Blood, 15 May 2001, Vol. 97, No. 10, pp. 3314-3316
CORRESPONDENCE
To the editor:
Acquired and inherited risk factors for splanchnic venous
thrombosis
We read with great interest the paper of Janssen et
al.1 They reported an increased risk for Budd-Chiari
syndrome (BCS) or portal vein thrombosis (PVT) among carriers of factor
V Leiden or inherited protein C deficiency. Overall, in 58% of
their patients a possible inherited or acquired cause of thrombophilia
was found; in 14% of cases there was the coexistence of inherited or
acquired risk factors. In particular, there was an associated overt
chronic myeloproliferative disease (CMD) in 28 (21%) of 135 patients. The authors did not consider the patients as affected by a CMD who did not meet all the diagnostic criteria but in whom the presence of spontaneous endogenous erythoid colonies (EECs) was detected. Indeed, such approach has repeatedly been reported as a useful diagnostic tool for identifying a CMD at very early
stages.2
The association of unusual or latent forms of CMD diagnosed by
means of the EECs assay has been reported in a large number of patients
with BCS or PVT.3-6 Review of 51 published cases with BCS
and 69 cases with portal and/or mesenteric vein thrombosis showed the
presence of an overt CMD in 49% of the patients with BCS and 23% of
the patients with portal/mesenteric vein thrombosis; the inclusion of
patients with latent CMD as defined by the presence of EECs increased
the diagnostic yield to 78% among patients with BCS and 48% among
patients with portal/mesenteric vein thrombosis.7 Therefore, we suggest that the exclusion of latent CMD as possible underlying cause of splanchnic vein thrombosis could have overestimated the role of inherited thrombophilia as a single risk factor for BCS or
PVT. In our series of 11 patients with BCS and 45 patients with
portal/mesenteric vein thrombosis, 14 (25%) of 56 had inherited thrombophilia (1 had antithrombin III deficiency; 2, protein C deficiency; 8, factor V Leiden mutation; and 3, prothrombin G20210A), in good agreement with the 23% reported by Janssen et
al.1 Among the 31 patients assayed for the presence of
EECs, 18 (58%) were considered to be affected by CMD, in 4 cases in
association with inherited thrombophilia. An overt polycythemia vera or
primary thrombocythemia was present in 7 (22%) of 31 such patients, in 4 cases at the time of thrombosis. Three of the patients with EECs as
the only sign of CMD at the time of thrombosis later developed an overt
thrombocythemia. Thus, in 14 patients the presence of a CMD even at
early stages should have been missed not applying the EECs
assay at the time of thrombosis. Among the 13 patients with no
detectable EECs, 4 had inherited thrombophilia (3, factor V Leiden
mutation; 1, prothrombin G20210A) and 4 had an acquired cause of
thrombosis (1 case each of antiphospholipid antibodies, puerperium,
trauma, and surgery). Therefore among the 31 patients exhaustively
investigated, 26 (84%) had an inherited or acquired cause of
thrombophilia or both. This percentage is higher than that reported by
Janssen et al1 and reflects the improvement in detection
of CMD as underlying cause of thrombosis, confirming that a thorough
search for CMD is mandatory in evaluating patients with splanchnic
venous thrombosis. Diagnostic yield of atypical or precocious forms of
CMD can be substantially increased by the use of the EECs assay or
novel additional assays such as the megakaryocyte expression of the
thrombopoietin receptor (c-mpl), whose decrease has been
recently reported as a hallmark of polycythemia vera.8
Valerio De Stefano, Luciana Teofili, and Giuseppe Leone
Correspondence: Valerio De Stefano, Divisione di Ematologia,
Universita Cattolica, Largo Gemelli 8, 00168 Roma, Italy
References
1.
Janssen HLA, Meinardi JR, Vleggaar FP, et al.
Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.
Blood.
2000;96:2364-2368[Abstract/Free Full Text].
2.
Westwood NB, Pearson TC.
Diagnostic applications of hematopoietic progenitor culture techniques in polycythaemias and thrombocythaemias.
Leuk Lymphoma.
1996;22(suppl 1):95-103.
3.
Valla D, Casadevall N, Lacombe C, et al.
Primary myeloproliferative disorder and hepatic vein thrombosis. A prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome.
Ann Intern Med.
1985;103:329-334.
4.
Valla D, Casadevall N, Huisse MG, et al.
Etiology of portal vein thrombosis in adults: a prospective evaluation of primary myeloproliferative disorders.
Gastroenterology.
1988;94:1063-1069[Medline]
[Order article via Infotrieve].
5.
Pagliuca A, Mufti GJ, Janossa-Tahernia M, et al.
In vitro colony culture and chromosomal studies in hepatic and portal vein thrombosis. Possible evidence of an occult myeloproliferative state.
Q J Med.
1990;76:981-989[Abstract/Free Full Text].
6.
Teofili L, De Stefano V, Leone G, et al.
Hematological causes of venous thrombosis in young people: high incidence of myeloproliferative disorders as underlying disease in patients with splanchnic vein thrombosis.
Thromb Haemost.
1992;67:297-301[Medline]
[Order article via Infotrieve].
7.
De Stefano V, Teofili L, Leone G, Michiels JJ.
Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis.
Semin Thromb Hemost.
1997;23:411-418[Medline]
[Order article via Infotrieve].
8.
Tefferi A, Yoon S-Y, Li C-Y.
Immunoistochemical staining for megakaryocyte c-mpl may complement morphologic distinction between polycythemia vera and secondary erythrocytosis.
Blood.
2000;96:771-772[Abstract/Free Full Text].
Response:
Acquired and inherited risk factors for Budd-Chiari
syndrome and portal vein thrombosis
De Stefano et al describe the role of diagnosing latent
myeloproliferative disorder in Budd-Chiari syndrome (BCS) and
mesenteric or portal vein thrombosis (PVT). Latent myeloproliferative
disorder is diagnosed by growth of erythroid cells in the absence of
erythropoietin, also referred to as spontaneous endogeneous erythroid
colonies (EECs). The association between the presence of EECs and BCS
or PVT is well known.1,2 We agree with De Stefano et al
that excluding EECs may lead to an underestimation of the number of patients with an acquired risk factor for thrombosis and, consequently, to an underestimation of those with a combination of acquired and
inherited risk factors for thrombosis. EEC assays are technically demanding and not amenable to external quality assurance. As stated in
our article, not all of the participating centers tested for the
presence of EECs. Thus our data did not allow us to evaluate the
relation between EECs and BCS or PVT. It should be emphasized that our
study focused on the role of prothrombotic coagulation disorders rather
than on myeloproliferative disorders. Risk estimates for coagulation
abnormalities are not affected by the underrepresentation of
EEC diagnoses.
In our opinion, several of the results presented by De Stefano et al
necessitate a balanced interpretation. First, the presence of EECs
alone is, using the current criteria, not sufficient to diagnose
myeloproliferative disease.3-5 Their presense is used merely as a confirmational criterion for this diagnosis. The
prognostic significance of the presence of EECs as an indication for
latent myeloproliferative disorder has not yet been elucidated. De
Stefano et al reported that 3 of 14 patients with EEC developed an
overt myeloproliferative disorder. Others have reported a lower
incidence of manifest myeloproliferative disorders after long-term
follow-up of patients with PVT.6 Second, De Stefano et al
describe the combined prevalence of myeloproliferative disorders in
patients with different diseases (BCS, PVT, and mesenteric vein
thrombosis). We did not study patients with isolated mesenteric vein
thrombosis. Third, the presented review in which 78% of BCS patients
and 48% of PVT patients exhibit a latent or overt myeloproliferative
disorder results from data pooling of small-scale studies and
early anecdotal reports of highly selected cases.7 The
expected publication bias of the reports collected in this review paper
is exemplified by successive studies from the group of Valla who
initially reported latent or overt myeloproliferative disorders in 75%
of BCS patients but, after 15 years of follow-up, in 31% of their
recently diagnosed patients.1,8 Fourth, it is likely that
the 31 patients exhaustively investigated by De Stefano et al are
selected patients who were referred to a specialized hematology unit.
It would be interesting to know the prevalence of, for example, liver
cirrhosis and pancreatitis in the PVT population studied. In our
opinion, the population studied by De Stefano et al is incomparable to
our wider recruited population, for which we attempted to minimize
patient selection.9 Therefore, comparison of rates of
acquired and/or inherited prothrombotic risk factors between their
and our population does not seem appropriate.
Harry L. A. Janssen and Frits
R. Rosendaal
Correspondence: Harry L. A. Janssen, Center for Basic Research
in Digestive Diseases, Mayo Clinic and Foundation, 200 First St, SW,
Rochester, MN 55905
References
1.
Valla D, Casadevall N, Lacombe C, et al.
Primary myeloproliferative disorder and hepatic vein thrombosis: a prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome.
Ann Intern Med.
1985;103:329-334.
2.
Valla D, Casadevall N, Huisse MG, et al.
Etiology of portal vein thrombosis in adults: a prospective evaluation of primary myeloproliferative disorders.
Gastroenterol.
1988;94:1063-1069.
3.
Pearson TC, Messinezy M.
The diagnostic criteria of polycythemia rubra vera.
Leuk Lymphoma.
1996;22(suppl 1):87-94.
4.
Murphy S, Peterson P, Iland H, et al.
Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival and leukemic transition by treatment.
Semin Hematol.
1997;34:29-39[Medline]
[Order article via Infotrieve].
5.
Michiels JJ.
Diagnostic criteria of the myeloproliferative disorders (MPD): essential thrombocythaemia, polycythaemia vera and chronic megakaryocytic granulocytic metaplasia.
Neth J Med.
1997;51:57-64[CrossRef][Medline]
[Order article via Infotrieve].
6.
Cardin F, Graffeo M, McCormick PA, McIntyre N, Burroughs A.
Adult "idiopathic" extrahepatic venous thrombosis: importance of putative "latent" myeloproliferative disorders and comparison with cases with known etiology.
Dig Dis Sci.
1992;37:335-339[CrossRef][Medline]
[Order article via Infotrieve].
7.
De Stefano V, Teofili L, Leone G, Michiels JJ.
Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis.
Semin Thromb Hemost.
1997;67:297-301.
8.
Denninger MH, Chait Y, Casadevall N, et al.
Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.
Hepatology.
2000;31:587-591[CrossRef][Medline]
[Order article via Infotrieve].
9.
Janssen HL, Meinardi JR, Vleggaar FP, et al.
Factor V leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study.
Blood.
2000;96:2364-2368.
