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.

• Ecchymosis

  A 69-year-old woman with essential thrombocythemia (ET) developed giant ecchymosis, and she was admitted to hospital. [ncbi.nlm.nih.gov]

  Case Presentation: A 73 year old female with borderline diabetes mellitus and hypertension presented to the emergency department with the sudden onset of nontraumatic swelling, pain and ecchymosis of her right leg. [shmabstracts.com]

  Bleeding is mostly mucocutaneous or in soft tissues such as hematuria, gastrointestinal bleeding, ecchymosis or hematomas, as compared to hemarthrosis in younger patients with congenital hemophilia. [cureus.com]

  Symptomatic patients often present with large hematomas, extensive ecchymosis or severe mucosal bleeding, including epistaxis, gastrointestinal bleeding, and haematuria. [en.wikipedia.org]

• Subcutaneous Bleeding

  Intrathoracic and subcutaneous bleeding occurred spontaneously on postoperative day (POD) 39. The APTT was prolonged, at 140 s, and factor VIII inhibitor was 36 Bethesda U/ml. [ncbi.nlm.nih.gov]

  Severe spontaneous bleeding may occur in patients with factor levels >5% Severe spontaneous bleeding usually occur in severe hemophilia A patients with factor levels <1% Extensive hematoma/Subcutaneous bleeding Common Rare Hemarthrosis Rare Common Mortality [e-ceth.org]

• Easy Bruising

  In this case report, we present a non-hemophiliac patient, who presented five months postpartum with intermittent heavy vaginal bleeding, easy bruising, hemarthrosis, and recurrent frank hematuria. [ncbi.nlm.nih.gov]

  This results in people bleeding longer after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. [play.google.com]

  Easy bruising. Frequent nosebleeds. Blood in the urine. Bleeding after dental work. Some people with milder types of the disease may not have symptoms until later in life. [northshore.org]

  They may experience joint bleeds or easy bruising.[21] Mild haemophilia may only be discovered later, usually after an injury or a dental or surgical procedure. [en.wikipedia.org]

• Spontaneous Hemorrhage

  If the initial aPTT is normal, we should therefore repeat the aPTT and also perform other coagulation studies including a mixing study, factor VIII level and inhibitor, to investigate the underlying diseases in elderly patients with spontaneous hemorrhaging [ncbi.nlm.nih.gov]

  Abstract Background: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. [portal.research.lu.se]

• Melena

  Additional symptoms may include epistaxis, gastrointestinal and/or urogenital bleeding, spontaneous bruising, melena, and hematuria. [orpha.net]

  Other manifestations include muscle hematoma, melena, and hematuria and gastrointestinal bleeding [1,2]. Similarly, our case had an 82-year-old male who presented with hematuria and dysuria. [cureus.com]

  He developed hematemesis and melena 2 d following the removal of the drainage tube. His anemia worsened and his hemoglobin (Hb) level reached 6.3 g/dL, requiring red blood cell (RBC) transfusions for 5 d consecutively. [wjgnet.com]

  As gastrointestinal bleeding (melena, due to multiple peptic ulcers) occurred one year earlier, treated with endoscopic haemostasis and blood transfusion, aspirin was stopped and substituted for clopidogrel. [hindawi.com]

  Subcutaneous bleeding (ecchymoses) is the most common manifestation of AH followed by muscle bleeding (hematoma), gastrointestinal (melena), genitourinary (hematuria), and retroperitoneal. Intracranial hemorrhage is rare, but can be fatal. [rarediseases.org]

• Epistaxis

  Additional symptoms may include epistaxis, gastrointestinal and/or urogenital bleeding, spontaneous bruising, melena, and hematuria. [orpha.net]

  Persistent wound bleeding and epistaxis suddenly began 6 hours after surgery. Computed tomography (CT) revealed a massive intracranial hematoma in the damaged parenchyma, although the patient was asymptomatic. [ncbi.nlm.nih.gov]

  Specific symptoms may include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria), and gastrointestinal or urogenital bleeding. [hemophilianewstoday.com]

  Symptomatic patients often present with large hematomas, extensive ecchymosis or severe mucosal bleeding, including epistaxis, gastrointestinal bleeding, and haematuria. [en.wikipedia.org]

  Specific symptoms can include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria) and gastrointestinal or urogenital bleeding. [rarediseases.org]

• Intracranial Hemorrhage

  While intracranial hemorrhage is a known complication of AHA, intracranial hemorrhage as the presenting manifestation of AHA has only been described in three previous case reports. [ncbi.nlm.nih.gov]

  Severe intracranial hemorrhage in a newborn infant with transplacental transfer of an acquired factor VII:C inhibitor. J Pediat, Oct 1995; 127(4): 649-50. 33. Zeitler H, Ulrich-Merzenich G, Marquardt N, et al. [revistahematologia.com.ar]

  Intracranial hemorrhage is the second most common cause of death and the most common cause of death related to hemorrhage. Of patients with severe hemophilia, 10% have intracranial bleeding, with a mortality rate of 30%. [emedicine.medscape.com]

• Hematuria

  The woman presented to the emergency room with hematuria. Coagulation screening tests showed a prolonged APTT. Using a standard diagnostic algorithm, a Factor VIII inhibitor was detected. [ncbi.nlm.nih.gov]

  Additional symptoms may include epistaxis, gastrointestinal and/or urogenital bleeding, spontaneous bruising, melena, and hematuria. [orpha.net]

  Other manifestations include muscle hematoma, melena, and hematuria and gastrointestinal bleeding [1,2]. Similarly, our case had an 82-year-old male who presented with hematuria and dysuria. [cureus.com]

  Hematuria may be troublesome. These patients represent therapeutic challenges. This study is one institution's results with 16 such patients followed up over an average of 31 months (range, four to 120 months; median, 19 months). [jamanetwork.com]

• Urogenital Bleeding

  Additional symptoms may include epistaxis, gastrointestinal and/or urogenital bleeding, spontaneous bruising, melena, and hematuria. [orpha.net]

  Specific symptoms may include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria), and gastrointestinal or urogenital bleeding. [hemophilianewstoday.com]

  Specific symptoms can include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria) and gastrointestinal or urogenital bleeding. [rarediseases.org]

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:

• The patient's negative family history and demographic data - AHA is typically diagnosed in peripartal women or elder adults with pre-existing autoimmune disease or malignancy - may suggest an acquired condition, but this assumption should be verified. This is most easily done by mixing the patient's plasma with normal plasma and checking whether this results in a normalization of APTT [4]. In the presence of an inhibitor, such as autoantibodies against factor VIII, coagulation factors deriving from the normal plasma are inactivated, and normalization doesn't occur [3].
• Russell’s Viper Venom Test or Staclot LA are the methods of choice to test for lupus anticoagulants.

Eventually, a specific approach consisting in the measurement of factor VIII activity and the determination of the inhibitor titer should be taken:

• While the majority of patients presents with activity levels <5 U/dl, higher levels are measured in about one-fourth of all cases, so residual activity of factor VIII is a rather common finding [3] [6].
• The titer is generally determined employing the Bethesda assay or modifications thereof. It is important to note that the inhibition of factor VIII by autoantibodies shows type-2 kinetics, i.e., the in vivo inhibition of the coagulation factor may be underestimated if the results of the aforementioned standard assays are interpreted based on reference values obtained from patients with congenital hemophilia A [4] [7].

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].

• Activated Partial Thromboplastin Time Prolonged

  The laboratory revealed isolated activated partial thromboplastin time prolongation with low FVIII activity and a presence of FVIII inhibitor. She was diagnosed with acquired hemophilia A. [ncbi.nlm.nih.gov]

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.

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