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An unusual cause of bleeding
CASE REPORT
Case report
An unusual cause of bleeding Rozemarijn S van Rijn, Leo F Verdonck In September, 2000, a previously healthy 44-year-old woman was admitted with a large haematoma of the right leg (figure A). Six weeks before admission she had noticed several bruises on her arms and legs, but had no antecedent trauma. We found nothing else of note on physical examination. She had a normal full blood count, serum ions and electrolytes, but a raised erythrocyte sedimentation rate (91 mm/h), and normochromic normocytic anaemia (haemoglobin 5·7 mmol/L). Her activated partial thromboplastin time was 58 s (control 33 s), prothrombin time 21 s (12 s), and thrombin time 58 s (17 s). Simplate bleeding time was 10 min (NR: 3–9 min), the fibrinogen level was normal (2·1 g/L) and D-dimers were not elevated. Factor II was 102%, V 67%, VII 77%, VIII 91%, IX 72%, X 39%, XI 79%, XII 51%, and XIII 69% of normal. Von Willebrand factor levels were normal. However, plasminogen and ␣-2 antiplasmin were decreased (27% and 33%, respectively). Plasmin-antiplasmin complexes were >5000 ng/ml, confirming a diagnosis of pathological fibrinolysis. Serum protein and immunoelectrophoresis showed a trace amount of IgM- paraprotein. Urinalysis showed microalbuminuria (0·2 g/L), with free lambda light chains. Bone marrow aspirate and biopsy contained 4–6% plasma cells which were monoclonal and IgM- positive on immunophenotyping. Congo red staining of the marrow biopsy appeared red under normal light microscopy (figure B), and apple green under polarised light (figure C). Abdominal and thoracic computed tomography were normal, and there was no amyloid on rectal biopsy or abdominal fat biopsy. Echocardiography and neurological examination showed no further localisation. We started daily infusions of fresh frozen plasma, switching to oral tranexamic acid (1 g, 4 times daily) after 3 days, as the plasminogen level had increased to 72%. Within 2 weeks, the clotting times, plasminogen and ␣-2antiplasmin levels had returned to normal, factor V increased to 81%, and factor X to 67%, and the patient was discharged from hospital. She was enrolled in the HOVON-41 study for treatment of AL amyloidosis with intensive chemotherapy, followed by autologous stem cell transplantation, which was done in March, 2001, without any complications. When last seen in May, 2001, she was in good health, with no bleeding tendency. She was continuing to take tranexamic acid which was to be tapered off in the near future.
Intramuscular haematoma (A), Congo red staining (B) and polarised light microscopy (C) of bone marrow biopsy.
Severe bleeding occurs as an initial symptom in about 3% of patients with amyloidosis, generally caused by deposition of the amyloid in blood vessels or adsorption of coagulation factors (mainly factor X), to the amyloid surface. However, bleeding can be occasionally attributed to pathological fibrinolysis.1,2 Pathological fibrinolysis also occurs in acute infections, liver or renal disease, and several malignancies.2 The major physiological inhibitor of pathological fibrinolysis, ␣-2-antiplasmin, is also useful for establishing the diagnosis; a deficiency is defined as a plasma level less than 50% of normal. Pathological fibrinolysis is also characterised by the formation of plasmin-antiplasmin complexes, and the consumption of plasminogen. High concentrations of tissue plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), or a low level of plasminogen activator inhibitor (PAI-1),2–4 have been identified as three potential activating mechanisms, but all three were normal in our patient (tPA 1·5 g/ml, uPA 2·6 g/ml, PAI 118 g/ml). It is important to recognise pathological fibrinolysis as the cause of acute bleeding, because tranexamic acid may help, and because primary amyloidosis might be the underlying disease. References 1
Lancet 2001; 358: 1424 Department of Hematology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands (R S van Rijn MD, L F Verdonck MD) Correspondence to: Dr van Rijn (email:[email protected])
1424
2
3
4
Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32: 45–59. Stump DC, Taylor FB, Nesheim ME, et al. Pathologic fibrinolysis as a cause of clinical bleeding. Semin Thromb Hemost 1990; 3: 260–73. Williams EC. Plasma alpha 2-antiplasmin activity. Role in the evaluation and management of fibrinolytic states and other bleeding disorders. Arch Intern Med 1989; 8: 1769–72. Sane DC, Pizzo SV, Greenberg CS. Elevated urokinase-type plasminogen activator level and bleeding in amyloidosis: case report and literature review. Am J Hematol 1989; 1: 53–7.
THE LANCET • Vol 358 • October 27, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Case report
An unusual cause of bleeding Rozemarijn S van Rijn, Leo F Verdonck In September, 2000, a previously healthy 44-year-old woman was admitted with a large haematoma of the right leg (figure A). Six weeks before admission she had noticed several bruises on her arms and legs, but had no antecedent trauma. We found nothing else of note on physical examination. She had a normal full blood count, serum ions and electrolytes, but a raised erythrocyte sedimentation rate (91 mm/h), and normochromic normocytic anaemia (haemoglobin 5·7 mmol/L). Her activated partial thromboplastin time was 58 s (control 33 s), prothrombin time 21 s (12 s), and thrombin time 58 s (17 s). Simplate bleeding time was 10 min (NR: 3–9 min), the fibrinogen level was normal (2·1 g/L) and D-dimers were not elevated. Factor II was 102%, V 67%, VII 77%, VIII 91%, IX 72%, X 39%, XI 79%, XII 51%, and XIII 69% of normal. Von Willebrand factor levels were normal. However, plasminogen and ␣-2 antiplasmin were decreased (27% and 33%, respectively). Plasmin-antiplasmin complexes were >5000 ng/ml, confirming a diagnosis of pathological fibrinolysis. Serum protein and immunoelectrophoresis showed a trace amount of IgM- paraprotein. Urinalysis showed microalbuminuria (0·2 g/L), with free lambda light chains. Bone marrow aspirate and biopsy contained 4–6% plasma cells which were monoclonal and IgM- positive on immunophenotyping. Congo red staining of the marrow biopsy appeared red under normal light microscopy (figure B), and apple green under polarised light (figure C). Abdominal and thoracic computed tomography were normal, and there was no amyloid on rectal biopsy or abdominal fat biopsy. Echocardiography and neurological examination showed no further localisation. We started daily infusions of fresh frozen plasma, switching to oral tranexamic acid (1 g, 4 times daily) after 3 days, as the plasminogen level had increased to 72%. Within 2 weeks, the clotting times, plasminogen and ␣-2antiplasmin levels had returned to normal, factor V increased to 81%, and factor X to 67%, and the patient was discharged from hospital. She was enrolled in the HOVON-41 study for treatment of AL amyloidosis with intensive chemotherapy, followed by autologous stem cell transplantation, which was done in March, 2001, without any complications. When last seen in May, 2001, she was in good health, with no bleeding tendency. She was continuing to take tranexamic acid which was to be tapered off in the near future.
Intramuscular haematoma (A), Congo red staining (B) and polarised light microscopy (C) of bone marrow biopsy.
Severe bleeding occurs as an initial symptom in about 3% of patients with amyloidosis, generally caused by deposition of the amyloid in blood vessels or adsorption of coagulation factors (mainly factor X), to the amyloid surface. However, bleeding can be occasionally attributed to pathological fibrinolysis.1,2 Pathological fibrinolysis also occurs in acute infections, liver or renal disease, and several malignancies.2 The major physiological inhibitor of pathological fibrinolysis, ␣-2-antiplasmin, is also useful for establishing the diagnosis; a deficiency is defined as a plasma level less than 50% of normal. Pathological fibrinolysis is also characterised by the formation of plasmin-antiplasmin complexes, and the consumption of plasminogen. High concentrations of tissue plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), or a low level of plasminogen activator inhibitor (PAI-1),2–4 have been identified as three potential activating mechanisms, but all three were normal in our patient (tPA 1·5 g/ml, uPA 2·6 g/ml, PAI 118 g/ml). It is important to recognise pathological fibrinolysis as the cause of acute bleeding, because tranexamic acid may help, and because primary amyloidosis might be the underlying disease. References 1
Lancet 2001; 358: 1424 Department of Hematology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands (R S van Rijn MD, L F Verdonck MD) Correspondence to: Dr van Rijn (email:[email protected])
1424
2
3
4
Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; 32: 45–59. Stump DC, Taylor FB, Nesheim ME, et al. Pathologic fibrinolysis as a cause of clinical bleeding. Semin Thromb Hemost 1990; 3: 260–73. Williams EC. Plasma alpha 2-antiplasmin activity. Role in the evaluation and management of fibrinolytic states and other bleeding disorders. Arch Intern Med 1989; 8: 1769–72. Sane DC, Pizzo SV, Greenberg CS. Elevated urokinase-type plasminogen activator level and bleeding in amyloidosis: case report and literature review. Am J Hematol 1989; 1: 53–7.
THE LANCET • Vol 358 • October 27, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.