Acquired Hemophilia

Etiology

In about half of the cases diagnosed with acquired hemophilia, no cause or precipitating factor is recognized.[6][2] An underlying disease or a precipitating factor can be identified for the other half.[5] Various factors that can predispose to the development of acquired hemophilia A (AHA) may include the following,

• Immunological Disorders (17 to 18%): Associated with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren syndrome, connective tissue diseases, autoimmune thyroiditis, Grave disease, antiphospholipid syndrome, multiple sclerosis, temporal arteritis, myasthenia gravis, Goodpasture syndrome, and other autoimmune diseases.[2][3][7][3][8][9]
• Obstetrical Causes: Post-partum state (one of the common causes of acquired hemophilia - 8.4% of total incidence). Any episode of abnormal bleeding in the post-partum period (up to 12 months after delivery) should raise suspicion for AHA. Autoantibody development usually occurs in the postpartum period, but there have been some reports that the antibody could be detected during labor. It can lead to life-threatening bleeding that requires a hysterectomy for management.[2][5][6][4][3]
• Hematological and Oncological Causes: Diagnosis of cancer, precancerous states, solid tumors (lung, prostate, pancreas, breast), hematological neoplasia, chronic lymphocytic leukemia, multiple myeloma, Waldenström macroglobulinemia, lymphoproliferative malignancies, non-Hodgkin lymphoma, monoclonal gammopathy of undetermined significance (MGUS), and polymyalgia rheumatic.[3][6][10][11][6][3]
• Dermatologic Disorders: Psoriasis, pemphigus, and epidermolysis bullosa.
• Pharmacological Causes: Beta-lactam antibiotics, penicillin, non-beta-lactam antibiotics, interferons, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), amiodarone, rivastigmine, sunitinib, heparin, phenytoin, chloramphenicol, methyldopa, and fludarabine.
• Infectious Diseases: Acute hepatitis B and C infections and others.[3]
• Transplant Related Disorders: Chronic graft versus host disease.
• Gastroenterological Diseases: Inflammatory bowel disease.
• Pulmonary Diseases: Asthma, chronic obstructive pulmonary disease (COPD).[3]
• Transfusion of blood products.[6]

Epidemiology

Acquired hemophilia is rare, with an overall incidence of 1.5 per million per year.[5][12] However, the incidence varies with age from 0.045 per million per year in children younger than 16 to 14.7 per million per year in adults older than 85.[3] Hence, the disease is more common in adults than in children.[4] There are reports that 80% of the patients are older than 65.[3] The median age ranges from 73.9 years to 78 years.[3] There has been no evidence of any genetic pattern, and there is overall equality between males and females.

Although in the age bracket 20 to 40, it is more common in females, while in adults older than 85 years, it is more commonly seen in males.[6] The increased incidence in females in the reproductive years (20 to 40 years) can be attributed to the higher risk of the disease during pregnancy, in the post-partum period until 12 months after delivery.[6]

Pathophysiology

Factor VIII (FVIII) serves as a cofactor to factor IX (FIX) for the conversion of factor X (FX) to Xa, hence leading to the production of thrombin on the activated platelets’ surface. Factor VIII is a 330-kDa precursor protein. The proteolytic processing converts the domain structure of factor VIII from A1-a1-A2-a2-B-a3-A3-C1-C2 into heterodimers of heavy and light chains. Most of the acquired inhibitors of FVIII bind to the A2, A3, or C2 domains. The domains A2 and A3 are responsible for factor VIII binding to factors IXa and X, while the domain C2 binds factor VIII to the phospholipids and von Willebrand factor. Autoantibodies that develop in patients with acquired hemophilia are non-complement fixing and non-precipitating and belong to the IgG class (mostly IgG1 and IgG4).[6]

These antibodies bind to the domains in time and a temperature-dependent manner in second-order kinetics. However, they do not result in complete factor VIII inactivation in vitro; the measurable factor activity offers little if no clinical benefit in controlling hemorrhage.[4] The kinetics of antibody interaction with factor VIII vary with the autoantibodies in acquired hemophilia A (AHA) and alloantibodies that appear in congenital hemophilia. Alloantibodies can abolish the factor activity altogether, whereas autoantibodies result in markedly decreased factor activity, although the slight residual FVIII activity is not clinically protective.[6][3] The breakdown of immune tolerance can result from genetic and environmental factors. FVIII deficiency results in insufficient thrombin production on the surface of activated platelets.

History and Physical

A complete history of immunological diseases, the medication, and the broad range of associated medical conditions predisposing the patient to acquired hemophilia should be taken.[5] The age, gender, presenting complaints, past medical history, previous surgical notes, and drug history should be carefully assessed for a differential diagnosis.[6] The diagnosis of acquired hemophilia A (AHA) should be considered in patients with a recent onset of abnormal bleeding, especially in the elderly and peripartum women.[3] The presentation of an elderly patient or 1 during the post-partum period with acute and new-onset bleeding with no prior history of any bleeding should raise suspicion for AHA in the mind of the provider.[5] However, it should be remembered that almost 50% of the patients diagnosed with acquired hemophilia do not have any precipitating or predisposing factor.[6]

Sometimes, the clinical picture is mild. However, they should not be neglected because they are often the first manifestation of a condition that can be life-threatening at any time with the occurrence of severe bleeding events.[13] The rarity of this pathology can be the reason for an excessive delay in diagnosis. Whenever the history points out any etiological factor, a complete and detailed physical examination should be carried out in addition to ordering investigations to reach the diagnosis. The patients develop spontaneous, extensive subcutaneous hematomas [3] without favoring factors. The classical presentation is with purpura and soft tissue bleeding. More severe hemorrhagic complications are also possible, which are discussed later. Unlike congenital hemophilia, hemarthrosis is uncommon.[14][4]

Evaluation

When the history and physical examination raise suspicion, a complete blood count and a coagulation profile should confirm the diagnosis of acquired hemophilia. The complete blood test reveals a normal platelet count, whereas the coagulation profile shows an isolated prolonged activated partial thromboplastin time (aPTT) by 2 to 3 times its normal value. Prolonged aPTT can be attributed to the deficiency of multiple intrinsic pathway factors, including FVIII, FIX, FXI, and FXII, as well as the presence of antibodies against these factors. Mixing studies helps rule out either of the causes of the functional deficiency of the factors.

These studies are performed by mixing normal plasma with the patient in a 1 to 1 ratio. An improvement in the aPTT after a mixing study points to the deficiency of coagulation factors in the patient. In contrast, if the mixing study does not correct the aPTT, it points to factor inhibitors that have rendered the normal plasma factors dysfunctional. The mixing study requires the plasma to be incubated for 1 to 2 hours before proceeding with the study.[15] The quantitative assays of factor activity and measurement of factor inhibitor levels should be performed and are considered diagnostic.[16][17][18] In addition to an isolated prolonged aPTT, a failed mixing study, and normal prothrombin time (PT), a patient with acquired hemophilia also shows a decreased FVIII activity and increased levels of factor inhibitor autoantibodies.[19] 

The antibody titers are described in the Bethesda unit (BU), which represents the inhibitor amount leading to 50% residual FVIII: C activity. The Nijmegen modification to the Bethesda method has helped to standardize the acidity and protein concentration in the testing mixture, reducing the probability of an artifactual measurement and leading to increased specificity of the test.[20]

The complete blood count may reveal decreased hemoglobin levels in cases with massive bleeding. There are rare cases where patients do not have a prolonged aPTT, hence in such incidents, the clinical judgment of the provider, as well as interprofessional team collaboration, is required.[5]

Treatment / Management

The treatment recommendations usually rely on the clinical judgment and expertise of the providers who have treated patients with acquired hemophilia A (AHA). The reason is the unavailability of an international consensus for management.[5]

The management of AHA, however, comprises a 2-pronged therapy approach in which both modalities go hand in hand. These are

1. Hemostasis management.
2. Eradication of Inhibitor.[3][21][22][23][24]
(A1)

Hemostasis Management

The requirement for hemostasis management is primarily dependent on the severity of bleeding and its location. It should be noted that the autoantibody titer is not directly correlated to the bleeding severity. As mentioned earlier, although some residual factor activity might be detectable, it does not play a vital role in the patient's clinical picture.

• Minor Bleeding

In a patient who presents with mild bleeding and does not need to undergo an emergent invasive procedure, with autoantibody titers of equal to or less than 5 BU, observation is sufficient. These titers have been reported to disappear in 25% of cases within a few months when these were secondary to pregnancy or antimicrobial therapy. In cases with minor bleeding that requires treatment, the approach is usually limited to avoiding invasive procedures and discontinuing medication associated with bleeding. In patients with residual factor VIII levels of more than 5 percent and autoantibody titers less than 2 BU, desmopressin (0.3–0.4 mg/kg) has been reported to be helpful with increasing the factor VIII levels. However, the rise in factor levels is transient but is usually useful in minor bleeding cases. Compared to desmopressin, the human factor VIII is superior in situations with low autoantibody titers. Still, the requirement of extraordinary amounts of FVIII to saturate the neutralizing autoantibody is a significant limitation.[6]

• Major Bleeding

Patients who present with major bleeding (72%) require initiation of appropriate antihemorrhagic treatment in a timely fashion. Suppose the antibody titer is low (<5BU). Treatments, including human factor VIII or desmopressin, may be considered the first-line therapy if the hemostatic levels of FVIII can be achieved, which is only possible with low titers of antibodies. In cases with high titers, first-line treatment uses bypassing agents. The bypassing agents are named so because of their mechanism of action. They bypass the need for factor VIII in the coagulation pathway to produce thrombin. These agents include activated prothrombin complex concentrate (aPCC) and recombinant activated Factor VII (rFVIIa). The prothrombin complex concentrate is plasma-derived and contains exogenously activated vitamin K-dependent factors (factors II, VII, IX, X).

Although both bypassing agents differ in their pharmacokinetics and biochemical properties, neither is more effective in clinical settings. Some studies do suggest that rFVIIa should be preferred over aPCC. However, the cost aspect of rFVIIa is a downside to its widespread usage.[12] The recommended dosage of aPCC is 100 U/kg per dose or 200 u/kg/day. In contrast, the dosage of rFVIIa is similar to the 1 used in congenital hemophilia, ie, 90 μg/kg every 2–3 hours until sufficient hemostasis has been achieved.[5] The half-life of rFVIIa is about 2 hours, while aPCC's is around 4 to 7 hours. Both bypassing agents can be used as a first-line in the treatment. However, the patient's history of response can influence the choice, the patient's convenience, preference (recombinant vs plasma-derived product), and product availability. If the first-line therapy fails, evidence suggests prompt initiation of the alternate bypassing agent may be useful. Using both agents simultaneously should be avoided except in cases of a failure of adequate response with 1 in a life-threatening bleeding scenario.(B3)

Treatment response is monitored clinically, as no laboratory test has been approved to assess the efficacy of the treatment. Global hemostatic assays have been used to determine thrombin generation, but the results show no correlation with the patient's clinical status. Older patients and patients with comorbidities (cardiovascular diseases, cancers, and pregnancy) are at a higher risk of developing complications, including arterial and venous thromboses, with the use of increased doses of these agents.[12](B3)

There is supporting evidence for the concomitant use of antifibrinolytic therapy in the case of mucosal bleeding.

Once treatment is successful, there are recommendations for prophylactic therapy, which uses low doses of bypassing agents to prevent bleeding in the future.[5]

Inhibitor Eradication

The treatment of AHA depends on correcting the pathophysiology that arises due to the presence of factor autoantibody. In the presence of the autoantibody, the patient is always at risk of life-threatening bleeding, and the complete eradication of the inhibitor is vital for improving survival in patients. Inhibitor eradication therapy should be initiated along with hemostatic therapy, as the delay has been associated with poor patient outcomes. For this purpose, the first-line treatment includes prednisone (1 mg/kg/day). It can be used alone, or cyclophosphamide (50 to 100 mg/day) can be added, although evidence suggests that the combined use correlates with better patient outcomes.

The inhibitor eradication therapy is considered successful with undetectable titers of autoantibody (<0.6 BU) along with normal factor VIII levels (>50%). Indications for second-line immunosuppression include factor VIII levels not increasing and autoantibody titers not decreasing at 3 to 5 weeks with appropriate treatment and adequate patient compliance.[3] Relapse may occur, which imposes a long follow-up. Rituximab is an anti-CD20 monoclonal antibody successfully applied in managing various autoimmune conditions and may be a valuable agent in managing acquired hemophilia. It may be considered an intolerance to standard immunosuppressive therapy or resistance.[13] 2-chlorodeoxyadenosine has also been shown to be effective in treating some trials.[2](A1)

Differential Diagnosis

The hemorrhage due to acquired hemophilia is challenging to differentiate from other bleeding diatheses. The main differential diagnosis includes

• Congenital hemophilia A, B, and C (mixing study; quantitative factor assays)
• Factor XII deficiency (the quantitative measurement of factor activity; titers of factor inhibitors)
• Medication usage-unfractionated heparin, warfarin, a direct thrombin inhibitor, direct factor Xa inhibitor (history; coagulation profile)
• Antiphospholipid syndrome (laboratory assays for anticardiolipin and anti-β-glycoprotein I antibodies; lupus anticoagulant)

Prognosis

Three extensive studies have shown that the mortality rate of acquired hemophilia A (AHA) lies between 8% and 22%. Still, more recent studies have shown lower mortality rates owing to the anti-hemorrhagic treatments.[4][2] Low FVIII is associated with a lower rate of complete remission and survival. Besides incomplete remission, other risk factors for death include advanced age and underlying malignancy.[25][26] The development of alloantibodies in congenital hemophilia has shown no correlation with mortality compared to the autoantibodies in acquired hemophilia.[5]

However, in the post-partum period, AHA has an excellent prognosis in about 97% of the patients.[5] In many cases of AHA that occur in the post-partum period, spontaneous remission has been reported with the disappearance of the autoantibodies at an average of 30 months.[2]

Complications

Acquired hemophilia can lead to several complications if the appropriate treatment is not initiated in a timely fashion. A few common complications include

• Intramuscular Bleeding: These episodes can be severe, resulting in compartment syndrome or even tissue death due to pressure on neurovascular structures.[6]
• Mucosal Bleeding: Nasal (epistaxis), gastrointestinal, genitourinary (hematuria), and respiratory (hemoptysis) bleed can occur.[2]
• Bleeding From the Wound/Operative Site: Invasive procedures, including surgeries and arterial puncture procedures, can predispose a patient with AHA to a life-threatening and uncontrollable hemorrhage.[4]
• Intracranial hemorrhages (rare).[6]
• Intra-articular bleeding episodes that frequently occur in congenital hemophilia are uncommon in the acquired form.
• Large spontaneous subcutaneous hematomas.[3]