Thromboembolic events and haematological diseases: a case of stroke as clinical onset of a paroxysmal nocturnal haemoglobinuria
© Gianluca et al; licensee BioMed Central Ltd. 2004
Received: 04 June 2004
Accepted: 11 November 2004
Published: 11 November 2004
Some haematological diseases are associated to an increased risk of thromboembolic events. We report a case of paroxysmal nocturnal haemoglobinuria (PNH) in which a cerebrovascular event represented the first clinical manifestation of disease. PNH is associated to thromboembolic events, generally of venous districts often involving unusual locations such as mesenteric vessels, sagittal veins, inferior vena cava and renal veins.
To our knowledge arterial thrombotic episodes are rare and the involvement of arterial cerebral vessels is exceptional. Then, our case points out the importance of investigating about haematological disorders in all patients presenting with a stroke, in which the common predisposing conditions are excluded.
Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of haematopoietic stem cells clinically characterized by acute intravascular haemolytic crisis, in particular nocturnal, often overlapped to chronic haemolysis, and by thrombotic events and bone marrow failure. It is associated with a somatic mutation in the phosphatidylinositol glycan complementation class A (PIG-A) gene, mapped to the X chromosome; the subsequent deficiency of glycosylphosphatidylinositol (GPI) and of GPI-anchored molecules, as the decay accelerating factor (DAF or CD55) and the membrane inhibitor of reactive lysis (MIRL or CD59), causes an increased susceptibility to complement-mediated lysis of erythrocytes, leukocytes and platelets .
The association between PNH and thromboembolic accidents, generally manifesting as thrombotic events of venous vessels sometimes complicated by pulmonary embolism, is well established. Arterial thrombotic episodes, particularly of cerebral vessels are enough rare .
We report a case of PNH presenting with thromboembolic events, both venous (proximal deep venous thrombosis of lower limbs) and arterial (stroke).
A 56-year-old woman, with history of peptic ulcer and family history for cerebrovascular disease was referred to our Division of Internal Medicine with asthenia and generalized discomfort. She reported a cerebrovascular accident manifesting as a right brachial and crural hyposthenia ten month ago, almost completely receded at observation time; she also referred recurrent episodes of proximal deep venous thrombosis (DVT) of lower limbs in the last seven months.
Thrombophilic tests (units of measurement)
Protein C (antigen) (%)
Protein S (antigen) (%)
Antithrombin (activity) (%)
Activated protein C resistance (Bertina)
Anti-cardiolipin antibodies IgG (U/GPL)
Anti-cardiolipin antibodies IgM (U/MPL)
Plasminogen activator inhibitor type 1 (ng/dl)
PTHRA20210 gene polimorphism
Factor V Leiden gene polimorphism
Apolipoprotein B gene polimorphism C9774T and G3775A
Apolipoprotein E gene polimorphism C3932T and C4070T
Methylene-tetrahydrofolate C677T gene polimorphism
Angiotensin converting enzyme deletion gene polimorphism
Prothrombin time (INR)
Activated partial thromboplastin time (ratio)
Other laboratory findings
Laboratory data (units of measurement)
Erytro-sedimentation rate 1° hour (mm)
lactate dehydrogenase (UI/l)
total bilirubin (mg/dl)
indirect bilirubin (mg/dl)
anti-extractable nuclear antigens antibodies
anti-smooth muscle antibodies
An abdominal ultrasonography excluded a hypersplenism and/or Kasabath-Merritt syndrome.
A peripheral blood smear did not show any finding suggestive for haematological disorders. A bone marrow biopsy showed a slight hyperplasia of erythrocytic bone marrow cell line.
Laboratory data (units of measurement)
red blood cells (cells/mm3)
4.200.000 – 5.400.000
mean corpuscolar volume (fl)
mean corpuscolar hemoglobin (pg)
mean corpuscolar hemoglobin concentration (g/dl)
white blood cells (cells/mm3)
4.800 – 10.800
130.000 – 400.000
Peripheral blood smear
Bone marrow biopsy
slight hyperplasia of erythrocytic cell line
Immunophenotypic profile of peripheral blood cells
15% of deficient CD59 erythrocytes
During her hospitalization two haemotrasfusions were necessary in occasion of two concurrent haemolytic crises. Following dismission, in order to prevent further thromboembolic events, the patient began oral anticoagulation therapy with warfarin according with INR value in range of 2–2,5. Moreover she was treated with B12 vitamin and folate supplementation.
The association between haematological diseases and thromboembolic events is well established. In particular high thrombotic risk is recognized in patients with essential thrombocythemia, polycythemia vera, PNH and drepanocytosis . PNH is associated to venous thrombosis in approximately one third of cases. The most frequently reported locations are unusual such as mesenteric vessels, sagittal veins, inferior vena cava and renal veins. When thrombosis occurs in the pre-hepatic or hepatic veins, the patient develops a Budd-Chiari syndrome . Arterial thrombosis is rare, even if few cases of cerebral arterial thrombosis  and acute myocardial infarction  are described in the literature.
The mechanism whereby PNH causes an hypercoagulable state is not clear. PNH platelets lack the GPI-linked proteins CD55 and CD59, and respond to the deposition of terminal complement components by vesiculations of portions of their plasma membrane, resulting an increased procoagulant property. PNH cells also lack the receptor of the GPI-linked urokinase plasminogen activator, which may result in impaired fibrinolysis . Also an increase of membrane-derived procoagulant microparticles (phosphatidylserin) stemming from the platelets of PNH patients has been described .
In our case, thrombotic events represented the clinical onset of PNH and involved both venous (DVT) and arterial (stroke) vessels. Neurological manifestations in PNH patients are generally due to cerebral venous thrombosis [7, 8], even if a few cases of cerebral arterial episodes, involving large vessels, are described. However, usually cerebral ischaemia in PNH did not occur as presenting sign of the disease nor affect small and middle cerebrovascular arteries . In our patient the relationship between PNH and thrombotic events is strongly suggested, especially after excluding inherited or acquired thrombophilia and atherosclerotic risk factors. Heterozigosities for gene polimorphism of tetrahydrofolate reductase and angiotensin converting enzyme, detected in our patient, are not associated to an increased risk of stroke, while acquired or inherited hyperhomocysteinemia may be involved [9–11].
Also haemotological findings agree with PNH diagnosis because of the association of thrombosis, anemia and thrombocytopenia. We excluded further causes of non-immune haemolityc anemia (i.e. spherocytosis, enzymatic disorders, microangiopathic anemia) and thrombocytopenia (i.e. disseminated intravascular coagulation, haematological malignancies, systemic erythematosus lupus, primary or secondary antiphospholipid syndrome, hypersplenism).
In conclusion, PNH is associated to thromboembolic events, especially in the venous district and should be considered as a possible cause of an hypercoagulable state, in particular when unusual vascular locations are involved. Our case indicates the possibility of arterial thrombotic episodes in a patient with PNH and suggests a thorough evaluation of any haematological disorders in patients presenting with stroke or myocardial infarction, especially in the absence of atherosclerosis risk factors and/or a thrombophilic state.
- J. Meletis, E. Terpos: Recent insights into the phatophysiology of the paroxysmal nocturnal haemoglobinuria. Med Sci Monit 2003, 9: RA161-172.PubMedGoogle Scholar
- Rosse WF, Nishimura J: Clinical manifestations of paroxysmal nocturnal haemoglobinuria: present state and future problems. Int J Hematol 2003, 77: 113-20.View ArticlePubMedGoogle Scholar
- Leone G, Sica S, Chiusolo P, Teofili L, De Stefano V: Blood cell diseases and thrombosis. Haematologica 2001, 86: 1236-44.PubMedGoogle Scholar
- Graham ML, Rosse WF, Halperin EC, Miller CR, Are RE: Resolution of Budd-Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1996, 92: 707-10. 10.1046/j.1365-2141.1996.365901.xView ArticlePubMedGoogle Scholar
- von Stuckrad-Barre S, Berkefeld J, Steckel D, Sitzer M: Cerebral arterial thrombosis in paroxysmal nocturnal haemoglobinuria. J Neurol 2003, 250: 756-7. 10.1007/s00415-003-1071-7View ArticlePubMedGoogle Scholar
- Melandri F, Gazzotti G, Fontana P, Accietto C: [Recurrent acute myocardial infarction in a patient with paroxysmal nocturnal haemoglobinuria]. Ital Heart J 2001, Suppl 2: 792-4 Italian.Google Scholar
- Van Vleymen B, Dhaene I, Van Hoof A, Pattyn G: Cerebral venous thrombosis in paroxysmal nocturnal haemoglobinuria. Acta Neurol Belg 1987, 87: 80-7.PubMedGoogle Scholar
- Alfaro A: Cerebral venous thrombosis in paroxysmal nocturnal haemoglobinuria. J Neurol Neurosurg Psychiatry 1992, 55: 412.PubMed CentralView ArticlePubMedGoogle Scholar
- Schwammenthal Y, Tanne D: Homocysteine, B-vitamin supplementation, and stroke prevention: from observational to interventional trials. Lancet Neurol 2004, 3: 493-5. 10.1016/S1474-4422(04)00826-9View ArticlePubMedGoogle Scholar
- Hankey GJ: Homocysteine-lowering therapy did not prevent stroke recurrence. ACP J Club 2004, 141: 21.PubMedGoogle Scholar
- Al-Delaimy WK, Rexrode KM, Hu FB, Albert CM, Stampfer MJ, Willett WC, Manson JE: Folate intake and risk of stroke among women. Stroke 2004, 35: 1259-63. 10.1161/01.STR.0000127813.12854.9cView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.