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].

Skin
Petechiae
  • Skin Petechiae Platelet Coagulation Purpura Ecchymoses Petechiae 9.[symptoma.com]
  • Platelet Coagulation Purpura Ecchymoses Petechiae 9.[slideshare.net]
  • Aside from the extensive bruising of both hands, no other bruising, petechiae or sites of active bleeding were discovered, and there was no evidence of hemarthrosis.[pubmedcentralcanada.ca]
  • Other authors, after reviewing the Veterans Administration population, state that this may be because of the fact that in blacks, the presence of petechiae and ecchymoses may not be recognized [20,21] .[journals.lww.com]
Skin Bleeding
  • Skin bleedings ranging from petechia to ecchymosis are common.[symptoma.com]
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  • urogenital
    Hematuria
    • [journals.lww.com] more... urogenital Hematuria Keywords: Hemophilia, systemic lupus erythematosus, factor VIII, hematoma, autoimmune diseases, hematuria .[symptoma.com]
    • Keywords: Hemophilia, systemic lupus erythematosus, factor VIII, hematoma, autoimmune diseases, hematuria.[eurekaselect.com]
    • Hematuria was relieved followed by normalization of creatinine.[ijccm.org]
    • Other frequent manifestations of acquired hemophilia include melena, hematuria, and iatrogenic bleeding, particularly after attempts to insert intravenous (IV) lines.[emedicine.medscape.com]
    • Signs and symptoms include prolonged bleeding, frequent nosebleeds, bruising throughout the body, solid swellings of congealed blood (hematomas), hematuria , and gastrointestinal or urologic bleeding.[rarediseases.info.nih.gov]
    Urogenital Bleeding
    • [rarediseases.info.nih.gov] Urogenital Bleeding 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[symptoma.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.[webmd.com]
    • 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.[cigna.com]
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  • hematological
    Subcutaneous Bleeding
    • Subcutaneous bleeding and ‘extremity NOS’ were not reported in the same patients.[journals.lww.com]
    • [cigna.com] more... hematological Subcutaneous Bleeding Subcutaneous bleeding and ‘extremity NOS’ were not reported in the same patients.[symptoma.com]
    • Severe bleeding following invasive procedures is almost inevitable, and venipuncture commonly results in extensive subcutaneous bleeding.[bmcresnotes.biomedcentral.com]
    • She was referred for hematology consultation because of spontaneous subcutaneous bleeding and bruising of her upper and lower extremities, with the largest ecchymotic area extending from her right groin to her knee.[omicsonline.org]
    • Diagnosis Clinical Presentation: Any recent onset of bleeding with unexplained aPTT prolongation should raise suspicion of AHA, especially in the setting of advanced age or the peripartal period. 1,3 The most common clinical presentation in AHA is subcutaneous[uspharmacist.com]
    Easy Bruising
    • They may experience joint bleeds or easy bruising. [20] Mild haemophilia may only be discovered later, usually after an injury or a dental or surgical procedure.[en.wikipedia.org]
    • Bruising They may experience joint bleeds or easy bruising . [20] Mild haemophilia may only be discovered later, usually after an injury or a dental or surgical procedure.[symptoma.com]
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  • cardiovascular
    Cyanosis
    • [en.wikipedia.org] more... cardiovascular Cyanosis [www.symptoma.com] more... cardiovascular Cyanosis ., fatigue, headaches, palpitations, dyspnea, and cyanosis .[symptoma.com]
    Palpitations
    • ., fatigue , headaches, palpitations , dyspnea , and cyanosis .[symptoma.com]
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  • gastrointestinal
    Melena
    • Other frequent manifestations of acquired hemophilia include melena, hematuria, and iatrogenic bleeding, particularly after attempts to insert intravenous (IV) lines.[emedicine.medscape.com]
    • [symptoma.com] more... gastrointestinal Melena [www.symptoma.com] Melena Other frequent manifestations of acquired hemophilia include melena , hematuria, and iatrogenic bleeding, particularly after attempts to insert intravenous (IV) lines.[symptoma.com]
    • Affected individuals may also experience frequent nose bleeds, gastrointestinal bleeding (black, tarry stools - melena) or genitourinary bleeding (blood in the urine), Hematomas, which are solid swellings of congealed blood, may form in the space behind[cigna.com]
    Hematochezia
    • [www.symptoma.com] more... gastrointestinal Hematochezia Furthermore, most patients experience epistaxis, gastrointestinal hemorrhages provoking melena and/or hematochezia , and hematuria due to lesions of the urinary tract.[symptoma.com]
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  • respiratoric
    Dyspnea
    • ., fatigue , headaches, palpitations , dyspnea , and cyanosis .[symptoma.com]
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  • neurologic
    Intracranial Hemorrhage
    • [symptoma.com] more... neurologic Intracranial Hemorrhage This particularly applies in the case of an intracranial hemorrhage .[symptoma.com]
    • Patients will typically present with subcutaneous bruising, mucosal and soft tissue bleeds such as intracranial hemorrhage, muscle bleeds and retroperitoneal hematoma [ 6 ].[omicsonline.org]
    • Subcutaneous/skin 81 23 Muscle 45 32 Subcutaneous only 24 Gastrointestinal/intrabdominal 23 14 Genital urinary 9 18 Retroperitoneal/thoracic 9 5 Other 9 23 Post-operative 11 Joint 7 2 None 4 Intracranial hemorrhage 3 Fatal 9 No haemostatic treatment required[bmcresnotes.biomedcentral.com]
    • Not all possible situations can be foreseen, but in general, retroperitoneal or retropharyngeal hematomas, muscle bleeds with or without compartment syndromes, intracranial hemorrhage, gastrointestinal, pulmonary or postoperative bleeding, severe hematuria[haematologica.org]
    Headache
    • ., fatigue , headaches, palpitations , dyspnea , and cyanosis .[symptoma.com]
    • […] bleeding inside joints or the brain . [1] Those with a mild case of the disease may have symptoms only after an accident or during surgery. [1] Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches[en.wikipedia.org]
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  • Face, Head & Neck
    Epistaxis
    • Face, Head & Neck Epistaxis Face, Head & Neck Epistaxis The etiology underlying the difference in bleeding symptomatology between acquired and congenital hemophilia is unknown. [ 8 ] Typical signs of acquired hemophilia A include overt bleeding, epistaxis[symptoma.com]
    • The etiology underlying the difference in bleeding symptomatology between acquired and congenital hemophilia is unknown. [ 8 ] Typical signs of acquired hemophilia A include overt bleeding, epistaxis, gastrointestinal (GI) and urologic bleeding, and retroperitoneal[emedicine.medscape.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.[webmd.com]
    • 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]
    • CLINICAL FEATURES OF BLEEDING DISORDERS Platelet Factor Disorders Coagulation disorders Site of bleeding Skin, Mucous membranes (epistaxis, gum, vaginal, GI tract) Deep in soft tissues (joints, muscles) Petechiae Yes No Ecchymoses (“bruises”) Small, superficial[slideshare.net]
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  • Entire body system
    Anemia
    • Here, anemia is the result of occult hemorrhages.[symptoma.com]
    • Laboratory evaluations were done and showed mild anemia (HB 10.7 gr/Dl) and prolonged partial thrombin time (PTT 80 second).[austinpublishinggroup.com]
    • […] hemophilia Deficiency factor VIII (with functional defect) Hemophilia NOS Hemophilia A Type 1 Excludes factor VIII deficiency with vascular defect ( D68.0 ) acquired D68.311 autoimmune D68.311 secondary D68.311 ICD-10-CM Codes Adjacent To D68.311 D64.9 Anemia[icd10data.com]
    • Laboratory tests showed profound anemia, owing to blood loss, a normal platelet count, and leukocytosis.[nature.com]
    • Blood transfusions are sometimes necessary for anemia (low blood counts) after losing a significant amount of blood.[rarebleedingdisorders.com]
    Ecchymosis
    • The patient manifested spontaneous ecchymosis (Fig. 1–3).[termedia.pl]
    • [rarebleedingdisorders.com] Ecchymosis The patient manifested spontaneous ecchymosis (Fig. 1–3).[symptoma.com]
    • She developed haematouria, ecchymosis, and intramuscular bleeding following the severe OHSS.[academic.oup.com]
    • FVIII. [3] The diagnosis of AH should be considered in the actively bleeding patient, with no personal or family history of bleeding diatheses, particularly in the elderly and during postpartum. [1] Our patient had 1.5 months, history of hematuria and ecchymosis[ijccm.org]
    • Presentation: Any recent onset of bleeding with unexplained aPTT prolongation should raise suspicion of AHA, especially in the setting of advanced age or the peripartal period. 1,3 The most common clinical presentation in AHA is subcutaneous bleeding and ecchymosis[uspharmacist.com]
    Fatigue
    • ., fatigue , headaches, palpitations , dyspnea , and cyanosis .[symptoma.com]
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  • Jaw & Teeth
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  • 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.

    Laboratory

    Serum
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  • 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.

    Complications

    Shock
    • Complications Shock In case of shock , standard medical treatment for shock should be implemented.[symptoma.com]
    • In case of shock, standard medical treatment for shock should be implemented.[businesswire.com]
    • We report the case of a 32-years-old woman, admitted in hemorrhagic shock, following a non-reversible bleeding after dental extraction.[degruyter.com]
    • She recovered from the hypovolaemic shock on hospital day 14.[academic.oup.com]
    • However, at presentation, she was in cardiogenic shock with low LVEF.[ijccm.org]
    Anemia
    • Here, anemia is the result of occult hemorrhages.[symptoma.com]
    • Laboratory evaluations were done and showed mild anemia (HB 10.7 gr/Dl) and prolonged partial thrombin time (PTT 80 second).[austinpublishinggroup.com]
    • […] hemophilia Deficiency factor VIII (with functional defect) Hemophilia NOS Hemophilia A Type 1 Excludes factor VIII deficiency with vascular defect ( D68.0 ) acquired D68.311 autoimmune D68.311 secondary D68.311 ICD-10-CM Codes Adjacent To D68.311 D64.9 Anemia[icd10data.com]
    • Laboratory tests showed profound anemia, owing to blood loss, a normal platelet count, and leukocytosis.[nature.com]
    • Blood transfusions are sometimes necessary for anemia (low blood counts) after losing a significant amount of blood.[rarebleedingdisorders.com]
    Bleeding Diathesis
    • [rarebleedingdisorders.com] Bleeding Diathesis Complications Bleeding Diathesis In less than 20% of patients, the bleeding diathesis is only registered upon trauma, childbirth or surgery.[symptoma.com]
    • Acquired hemophilia is a rare clinical entity characterized by bleeding diathesis induced by circulating inhibitors to coagulation factors (VIII ou IX) that compromise hemostasis.[endocrine-abstracts.org]
    • Available from: » Introduction Acquired hemophilia (AH) is a rare bleeding diathesis characterized by development of autoantibody against coagulation factor VIII (FVIII) and significant bleeding episodes causing high morbidity and mortality. [1] The severity[ijccm.org]
    Cerebral Hemorrhages
    • Prolonged postpartum bleeding, excessive bleeding after trauma or surgery, and, occasionally, cerebral hemorrhage may also occur. [1][emedicine.medscape.com]
    • […] brain ( cerebral hemorrhage ).[symptoma.com]
    • In rare cases, affected individuals have developed bleeding on the brain (cerebral hemorrhage).[cigna.com]
    • Muscle bleeding episodes can be severe and can lead to compartment syndrome and tissue death. [8] Other manifestations include prolonged postpartum bleeding, excessive bleeding following surgery or trauma , and, occasionally, cerebral hemorrhage. [1,[emedicine.medscape.com]
    Epistaxis
    • Face, Head & Neck Epistaxis Face, Head & Neck Epistaxis The etiology underlying the difference in bleeding symptomatology between acquired and congenital hemophilia is unknown. [ 8 ] Typical signs of acquired hemophilia A include overt bleeding, epistaxis[symptoma.com]
    • The etiology underlying the difference in bleeding symptomatology between acquired and congenital hemophilia is unknown. [ 8 ] Typical signs of acquired hemophilia A include overt bleeding, epistaxis, gastrointestinal (GI) and urologic bleeding, and retroperitoneal[emedicine.medscape.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.[webmd.com]
    • 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]
    • CLINICAL FEATURES OF BLEEDING DISORDERS Platelet Factor Disorders Coagulation disorders Site of bleeding Skin, Mucous membranes (epistaxis, gum, vaginal, GI tract) Deep in soft tissues (joints, muscles) Petechiae Yes No Ecchymoses (“bruises”) Small, superficial[slideshare.net]
    Gastrointestinal Hemorrhage
    • Hemorrhage [www.symptoma.com] Gastrointestinal Hemorrhage Furthermore, most patients experience epistaxis, gastrointestinal hemorrhages provoking melena and/or hematochezia, and hematuria due to lesions of the urinary tract.[symptoma.com]
    Compartment Syndrome
    • syndrome, with compression of the neurovascular bundles.[emedicine.medscape.com]
    • Muscle bleeds may lead to compartment syndrome .[symptoma.com]
    • She was initially diagnosed to have compartment syndrome of her left upper extremity secondary to an expanding hematoma after multiple unsuccessful venipuncture attempts.[anesthpain.com]
    • Along with severe bleeding, patients may experience complications such as compartment syndrome and hemorrhagic stroke.[pubmedcentralcanada.ca]
    Hemarthrosis
    • Mots clés : Hemarthrosis ; Acquired hemophilia ; Anti-factor VIII antibody.[em-consulte.com]
    • [pubmedcentralcanada.ca] Hemarthrosis Mots clés : Hemarthrosis ; Acquired hemophilia ; Anti-factor VIII antibody.[symptoma.com]
    • Patient was ultimately found to have a renal cell carcinoma (RCC) and diagnosed with hemarthrosis likely secondary to acquired Factor VIII inhibitor from his underlying RCC.[uscmedicine.blog]
    • Unlike in congenital hemophilia, hemarthrosis is rare.[pubmedcentralcanada.ca]
    Postpartum Hemorrhage
    • Hemorrhage Other comorbidities included surgery/intervention (11.7%), postpartum hemorrhage (PPH) (3.4%), trauma (1.4%), other (15.9%), and not specified (44.1%) (Tables 2 and 3).[symptoma.com]
    • Other comorbidities included surgery/intervention (11.7%), postpartum hemorrhage (PPH) (3.4%), trauma (1.4%), other (15.9%), and not specified (44.1%) (Tables 2 and 3).[journals.lww.com]
    Retroperitoneal Hematoma
    • The etiology underlying the difference in bleeding symptomatology between acquired and congenital hemophilia is unknown. [ 8 ] Typical signs of acquired hemophilia A include overt bleeding, epistaxis, gastrointestinal (GI) and urologic bleeding, and retroperitoneal[emedicine.medscape.com]
    • Retroperitoneal hematoma has repeatedly been reported.[symptoma.com]
    • Patients will typically present with subcutaneous bruising, mucosal and soft tissue bleeds such as intracranial hemorrhage, muscle bleeds and retroperitoneal hematoma [ 6 ].[omicsonline.org]
    Hematoma
    • . [1, 8 , 5] Spontaneous bruising and muscle hematomas are most frequent. [ 4 ] If untreated, bleeding into the muscles may progress into a compartment syndrome, with compression of the neurovascular bundles.[emedicine.medscape.com]
    • Retroperitoneal hematoma has repeatedly been reported.[symptoma.com]
    • Keywords: Hemophilia, systemic lupus erythematosus, factor VIII, hematoma, autoimmune diseases, hematuria.[eurekaselect.com]
    • Therefore, surgical exploration, fasciotomy, and evacuation of a large hematoma were performed.[anesthpain.com]
    • Large hematomas of the right kidney and the right psoas.[nature.com]

    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

    Causes

    Gastrointestinal Hemorrhage
    • Hemorrhage [www.symptoma.com] Gastrointestinal Hemorrhage Furthermore, most patients experience epistaxis, gastrointestinal hemorrhages provoking melena and/or hematochezia, and hematuria due to lesions of the urinary tract.[symptoma.com]

    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.

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    References

    1. Franchini M, Lippi G, Favaloro EJ. Acquired inhibitors of coagulation factors: part II. Semin Thromb Hemost. 2012;38(5):447-453.
    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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