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Journal of Postgraduate Medicine
Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India
ISSN: 0022-3859 EISSN: 0972-2823
Vol. 51, Num. 2, 2005, pp. 137-139

Journal of Postgraduate Medicine, Vol. 51, No. 2, April-June, 2005, pp. 137-139

Grand Round Case

A case of cranial venous sinus thrombosis and proteinuria

Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow

Correspondence Address: Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,Email: vikasagr@sgpgi.ac.in

Date of Submission: 11-Dec-2004
Date of Decision: 16-Jan-2005
Date of Acceptance: 08-Apr-2005

Code Number: jp05055

An 18-year-old male, presented with history of dyspnoea on exertion, intermittent icterus, colicky abdominal pain, and cola-colored urine (of 6 months duration). There was no history of fever, bleeding, intake of drugs or exposure to radiation. Past history and family history were non-contributory. Examination showed heart rate of 110/minute, respiratory rate of 22/minute, blood pressure of 120/80 mm of Hg, severe pallor and icterus. There was absence of lymphadenopathy, hepato-splenomegaly, skin purpura or bone tenderness.

Q. What is the most likely diagnosis?

Answer: The clinical presentation is suggestive of intravascular haemolysis. Various causes of intravascular haemolysis include:

1) enzyme deficiencies in the red blood cells (RBC); Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency, and glutathione deficiency,

2) defect in the microvasculature leading to microangiopathic haemolytic anaemia (MHA); prosthetic valve, arterio-venous anastomosis, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS),

3) complement activating antibodies; paroxysmal cold haemoglobinuria (PCH) and

4) acquired defect on the RBC membrane; paroxysmal nocturnal haemoglobinuria (PNH).

Rarely, severe extravascular haemolysis, either due to haemoglobinopathies or warm antibody-mediated phenomenon may give rise to similar clinical manifestations. In view of the age of the patient, episodic nature and duration of six months, G6PD deficiency, microangiopathic haemolysis, PNH and PCH seem to be the more likely possibilities.

Q. Which laboratory investigations will you ask for?

Answer: Haemoglobin concentration, reticulocyte count, peripheral blood picture, RBC indices, total leukocyte and platelet counts will reflect the degree and type of anaemia and whether the defect is mono-, bi-, or tri-lineage whereas serum bilirubin (direct and indirect), plasma haemoglobin and haptoglobin, urine haemosiderin or haemoglobin will confirm intravascular haemolysis.

Laboratory investigations showed haemoglobin 7.3 gm/dl, total leukocyte count 4200/mm3 (neutrophils 70%, lymphocytes 26%, monocytes 2% and eosinophils 2%), platelet count 60,000/mm3, corrected reticulocyte count of 10%, mean corpuscular volume of 110 fl, mean corpuscular haemoglobin of 35 pg, mean corpuscular haemoglobin concentration of 32 g/dl, macrocytes on peripheral film, and unconjugated hyperbilirubinemia (total 3.2 mg/dl, direct 1.0 mg/dl) with normal aspartate and alanine transaminase and alkaline phosphatase enzymes. Plasma haemoglobin was 30 mg/dl (normal <10).

Q. What are the clinical possibilities now?

Answer: In view of anaemia and thrombocytopenia, G6PD deficiency and PCH seem less likely. As there is no history suggestive of prosthetic cardiac valves, bleeding manifestations, fever, renal or central nervous system involvement, MHA too seems to be less likely. This leaves out PNH as a strong possibility.

His G6PD enzyme in the RBC and osmotic fragility were normal. Direct and indirect Coombs test and cold antibodies were negative.

Q. How will you confirm the diagnosis of PNH?

Answer: The gold standard laboratory test is to detect CD59 and CD55 on the red blood cells by flowcytometry.[1],[2] Absence of these CD markers is diagnostic of PNH. However, in centres where flowcytometry is not available, Ham′s test or sucrose lysis tests coupled with the classical presentation will suggest the diagnosis.

Ham′s test and Sucrose lysis test were positive in the patient. Flow cytometric analysis of RBCs revealed deficiency of CD59 on more than 80% of the RBCs.

Q. What is PNH and how does it present?

Answer: Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal haematological disorder, which manifests by complement-mediated intravascular haemolysis, venous thrombosis and bone marrow failure.[1] PNH can have diverse clinical presentations varying from iron deficiency anaemia to severe intravascular haemolysis, aplastic anaemia, hypercoagulable state, acute renal failure, and nephrotic syndrome.[2]

Q. Why are red blood cells prone for complement-mediated intravascular haemolysis?

Answer: In PNH there is an acquired mutation in the X-linked phosphatidylinositol glycan class- A (PIG-A) gene in the pluripotent hematopoietic stem cell. PIG-A protein is required for the synthesis of the glycosylphosphatidylinositol (GPI) anchor.[1],[2] Due to deficiency of the GPI anchor there is deficiency of CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) on the surface of erythrocytes making them prone to lysis by the spontaneously activating products of the complement cascade. Normally, alternative complement cascade is in a constant state of low-level activation. It generates C3b, which further cleaves C5 to C5b and initiates the formation of membrane attack complex (C5b-C9) and polymerization of the C9 into molecular tubes that puncture the cell membrane and cause cell lysis. On the surface of the erythrocyte membrane CD55 binds to the C3b and prevents further activation of the complement cascade. CD59 inhibits the insertion of C9 into the erythrocyte membrane, thereby preventing the complement-mediated lysis of the erythrocytes.[2]

Q. How common is it in adolescence?

Answer: PNH is usually a disease of adulthood, though it has been described in young children and adolescents occasionally.[3],[4]

The patient was treated with prednisolone 60 mg/ day along with iron and folic supplements. Two weeks later he developed headache not associated with fever, altered sensorium, seizures, or neurological deficit. Examination of the fundus and the central nervous system revealed absence of any abnormality.

Q. What has happened in the present case?

Answer: Thrombosis is a frequent complication of PNH and contributes significantly to morbidity and mortality. The common sites of thrombosis include cortical, hepatic and mesenteric veins. A few cases with cerebral arterial and coronary vessel thrombosis have been described.[2],[5],[6],[7],[8],[9],[10],[11] Cranial venous sinus thrombosis (CVT), though rare, is a strong possibility. However, in a comprehensive review of 38 cases, Bousser et al failed to list PNH among the possible causes of CVT.[12] Benign intracranial hypertension may present similarly.

Investigation revealed bilateral infarcts in the parieto-occipital region on non-contrast computerized tomogram. Magnetic resonance imaging showed the infarcts [Figure - 1]along with bilateral transverse and left sigmoid sinus thrombosis. Urine microscopy showed albumin 3+ without any cells or casts. Twenty-four hour urine albumin was 3.5 gm. Ultrasound of abdomen and colour Doppler for renal veins were normal.

Q. What are the mechanisms postulated for thrombosis in PNH?


Answer: The proposed mechanisms of thrombosis are: increased platelet activation with platelet microparticle formation and depression of cell surface-mediated fibrinolysis.[13] Increased production of the thrombin during the haemolytic process has been reported to be a predisposing factor for thrombosis. In our case, this being the cause could not be ruled out.

Q. How common is proteinuria in PNH and what are the other renal manifestations of PNH?


Answer: Proteinuria is extremely uncommon in PNH. Few documented causes include focal segmental glomerular disease,[14] antiglomerular basement disease,[15] and thrombosis of the renal vessels.[16] Kidneys in PNH have been reported to be larger than normal, presumably due to venous congestion and sludging. Marked haemosiderin deposit in the proximal tubule is a common feature. Renal failure has been reported concomitant to pre-existing renal disease or transfusion reactions. Clark et al , in a study evaluating 21 patients of PNH with renal dysfunction, have reported that urinalysis had microscopic haematuria and intermittent proteinuria in addition to haemoglobinuria at some or the other time during the course of the disease. In the same report, cortical infarcts, papillary necrosis, decreased glomerular filtration rate, failure to visualize cortical arterioles and prolonged venous phase on renal angiograms and defect in the concentrating ability have also been reported.[16] Since nephrotic range proteinuria is distinctly uncommon in PNH one should rule out other disorders such as antineutrophilic antibody-associated vasculitis, systemic lupus erythematosus and Goodpasture syndrome.

In our patient, the serology for antinuclear, antineutrophil cytoplasmic and antiglomerular basement antibodies were negative. A renal biopsy revealed deposition of haemosiderin in the tubules without any evidence of glomerular or interstitial pathology.

Q. What could have been the cause of renal involvement in this patient?

Answer: In this case the exact cause remained unknown. However, since the renal pathology was noticed at the time of CVT and improved with glucocorticoid and anticoagulant therapy, a possibility of microvascular thrombosis[16] being the cause of renal dysfunction cannot be excluded.

Q. How is PNH treated?

Answer: During acute haemolytic episodes transfusion therapy is helpful in raising the haemoglobin level and suppressing the bone marrow production of RBC. Glucocorticoids and danazol have been reported to reduce the rate of haemolysis. Patients presenting with acute thrombosis require urgent thrombolytic/anticoagulant therapy. Long-term oral anticoagulation therapy is required in cases with cerebral thrombosis or Budd-Chiari syndrome.[4] Bone marrow transplantation should be considered early in the disease course in patients with either bone marrow failure or thrombosis.

Q. How is response to therapy monitored?

Answer: Response to therapy is monitored by normalization of haemoglobin level, reticulocyte count, platelet count, plasma haemoglobin levels and proteinuria.

Two weeks later his haemogram normalized. Six weeks later urine examination showed albuminuria to be within the normal range [Figure - 2]. Computerized tomogram, 11 months later, did not reveal any infarct in the brain or thrombus in the cranial venous sinus. He did not have any more episodes of thrombosis during the past 12 months.

Q. How common is bone marrow failure in PNH?

Answer: The exact cause of bone marrow failure in PNH is not known. In about 10% of patients, aplastic anaemia evolves and 5% of the known aplastic anaemia patients eventually develop PNH.[2]

ACKNOWLEDGEMENT

The authors are grateful to Professor Neelam Varma, Department of Haematology, Postgraduate Institute of Medical Education and Research, Chandigarh, for carrying out the flowcytometric analysis.

REFERENCES

1.Shichishima T, Noji H. A new aspect of the molecular pathogenesis of paroxysmal nocturnal hemoglobinuria. Hematology 2002;7:211-27.   Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Schwartz RS. Black mornings, yellow sunsets- A day with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350:537-9.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Ware RE, Hall SE, Rosse WF. Paroxysmal nocturnal hemoglobinuria with onset in childhood and adolescence. N Engl J Med 1991;325:991-6.  Back to cited text no. 3  [PUBMED]  
4.Hillmen p, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995;333:1253-8  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Quentin V, Dinasquet M, Rioux-Leclercq N, de Lajarte-Thirouard AS, Lotrian D, Lamy T, et al . Paroxysmal nocturnal hemoglobinuria associated with intestinal ischemia leading to small bowel perforation. Gastroenterol Clin Biol 2003;27:927-31.  Back to cited text no. 5    
6.Hyafil F, Montalescot G, Amoura Z, Choussat R, Collet JP, Piette JC. Images in cardiovascular medicine. Recurrent myocardial infarction in a patient with paroxysmal nocturnal hemoglobinuria. Circulation 2003;108:e91-2.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Tsatalas C, Margaritis D, Pantelidou D, Kotsianidis I, Karayiannakis AJ, Spanoudakis E, et al . Splenectomy for massive splenic infarction unmasks paroxysmal nocturnal hemoglobinuria. Acta Haematol 2003;110:193-6  Back to cited text no. 7    
8.von Stuckrad-Barre S, Berkefeld J, Steckel D, Sitzer M. Cerebral arterial thrombosis in paroxysmal nocturnal hemoglobinuria. J Neurol 2003;250:756-7.  Back to cited text no. 8  [PUBMED]  
9.Titton RL, Coakley FV. Case 51:Paroxysmal nocturnal hemoglobinuria with thrombotic Budd-Chiari syndrome and renal cortical hemosiderin. Radiology 2002;225:67-70.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Sareen D, Nagrani SK, Raina S. Paroxysmal nocturnal hemoglobinuria presenting as recurrent episodes of cerebral venous thrombosis. J Assoc Physicians India 2001;49:485-7.  Back to cited text no. 10    
11.Gayer G, Zandman-Goddard G, Raanani P, Hertz M, Apter S. Widespread abdominal venous thrombosis in paroxysmal nocturnal hemoglobinuria diagnosed on CT. Abdom Imaging 2001;26:414-9.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Bousser MG, Chiras J, Bories J, Castaigne P. Cerebral venous thrombosis- a review of 38 cases. Stroke 1985;16:199-213.  Back to cited text no. 12  [PUBMED]  
13.Liebman HA, Feinstein DI. Thrombosis in patients with paroxysmal nocturnal hemoglobinuria is associated with markedly elevated plasma levels of leukocyte-derived tissue factor. Thromb Res 2003;111:235-8.   Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Takahashi K, Yoshimura A, Inoue Y, Takahashi N, Sugenoya Y, Morita H, et al . A case of paroxysmal nocturnal hemoglobinuria combined with focal segmental glomerular sclerosis. Nippon Jinzo Gakkai Shi 2001;43:39-43. (Abstract)  Back to cited text no. 14    
15.Sogabe H, Nangaku M, Ishibashi Y, Wada T, Fujita T, Sun X, et al . Increased susceptibility of decay-accelerating factor deficient mice to anti-glomerular basement membrane glomerulonephritis. J Immunol 2001;167:2791-7.   Back to cited text no. 15    
16.Clark DA, Butler SA, Braren V, Hartmann RC, Jenkins DE Jr. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood 1981;57:83-9.  Back to cited text no. 16  [PUBMED]  

Copyright 2005 - Journal of Postgraduate Medicine


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