Case reports © The Intensive Care Society 2012 Volume 13, Number 4, October 2012 JICS 346 Acquired haemophilia A (AHA) is an uncommon but potentially life-threatening cause of bleeding. It is an autoimmune disease caused by the spontaneous development of an autoantibody (inhibitor) to endogenous factor VIII (FVIII) 1-3 in individuals with previously normal coagulation. The worldwide incidence of AHA is estimated to be between 1 and 4.8 per million per year. 1,3,4 Patients may require intensive care due to complications of haemorrhage or immunosuppressive therapy. Half of the cases of AHA are idiopathic and the other half may be associated with malignancy, autoimmune disorders, vaccination, acute infection, pregnancy or respiratory disorders. 1-5 Clinical presentation is typically subcutaneous bruising, mucosal and soft tissue bleeding and retroperitoneal or intracerebral haemorrhage. 1,2,5,6 Case report A 68-year-old man presented to his local district general hospital with a two-day history of left groin pain and numbness in the left thigh. He had a past medical history of severe chronic obstructive pulmonary disease, previous splenectomy for a benign cyst and high alcohol intake. Examination revealed a very tender left leg and thigh with groin swelling. Blood tests showed a haemoglobin of 7.2 g/dL, platelet count 349 × 10 9 /L. The patient had acute kidney injury (stage 2). An abdominal and pelvic CT scan revealed an ilio- psoas haematoma but no aortic aneurysm. The patient was transferred urgently to the local vascular unit where a coagulation profile was requested. A femoral angiogram was performed on the following day, which failed to reveal a source of the bleeding. Haemostasis at the femoral puncture site was achieved with an Angio-seal TM . The clotting profile was subsequently noted to be abnormal and was discussed with a haematology specialist who requested further investigations. The patient was admitted to the intensive care unit (ICU) that evening with worsening renal function, hypoxaemia and persistent hypotension. He had extensive superficial bruising on the trunk, arms and genitalia, and haematuria. Progressively worsening renal function necessitated continuous renal replacement therapy. Further organ support with mechanical ventilation and vasopressor therapy were commenced as indicated by the clinical deterioration. After 12 hours on the ICU, bleeding was noted from puncture sites. A review of coagulation was summarised as follows: • activated partial thromboplastin time (APTT), 70.4s (normal range 27.2-35.2s) • prothrombin time (PT), normal • fibrinogen 4.5 g/L (1.5-4.5 g/L). In light of the prolonged APTT, correction studies were performed. Initial 50:50 mixing studies showed correction to APTT 41.6s. Further studies, however, indicated time- dependent progressive inhibition of the APTT with incubation. A factor VIII level of 8% was obtained with a Bethesda inhibitor assay of 16.0 Beth U/mL (normal <1 Beth U/mL). A diagnosis of AHA was made. Factor eight bypassing activity (FEIBA) 6,000 units IV tds and methylprednisolone were started. The patient continued to require transfusions of red cells, fresh frozen plasma and FEIBA. Weekly cyclophosphamide was commenced on the haematology team’s advice. After six days on the ICU, he developed pancytopenia and gram-negative sepsis with Klebsiella sp and Serratia marsecens. His clinical condition progressively deteriorated despite aggressive management. He died after 12 days of ICU care. Discussion We present a case of a patient with an ilio-psoas haematoma who was initially referred to the vascular surgeons with a presumed diagnosis of aortic or iliac aneurysm. Although there was a history of spontaneous bruising and no obvious source of bleeding, a bleeding diathesis was only considered relatively late in the patient’s admission. This report highlights the fact that lack of awareness of AHA may contribute to under- diagnosis. It also emphasises the importance of requesting a complete coagulation screen including a PT, APTT and fibrinogen to fully assess a patient’s coagulation system. Acquired haemophilia A — a rare cause of bleeding 3A13 V Patle, SE Crawford, RJ Grace, RE Edwards This article reports a patient with acquired haemophilia who presented with life-threatening haemorrhage. Acquired haemophilia A is a rare autoimmune disorder caused by the development of an autoantibody to endogenous factor VIII. The diagnosis and management of the condition are reviewed. A high index of suspicion is essential for the accurate and prompt diagnosis of acquired haemophilia A, when the patient is bleeding and has an isolated abnormality in APTT. Keywords: acquired haemophilia; intensive care; mixing test; APTT
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Acquired Haemophilia A – A Rare Cause of BleedingCase reports © The Intensive Care Society 2012
Volume 13, Number 4, October 2012 JICS346
Acquired haemophilia A (AHA) is an uncommon but potentially life-threatening cause of bleeding. It is an autoimmune disease caused by the spontaneous development of an autoantibody (inhibitor) to endogenous factor VIII (FVIII)1-3 in individuals with previously normal coagulation. The worldwide incidence of AHA is estimated to be between 1 and 4.8 per million per year.1,3,4 Patients may require intensive care due to complications of haemorrhage or immunosuppressive therapy. Half of the cases of AHA are idiopathic and the other half may be associated with malignancy, autoimmune disorders, vaccination, acute infection, pregnancy or respiratory disorders.1-5 Clinical presentation is typically subcutaneous bruising, mucosal and soft tissue bleeding and retroperitoneal or intracerebral haemorrhage.1,2,5,6
Case report A 68-year-old man presented to his local district general hospital with a two-day history of left groin pain and numbness in the left thigh. He had a past medical history of severe chronic obstructive pulmonary disease, previous splenectomy for a benign cyst and high alcohol intake.
Examination revealed a very tender left leg and thigh with groin swelling. Blood tests showed a haemoglobin of 7.2 g/dL, platelet count 349 × 109/L. The patient had acute kidney injury (stage 2). An abdominal and pelvic CT scan revealed an ilio- psoas haematoma but no aortic aneurysm. The patient was transferred urgently to the local vascular unit where a coagulation profile was requested. A femoral angiogram was performed on the following day, which failed to reveal a source of the bleeding. Haemostasis at the femoral puncture site was achieved with an Angio-sealTM. The clotting profile was subsequently noted to be abnormal and was discussed with a haematology specialist who requested further investigations.
The patient was admitted to the intensive care unit (ICU) that evening with worsening renal function, hypoxaemia and persistent hypotension. He had extensive superficial bruising on the trunk, arms and genitalia, and haematuria.
Progressively worsening renal function necessitated continuous renal replacement therapy. Further organ support with mechanical ventilation and vasopressor therapy were commenced as indicated by the clinical deterioration. After 12 hours on the ICU, bleeding was noted from puncture sites. A review of coagulation was summarised as follows: • activated partial thromboplastin time (APTT), 70.4s
(normal range 27.2-35.2s) • prothrombin time (PT), normal • fibrinogen 4.5 g/L (1.5-4.5 g/L).
In light of the prolonged APTT, correction studies were performed. Initial 50:50 mixing studies showed correction to APTT 41.6s. Further studies, however, indicated time- dependent progressive inhibition of the APTT with incubation. A factor VIII level of 8% was obtained with a Bethesda inhibitor assay of 16.0 Beth U/mL (normal <1 Beth U/mL).
A diagnosis of AHA was made. Factor eight bypassing activity (FEIBA) 6,000 units IV tds and methylprednisolone were started. The patient continued to require transfusions of red cells, fresh frozen plasma and FEIBA. Weekly cyclophosphamide was commenced on the haematology team’s advice.
After six days on the ICU, he developed pancytopenia and gram-negative sepsis with Klebsiella sp and Serratia marsecens. His clinical condition progressively deteriorated despite aggressive management. He died after 12 days of ICU care.
Discussion We present a case of a patient with an ilio-psoas haematoma who was initially referred to the vascular surgeons with a presumed diagnosis of aortic or iliac aneurysm. Although there was a history of spontaneous bruising and no obvious source of bleeding, a bleeding diathesis was only considered relatively late in the patient’s admission. This report highlights the fact that lack of awareness of AHA may contribute to under- diagnosis. It also emphasises the importance of requesting a complete coagulation screen including a PT, APTT and fibrinogen to fully assess a patient’s coagulation system.
Acquired haemophilia A — a rare cause of bleeding 3A13
V Patle, SE Crawford, RJ Grace, RE Edwards
This article reports a patient with acquired haemophilia who presented with life-threatening haemorrhage. Acquired
haemophilia A is a rare autoimmune disorder caused by the development of an autoantibody to endogenous factor VIII.
The diagnosis and management of the condition are reviewed. A high index of suspicion is essential for the accurate and
prompt diagnosis of acquired haemophilia A, when the patient is bleeding and has an isolated abnormality in APTT.
Keywords: acquired haemophilia; intensive care; mixing test; APTT
JICS Volume 13, Number 4, October 2012 347
Although a rare condition, the diagnosis of AHA should be considered in patients over 60 years of age who present with spontaneous bleeding5 and an isolated finding of a raised APTT. Early diagnosis and treatment may improve outcome. It may present as subcutaneous haematomata or soft tissue bleed such as a muscle haematoma or mucosal bleed.1,2,5,6 It may also present as an unexplained post-surgical bleed, post-partum haemorrhage, retroperitoneal haemorrhage or intra-cerebral bleed. The differential diagnosis of a similar clinical picture includes trauma (including non-accidental injury), other bleeding disorders such as clotting factor deficiency, haemolytic conditions or platelet dysfunction.
The diagnosis of AHA can be difficult as there is usually no history of personal or family bleeding disorders and the disease is rare. The European Acquired Haemophilia Registry (EACH2) reports a delay of an average of three days between the onset of bleeding and diagnosis.1 All blood results including coagulation tests may be normal except for an isolated rise in APTT. A high index of suspicion is therefore essential for the accurate and prompt diagnosis of AHA. Our patient had the diagnosis made on day one of intensive care following the finding of an isolated raised APTT (sometimes expressed as a ratio of patient’s result/control result – APTT-R) in the context of spontaneous and severe bleeding. The morbidity and mortality from AHA can be very high and may be related to bleeding, underlying pathology or as a complication of treatment. Our patient had significant co- morbidities, which contributed to his poor outcome.
AHA can be confirmed by the presence of low factor VIII level and evidence of inhibitor (FVIII antibody) in the plasma, in the presence of an isolated raised APTT. After ruling out other causes of prolonged APTT such as heparin contamination, a ‘mixing test’ should be performed. This is done by mixing the patient’s plasma with normal plasma (usually in equal volumes – the 50:50 mix), followed by incubation at 37°C. The mixing test results in correction of APTT if the prolonged APTT is simply the result of a coagulation factor deficiency. If the APTT is not corrected on the mixing test and lupus anticoagulant is negative, this implies the presence of an inhibitor of one or more of the coagulation factors in the intrinsic coagulation pathway, most commonly an inhibitor to factor VIII (AHA). The activity of this inhibitor is time-dependent, ie its effect is more pronounced if the APPT test is performed after incubation of the patient and normal plasma for two hours. In AHA, in most cases APTT will not be corrected on the addition of normal test, but in others (as in our case), there is immediate correction, followed by lengthening of APTT over time.7
Treatment must be commenced promptly once AHA is diagnosed, and consists of control of bleeding, eradication of the inhibitor and treatment of the underlying disorder. The treatment of choice for the control of bleeding consists of recombinant activated factor VII (rVIIa) and factor VIII inhibitor bypassing activity (FEIBA). Both these agents act as bypassing agents for achieving adequate haemostasis. Factor VIII concentrates and desmopressin may have some role in haemostasis in the presence of low inhibitor titre and act by
increasing the levels of circulating factor VIII.1,8-10 Inhibitor inhibition is achieved by using immunosuppressive agents. Steroids alone or in combination with cyclophosphamide are usually started as first-line treatment for eradication of inhibitors.5 Remission in AHA can be expected after a few weeks of commencing immunosuppression.5,7 Other agents used for inhibitor eradication are intravenous immunoglobulins, rituximab, cyclosporin A and vincristine.1,5,11 Twenty percent of the patients experience a relapse and may require further immunosuppression.1
Our patient was already critically ill when he was referred to intensive care. Significant co-morbidity, renal failure and then sepsis with multiple organ failure in the presence of pancytopenia and therapeutic immunosuppression contributed to his death. Patients who respond well to treatment will typically go into remission.
References 1. Collins PW. Management of acquired haemophilia A. J Thromb Haemostat
2011; 9 (suppl.1): 226-35. 2. Holme PA, Brosstad F, Tjonnfjord GE. Acquired haemophilia:
management of bleeds and immune therapy to eradicate autoantibodies. Haemophilia 2005;11:510-15.
3. Huth-Kuhne A, Baudo F, Collind P et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009;94:566-75.
4. Harper M, Obolensky L, Roberts P, Mercer M. A case of acute upper and lower airway obstruction due to retropharyngeal haemorrhage secondary to acquired haemophilia A. Anaesthesia 2007;62:627-30.
5. Shetty S, Bhave M, Ghosh K. Acquired haemophilia A: Diagnosis, aetiology, clinical spectrum and treatment options. Autoimmune Rev 2011; 10:311-16.
6. Collins P, Macartney N, Davies R et al. A population based, unselected, consecutive cohort of patients with acquired haemophila A. Br J Haematol 2004;124:86-90.
7. World Federation of Hemophilia. Mixing tests for further investigation of abnormal PT and APTT. 2010. Accessed at http://www.wfh.org/2/docs/ Publications/Diagnosis_and_Treatment/Lab_Manual2010/Lab_Manual_Se ction-14.pdf. Accessed 31 May 12.
8. Franchini M, Lippi G. The use of desmopressin in acquired haemophilia A: a systematic review. Blood Transfusion 2011;9:377-82.
9. Tufano A, Coppola A, Guida A et al. Acquired haemophilia A in the elderly: Case Reports. Curr Gerontl Geriatr Res 2010;2010:927503.
10.Brack A, Vogeler S, Hilpert J et al. Acquired Factor VIII inhibitor. Anesthesiol 2009;111:1151-54.
11.Clatworthy M, Jayne D R W. Acquired haemophilia in association with ANCA-associated vasculitis: Response to rituximab. Am J Kidney Dis 2006;47:680-82.
Vidhi Patle Registrar, Anaesthesia
Rhian E Edwards Consultant, Anaesthesia and Intensive Care
Medicine
[email protected]
Case reports
Commentary:
Acquired haemophilia is a rare disease that is due to the production of IgG autoantibodies directed against a
coagulation factor, most commonly factor VIII. This results in a much-reduced generation of thrombin through the intrinsic coagulation pathway and consequently potentially severe spontaneous bleeding. This autoimmune disease occurs without any clear cause in over half of all cases, but in other instances may be associated with a wide range of disorders including autoimmune conditions, ulcerative colitis, malignancies, pregnancy, and secondary to some drugs. Unlike inherited sex-linked haemophilia A, which affects males, it occurs in both sexes and is most commonly seen in the elderly. In the UK the incidence has been reported as 1.48 per million per year.
Spontaneous bleeding can occur into the skin, muscles, soft tissue and mucous membranes, as well as following trauma, surgery, or childbirth and can occasionally be intra-cerebral. The bleeding can be severe and life threatening – the mortality of acquired haemophilia is variously estimated to be between about 8% and 20%, depending on the response to treatment.1
The platelet count and prothrombin time are normal in acquired haemophilia, but the activated partial thromboplastin time (APTT), which reflects the intrinsic coagulation pathway, is prolonged. This prolongation is not corrected by the addition of normal plasma to the in vitro test plasma (the mixing study), which differentiates it from a factor deficiency,
in which such a mixing study results in correction of the APTT. Additional laboratory tests differentiate it from other inhibitors (eg the lupus anticoagulant, heparin).
Treatment is initially directed at the management of the acute bleeding episode with the use of either factor VIII concentrate (if the inhibitor level is low) or other concentrates (recombinant factor VII, FEIBA – factor eight inhibitor bypassing activity). Immuno-adsorption and plasmapheresis may be used if the titre of the antibody is high. Immunosuppression is then usually required in the long term to reduce the level of the autoantibody. Immunosuppressive agents include steroids, cyclophosphamide, rituximab, intravenous immunoglobulin, and cyclosporine. If the patient is found to have an associated malignancy then this should be treated, as control of the autoantibody is then made easier.
Reference 1. Collins PW, Hirsch S, Baglin T 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: 1870-77.
Francis Matthey Haematologist, Chelsea and Westminster
Hospital
[email protected]
Volume 13, Number 4, October 2012 JICS346
Acquired haemophilia A (AHA) is an uncommon but potentially life-threatening cause of bleeding. It is an autoimmune disease caused by the spontaneous development of an autoantibody (inhibitor) to endogenous factor VIII (FVIII)1-3 in individuals with previously normal coagulation. The worldwide incidence of AHA is estimated to be between 1 and 4.8 per million per year.1,3,4 Patients may require intensive care due to complications of haemorrhage or immunosuppressive therapy. Half of the cases of AHA are idiopathic and the other half may be associated with malignancy, autoimmune disorders, vaccination, acute infection, pregnancy or respiratory disorders.1-5 Clinical presentation is typically subcutaneous bruising, mucosal and soft tissue bleeding and retroperitoneal or intracerebral haemorrhage.1,2,5,6
Case report A 68-year-old man presented to his local district general hospital with a two-day history of left groin pain and numbness in the left thigh. He had a past medical history of severe chronic obstructive pulmonary disease, previous splenectomy for a benign cyst and high alcohol intake.
Examination revealed a very tender left leg and thigh with groin swelling. Blood tests showed a haemoglobin of 7.2 g/dL, platelet count 349 × 109/L. The patient had acute kidney injury (stage 2). An abdominal and pelvic CT scan revealed an ilio- psoas haematoma but no aortic aneurysm. The patient was transferred urgently to the local vascular unit where a coagulation profile was requested. A femoral angiogram was performed on the following day, which failed to reveal a source of the bleeding. Haemostasis at the femoral puncture site was achieved with an Angio-sealTM. The clotting profile was subsequently noted to be abnormal and was discussed with a haematology specialist who requested further investigations.
The patient was admitted to the intensive care unit (ICU) that evening with worsening renal function, hypoxaemia and persistent hypotension. He had extensive superficial bruising on the trunk, arms and genitalia, and haematuria.
Progressively worsening renal function necessitated continuous renal replacement therapy. Further organ support with mechanical ventilation and vasopressor therapy were commenced as indicated by the clinical deterioration. After 12 hours on the ICU, bleeding was noted from puncture sites. A review of coagulation was summarised as follows: • activated partial thromboplastin time (APTT), 70.4s
(normal range 27.2-35.2s) • prothrombin time (PT), normal • fibrinogen 4.5 g/L (1.5-4.5 g/L).
In light of the prolonged APTT, correction studies were performed. Initial 50:50 mixing studies showed correction to APTT 41.6s. Further studies, however, indicated time- dependent progressive inhibition of the APTT with incubation. A factor VIII level of 8% was obtained with a Bethesda inhibitor assay of 16.0 Beth U/mL (normal <1 Beth U/mL).
A diagnosis of AHA was made. Factor eight bypassing activity (FEIBA) 6,000 units IV tds and methylprednisolone were started. The patient continued to require transfusions of red cells, fresh frozen plasma and FEIBA. Weekly cyclophosphamide was commenced on the haematology team’s advice.
After six days on the ICU, he developed pancytopenia and gram-negative sepsis with Klebsiella sp and Serratia marsecens. His clinical condition progressively deteriorated despite aggressive management. He died after 12 days of ICU care.
Discussion We present a case of a patient with an ilio-psoas haematoma who was initially referred to the vascular surgeons with a presumed diagnosis of aortic or iliac aneurysm. Although there was a history of spontaneous bruising and no obvious source of bleeding, a bleeding diathesis was only considered relatively late in the patient’s admission. This report highlights the fact that lack of awareness of AHA may contribute to under- diagnosis. It also emphasises the importance of requesting a complete coagulation screen including a PT, APTT and fibrinogen to fully assess a patient’s coagulation system.
Acquired haemophilia A — a rare cause of bleeding 3A13
V Patle, SE Crawford, RJ Grace, RE Edwards
This article reports a patient with acquired haemophilia who presented with life-threatening haemorrhage. Acquired
haemophilia A is a rare autoimmune disorder caused by the development of an autoantibody to endogenous factor VIII.
The diagnosis and management of the condition are reviewed. A high index of suspicion is essential for the accurate and
prompt diagnosis of acquired haemophilia A, when the patient is bleeding and has an isolated abnormality in APTT.
Keywords: acquired haemophilia; intensive care; mixing test; APTT
JICS Volume 13, Number 4, October 2012 347
Although a rare condition, the diagnosis of AHA should be considered in patients over 60 years of age who present with spontaneous bleeding5 and an isolated finding of a raised APTT. Early diagnosis and treatment may improve outcome. It may present as subcutaneous haematomata or soft tissue bleed such as a muscle haematoma or mucosal bleed.1,2,5,6 It may also present as an unexplained post-surgical bleed, post-partum haemorrhage, retroperitoneal haemorrhage or intra-cerebral bleed. The differential diagnosis of a similar clinical picture includes trauma (including non-accidental injury), other bleeding disorders such as clotting factor deficiency, haemolytic conditions or platelet dysfunction.
The diagnosis of AHA can be difficult as there is usually no history of personal or family bleeding disorders and the disease is rare. The European Acquired Haemophilia Registry (EACH2) reports a delay of an average of three days between the onset of bleeding and diagnosis.1 All blood results including coagulation tests may be normal except for an isolated rise in APTT. A high index of suspicion is therefore essential for the accurate and prompt diagnosis of AHA. Our patient had the diagnosis made on day one of intensive care following the finding of an isolated raised APTT (sometimes expressed as a ratio of patient’s result/control result – APTT-R) in the context of spontaneous and severe bleeding. The morbidity and mortality from AHA can be very high and may be related to bleeding, underlying pathology or as a complication of treatment. Our patient had significant co- morbidities, which contributed to his poor outcome.
AHA can be confirmed by the presence of low factor VIII level and evidence of inhibitor (FVIII antibody) in the plasma, in the presence of an isolated raised APTT. After ruling out other causes of prolonged APTT such as heparin contamination, a ‘mixing test’ should be performed. This is done by mixing the patient’s plasma with normal plasma (usually in equal volumes – the 50:50 mix), followed by incubation at 37°C. The mixing test results in correction of APTT if the prolonged APTT is simply the result of a coagulation factor deficiency. If the APTT is not corrected on the mixing test and lupus anticoagulant is negative, this implies the presence of an inhibitor of one or more of the coagulation factors in the intrinsic coagulation pathway, most commonly an inhibitor to factor VIII (AHA). The activity of this inhibitor is time-dependent, ie its effect is more pronounced if the APPT test is performed after incubation of the patient and normal plasma for two hours. In AHA, in most cases APTT will not be corrected on the addition of normal test, but in others (as in our case), there is immediate correction, followed by lengthening of APTT over time.7
Treatment must be commenced promptly once AHA is diagnosed, and consists of control of bleeding, eradication of the inhibitor and treatment of the underlying disorder. The treatment of choice for the control of bleeding consists of recombinant activated factor VII (rVIIa) and factor VIII inhibitor bypassing activity (FEIBA). Both these agents act as bypassing agents for achieving adequate haemostasis. Factor VIII concentrates and desmopressin may have some role in haemostasis in the presence of low inhibitor titre and act by
increasing the levels of circulating factor VIII.1,8-10 Inhibitor inhibition is achieved by using immunosuppressive agents. Steroids alone or in combination with cyclophosphamide are usually started as first-line treatment for eradication of inhibitors.5 Remission in AHA can be expected after a few weeks of commencing immunosuppression.5,7 Other agents used for inhibitor eradication are intravenous immunoglobulins, rituximab, cyclosporin A and vincristine.1,5,11 Twenty percent of the patients experience a relapse and may require further immunosuppression.1
Our patient was already critically ill when he was referred to intensive care. Significant co-morbidity, renal failure and then sepsis with multiple organ failure in the presence of pancytopenia and therapeutic immunosuppression contributed to his death. Patients who respond well to treatment will typically go into remission.
References 1. Collins PW. Management of acquired haemophilia A. J Thromb Haemostat
2011; 9 (suppl.1): 226-35. 2. Holme PA, Brosstad F, Tjonnfjord GE. Acquired haemophilia:
management of bleeds and immune therapy to eradicate autoantibodies. Haemophilia 2005;11:510-15.
3. Huth-Kuhne A, Baudo F, Collind P et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009;94:566-75.
4. Harper M, Obolensky L, Roberts P, Mercer M. A case of acute upper and lower airway obstruction due to retropharyngeal haemorrhage secondary to acquired haemophilia A. Anaesthesia 2007;62:627-30.
5. Shetty S, Bhave M, Ghosh K. Acquired haemophilia A: Diagnosis, aetiology, clinical spectrum and treatment options. Autoimmune Rev 2011; 10:311-16.
6. Collins P, Macartney N, Davies R et al. A population based, unselected, consecutive cohort of patients with acquired haemophila A. Br J Haematol 2004;124:86-90.
7. World Federation of Hemophilia. Mixing tests for further investigation of abnormal PT and APTT. 2010. Accessed at http://www.wfh.org/2/docs/ Publications/Diagnosis_and_Treatment/Lab_Manual2010/Lab_Manual_Se ction-14.pdf. Accessed 31 May 12.
8. Franchini M, Lippi G. The use of desmopressin in acquired haemophilia A: a systematic review. Blood Transfusion 2011;9:377-82.
9. Tufano A, Coppola A, Guida A et al. Acquired haemophilia A in the elderly: Case Reports. Curr Gerontl Geriatr Res 2010;2010:927503.
10.Brack A, Vogeler S, Hilpert J et al. Acquired Factor VIII inhibitor. Anesthesiol 2009;111:1151-54.
11.Clatworthy M, Jayne D R W. Acquired haemophilia in association with ANCA-associated vasculitis: Response to rituximab. Am J Kidney Dis 2006;47:680-82.
Vidhi Patle Registrar, Anaesthesia
Rhian E Edwards Consultant, Anaesthesia and Intensive Care
Medicine
[email protected]
Case reports
Commentary:
Acquired haemophilia is a rare disease that is due to the production of IgG autoantibodies directed against a
coagulation factor, most commonly factor VIII. This results in a much-reduced generation of thrombin through the intrinsic coagulation pathway and consequently potentially severe spontaneous bleeding. This autoimmune disease occurs without any clear cause in over half of all cases, but in other instances may be associated with a wide range of disorders including autoimmune conditions, ulcerative colitis, malignancies, pregnancy, and secondary to some drugs. Unlike inherited sex-linked haemophilia A, which affects males, it occurs in both sexes and is most commonly seen in the elderly. In the UK the incidence has been reported as 1.48 per million per year.
Spontaneous bleeding can occur into the skin, muscles, soft tissue and mucous membranes, as well as following trauma, surgery, or childbirth and can occasionally be intra-cerebral. The bleeding can be severe and life threatening – the mortality of acquired haemophilia is variously estimated to be between about 8% and 20%, depending on the response to treatment.1
The platelet count and prothrombin time are normal in acquired haemophilia, but the activated partial thromboplastin time (APTT), which reflects the intrinsic coagulation pathway, is prolonged. This prolongation is not corrected by the addition of normal plasma to the in vitro test plasma (the mixing study), which differentiates it from a factor deficiency,
in which such a mixing study results in correction of the APTT. Additional laboratory tests differentiate it from other inhibitors (eg the lupus anticoagulant, heparin).
Treatment is initially directed at the management of the acute bleeding episode with the use of either factor VIII concentrate (if the inhibitor level is low) or other concentrates (recombinant factor VII, FEIBA – factor eight inhibitor bypassing activity). Immuno-adsorption and plasmapheresis may be used if the titre of the antibody is high. Immunosuppression is then usually required in the long term to reduce the level of the autoantibody. Immunosuppressive agents include steroids, cyclophosphamide, rituximab, intravenous immunoglobulin, and cyclosporine. If the patient is found to have an associated malignancy then this should be treated, as control of the autoantibody is then made easier.
Reference 1. Collins PW, Hirsch S, Baglin T 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: 1870-77.
Francis Matthey Haematologist, Chelsea and Westminster
Hospital
[email protected]
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