engleski

Acquired hemophilia in patient previously diseased from myasthenia gravis. Case report

INTRODUCTION: Acquired hemophilia is a rare condition in which autoantibodies against clotting factor VIII induce hemorrhagic diathesis and it is associated with an increased morbidity and mortality. The incidence of aquired haemophilia is not known, some studies report an incidence of 1-4 per million/year (A), but most studies are retrospective in design and not population based. 1 This disease occurs most commonly in the elderly and may be associated with a variety of underlying pathological conditions like autoimmune diseases, inflammatory bowel diseases, chronic pulmonary diseases, underlying hematologic or solid malignancy. Acquired haemophilia A can also occurs in postpartum period or after use of medications (antibiotics, interferon, levodopa, clopidogrel, fludarabibe ...). The age of distribution of autoantibodies is biphasic with a small peak between 20-30 years due to postpartum F VIII autoantibodies but this disease occurs most commonly in the elderly. Although it may be associated with a variety of underlying pathological conditions, up to 50% of reported cases remain idiopathic, and patients lacking any relevant concomitant disease or any other risk factors. Majority of patients presented with sudden onset of bleeding without any past or family history of a bleeding disorder. The bleeding pattern of acquired haemophilia is rather different from congenital form of F VIII defficency. The most patients with acquired haemophilia A have haemorrhages in the mucous membranes (epistaxis, gastrointestinal bleeding, haematuria, postpartum bleeds etc), haematomas in the skin, muscles and soft tissues. The typical feature of congenital haemophilia A are haemarthroses. The haemorrages are often dramatic, serious and life threatening excessive bleeding after trauma or surgery. The mortality rate of AH is as high ranging 8%-22% (A) , and current treatment options are associated with adverse side effects (5). The published studies describe various immunosuppressive regimens to eradicate factor VIII inhibitors but usually lack control patients (B). A wide range of treatment modalities were used in these cases with no gold standard of treatment or widely accepted guidelines existing. In some reports there were patients undrewent spontaneous remission, or require no hemostatic treatment (B). The diagnosis of acquired hemophilia was confirmed by the presence of FVIII inhibitors, low activity of factor VIII, and prolonged activated partial thromboplastin time (APTT). The basic aspects of therapeutics strategy in patients with acqiured haemophilia A are the treatment of acute bleeding episodes and long term eradication of the autoantibodies. Therapy of the underlying associated disease can in some cases lead to the disappearance of the inhibitors. Treatment of acute bleeding episode are provided using bypassing agents: recombinant activated factor VII (rFVIIa) and the activated prothrombin complex concentrate (aPCC). The elimination of the FVIII autoantibody may be achieved through various therapeutic options including immunosupresive agents (corticosteroids), cytotoxic drugs (cyclophosphamide, azatioprin, vincristine), cyclosporine, rituximab (antiCD20 monoclonal antibody), high-dose intravenous immunoglobuline, immunoadsorbtion etc. Myasthenia gravis (MG) is autoimmune neuromuscular disorder characterized by variable muscle weakness and fatigue. The muscle weaknes is caused by autoimmune reaction against skeletal muscle acetylcholine receptors (AChR). The main feature of MG is a fluctuating weakness of certain voluntary muscles, particularly those inervated ba motor nuclei of the brainstem (oculary, masticatory, facial). Manifest weakening during continued activity, quick restoration of power with rest, and dramatic imrpovement in strength following the administraton of anticholinesterase drugs, such as neostigmine, are the other notable characteristics of the myasthenic weakness. The MG diagnosis is based on clinical presentation, and measurement of specific auto antobodies against AchR, electophysiological testing and neostigmine test. The treatment of this disease involves the careful use of two groups of drugs: anticholinesterase drugs and immunosuppresants. The thymectomy is considered an appropriate procedureina practically all patienst with uncopmlicated MG between puberty and 55 years of age. Plasma exchange and intravenous immune globulin administratios are advisable as additional treatment during the worsening of MG symptoms to prevent myasthenic crisis development. A rapid and severe deterioration of the mysthenia itself, termed myasthenic crisi, can bring the patient to the brink of respiratory failure and quadriparesis ina a matter of hours. OBJECTIVES: In this case report the male patient suffering from MG and AH is presented. We consider this case of interest because of possible shared autoimmune mechanism or antigen similarity (AChR and FVIII) as possible cause of both autoimmune diseases. REPORT: The 68-year old male patient, previously diagnosed as generalised form of myasthenia gravis, was reffered to the Emergency department because of the severe bleedeng from gastrintestinal tract and generalised weakness of voluntary muscles. MG was for years treated with corticosteroids and pyridostigmine and the bleeding from GI tract was suspected to be the consequence of prolonged corticosteroid therapy. Hemostatic tests indicated prolonged activated partial thromboplastin time (APTT) to 72 sec (norm 23-33 sec), normal value of the prothrombin index which was 82% (norm 70-130%), increased fibrinogen concentration to 5, 1 g/l (normal value 1, 8-4, 5 g/l), the bleeding time was 5 min and 20 s (norm < 10 min) and the platelet count was 366 x 10 9 /L (norm 150-400). The autoantibody against factor VIII was in a titer of 78 Bethesda Units/ml (BU/ml) and decreased factor VIII activity to 2% (norm 50-150%) with normal plasma concentration of factor IX. After administration of recombinant activated factor VII (rFVIIa ; NovoSeven®, Novo Nordisk, Denmark) in the two doses of 90 µg/kg each, separated by 3 hours interval, gastric bleeding was stopped. The treatment of MG was also adjusted to this rapid worsening of MG symtpoms (generalised weakness) , the dose of pyridostigmine was elevated to daily dose of 360 mg and four plasma exchange procedures were performed. After two weeks the MG remission was reached and hemathological parameters showed a gradual normalisation of coagulation processes. After two months the the autoantibody against factor VIII was not detectable and factor VIII activity was normal (90%). CONCLUSION: Comorbidity of several autoimmune diseases is many times described and well known. Both autoimmune diseases, AH and MG, may occur in the elderly and may be associated with a variety of underlying pathological conditions like autoimmune diseases, inflammatory bowel diseases, chronic pulmonary diseases, underlying hematologic or solid malignancy, reumathoid artritis, Hashimoto thyroiditis and thyrotixicosis, lupus or as a part of paraneoplastic syndrome. The MG patients and other patients suffering from autoimmune diseases are frequently on prolonged peroral corticosteroid therapy and exposed to increased risk for GI bleeding. We consider this case report of potential interest for clinical practice because it shows that GI bleeding in patient on prolonged corticostroid therapy may be a consequence of AH also, and every patient with GI bleeding, should undergone the wide laboratory analysis of coagulation parameters.

myasthenia gravis; hemophilia

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