Widespread abdominal venous thrombosis in paroxysmal nocturnalhemoglobinuria diagnosed on CT

G. Gayer,1 G. Zandman-Goddard,2 P. Raanani,3 M. Hertz,1 S. Apter11Department of Diagnostic Imaging, Sheba Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer52621, Israel2Department of Internal Medicine B, Sheba Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer52621, Isreal3Institute of Hematology, Sheba Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621,Israel

Received: 3 October 2000/Accepted: 15 November 2000

AbstractParoxysmal nocturnal hemoglobinuria is a rare disordercharacterized by pancytopenia. One of the main manifes-tations of this disease is development of widespread life-threatening venous thrombosis, which may involve mul-tiple abdominal veins. We describe two patients withparoxysmal nocturnal hemoglobinuria with clinically un-suspected portal, splenic, and mesenteric venous throm-boses that were diagnosed on computed tomography. Thiscomplication should be clinically suspected in patientssuffering from paroxysmal nocturnal hemoglobinuriawho present with abdominal pain, and it should be soughtby the radiologist on pre- and postcontrast computedtomography.

Key words: Paroxysmal nocturnal hemoglobinuria—Por-tal vein thrombosis—Mesenteric vein thrombosis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rareacquired clonal disorder of the hematopoietic systemcharacterized by pancytopenia due to bone marrow hypo-plasia and intravascular hemolysis [1, 2]. The two mainmanifestations of this disease are repeated episodes ofhemoglobinuria and the development of widespread life-threatening venous thrombosis. Such thrombosis may in-volve the hepatic, renal, splenic, or mesenteric vein, theinferior vena cava, superficial and deep veins of the limbs,and cerebral veins [2]. We describe two patients whopresented with portal and mesenteric vein thromboses,

one with known PNH and the other in whom the diagno-sis was established at admission. Repeat computed tomo-graphic (CT) studies showed extensive thrombosis of theportal, splenic, and superior mesenteric veins, the evolu-tion of the thrombosis in both patients, and its effects onthe colon in one of them.

Case reports

Case 1

A 48-year-old man was first admitted with abdominalpain and rectal bleeding. His medical history includedrecurrent abdominal pain over many years. He had expe-rienced a similar event of abdominal pain and rectalbleeding 18 months previously. Physical examination wasnormal, and laboratory results showed a thrombocytope-nia level of only 503 109/L. Colonoscopy did not detectan underlying cause for the rectal bleeding, and the pa-tient was discharged. He was readmitted 3 weeks later forpersistent fever of 2 weeks’ duration and a sudden dis-turbance of vision in the right temporal field. Physicalexamination showed fever and right hemianopsia. Labo-ratory results showed anemia with a hemoglobin level of10.5 g/dL and a thrombocytopenia level of 543 109/L;lactic dehydrogenase (LDH), fibrinogen, and fibrinogensplit product levels were elevated. CT of the brain dem-onstrated a left occipital infarct. Abdominal CT per-formed to evaluate the fever showed superior mesenteric,splenic, and portal vein thromboses and a small amount ofascites (Fig. 1A–C). The hepatic veins were patent. Theperipheral blood smear showed a shift to the left, withCorrespondence to:G. Gayer

Abdom Imaging 26:414–419 (2001)DOI: 10.1007/s002610000183 Abdominal

Imaging© Springer-Verlag New York Inc. 2001

Fig. 1. A 48-year-old man with recurrent abdominal pain, rectal bleed-ing, and recurrent cerebrovascular accidents.A–C First admission.ACT of the liver after intravenous contrast injection shows a slightlydilated thrombosed portal vein (arrow). At higher levels, thrombosis ofperipheral branches of the portal veins was evident.B CT at the level ofthe origin of the superior mesenteric artery shows the splenic vein to behypodense due to thrombosis (arrowheads). C A more caudal scan atthe level of the uncinate process of the pancreas demonstrates a throm-bus within the superior mesenteric vein (arrow). The vein is slightlydilated and its wall is thickened and enhanced. There is mild infiltration

of the mesenteric fat surrounding the thrombosed vein.D–E Twomonths later.D CT of the liver now shows multiple small vessels(arrow) at the hilum, representing collaterals, also known as cavernoustransformations.E Marked thickening of the wall of both ascending anddescending colons (arrows) is seen with slight infiltration of the peri-colic fat. F–H Four months after the first CT.F The wall of the colonis no longer thickened. A filter has been inserted into the inferior venacava for recent thrombosis of the common external iliac, left externaliliac (G), and femoral (H, arrows) veins.

G. Gayer et al.: Venous thrombosis in PNH 415

myeloid precursors. Bone marrow biopsy was compatiblewith a reactive bone marrow without evidence of malig-nancy. A Ham test obtained at that time to rule out PNHwas negative. The patient was discharged.

The patient was readmitted 2 months later with com-plaints of abdominal pain and rectal bleeding. Visualdisturbances, difficulty in swallowing, and nasal speechdeveloped 2 days after admission. Physical examinationshowed nystagmus, paralysis of eye movements to theleft, and left Horner. There was no change in the labora-tory data. CT of the brain showed an old occipital infarctwithout evidence of an acute event. The patient wasdiagnosed on clinical grounds as having suffered a ver-tebrobasilar stroke. Because of the abdominal pain andrectal bleeding, a second abdominal CT was performed.The superior mesenteric, splenic, and portal veins stillshowed evidence of thrombosis, but the veins were lessdilated and collateral vessels were evident, particularly atthe porta hepatis (Fig. 1D). The striking finding was amarked thickening of the colonic wall, predominantly ofthe cecum and ascending and descending colon (Fig. 1E).Treatment with low-molecular-weight heparin was initi-ated, and the patient was discharged.

The patient was readmitted for the fourth time 6weeks later with left hemiparesis. Brain CT showed aright frontoparietal intracerebral hemorrhage, which wassurgically drained, but the patient still had a persistentneurologic deficit. Because the diagnosis of PNH wasstrongly suspected, another Ham test was performed,which was positive, and confirmed the diagnosis. A thirdabdominal CT was performed, showing resolution of thebowel wall thickening and newly developed extensivethrombosis of the left common and external iliac andfemoral veins (Fig. 1F–H). A filter was inserted into theinferior vena cava. The patient’s condition progressivelydeteriorated and he died 3 weeks later. Autopsy was notperformed.

Case 2

A 46-year-old woman was admitted for abdominal pain.A diagnosis of aplastic anemia had been made 5 yearspreviously. Further evaluation established the diagnosisof PNH based on a positive Ham test. Two years beforeadmission, the patient was hospitalized for deep veinthrombosis in the left leg and suspected pulmonary em-bolism. At that time, abdominal ultrasound showed patenthepatic and portal veins. Anticoagulant treatment wasinitiated. The therapeutic range of anticoagulation deter-mined by prothrombin time international normalized ratio(INR) was maintained at a suboptimal range of 1.5–2 dueto the development of thrombocytopenia and an increasedrisk of bleeding. The patient complained of worseningabdominal pain in the days before admission and wasadmitted for reevaluation. She had fever (37.8°C) and a

distended abdomen with diffuse tenderness of the rightupper quadrant. The rest of the physical examination waswithin normal limits.

Laboratory results showed anemia with a hemoglobinlevel of 9.9 g/dL and a thrombocytopenia level of 653109/L. The LDH level was elevated.

Abdominal CT demonstrated thrombosis of thesplenic, portal, and superior mesenteric veins (Fig. 2A–E). Anticoagulation therapy was intensified (the INR wasmaintained at the therapeutic range of 2.5–3.5) and thepatient was discharged. The patient returned to the emer-gency room 5 weeks later because of acute abdominalpain. CT demonstrated partial recanalization of the supe-rior mesenteric vein and collateral blood vessels (Fig. 2F).The patient was discharged after 24 h of observationwhen her clinical condition improved. She was followedover the next 7 months, without any major event.

Discussion

PNH is a rare acquired disorder of hematopoietic stemcell origin [1]. This condition affects all three hematopoi-etic lineages. It has a wide range of manifestations in-cluding intravascular hemolysis with or without grosshemoglobinuria, bone marrow hypoplasia with pancyto-penia, increased sensitivity to infections, and venousthromboses [1, 2]. The diagnosis is based on a positiveHam test (acid hemolysis test) and a low CD59 level onimmunophenotyping [1, 2].

One or more episodes of venous thromboses havebeen reported to affect about 40% of patients during thecourse of their illness [1]. Thrombotic complications arethe most common cause of death in PNH, with the mostserious life-threatening complication being thrombosis ofintraabdominal veins [3]. This can involve the hepaticveins with subsequent Budd–Chiari syndrome and theportal, splenic, and mesenteric veins [3]. Hepatic veinthrombosis is more prevalent than portal venous throm-bosis in PNH patients [3, 4]. To the best of our knowl-edge, only eight patients with PNH associated with portalvein thrombosis have been described in the English-language literature and none in the radiology literature[3–8]. We reviewed these eight cases and our two pa-tients and summarized the pertinent information in Table1. In three patients, only the portal vein was thrombosed.In the other seven patients, at least one more vein wasinvolved including thrombosis of the mesenteric veins infive patients, of the hepatic and splenic veins in fourpatients, respectively, and of the inferior vena cava inone.

The course of this disease is characterized by multiplesevere hemolytic attacks and clinically distinguished bymalaise, fever, headache, and abdominal pain. However,the same clinical symptoms may be caused by vascularthrombosis, which is also a manifestation of PNH. Imag-

416 G. Gayer et al.: Venous thrombosis in PNH

Fig. 2. A 46-year-old woman with known paroxysmal nocturnal hemo-globinuria admitted for abdominal pain.A Precontrast scan shows thesuperior mesenteric vein as dilated and hyperdense because of a freshthrombus within it (arrow). B–E Postcontrast scans.B A thrombus isseen as an intraluminal filling defect in the main portal vein (arrow) andat its bifurcation. Some contrast material is seen outlining the thrombus.The spleen is enlarged.C The thrombus extends into the superiormesenteric vein (arrows). Multiple collateral vessels are seen anterior tothe pancreas and medial to the spleen.D Same level asA after intra-venous contrast: more caudal extension of the thrombus in the superiormesenteric vein (arrowhead). Its wall is slightly enhanced, probably due

to enhancement of the vasa vasorum. Free fluid is seen in Morison’spouch.E Multiple collateral vessels are seen at the root of the mesenteryanterior to the third part of the duodenum. The mesenteric fat isinfiltrated, and there is some free fluid anterior to the lower pole of theright kidney.F Same level asC 5 weeks later. The lumen of the superiormesenteric vein has partly recanalized. The collaterals near the pancreasare more prominent. Multiple, poorly defined hypodense areas arescattered in the periphery of the liver representing areas of compromisedblood supply. Such hypodense areas were visualized in all sections ofthe liver.

G. Gayer et al.: Venous thrombosis in PNH 417

ing studies are necessary to confirm or exclude thrombo-sis to administer appropriate treatment [3].

On sonography, the thrombosed superior mesenteric orportal vein usually appears enlarged and filled with echo-genic material, but this study is of limited value because ofthe frequent presence of overlying bowel gas [3].

On postcontrast CT, the thrombus in the mesenteric andportal vein is typically of low or mixed attenuation. The wallof the vein is often thickened and may enhance, probablybecause of enhancement of the vasa vasorum. Peripheralcalcification of the thrombus has been described but is a rarephenomenon [9, 10]. A thrombus may be identified even ona scan before intravenous contrast administration as hyper-dense intraluminal material only when the thrombus is acute.The density of the thrombus subsequently decreases due toclot lysis, and the thrombus then appears isodense withcirculating blood [9]. Additional associated CT findings ofportal vein thrombosis are focal or segmental parenchymalabnormalities consisting of peripheral hypodense areaswithin the liver parenchyma, reflecting altered hepatic per-fusion and splenomegaly, as seen in case 2. However, he-patic perfusion may be maintained by hepatopetal collateralflow around the thrombosed vein. These collaterals, knownas cavernous transformations of the portal vein, may take1–12 months to develop [11].

Case 1 had suffered from recurrent abdominal pain formany years before the diagnosis of PNH was established.CT demonstrated extensive thrombosis of the superiormesenteric vein extending into the main and lobar portalveins. Thrombosis of the mesenteric venous tree caninitially affect the small peripheral mesenteric veins, in-ducing transient intestinal ischemia or limited intestinalinfarction, and might account for the recurrent episodes ofabdominal pain, fever, and obstruction that occur fre-

quently in PNH patients [2]. In some of these cases,thrombosis probably progresses proximally to the supe-rior mesenteric and portal veins. Alternatively, thrombo-sis may begin in a major venous-outflow vessel such asthe portal or superior mesenteric vein [12]. The develop-ment of abdominal pain is more acute in the latter situa-tion than in cases of peripheral thrombosis. Acute bowelinfarction may result when portal vein thrombosis isassociated with superior mesenteric vein thrombosis. OnCT, the affected bowel wall may appear thickened andwith persistent enhancement, or there may be segmentaldilatation, air–fluid levels, and mural air [9]. The thick-ened wall of the colon and the infiltration of the pericolicfat seen in the second CT study in case 1 probably reflectchronic rather than acute ischemic changes induced by themesenteric vein thrombosis. The resolution of the CTfindings 2 months later is proof of the reversible nature ofthese changes. We assume that the involvement of thedescending colon, like that of the ascending colon, can beattributed to involvement of the inferior mesenteric veindraining this more distal part of the colon.

Because PNH patients with thrombosis often havethrombocytopenia, anticoagulant therapy is complicatedand is often avoided in the presence of severe thrombo-cytopenia, but some thrombocytopenic patients need an-ticoagulant therapy because of frequent thrombotic events[4]. Patient 2 was not optimally anticoagulated because ofthrombocytopenia, which might have contributed to thedevelopment of thrombosis in the abdominal veins.

PNH is a rare underlying cause of portal and mesen-teric vein thrombosis. Portal vein thrombosis is foundmost often in patients with cirrhosis. Other, less frequent,associated conditions include abdominal malignancies(e.g., pancreatic or hepatocellular carcinoma), inflamma-

Table 1. Summary of findings in 10 patients with portal vein thrombosis complicating paroxysmal nocturnal hemoglobinuria

Patient no./age(years)/sex

Symptoms Signs Thrombosed veins Diagnosis Patientoutcome

Duration of disease(years)

Reference

1/45/F Fatigue, dyspnea, increaseof abdominal girth

Hepatosplenomegaly,ascites

S 1 MV 1 P 1 H Autopsy D 7 5

2/27/F Hematemesis, melena Hepatosplenomegaly,ascites

S 1 P Angiography A 1 6

3/25/M Jaundice Ascites MV1 P 1 H Autopsy D 6 74/51/M Acute abdominal pain NS MV1 P 1 H MRI D 6 35/18/F Acute abdominal pain NS P MRI A 1 36/18/F Acute abdominal pain NS P MRI A Presentation 37/12/M Jaundice, nausea,

abdominal painHepatosplenomegaly P1 H 1 IVC MRI A Presentation 8

8/28/M Nausea, vomiting,abdominal pain, fever

Hepatomegaly, ascites P CT and US A 0.5 4

9/48/M Acute abdominal pain,fever

None S1 MV 1 P CT D Presentation Present study

10/46/F Acute abdominal pain,fever

Abdominal distentionand tenderness

S 1 MV 1 P CT A 5 Present study

A, alive; D, death; F, female; H, hepatic vein; IVC, inferior vena cava; M, male; MV, mesenteric vein; NS, not specified; P, portal vein; S, splenicvein

418 G. Gayer et al.: Venous thrombosis in PNH

tory conditions such as pancreatitis, and infectionsdrained by the portal venous system including appendi-citis and diverticulitis. Rare causes of portal vein throm-bosis include myeloproliferative disorders, injury to thevein at surgery or from blunt trauma, and hypercoagula-ble states such as protein C or protein S deficiency [11].Mesenteric venous thrombosis has been strongly associ-ated with previous abdominal surgery, intraabdominalcancer, inflammatory bowel disease, portal hypertension,and hypercoagulable states [12].

Portal and mesenteric vein thrombosis should be sus-pected in PNH patients with abdominal pain. Conversely,in patients presenting with portal and mesenteric venousthrombosis without evidence of the more common under-lying conditions, the diagnosis of PNH should be consid-ered. CT is a sensitive method for the diagnosis of ab-dominal venous thrombosis. However, iodinated contrastagents may induce acute hemolysis in PNH patients; thus,magnetic resonance has been recommended in these pa-tients as a safe and sensitive imaging modality [3].

References

1. Hillmen P, Lewis SM, Bessler M, et al. Natural history of parox-ysmal nocturnal hemoglobinuria.N Engl J Med1995;333:1253–1258

2. Valla D, Dhumeaux D, Babany G, et al. Hepatic vein thrombosis inparoxysmal nocturnal hemoglobinuria.Gastroenterology1987;93:569–575

3. Mathieu D, Rahmouni A, Villeneuve P, et al. Impact of magneticresonance imaging on the diagnosis of abdominal complications ofparoxysmal nocturnal hemoglobinuria.Blood 1995;85:3283–3288

4. Tomizuka H, Hatake K, Kitagawa S, et al. Portal vein thrombosis inparoxysmal nocturnal hemoglobinuria.Acta Haematol1999;101:149–152.

5. Heitzman EJ, Campbell JS, Stefanini M. Paroxysmal nocturnalhemoglobinuria with hemosiderin nephrosis.Am J Clin Pathol1953;23:975–986

6. Grossman JA, McDermott WV. Paroxysmal nocturnal hemoglobin-uria associated with hepatic and portal venous thrombosis.Am JSurg1974;127:733–736

7. Powell-Jackson PR, Melia W, Canalese J, et al. Budd–Chiari syn-drome: clinical patterns and therapy.Q J Med1982;201:79–88

8. Graham ML, Rosse WF, Halperin EC, et al. Resolution ofBudd–Chiari syndrome following bone marrow transplantationfor paroxysmal nocturnal hemoglobinuria.Br J Haematol1996;92:707–710

9. Mathieu D, Vasile N, Grenier P. Portal thrombosis: dynamic CTfeatures and course.Radiology1985;154:737–741

10. Balotin RJ, McAdams HP, Dachman AH. Calcified intrahepaticportal vein thrombus: distinction from intrahepatic choledocholithi-asis.J Comput Assist Tomogr1992;16:977–979

11. Cohen J, Edelman RR, Chopra S. Portal vein thrombosis: a review.Am J Med1992;92:173–182

12. Scully RE, Mark EJ, McNeely WF, et al. Case records of theMassachusetts General Hospital Case 6 1997.N Engl J Med1997;336:567–573

G. Gayer et al.: Venous thrombosis in PNH 419