Acquired hemophilia A (AHA) is a rare coagulation disorder, yet it's the most common type of acquired hemophilia. Due to an autoimmune reaction triggered by as-of-yet unknown factors, AHA patients produce autoantibodies against coagulation factor VIII. Accordingly, AHA may also be referred to as acquired factor VIII deficiency. Affected individuals usually present with extensive subcutaneous and soft tissue bleedings. As long as the inhibitors persist, they are at risk of life-threatening hemorrhages, so immediate hemostatic control is as important as the eradication of the autoantibodies. The patients' prognosis largely depends on their age and general condition.
AHA is associated with a propensity to bleed, but the severity of hemorrhages varies largely and may change over time. The most common cause of presentation is a spontaneous bleeding event, namely hematoma, bruises or purpura, deep muscle or retroperitoneal bleedings [1]. Mucosal hemorrhages in the upper respiratory tract or oral cavity, the digestive system or urogenital tract may also occur [2]. Hemorrhages in the central nervous system are rare but pose an ongoing threat to AHA patients. Hemarthroses are uncommon, which is in contrast to the clinical presentation of congenital hemophilia A with alloantibodies [3].
If the diagnosis and treatment of AHA are delayed, patients may lose considerable amounts of blood and develop anemia, which manifests in generalized weakness, fatigue, dizziness, dyspnea, and pallor [4] [5]. Severe muscle bleeds may lead to compartment syndrome.
Anamnestic and clinical data may suggest hemophilia but don't allow for the identification of its cause. Thus, coagulation studies including the assessment of platelet count, fibrinogen levels, activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) have to be realized. When interpreting the results, it should be considered that APTT, PT, and TT reflect the integrity of the intrinsic and final common pathways of coagulation, of the extrinsic and common pathways, and of the common pathway, respectively. Because AHA interferes with the intrinsic system only, prolonged APTT would be expected, while PT and TT remain within reference ranges.
There are several differential diagnoses for prolonged APTT, such as deficiencies of factors IX, XI, and XII, prekallikrein, or high-molecular-weight kininogen, as well as von Willebrand disease, liver disease, disseminated intravascular coagulation, and the presence of lupus anticoagulants. Bleeding times neither reveal whether an individual suffers from a hereditary or acquired coagulation disorder, so further studies have to be carried out to answer these questions:
Eventually, a specific approach consisting in the measurement of factor VIII activity and the determination of the inhibitor titer should be taken:
Of note, activity levels may be determined before mixing studies, but the results don't release from the obligation to check for the presence of an inhibitor [8].
Prompt hemostatic control is required to reduce morbidity and mortality, and mainly consists in the transfusion of blood and blood products, and plasmapheresis. Additionally, bypassing agents such as recombinant activated factor VII or activated prothrombin complex concentrates, which correspond to products of the extrinsic or common pathways of coagulation, may be administered to limit blood loss [3]. The application of factor VIII concentrates or desmopressin, which induces the release of von Willebrand factor from endothelial cells, has the same objective [6]. However, those with antibody titers >5 BU/ml are unlikely to benefit from the administration of human factor VIII, and few AHA patients are below that threshold before immunosuppression is induced. Replacement by porcine factor VIII may constitute an alternative [8].
In order to inhibit the underlying autoimmune reaction, immunosuppressive drugs may be applied. Corticosteroids are generally used as first-line single agents, but they may be combined with cyclophosphamide, rituximab or intravenous immunoglobulins [6] [7]. Extracorporal immunoadsorption has been described as a method to diminish autoantibody levels and thus make the patient susceptible to factor VIII replacement therapy, as indicated above [3].
Finally, if AHA is related to a primary disease such as systemic lupus erythematosus or cancer, adequate treatment should be provided, be it with curative or palliative intent.
Regardless of the severity of hemorrhages at the initial presentation, patients remain at risk of life-threatening bleedings as long as autoantibodies against factor VIII persist [3]. Thus, the timely initiation of adequate treatment is essential to avoid future bleeding events, morbidity, mortality. Special care should be taken when striving for hemostasis, since the induction of a prothrombotic state may have fatal consequences [1]. Of note, thromboprophylaxis is indicated if factor VIII activity levels rise >50 U/dl [8]. Aggressive immunosuppression favors the onset of infection and sepsis, which have been reported as a cause of death in AHA patients. Fortunately, complete remission is achieved by >70% of AHA patients, and factor VIII activity levels can be significantly increased in most of the others. Still, recurrence may occur [4].
In sum, long-term survival depends on the age of the patient and rates are significantly higher for younger individuals [4] [9]. Mortality may reach 20% in the elderly, but this is not a disease-specific rate. Here, death frequently occurs due to the underlying disorder or comorbidities [1] [8].
AHA is an autoimmune disease of unknown cause, where both genetic and environmental factors have been proposed as contributors [8]. The production of autoantibodies against factor VIII results in an interruption of the intrinsic pathway of coagulation, but it has yet to be clarified how the underlying autoimmune reaction is triggered. Interestingly, there is a high prevalence of other autoimmune disorders, such as rheumatoid arthritis, and cancer among AHA patients. Similarly, pregnancy seems to predispose for AHA, but the formation of antibodies against factor VIII has also been related to infectious diseases, dermatological conditions, polymyalgia rheumatica, and the administration of distinct drugs. In sum, a link between AHA and some primary condition is established in about half of all cases. The remainder is deemed idiopathic [6].
The overall incidence of AHA has been estimated at 1.5 per million inhabitants per year. However, the disease' incidence varies depending on the age of the population: It is rarely diagnosed in pediatric patients, where it's incidence is <0.1 per million and year, but it's not uncommon in the elderly. The incidence among those aged <85 year amounts to 15 per million and year. The median age at diagnosis is 74 years. Pediatric cases are rare but have been reported; they may be related to the transplacental crossing of maternal autoantibodies [9]. While males and females are affected in all age groups, there are notable peaks of incidence in women during fertile age and old men [6]. Black people are more likely to develop AHA than other races [3].
Homeostasis is maintained by a complex network of factors favoring or inhibiting the formation of blood clots. In general, clotting may be induced by endothelial lesions or tissue damage, which serve as starting signals for the intrinsic and extrinsic pathways, respectively. Coagulation factors VIII, IX, XI, and XII are the protagonists of the intrinsic pathway. In detail, binding of factor XII to negatively charged surfaces results in its conversion to factor XIIa. Subsequent reactions comprise the activation of factors XI and IX, yielding factors XIa and IXa. Then, factor IXa catalyzes the conversion of factor X to factor Xa. After its activation, factor VIII serves as a cofactor of factor IXa and is thus a requirement for the continuation and completion of coagulation. In AHA patients, the coagulation cascade is interrupted at this point. By contrast, the extrinsic and final common pathways remain unaltered.
Autoantibodies have been shown to bind to the C2 domain of factor VIII, thereby inhibiting binding to phospholipids and von Willebrand factor. The autoantibodies also hinder the cleavage of the factor VIII-von Willebrand factor complex by thrombin, so factor VIIIa, the activated form of factor VIII isn't produced. Only factor VIIIa is able to interact with factor IXa [7].
Because the triggers of the autoimmune reaction underlying AHA remain unknown, no recommendations can be given to prevent the production of antibodies against factor VIII.
AHA patients at high risk for bleeding should receive prophylactic hemostatic therapy. This may apply to those requiring surgery, although invasive procedures should be avoided whenever possible, to peripartal women, and patients diagnosed with other disorders implicating blood loss, such as gastric ulcers [8] [10].
AHA is an autoimmune disease characterized by the production of antibodies against coagulation factor VIII. The inactivation of factor VIII results in the disruption of the intrinsic pathway of coagulation and induces a hemorrhagic diathesis. The disease is most frequently diagnosed in elderly patients with comorbidities such as other autoimmune disorders and cancer, but it may also affect women in the peripartal phase. The severity of bleedings at presentation varies, but all AHA patients are considered at risk of life-threatening hemorrhages until remission is achieved. AHA therapy is based on controlling and preventing hemorrhages, eradicating the inhibitor, and treating the underlying disease [8].
Of note, autoimmune AHA should be distinguished from the condition induced by the formation of alloantibodies against exogenous factor VIII, which may be administered to treat congenital hemophilia A [7]. The clinical presentation is different [3].
Homeostasis may be defined as the delicate balance between blood clotting and anticoagulation. It is maintained by a complex network of factors and may be inclined to either side if circumstances so require. Coagulation factor VIII is part of this network and is a component of the so-called intrinsic pathway of coagulation. In its absence, blood clotting is inhibited, and patients may suffer extensive, potentially life-threatening hemorrhages. This condition may be congenital, i.e., those who inherited defective genes are unable to synthesize functional factor VIII. On the other hand, activity levels of factor VIII may be decreased if the patient's body starts producing antibodies against it. This is referred to as acquired deficiency of factor VIII or acquired hemophilia A (AHA), and it's an autoimmune disease.
The triggers of AHA remain unknown, but individuals suffering from other autoimmune disorders, such as rheumatoid arthritis or systemic lupus erythematosus, or cancer, seem to be predisposed to AHA. Similarly, pregnant women and those who recently gave birth are at increased risks of developing AHA. The disease typically manifests in a spontaneous bleeding event: Patients suddenly develop large bruises, hematoma, or present with mucosal bleedings of the upper respiratory tract (nosebleeds), oral cavity (bleeding gums), urogenital tract (bloody urine) or digestive system (bloody stools).
In the first place, treatment aims at arresting the hemorrhage and compensating for blood loss, so pro-coagulatory drugs may be administered, and the patient may receive blood transfusions. Still, affected individuals remain at risk of additional bleeding events as long as the autoantibody against factor VIII persists. Immunosuppressive therapy is employed to halt the underlying immune reaction, and cure can be achieved in the majority of patients. Finally, if the patient is diagnosed with a primary disease such as rheumatoid arthritis or cancer, they should receive adequate treatment for it.