Background

Acquired Hemophilia is a rare and potentially life-threatening bleeding disorder showing the development of autoantibodies called inhibitors against clotting factor VIII (FVIII), essential for normal blood clotting. Unlike hemophilia A, an inherited disorder caused by a deficiency of FVIII acquired hemophilia occurs in individuals with no history of bleeding problems and can affect people of any age or gender.

Hemophilia is a group of bleeding disorders, and there are two primary types: hemophilia A, and hemophilia B. Hemophilia A is the more common form caused by a deficiency of FVIII. In contrast, hemophilia B occurs because of factor IX (FIX) deficiency. These deficiencies result in prolonged and spontaneous internal and external bleeding after injuries or surgeries.

Acquired Hemophilia, on the other hand, occurs when the immune system mistakenly attacks and neutralizes FVIII, leading to a sudden and severe deficiency of this clotting factor.

Epidemiology

The epidemiology of acquired hemophilia can vary depending on geographic regions, age groups, and underlying conditions. Here are some about the epidemiology of acquired hemophilia:

• Prevalence: The exact prevalence of acquired hemophilia is challenging to determine due to its rarity. It is estimated to occur in about 1 to 4 individuals per million people annually. This rarity makes it a challenging condition to diagnose and manage.
• Age: Acquired hemophilia is commonly diagnosed in older adults, particularly in individuals over 60. It is relatively uncommon in children and young adults.
• Gender: Acquired hemophilia affects males and females, with no significant gender predilection.
• Underlying Conditions: Acquired hemophilia can be associated with various underlying conditions, including autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus), malignancies (e.g., solid tumors, lymphoproliferative disorders), pregnancy, drug reactions, and certain infections.
• Clinical Presentation: The clinical presentation of acquired hemophilia is characterized by spontaneous bleeding into the skin, muscles, and soft tissues, as well as mucosal bleeding. Bleeding can be severe and life-threatening, mainly if not promptly diagnosed and managed.
• Diagnosis: Diagnosing acquired hemophilia involves laboratory tests to measure clotting factors, inhibitor levels, and other coagulation parameters. The presence of isolated prolongation of activated partial thromboplastin time (aPTT) and the absence of a personal or family history of bleeding disorders are clues that may prompt further investigation for acquired hemophilia.
• Treatment: The treatment of acquired hemophilia aims to control bleeding episodes and eradicate the inhibitors. The primary treatment approach is immune tolerance induction (ITI) therapy with high-dose factor VIII concentrates. Other treatments may include immunosuppressive medications, clotting factor replacement therapy, and supportive care.

Anatomy

Pathophysiology

The pathophysiology of acquired hemophilia involves the development of autoantibodies (inhibitors) against factor VIII (FVIII), a crucial clotting factor in the blood coagulation cascade. These inhibitors neutralize FVIII, leading to a severe clotting factor deficiency and a bleeding disorder. The underlying mechanisms that trigger the production of these inhibitors have yet to be fully understood, but several factors have been implicated.

The primary steps involved in the pathophysiology of acquired hemophilia are as follows:

• Autoimmune Response: In acquired hemophilia, the body’s immune system mistakenly identifies FVIII as a foreign substance (antigen) and mounts an immune response against it. The exact trigger for this autoimmune response is often unknown. Still, it can be associated with various underlying medical conditions or situations, such as autoimmune diseases, the postpartum period, certain medications, or malignancies.
• Formation of Inhibitors: B lymphocytes produce antibodies specifically targeting FVIII during the immune response. These antibodies are known as inhibitors because they inhibit the normal clotting function of FVIII by binding to it and preventing its interaction with other clotting factors (factor IX, factor X) in the coagulation cascade.
• Inhibition of Clotting Process: FVIII plays a vital role in the intrinsic pathway of the blood coagulation cascade. It acts as a cofactor for factor IX, helping to activate factor X, which is essential for forming a stable blood clot. When inhibitors neutralize FVIII, this clotting process is disrupted, leading to impaired blood clot formation.
• Uncontrolled Bleeding: The deficiency of functional FVIII and the impaired clotting process result in uncontrolled internal and external bleeding. Patients with acquired hemophilia can experience spontaneous bleeding into muscles, joints, skin, and other organs without an apparent cause or history of bleeding disorders.

The severity of acquired hemophilia can vary among individuals, depending on the level of FVIII inhibitors and the remaining activity of functional FVIII in the blood. In some cases, the inhibitors may be transient and resolve independently; in others, they may persist and require specific treatments to eliminate them.

Etiology

The pathophysiology of acquired hemophilia involves the development of autoantibodies (inhibitors) against factor VIII (FVIII), a crucial clotting factor in the blood coagulation cascade. These inhibitors neutralize FVIII, leading to a severe clotting factor deficiency and a bleeding disorder. The underlying mechanisms that trigger the production of these inhibitors have yet to be fully understood, but several factors have been implicated.

The primary steps involved in the pathophysiology of acquired hemophilia are as follows:

• Autoimmune Response: In acquired hemophilia, the body’s immune system mistakenly identifies FVIII as a foreign substance (antigen) and mounts an immune response against it. The exact trigger for this autoimmune response is often unknown. Still, it can be associated with various underlying medical conditions or situations, such as autoimmune diseases, the postpartum period, certain medications, or malignancies.
• Formation of Inhibitors: B lymphocytes produce antibodies specifically targeting FVIII during the immune response. These antibodies are known as inhibitors because they inhibit the normal clotting function of FVIII by binding to it and preventing its interaction with other clotting factors (factor IX, factor X) in the coagulation cascade.
• Inhibition of Clotting Process: FVIII plays a vital role in the intrinsic pathway of the blood coagulation cascade. It acts as a cofactor for factor IX, helping to activate factor X, which is essential for forming a stable blood clot. When inhibitors neutralize FVIII, this clotting process is disrupted, leading to impaired blood clot formation.
• Uncontrolled Bleeding: The deficiency of functional FVIII and the impaired clotting process result in uncontrolled internal and external bleeding. Patients with acquired hemophilia can experience spontaneous bleeding into muscles, joints, skin, and other organs without an apparent cause or history of bleeding disorders.

The severity of acquired hemophilia can vary among individuals, depending on the level of FVIII inhibitors and the remaining activity of functional FVIII in the blood. In some cases, the inhibitors may be transient and resolve independently; in others, they may persist and require specific treatments to eliminate them.

Genetics

Prognostic Factors

Prognostic factors in acquired hemophilia refer to the variables and characteristics that can help predict the likely outcome or course of the disease in affected individuals. These factors are essential for determining the condition’s severity, treatment response, and overall prognosis. Prognostic factors in acquired hemophilia include:

• Inhibitor Titer Level: The level of factor VIII (FVIII) inhibitors in the blood is a critical prognostic factor. Higher inhibitor titers generally indicate more severe disease and may be associated with a poorer response to treatment.
• Time to Diagnosis and Treatment Initiation: An early diagnosis and prompt initiation of treatment are crucial for better outcomes in acquired hemophilia. Delayed diagnosis and treatment can lead to more extensive bleeding and complications.
• Bleeding Severity: The extent and severity of bleeding episodes can influence the prognosis. Frequent or severe bleeding into critical organs, such as the brain or gastrointestinal tract, can lead to life-threatening situations.
• Underlying Cause: If known, identifying and addressing the underlying cause of acquired hemophilia can impact the prognosis. For example, treating an associated malignancy may improve hemostatic control and inhibit further inhibitor development.
• Patient’s Age and Overall Health: The patient’s age and general health condition can affect the prognosis. Older adults or those with pre-existing health issues may have a higher risk of complications.
• Treatment Response: The response to treatment is a significant prognostic factor. Some individuals may achieve complete remission and elimination of inhibitors with appropriate therapy, while others may experience persistent or recurrent inhibitors.
• Inhibitor Type and Specificity: The type and specificity of the FVIII inhibitor can influence treatment options and response. Some inhibitors may be more challenging to manage than others.
• Comorbidities: Other medical conditions, such as cardiovascular diseases or renal impairment, can impact the overall prognosis and the ability to manage acquired hemophilia effectively.
• Immune Tolerance Induction (ITI) Success: Immune tolerance induction is a treatment approach to promote immune tolerance to FVIII. The success of ITI in achieving sustained remission can significantly affect the long-term prognosis.
• Treatment Compliance: Adherence to treatment plans and regular follow-up care is essential for managing acquired hemophilia effectively and improving the prognosis.

Clinical History

Non-specific signs & symptoms

• Unexplained bleeding
• Easy bruising
• Prolonged bleeding from wounds
• Gastrointestinal bleeding
• Hematuria
• Nosebleeds
• Joint pain & swelling
• Weakness & fatigue
• Unexplained hemorrhage & surgery

    Systemic signs & symptoms

• Anemia
• Hypotension
• Tachycardia
• Hemorrhagic shock
• Hematuria
• Gastrointestinal bleeding
• Neurological symptoms
• Respiratory distress
• Abdominal pain
• Cardiovascular symptoms

Age Group:

• Elderly Adults
• Young Adults
• Postpartum women
• Children & adolescents
• Infants

Associated Comorbidity or Activity:

• Autoimmune disease
• Postpartum period
• Malignancies
• Certain medications
• Infections
• Surgery
• Hemodialysis

The Acuity of Presentation:

The acuity of presentation in acquired hemophilia can vary depending on the severity and location of bleeding episodes and the condition’s underlying cause. Acquired hemophilia can present suddenly and with significant, life-threatening bleeding or more gradually with milder symptoms. The acuity of presentation is influenced by several factors, including:

• Severity of Bleeding: Some individuals with acquired hemophilia may experience severe and uncontrolled bleeding, leading to critical situations requiring urgent medical attention. This can include spontaneous bleeding into vital organs, such as the brain, leading to neurological symptoms or gastrointestinal bleeding resulting in melena or hematemesis. In such cases, the acuity of presentation is high, and immediate medical intervention is essential.
• Bleeding into Joints and Muscles: Bleeding into joints (hemarthrosis) or muscles can cause significant pain, swelling, and limited range of motion. If not promptly recognized and treated, these episodes can lead to joint damage and long-term disability.
• Acute Anemia: Acute and severe bleeding episodes can rapidly drop hemoglobin levels, leading to acute anemia. This can cause symptoms such as weakness, fatigue, dizziness, and pallor.
• Unexplained Bleeding: Acquired hemophilia may be particularly challenging to diagnose early, as the bleeding episodes may appear unexplained or disproportionate to the apparent injury. If a patient presents with recurrent or severe bleeding with no history of bleeding disorders, acquired hemophilia should be considered, and prompt investigation is crucial.
• Postpartum Period: Acquired hemophilia may present during the postpartum period, which is the time following childbirth. Bleeding complications during this time can be critical and may require immediate medical attention.
• Associated Comorbidities: The acuity of presentation may be influenced by underlying comorbidities, such as malignancies or infections, which can impact the severity of bleeding and overall clinical condition.

Physical Examination

• Vital Signs: Measure vital signs, including blood pressure, heart rate, respiratory rate, and temperature, to assess hemodynamic stability and the presence of any signs of shock.
• Skin Examination: Examination of the skin for ecchymosis (large bruises), petechiae (small red or purple spots), or other signs of bleeding.
• Musculoskeletal Examination: Assessment of joints and muscles for signs of bleeding or hemarthrosis. The examiner may look for joint swelling, warmth, tenderness, and limited range of motion.
• Neurological Examination: For patients with suspected intracranial bleeding, a thorough neurological examination may assess mental status, cranial nerve function, motor strength, reflexes, and coordination.
• Gastrointestinal Examination: Examine the abdomen for signs of tenderness, distension, or gastrointestinal bleeding.
• Respiratory Examination: Evaluation of the respiratory system for signs of hemoptysis (coughing up blood) or respiratory distress.
• Cardiovascular Examination: Examination of the heart and cardiovascular system for signs of anemia, such as a rapid heart rate or signs of cardiac decompensation.
• Genitourinary Examination: Assessment of the genitourinary system for hematuria (blood in the urine).
• Examination of Mucous Membranes: Inspection of mucous membranes, such as oral and conjunctival mucosa, for signs of bleeding.
• Assessment of Hemodynamic Stability: Monitoring for signs of bleeding-related hemodynamic instability, such as hypotension, tachycardia, or signs of hemorrhagic shock.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

• Hemophilia A and Hemophilia B: Inherited bleeding disorders caused by deficiencies in factor VIII (hemophilia A) or factor IX (hemophilia B). Unlike acquired hemophilia, these are genetic conditions present from birth and often have a family history of bleeding disorders.
• Von Willebrand Disease (VWD): Another inherited bleeding disorder caused by a deficiency or dysfunction of the von Willebrand factor, which plays a crucial role in platelet function and clotting.
• Platelet Function Disorders: Disorders that affect the function or number of platelets, leading to bleeding tendencies. Examples include Glanzmann thrombasthenia and Bernard-Soulier syndrome.
• Liver Disease: Advanced liver disease can lead to impaired production of clotting factors, causing bleeding tendencies.
• Disseminated Intravascular Coagulation (DIC): A severe condition characterized by bleeding and clotting due to widespread activation of the coagulation system.
• Vitamin K Deficiency: A deficiency of vitamin K, which is essential for synthesizing clotting factors in the liver, can lead to bleeding disorders.
• Anticoagulant Medication Use: Anticoagulant medications, such as warfarin or direct oral anticoagulants, can cause bleeding complications.
• Thrombocytopenia: Low platelet count, which various factors, including certain medications, infections, or autoimmune disorders, can cause.
• Connective Tissue Disorders: Some connective tissue disorders, such as Ehlers-Danlos syndrome, can present with easy bruising and bleeding tendencies.
• Immune Thrombocytopenic Purpura (ITP): An autoimmune disorder characterized by a decreased platelet count and increased risk of bleeding.
• Vasculitis: Inflammation of blood vessels can lead to bleeding into the skin and mucous membranes.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The treatment paradigm for acquired hemophilia aims to control bleeding episodes, eliminate FVIII inhibitors, and manage underlying conditions if present. Managing acquired hemophilia requires a multidisciplinary approach involving hematologists, immunologists, and other specialists. The treatment strategy may vary depending on the severity of bleeding, the patient’s overall health, and the underlying cause of acquired hemophilia. The main components of the treatment paradigm include:

• Specialized Treatment Centers: Whenever possible, treatment of acquired hemophilia should be conducted in specialized hemophilia treatment centers or centers with expertise in managing bleeding disorders. These centers have the necessary resources, personnel, and experience to provide comprehensive care and address the complexities of acquired hemophilia.
• Multidisciplinary Care Team: The treatment team should comprise a multidisciplinary group of healthcare professionals, including hematologists, immunologists, nurses, physical therapists, and social workers. This collaborative approach ensures comprehensive and coordinated care.
• Education and Support: Patients and their families should receive education about acquired hemophilia, including its nature, treatment options, and potential complications. Support groups and counseling services can also provide valuable emotional and psychological support.
• Bleeding Management Plan: Each patient should have an individualized bleeding management plan that outlines the steps to take in case of a bleeding episode, including when and how to seek medical attention and administer clotting factor replacement therapy.
• Emergency Preparedness: Treatment centers and patients should be prepared for emergencies related to bleeding episodes. This may include having access to emergency medical services, clotting factor concentrates, and communicating with healthcare providers 24/7.
• Medication and Allergy Management: Awareness of potential medications or substances that may interact with clotting factor concentrates or trigger allergic reactions is crucial. Patients should inform healthcare providers about their medical history and any known allergies.
• Infection Prevention: Patients with acquired hemophilia may receive treatment with immunosuppressive medications. Proper infection prevention measures should be followed to reduce the risk of infections.
• Regular Follow-Up: Patients should have regular follow-up appointments with their healthcare providers to monitor treatment response, clotting factor levels, and inhibitor titers. This allows for adjustments in treatment as needed.
• Assistance with Accessibility: For patients with mobility challenges or who live in remote areas, efforts should be made to improve accessibility to treatment centers and healthcare services.
• Patient Empowerment: Encourage patients to participate actively in treatment and care. This includes understanding their condition, adhering to treatment plans, and proactively managing their health.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

Future Trends

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References

https://www.ncbi.nlm.nih.gov/books/NBK560494/