, leading to thrombocytopenia. Examples include heparin, quinine, and certain antibiotics. 
• Bone Marrow Disorders: Conditions affecting the bone marrow, such as leukemia, myelodysplastic syndromes (MDS), and aplastic anemia, can result in decreased platelet production. 

Coagulation Disorders: 

• Disseminated Intravascular Coagulation (DIC): DIC is a systemic activation of coagulation cascade, leading to widespread microthrombi formation, consumption of platelets, and bleeding. 
• Vitamin K Deficiency: Inadequate levels of vitamin K can impair the synthesis of clotting factors, leading to bleeding. 

Vasculitis: 

• Immune-Mediated Vasculitis: Some autoimmune vasculitides can cause thrombocytopenia and purpura, such as immune complex-mediated vasculitis or small-vessel vasculitis like Henoch-Schönlein purpura. 

Infections: 

• Septicemia: Severe infections, especially those leading to septicemia, can cause thrombocytopenia and may present with purpura. 
• Viral Infections: Some viral infections, including HIV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), can be associated with thrombocytopenia. 

Hematologic Disorders: 

• Thrombotic Microangiopathies (TMA): Besides TTP, other TMAs, such as hemolytic-uremic syndrome (HUS) and atypical hemolytic uremic syndrome (aHUS), can present with thrombocytopenia and purpura. 
• Paroxysmal Nocturnal Hemoglobinuria (PNH): PNH is characterized by complement-mediated hemolysis and can be associated with thrombocytopenia. 

Liver Disease: 

• Cirrhosis: Severe liver disease can lead to splenic sequestration of platelets and thrombocytopenia. 

Autoimmune Disorders: 

• Systemic Lupus Erythematosus (SLE): Autoimmune diseases like SLE can present with various hematologic abnormalities, including thrombocytopenia. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Immune Thrombocytopenic Purpura (ITP): 

• Observation: In cases of mild or asymptomatic thrombocytopenia, observation without immediate intervention may be appropriate. 
• Corticosteroids: First-line treatment for moderate to severe cases, corticosteroids (e.g., prednisone) can help increase platelet counts by suppressing the immune response. However, their long-term use is limited due to side effects. 
• Intravenous Immunoglobulin (IVIG): IVIG is used to rapidly increase platelet counts, especially in acute situations or prior to surgery. 
• Anti-D Immunoglobulin (Rho(D) Immune Globulin): Rh-positive individuals may receive anti-D immunoglobulin if they are unresponsive to other treatments. 

Thrombotic Thrombocytopenic Purpura (TTP): 

• Plasma Exchange (Therapeutic Plasma Exchange – TPE): Urgent initiation of TPE to remove autoantibodies and replenish ADAMTS13. This is a critical and standard treatment for TTP. 
• Corticosteroids: High-dose corticosteroids may be used with TPE to suppress the immune response. 

• Rituximab: An anti-CD20 monoclonal antibody, rituximab, may be considered in refractory or relapsing cases. 

Hemolytic-Uremic Syndrome (HUS): 

• Supportive Care: Management focuses on supportive care, including fluid and electrolyte balance and addressing complications such as renal failure. 
• Avoidance of Antibiotics: In cases associated with STEC infection, avoiding antibiotics that may increase toxin release is recommended. 
• Eculizumab: In some cases of atypical HUS, eculizumab, a complement inhibitor, may be considered. 

Drug-Induced Thrombocytopenic Purpura: 

• Discontinuation of Causative Drug: The primary intervention is the prompt discontinuation of the implicated medication. 
• Supportive Care: Supportive measures, such as platelet transfusions, may be considered in severe cases. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

non-pharmacological-treatment-of-thrombocytopenic-purpura

Lifestyle modifications: 

Avoiding Trauma and Injury: 

• Safety Measures: Practice safety precautions to minimize the risk of falls and injuries. Use handrails, wear non-slip shoes, and take precautions in the home to prevent accidents. 
• Protective Gear: Depending on individual circumstances, wearing protective gear such as helmets or padding may be advisable, especially during activities with an increased risk of injury. 

Dietary Considerations: 

• Balanced Nutrition: Maintain a well-balanced diet rich in vitamins and minerals to support overall health.  
• Avoidance of Certain Foods: In cases of specific conditions like HUS related to STEC infection, there may be dietary restrictions. Follow healthcare provider recommendations for any dietary modifications. 

Medication Management: 

• Adherence to Prescribed Medications: Take medications as prescribed by healthcare providers. Adherence to treatment plans is crucial for managing TP effectively. 

Physical Activity: 

• Moderate Exercise: Engage in regular, moderate exercise to promote cardiovascular health and overall well-being. Discuss exercise plans with healthcare providers to ensure they are safe for the individual’s condition. 

Psychological Well-being: 

• Stress Management: Practice stress-reducing techniques, such as mindfulness, meditation, or yoga, to manage stress levels. Chronic stress may impact the immune system and overall health. 

Use of Corticosteroids in the treatment of Thrombocytopenic Purpura

Corticosteroids have anti-inflammatory and immunosuppressive properties. In the context of Thrombocytopenic Purpura, they work to suppress immune response and decrease the destruction of platelets by the immune system. 

Prednisone: 

• Prednisone is a commonly used corticosteroid in the treatment of immune-mediated conditions. It can be administered orally and is often prescribed in a tapering dose to gradually reduce the dosage over time. 
• Thrombocytopenic Purpura involves the immune system mistakenly attacking and destroying platelets. Corticosteroids help modulate the immune response, reducing the activity of immune cells responsible for platelet destruction. 
• In some cases, corticosteroids may be used in combination with other immunosuppressive medications or treatments, especially if the condition is chronic or resistant to initial therapy. 

Use of intravenous Immunoglobulins in the treatment of Thrombocytopenic Purpura

Intravenous immunoglobulin (IVIG) is a therapeutic option in the treatment of Thrombocytopenic Purpura, specifically in cases of immune thrombocytopenic purpura (ITP). 

• IVIG is a preparation of concentrated antibodies obtained from pooled plasma of thousands of donors. The exact mechanism of action in ITP is not fully understood, but IVIG is believed to modulate the immune system, affecting autoantibody production and platelet destruction. 
• IVIG has immunomodulatory effects on the immune system, potentially influencing the activity of immune cells and the production of autoantibodies targeting platelets. 

• IVIG is administered intravenously and is known to raise platelet counts in some individuals with ITP. The response to IVIG can be rapid, making it a valuable option in situations where a quick increase in platelet count is needed. 
• In some cases, IVIG may be used in combination with other treatments, such as corticosteroids or immunosuppressive medications, to enhance its effectiveness or as part of a sequential treatment plan. 

Plasma exchange in the treatment of Thrombocytopenic Purpura

Plasma exchange, also known as plasmapheresis, is a therapeutic procedure that involves removing and replacing a patient’s plasma. While it is not a first-line treatment for immune thrombocytopenic purpura (ITP), it may be considered in specific situations.

Plasma exchange removes the patient’s plasma, which may contain autoantibodies targeting platelets. The exchanged plasma is replaced with a substitute, often a combination of albumin and saline. 

Reduction of Autoantibodies: 

• The primary goal of plasma exchange in Thrombocytopenic Purpura is to reduce the circulating autoantibodies that contribute to the destruction of platelets. 

Acute Situations: 

• Plasma exchange is more commonly considered in acute situations where there is a need for rapid improvement in platelet counts, such as before surgery or in life-threatening bleeding. 

Temporary Platelet Increase: 

• Plasma exchange can lead to a temporary increase in platelet counts, providing a short-term solution to manage acute episodes of thrombocytopenia. 

Adjunct to Other Treatments: 

• Plasma exchange may be used as an adjunct to other treatments, especially in situations where conventional therapies such as corticosteroids or intravenous immunoglobulin (IVIG) have not been effective. 

Use of rituximab in the treatment of Thrombocytopenic Purpura

Rituximab is the monoclonal antibody that targets a protein on the surface of B cells, and it has been used in the treatment of various immune-mediated disorders, including Thrombocytopenic Purpura. Mechanism of Action: 

• Rituximab targets and depletes B cells by binding to the CD20 antigen on their surface. This depletion of B cells is thought to modulate the immune response and may be beneficial in conditions where autoantibodies contribute to platelet destruction. 

Reduction of Autoantibodies: 

• In Thrombocytopenic Purpura, rituximab is used to reduce the production of autoantibodies, particularly those targeting platelets. By depleting B cells, rituximab may interfere with the autoimmune process that leads to platelet destruction. 

Treatment for Refractory Cases: 

• Rituximab is often considered in cases of Thrombocytopenic Purpura that are refractory to other treatments, such as corticosteroids or splenectomy. It may be used in both adults and children. 

Use in Chronic ITP: 

• Rituximab is more commonly considered for individuals with chronic ITP who have not responded to initial treatments or who have relapsed after previous interventions. It may be used as a second-line or later therapy. 

splenectomy-for-thrombocytopenic-purpura

Splenectomy is the surgical removal of spleen, is a treatment option for individuals with Thrombocytopenic Purpura (TTP), specifically in cases of chronic and refractory immune thrombocytopenic purpura (ITP). 

The procedure may be performed traditionally as an open surgery or using minimally invasive techniques (laparoscopic splenectomy). After splenectomy, individuals are closely monitored for changes in platelet counts and overall improvement in symptoms. Platelet counts may take some time to normalize postoperatively. 

Splenectomy is associated with certain risks and complications, including the risk of infection due to the loss of the spleen’s immune function. Individuals may receive vaccinations before or after the procedure to help prevent certain infections. 

Splenectomy is generally reserved for cases of chronic ITP where other treatments have not been effective. The decision to proceed with splenectomy is made after careful consideration of the individual’s medical history, overall health, and response to previous treatments.

It is important for individuals considering splenectomy to discuss the potential risks, benefits, and alternatives with their healthcare team to make an informed decision based on their specific circumstances.

management-of-thrombocytopenic-purpura

Acute Phase: 

• Diagnosis and Initial Assessment: Diagnosis and assessment of severity of thrombocytopenia and bleeding symptoms. 
• Immediate Intervention: In severe cases with life-threatening bleeding, immediate interventions may be necessary, such as platelet transfusions or other measures to control bleeding. 

• Corticosteroid Therapy: Administration of corticosteroids (e.g., prednisone) to suppress the immune system and destruct platelets. 
• Intravenous Immunoglobulin (IVIG): IVIG may be administered to raise platelet counts quickly by modulating the immune response. It is particularly useful in acute situations. 
• Platelet Transfusions: In cases of severe bleeding, platelet transfusions may be necessary to increase platelet levels rapidly. 
• Monitoring: Frequent monitoring of platelet counts and clinical symptoms to assess response to treatment. 

Maintenance Phase: 

• Assessment of Response: Once the acute phase is controlled, assess the patient’s response to initial treatments. Evaluate platelet counts and overall clinical improvement. 
• Adjustment of Therapy: Based on the response, medications may be adjusted. For example, the dosage of corticosteroids may be tapered gradually. 
• Longer-Term Immunosuppression: In cases of chronic or recurrent Thrombocytopenic Purpura, additional treatments, such as rituximab, may be considered for longer-term immunosuppression. 
• Monitoring and Follow-Up: Regular monitoring of platelet counts and clinical symptoms during the maintenance phase. Adjustments to treatment plans may be made based on ongoing assessment. 

Medication

Future Trends

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References

ITP-Immune Thrombocytopenic Purpura – statpearls 

Thrombotic Thrombocytopenic Purpura (TTP)