Acquired Hemophilia (Acquired Haemophilia)

Acquired hemophilia is a rare autoimmune disease characterized by the presence of autoantibodies directed against coagulation factors like factor VIII. The disease' etiology remains largely unknown; affected individuals present with a bleeding diathesis and potentially life-threatening hemorrhages.

Presentation

AH is characterized by spontaneous hemorrhages in patients without prior history of hemophilia. Skin bleedings ranging from petechia to ecchymosis are common. Furthermore, most patients experience epistaxis, gastrointestinal hemorrhages provoking melena and/or hematochezia, and hematuria due to lesions of the urinary tract. Retroperitoneal hematoma has repeatedly been reported. Affected individuals are prone to soft tissue hematomas and muscle bleeds. While the latter is also typical of congenital hemophilia, the genetic disorder is generally associated with hemarthroses, but these are rarely observed in AH patients [2]. Muscle bleeds may lead to compartment syndrome. Fortunately, few patients sustain an intracranial hemorrhage [7], but the aforementioned bleedings may still cause life-threatening hemorrhagic shock. In less than 20% of patients, the bleeding diathesis is only registered upon trauma, childbirth or surgery [5]. On the other hand, patients may present with symptoms consistent with anemia, i.e., fatigue, headaches, palpitations, dyspnea, and cyanosis. Here, anemia is the result of occult hemorrhages. Symptoms may vary over time, hemorrhages aren't usually limited to a specific organ system, may become apparent after an episode of occult bleedings a vice versa. A minority of patients, about 6%, remains asymptomatic and the suspicion of coagulopathy arises from routine measurements of coagulation times and incidental detection of anomalies [3].

Workup

Anamnestic data are of major importance in AH diagnosis since the clinical picture gives little clues as to the cause of an observed bleeding diathesis. In this line, AH may be suspected in the case of elder patients, possibly suffering from malignancies or another autoimmune disease, or in post-partal women without a family history of coagulopathies. In any case, coagulation times should be measured if a patient presents with hemophilia. AH may be associated with normal or prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT). In detail, the distinct forms of AH typically present as follows [1]:

  • Prolonged APTT, normal PT: consistent with inhibition of factors VIII, IX, XI, XII
  • Prolonged APTT and PT: to be expected in case of an autoimmune response against factors II, V, X
  • Normal APTT, altered PT: indicates acquired deficiency of factor VII

Contrary to congenital hemophilia due to deficiency of coagulation factors, mixing with normal plasma may appear to correct prolonged APTT and PT, but will eventually demonstrate the presence of a time-dependent inhibitor of the respective factor (non-linear inactivation pattern consistent with type 2 kinetics). This effect is more readily observable after an incubation of the mixture at 37 °C for one or two hours; analysis prior to incubation may lead to a false-negative result [8].

Of note, complexes formed by coagulation factors and autoantibodies may present residual activity. Thus, high titers aren't necessarily accompanied by the complete absence of coagulation factor activity. Both parameters are to be evaluated, though, to determine the subtype of AH in an approach often referred to as "Bethesda assay" and respective modifications [9].

Platelet counts are not usually altered.

Treatment

Patients presenting with severe hemorrhages require immediate attention to prevent complications from ischemia, blood loss, and pressure-induced tissue damage. This particularly applies in the case of an intracranial hemorrhage. To this end, bypassing agents like recombinant activated factor VII and plasma-derived activated prothrombin may be applied. These compounds allow the body to "skip" dysfunctional steps of the coagulation cascade and thus aid to control hemorrhages. Moreover, recombinant porcine factor VIII has recently been approved for therapy of AH-associated bleedings [10], but is currently considered a second-line option [11]. The latter also applies to desmopressin. Patients should be protected from trauma; elective surgery should be postponed until successful eradication of autoantibodies. It is recommended to carefully consider the benefits and risks of non-elective interventions.

Further therapeutic measures aim at curing the underlying disease, if known and feasible, suppressing the autoimmune response and eradicating the inhibitor of the coagulation cascade. With regards to the latter, treatment recommendations have been published for patients suffering from acquired hemophilia A [11]. First-line therapy consists of corticosteroids (e.g., prednisolone at a dose of 1 mg/kg/d) or a combination of corticosteroids with cyclophosphamide (at a dose of 1.5-2 mg/kg/d); no differences have been encountered in response to therapy and mortality of patients submitted to either regimen. If the patient fails to respond to this treatment, or if those drugs are contraindicated, rituximab may be administered. Immunosuppression has occasionally been achieved with alternative drugs like azathioprine or cyclosporin A, but these are no longer considered in treatment recommendations.

Recurrence after discontinuation of immunosuppressive therapy occurs in up to 20% of AH patients [4]. Therefore, regular follow-ups are highly recommended and should extend over more than one year. Patients who relapse may undergo renewed immunosuppressive treatment and may achieve a second complete remission or require long-term maintenance immunosuppression [12].

Prognosis

AH most frequently affects elder individuals suffering from comorbidities that may be related to considerable morbidity and mortality. Thus, survival times of these patients are generally limited to a few years, but death is not necessarily caused by hemorrhages and blood loss. In turn, AH may remain undiagnosed despite accounting for premature death. During a 2-year observational study realized in Wales, 9% of patients diagnosed with acquired hemophilia A died because of bleedings [4]. According to a retrospective study conducted in Europe, four-year survival rates of AH patients younger than 75 years amounted to 62%, while only 40% of elder individuals remained alive after that same time [5]. Besides young age, a patient's response to immunosuppressive therapy directly affected their prognosis. The aforecited study also included 42 cases of pregnancy-related AH; all of these patients survived.

Etiology

AH is an autoimmune disease; the production of autoantibodies directed against coagulation factors provokes a deficiency of the respective factor and thus interrupts the coagulation cascade. Similar to other autoimmune disorders, the precise trigger of the immune response against endogenous proteins remains unknown. However, an underlying disease may be detected in up to half of AH patients, and the disease is frequently related with malignant neoplasms, infectious diseases, additional autoimmune disorders, drug intake or pregnancy [2]. Due to the low incidence of AH in the respective groups of patients, additional, as-of-yet unknown factors are likely to be involved in the pathogenesis of AH. To date, affected individuals have not yet been shown to be genetically predisposed for AH.

AH may be associated with the presence of antibodies against the following coagulation factors [1] [3]:

  • Factors I, II, V, VII
  • Factor VIII (acquired hemophilia A)
  • Factor IX (acquired hemophilia B)
  • Factor X, XI, XII, XIII
  • Vitamin-K dependent proteins

Epidemiology

The overall incidence of acquired hemophilia A in UK has been estimated to be 1.5 per million per year [4]. Under the assumption that acquired hemophilia A accounts for about half of all AH cases, an annual incidence of 3 per million inhabitants may be assumed for the latter. However, diagnosis of AH is a major challenge and most patients are elder people with comorbidities. Thus, incidence rates are likely to be underestimated.

A predilection for Blacks has been suggested [2]. With regards to gender and age, a biphasic pattern may be recognized: The median age at symptom onset is >70 years, and 57% of elder patients presenting with AH are males. However, about one in ten cases is related to pregnancy and post-partal appearance of autoantibodies in females with a median age of 34 years [5]. Of note, these data refer to acquired hemophilia A. Reliable epidemiological data regarding other forms of AH cannot be provided at this moment.

Sex distribution
Age distribution

Pathophysiology

As has been indicated above, considerable knowledge gaps remain regarding the etiology and pathogenesis of AH. Both genetic and environmental factors may be involved in those processes, and it has been proposed that an aging immune system becomes increasingly susceptible to such influences [3]. In any case, the production of autoantibodies directed against coagulation factors implies a breakdown of immune tolerance. Because of distinct subsets of immune cells, namely CD4+ T helper cells, affect B cell mediated antibody release, it may be speculated that a dysfunctional regulation of antibody production was the result of T-cell anomalies [6].

Little is known about the pathophysiological relation between malignancies, infectious diseases, autoimmune disorders, pregnancy and the induction of an autoimmune response. However, tumor- or pathogen-derived antigens may trigger an immune response directed against degenerated cells or microorganisms, and in the case of cross-reactivity, produced antibodies may bind to endogenous structures. Although this theory seems plausible, epidemiological studies did not yet reveal a certain type of tumor or group of pathogens that would significantly increase a person's risk of developing AH.

Prevention

No specific measures can be recommended to prevent AH.

Summary

Acquired hemophilia (AH) is a rare disorder of unknown etiology. Production of autoantibodies of immunoglobulin types G, A, or M, directed against coagulation factors causes a propensity to bleed that manifests in form of spontaneous hemorrhages, e.g., epistaxis, melena and hematochezia, hematuria, and possibly intracranial hemorrhage.

A myriad of coagulation factors comprises what is commonly known as the coagulation cascade, a complex network of biochemical reactions whose respective products are required for the next step towards fibrin production, platelet aggregation, and clot formation. Autoantibodies may be directed against any coagulation factor, but half of AH patients develops a bleeding diathesis due to an autoimmune-mediated deficiency of factor VIII [1] [2]. Because patients suffering from an inherited deficiency of factor VIII are diagnosed with hemophilia A, the respective form of AH is designated acquired hemophilia A. Similarly, an autoimmune response to factor IX triggers acquired hemophilia B.

The majority of AH patients are older than 70 years, and about half of them present with malignancies or apparently unrelated autoimmune disease. Still, the remaining half of cases cannot be ascribed to any primary disease and is thus deemed idiopathic. Of note, women of child-bearing age may also develop AH. Here, pregnancy-related factors seem to induce the respective autoimmune response. In neither case, precise triggers are not identified. Lack of anamnestic data indicating a cause of hemophilia complicates the diagnosis of AH. In fact, it is currently assumed that AH is largely underdiagnosed.

Hemophilia is diagnosed by means of standard measures like measurements of coagulation times. Identification of an individual type of AH requires a more thorough workup that may include the assessment of the activity of single coagulation factors and inhibitor kinetics. With regards to treatment, severe hemorrhages require immediate attention, but therapy aims at eradicating the autoantibodies and reestablishing the coagulation cascade.

Patient Information

Hemophilia is a medical term that refers to a bleeding tendency; hemophilia is provoked by disturbances of the coagulation cascade, a complex network of biochemical reactions whose respective products are required for the next step towards fibrin production, platelet aggregation, and clot formation. For instance, a determined coagulation factor may be activated and thereby become the catalyst of the activation of the next coagulation factor. Any interruption of that cascade, possibly due to a deficiency of a coagulation factor, renders the affected individual prone to hemorrhages.

People suffering from congenital hemophilia have inherited defective genes encoding for dysfunctional coagulation factors. In contrast, acquired hemophilia (AH) is the result of an autoimmune reaction, i.e., of the production of antibodies directed against endogenous structures and subsequent inhibition of any coagulation factor. To date, it is not known how this autoimmune response is triggered, but a considerable share of AH patients present with cancer, another autoimmune disease, or an infection. Moreover, pregnant women are susceptible to AH. Otherwise, AH is typically diagnosed in patients aged 70 years and older.

Treatment consists of the control of hemorrhages - they may manifest in form of cutaneous hemorrhages, hematomas, nosebleeds, bloody urine or feces, etc. - and in suppressing the autoimmune response. Most patients respond well to therapy, but primary diseases like cancer may be associated with a poor prognosis.

Self-assessment

References

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  2. Kessler CM, Knobl P. Acquired haemophilia: an overview for clinical practice. Eur J Haematol. 2015;95(Suppl 81):36-44.
  3. Chang HH, Chiang BL. The diagnosis and classification of autoimmune coagulopathy: an updated review. Autoimmun Rev. 2014;13(4-5):587-590.
  4. Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood. 2007;109(5):1870-1877.
  5. Knoebl P, Marco P, Baudo F, et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost. 2012;10(4):622-631.
  6. Reding MT. Immunological aspects of inhibitor development. Haemophilia. 2006;12(Suppl 6):30-36.
  7. Burish MJ, Aysenne A, Singh V. Multifocal subdural hematomas as the presenting sign of acquired hemophilia A: a case report. BMC Res Notes. 2014;7:134.
  8. Ma AD, Carrizosa D. Acquired factor VIII inhibitors: pathophysiology and treatment. Hematology Am Soc Hematol Educ Program. 2006;2006:432-437.
  9. Collins P, Baudo F, Huth-Kuhne A, et al. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes. 2010; 3:161.
  10. Janbain M, Leissinger CA, Kruse-Jarres R. Acquired hemophilia A: emerging treatment options. J Blood Med. 2015;6:143-150.
  11. Huth-Kühne A, Baudo F, Collins P, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. 2009;94(4):566-575.
  12. Hay CR, Brown S, Collins PW, Keeling DM, Liesner R. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol. 2006;133(6):591-605.



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