Document EqOqJn7B3OYnYwgg8g4XGXZ2N

t Annotation i FIBROSIS OF THE BONE MARROW: CONTENT AND CAUSES * Fibrosis of the bone marrow accompanies many diseases (Table 11. When excessive it presumably impedes haemopoiesis. The relative contributions of the fibrosisper se and of the , underlyini pathological state to theTone marrow failure are not clear; it is also unclear to what extent any future treatment would be beneficial if it were aimed specifically at limiting the development of fibrosis. The precise composition of the fibrous tissue present in the marrow in most haernatological conditions has not been studied; similarly the mechanisms by which it develops are largely unknown. Progress has recently been made in two areas: firstly, the nature of the connective tissue matrix of normal marrow and of that from patients with idiopathic myelofibrosis and agnogenic myeloid metaplasia (IMF)has been largely elucidated: secondly, the sequence of events that leads to fibrosis in the myeloproliferative syndromes with a prominent megakaryoblastic/megakaryocyticcomponent is now better understood. Bone marrow matrix Although the term reticulin was originally applied to the powdery residue which remained after extraction of gelatin from reticulum fibres (Sieghed, 1892) it is commonly used nowadays to denote the fibrous network stainable by silver impregnation techniques. As these techniques are not specific for a particular protein, there is still some debate about the precise composition of reticulin. Puchtler 8r M'aldrop (1978) reviewed early data which showed that silver bound to a substance that could be removed from collagen fibres by relatively gentle washing: the remaining collagen still stained with the Van Gieson's Picro-fuchsin technique. Collagen types I and III were identified in histological sections of normal human bone marrow (Bentley et al. 1981) and in cultured marrow (Bentley & Foidart. 1980; Zuckerman & M'icha, 198 3 ) with specificfluorescein-labelled antibodies: the network of collagen appeared. however. more extensive than that identified with silver staining (Jkntley, 1982). There is a close correlation between the quantity of collagen `measured by its hydroxyproline content) and the quantity of reticulin (assessed by phometry) both in marrow from normal individuals and those with IMF (Charron et al. 9 1. However, fibronectin identified by immunofluorescence also corresponded closely to (Stenman & Vaheri, 1978). Gay et al (1984) claim that type Ill collagen ally increases in the early stages of ZMF and type I in the later stages. The elevation Of serum procollagen III aminoterminal peptide (cleaved from procollagen extracellularly biosynthesis of collagen) in IMF supports the contention that type I11 collagen Correspondence:Dr Donald M. McCarthy. Department of Haematology. Charing Cross Hospital and WestminsterMedical School. Westminster Hospital. Horseferry Road. London S W l P ZAP. 1 2 Annotution Table I. Conditions associated with rnyelotibrosis Malignant Acute megakaryoblasticleukaemia Lewis & Szur. 1963: Den Ottolander et ul. t979 Idiopathic myelofibrosis Jacobson et a/. 1978 Chronic granulocytic leukaemia Clough et al, 1979 Acute myeloid leukaemia Manoharan et al. 1979 Acute lymphoblastic leukaemia Manoharan et al. 1979 Hairy cell leukaemia Hasselbalch et a/. 1984 Transitional myeloproliferative syndrome Pettit r t al. 1 9 i 9 Polycythaemia rubra vera Silverstein. 1976 Systemic mastocytosis Lennert & Parwaresch. 1979 Hodgkin's disease Myers et a/. 1974 Myeloma Coughlin et al. 197s Carcinoma Kiang et al, 1978 Nonmalignant Renal osteodystrophy Vitamin D deficiency Hypopara thyroidism Hyperparathyroidism Grey platelet syndrome Systemic lupus erythematosis Systemic sclerosis Thorium dioxide administration Weinberg et al. 1977 Cooperberg & Singer. 1966 Yetgin & Ozsoylu. 1982 Simpson et a / . 198 3 Boxer et al. 1977 Ekrndt et a/. 1983 Daly & Scott. 1983 Gisser I%Chung. 1979 Johnson et a/. 1977 Some other causes of myelofibrosis are discussed in Lancet (Editorial. 1980). synthesis is increased (Hochweiss et al, 1983: Vellenga et al. 1983).One must conclude that the fibrous network of normal and IMF marrow is collagenous, contains fibronectin and that the reticulin stain identities the matrix by reacting with a substance closely related with regard to its position and its quantity to collagen. The fibrous network in other conditions with myelofibrosis has not been analysed but its nature is likely to be similar. Growthfactors and myelofibrosis Groopman (1980) proposed that plateletderived growth factor (PDCF)was inappropriately released from platelets of some patients with myeloproliferative disorders: it then stimulated - fibroblasts to divide and secrete collagen. Subsequently Castro-Malaspina et al(1981) showed that homogenates of megakaryocytes isolated from normal human bone marrow stimulated fibrogenesis: they proposed that abnormal megakaryocytes could release PDGF in vivo and cause fibrosis and that degradation of the newly formed collagen was inhibited by simultaneous release of platelet factor IV which can inhibit collagenase. The fact that the numbers of megakaryocytes and their precursors are increased in idiopathic myelofibrosis Annotation 3 and in malignant myelosclerosis (acute megakaryoblastic leukaemia 1 supported this model. Further support derives from the fact that myelofibrosis occurs with the rare 'grey platelet syndrome' in which excessive release of PDGF occurs (Drouet et al. 1981: Coller et al. 1983). In a disorganized marrow collagen fibres may come into contact with megakaryocytes and platelets; this contact could conceivably cause the platelets to aggregate. degranulate and release further PDGF. In addition. another growth factor termed transforming growth factor-B (TGF-B)and a peptide similar to epidermal growth factor which have recently been identified in platelet extracts (Assoian et al, 1984) may be released and also stimulate fibroblastprohfkration. These postulates.ZRhough satisfactory in those cases of myelofibrosis associated with proliferation of cells of the megakaryocytic lineage. cannot directly be applied to the fibrous tissue that accumulates in other diseases such as hairy cell leukaemia, acute myeloid leukaemia and disseminated carcinoma. It is possible that other mediators of fibrogenesis are released from these malignant cells as they replace normal marrow. Such mediators have already been identified in, although not purified from, supernatants and homogenates of normal cells. For example, macrophages from guinea-pigs release a non-dialysable heat stable factor that stimulates fibroblaststo proliferate (Leibovich& Ross, 1976). Rodent macrophages treated with silica generate a factor that stimulates collagen synthesis (Aalto et al. 1 9 i 6 ) : guinea-pig T-lymphocytes challenged with specific antigens release activity which causes dermal fibroblasts to synthesize DNA and both collagenous and non-collagenous proteins (Wahl et ai. 1978).Supernatant medium from human peripheral blood mononuclear cells treated with phytohaemagglutinin enhanced collagen accumulation by human embryonic lung fibroblasts (Johnson & ZX, 1976). Thus malignant cells that have no connection with the megakaryocytic lineage may induce fibrosisin the marrow by releasing analogous factors. ' Reversibility of myeiofibrosis IZ'e know something of the factors that control the way in which fibroblasts proliferate and synthesize collagen but the nature of the factors that regulate how fibrous tissue is degraded and removed from the bone marrow is unknown. in tissues other than bone marrow the turnover of collagen is very slow indeed but data which relate speci6cally to marrow collagen turnover in the steady state are not available. It is certain. however, that the quantity of collagen present in excess in some conditions can on occasion diminish rapidly. For example, a patient with polycythaemia rubra vera (PRV) has been reported who developed myelofibrosis with myeloid metaplasia and subsequently redeveloped PRV with resolution of the fibrosis (Pettitet al. 19781. This resolution identified by bone marrow trephine biopsy was not due to local variation in the cellularity and fibre content of the marrow as scanning the whole skeleton with 52Feconfirmed the generalized nature of the return of erythropoiesis. The fibrosis associated with Hodgkin's disease (Myers et ai, 1974). metastatic breast carcinoma (Kiang et ai. 1978). acute lymphoblastic and myeloid leukaemia (Manoharan et ai. 1979)may resolve after chemotherapy: similar resolution occurred in patients with acute megakaryoblastic leukaemia (Wolf et al. 1982: Mehta et al. 1983) and chronic myeloid leukaemia (Rappeport er d.1978: Oblon e? a]. 1 983) after bone marrow transplantation. 4 Annotation Treatment with steroids caused resolution of the myelofibrosis in a patient with systemic lupus (Daly Cyr Scott. 1983 ). Presumably. in these cases the breakdown and removal of the collagen was mediated by monocytes, macrophages and granulocytes which contain collagenase (Horwitzet al, 19'77).Other proteases may depolymerize the crosslinked collagen and facilitate the action of collagenase (Perez-Tamayo. 1978 ). A decrease in the numbers of normally functional monocytes and macrophages could thus facilitate the development of the fibrosis in some of the conditions where normal myeloid tissue is replaced by malignant cells. Indeed. in hairy cell leukaemia, which often is associated with fibrosis, monocyte depletion is a characteristic feature. Vitamin D and myelofibrosis Myelofibrosis occurs in a number of non-malignant conditions. Cooperberg & Singer ( 1966, described an infant with rickets and myelofibrosis. The myelofibrosis regressed after treatment with vitamin D. More recently Yetgin & Ozsoylu ( 1982)described 11 children with rickets, myelofibrosis and myeloid metaplasia. The blood pictures and spleen sizes of four patients retuned to normal after treatment with vitamin D and the other two patients who were treated improved both haematologically and clinically. Arlet et a1 (1987)treated with 1.25 dihydroxyvitamin D3 (125(OH).D3)two patients who had myelofibrosis associated with respectively essential thrombocythaemia and myelomonocytic leukaemia and OMwith `acutemyelofibrosis';these patients apparently improved. 1.1.5(OH)lD,,the active honjbonal metabolite of vitamin D3 inhibits the proliferation of human megakaryocytes in vitro and induces myeloid cells from normal individuals and from patients with chronic granulocytic leukaemia to mature in the direction of monocytes and macrophages (McCarthy et al. 198 3. 1984a: Moore et al. 1983).Because megakaryocytes may promote collagen formation and monocytes may degrade it, 1,25(OH)2D3may thus indirectly modulate collagen formation (McCarthy et al. 1984b).Chronic renal failure (CRF) is usually accompanied by low serum levels of 1,25(OH)2D3and sometimes also by myelofibrosis (Weinberg et al, 1977);in view of the data discussed above one may postulate that the low level of 1.25(OH)2D3contributes to evolution of myelofibrosis in CRF and may therefore contribute to the anaemia in some such patients. However, the endocrine abnormalities in CRF are complex and increased concentrations of parathyroid hormone may also enhance the accumulation of collagen in the bone marrow (Boxer et al. 1977). Conclusions Fibrous tissue is conventionally d e r n o n s 6 k d with the reticulin stain: this reacts with many proteins but in bone marrow identifies coliagen and fibronectin. In acute megakaryoblastic - leukaemia and `idiopathic myelofibrosis' abnormal megakaryocytes and their precursors proliferate and release PDGF. This in turn stimulates fibroblasts to proliferate and synthesize collagen. It may thus no longer be correct to regard the fibrosis in these conditions as `idiopathic' and perhaps the term `idiopathic myelofibrosis' should be dropped. In other neoplasia poorly characterized factors released from malignant cells cause myelofibrosis. In a Annotation 5 ' similarmanner. Collagenase released from monocytes. macrophages and granulocytes may degrade fibrous tissue and probably mediates the resolution of myelofibrosis seen in some patients after chemotherapy and bone marrow transplantation. There is laboratory and clinical evidence that metabolites of vitamin D and parathyroid hormone regulate collagen deposition in the bone marrow: a therapeutic role for 1.25(OH)lD3in some patients with myelofibrosis has been suggested. ACKNOWLEDGMENTS - I wish to thank Drs Jill Hibbin and JohnGoldman and Professor David Galton for their help and for critically reading the manuscript: and Mrs Paulette Memman for processing it. The Leukaemia Research Fund of Great Britain provided financial support. MRC Leukaemia Unit, Royal Postgraduate Medical School. DuCane Road. London DONALD M.MCCARTHY REFERENCES &TO. M., POTILA,M. & KUBONEX:E. . (1976) The BOXER.M.. ELLMAN.L.. GELLERR, . & WANG,C-A. e6ect of silica-treated macrophages on the ( 1977) Anemia in primary hyperparathyroid- synthesis of collagen and other proteins in ism. Archives of Internal Medicine. 137, 588- vim. Experimental Cell Research. 97, 193-202. 590. UT. PR.,NICODEMER.. AWUE.D.. LARRFSAIN- CA~O-MALASPINAM. .. RABELLINOE. .M., YEN, A.. ~ ~ I E R , D . . D E L s o L . G . & L E T A L L E c . Y . ( N~A~C~H~M) AN. R.L. & MOORE. M.A.S. (1981) Clinical evidence.for 1.25-hpdroxycholecalci- Human megakaryocyte stimulation of prolifer- ferol action ini! myelofibrosis. Lancet. i. 1013-1014. I( ation of bone marrow fibroblasts. Blood, 57. 781-787. .+SWlAS. R.K.. GROTENDOWG. .R.. AILLAR. D.M. 8- CHARRON. D.. ROBERL. ., Corn.M.C. & BINET, J-C, SWR!. M.B.(1984)Cellular transformation by 11979)Biochemicaland histological analysis of coordinated action of three peptide growth bone marrow collagen in myelofibrosis. British factors from human platelets. K a m e . 309, journal of Haematology. 41, 1 5 1-1 6 1 . soh-806. CLOUCHV. .. GEAR\.C.G., HASHMIK. .. DAWSOX1.. & HFYTLEF. S.A. ( 1 982) Bone mamow connective KNOWWN.T. ( 1979) Myelofibrosis in chronic tissue and the haemopoietic microenviron- granulocytic leukaemia. British journal o/ Hae- ment. British journal of Haematnlogy. 50, 1-6. matology. 42, 51 5-526. l i t Y T L E ~ . S.A.. ALABASTER. 0. & FOIDART. J-M. CULLER. B.S.. HULTIXM. .B.. NURDEN.A.T.. Rosa. t I 98 1 Collagen heterogeneity in normal J-P. & LANE. B.P. (1983) Isolated 3-granule human bone marrow. British lournal of Haema- @4b8,2.8 7-29 I. 5w.S.A. & FOIDART.J-M. (1980) Some deficiency (gray platelet syndrome)with slight increase in bone marrow reticulin and possible glycoprotein and/or protease defect. (Abstract). mpatks of mmwderived adherent cells in Thrombosisand Haemostasis,50. 211. tissue culture. Blood, 56.1006-1012. COOPERBERG. A.A. & SINGER. O.P. (1966) Rever- RFRNm. M.C..CASTALDIP. .A.. GORDOS.S., HAL- sible myelofibrosis due to vitamin D deficiency L-. H.& MCPHERSONV..J. ( 198 3 I Morphologi- rickets. CanadianMedical Association journal. 94, cal and biochemical c o n h a t i o n of grey plate- 392-395. kt syndrome in two siblings. !Sew Zealand COUGHLINC... GREENWALDE..S.. SCHRAFWT.C. & M&al journal. 1 3 , 387-390. GROSSMANS.. ( 19 7 8 ) Myelofibrosis associated 6 Annotution with multiple myeloma. Archives of Internal liferation of haematopoietic cells with second- Medicine, 138. 590- 592. ary myelofibrosis. Blood. 5 1. 189-1 94. DALY. H.M. & S c m . G.L. ( 1 9 8 3 )Myelofibrosis as JOHNSON. R.L. & ZIFF. M. I 19761 Lymphokine a cause of pancytopenia in systemic lupus stimulation of collagen accumulation. lournu! erythematosis. Journal of Clinical Pathology. 36, of Clinical Investigation. 58, 240-2 52. 1219-1222. JOHNSON. S.A.N.. BATEMANC. .J.T.,BEARD. M.E.J.. DEN OITOLANDER.G.J., TE VELDE.J.. BREDEROOP, .. WHITEHOUSEJ.M.A. & WATERS, A.H. ( 1 9 7 7 G E R . ~ J. .P.M.,SLEE. P.H.T.. WILLEMZER... Long-term haematological consequences of ZWAAN, F.E., HAAK. H.L., MULLER. H.P. & thorotrast. Quarterly Journal of Medicine. 16, BIEGER. R. (1979)Megakaryoblastic leukaemia 2 59-269. (acute myelofibrosis): a report of three cases. KIANG. D.T.. MCKENNA.R.W. & KENNEDY. B.J. British journal of Haematology. 42. 9-20. ( 197 8J Reversal of myelofibrosis in advanced DROC'ETL... PRALORAN. V.. CYWINER-GOLENZECR.. . breast cancer. American ]ournu/of Medicine. 64, TREHEN. C.. FLANDRING. . (Y, CAEV. J. (1981) 173-1 7 6 . Deficit congenital en alpha granules plaquet- LEIBOVICH. S.J.& ROSS. R. I19761A macrophage- takes et fibrose reticulinique medullaire. dependent factor that stimulates the prolifer- Hypothese physiopathogenique. Nouvelle Revue ation of fibroblasts in vitro. .herican journal oj Francaise d'He'matologie. 23. 9 5- 100. Pathology. 84,501-513. EDITORIAL ( 1 9 8 0 ) Myelofibrosis. Lancet. i, LENNERT. K. & PARWARESCHM..R. 11979) Mast 1 27-129. cells and mast cell neoplasia: a review. Histo- GAY. S.. GAY. R. & PRCHALJ. .T. 11984)Immuno- pathology. 3, 319-365. histological studies of bone marrow collagen. LEWIS. S.M. & UR. L. ( 1 9 6 3 ) Sfalignant myelo- In: Myelofibrosis and the Biology of Connective sclerosis. Britt h ,Medical journal. ii, 4 7 2 4 7 7 . Tissue (ed. by P. D. Berk and M. Castro-Malas- MANOHARAN.A.. HORSLEYR. . & PITNEY.W.R. pina). Alan R. Liss. New York. (1 979) Thereticulin content of bone marrow in GISSER. S.D. & CHUNGK, .B. ( 1979) Acute myelofi- acute leukaemia in adults. British lournu1 of brosis of progressive systemic sclerosis. Ameri- Haematology. 43. 185-190. can journal of Medicine. 67, 1 5 1-154. MEHTA. A B . . BAUCHAN. A.S.J.. CATOVSKY. D.. GROOPMANJ..E. (1980)The pathogenesis of mye- GOLDMAN.J.M.. JOHNSON. S.A.N. & GALTON. lofibrosisin myeloproliferativedisorders. Annals D.A.G. ( 1 9 8 3 ) Reversal of marrow fibrosis in of Internal Medicine, 92. 8 5 7-8 58. acute megakaryoblastic leukaemia after remis- HASSELBALCH. H.. LISSE.I.. BERILD, D. & VIDEBAEK. sion induction and consolidation chemo- A. ( 1984) Spongy lymphoid myelofibrosis as a therapy followed by bone marrow transplan- predictor ofhairy cell leukaemia or a variant of tation. British journal of Haematology, 53. hairy cell leukaemia without hairy cells. Scan- - 1 4 5 4 4 9 . dinavian Journal of Hacmatology, 32, 135-144. MCCMTHY.D.M.. HIBBIN. 1.A. & GOLDMANJ..M. HOCHWEISSS... FRACHTMAN. S.. HAHN. E.G.. Grt- (1984b) A role for 1.25-hydroxyvitamin D3 in BERT. H..DONOVANP..B.. JOHNSON.&.GOLDBERC. control of bone marrow collagen deposition? J.D. & BERK. P.D. (1983) Increased serum Lancet. i, 78-80. procollagen IIIaminoterminalpeptidein myelo- MCCARTHYD.M., HIBBIN,J.A.. SAX MIGUELJ..F.. fibrosis. A m e r i c ~ l o u r n dof Hematologg. 15, F w , H.. RODRIGUESB, .. ANDREWS, C.. PINCH- 343-3 S 1. ING. A.. CATOVSKY. D. &GOLDMANJM. . (1981a) HORWITZ. A.L.. HANCE. A.J. & CRYSTAL, R.C. The effect of vitamin D3 metabolites on normal - ( 1 9 7 7 ) Granulocyte collagenase: selective and leukemic bone marrow cells in vitro. degradation of type I relative to type I11 col- International journal ofCrl2 Cloning. 2 , 2 27-24?. lagen. Proceedings of the .Vutional Academy of MCC.IRTHYD. .M.. SAXM I G ~ E LJ..F.. FREAKE. H.C.. Sciences of the L'nitPd States or .4rnerica. 79, GREEN. P.M.. ZOLA.H.. CATOVSKY. D. & GOLD- 897-90 1. MAS. J.M. (1983) 1.25dihydroxyvitarnin D3 JACOBSON. R.J.. SALO. A. & FIALKOW. P.J. (1978) inhibits proliferation of human promyelocytic Agnogenic myeloid metaplasia: a clonal pro- leukaemia 1HL60)cells and induces monocyte- Annomion c / macrophage differentiation in HL60 and nor- Leipzig. Quotedby Puchtler. H. & N'aldrop. F.S. mal human bone marrow cells. LPukernia (19781 Histochemistry. 57, 177-187. Research. 7. 51- 55. SIL\TRSTEISM. .N. (1976'1The evolution into and MOORE. M.A.S.. GABRILOVE.J. & SHERIDAAN..P. the treatment of late stage polycythemia vera. (1983) Induction of myeloid leukaemia cell Seminars in Hematology. 13, 79-84. differentiation by endogenous cytokines and SIMPSONH. .K.L.. HOWDENC, .W.. ELLIUIT. H.L. & vitamin analogues. Leukemia Research: THOMPSON, T.J. (1983) Idiopathic hypopara- Mvunces in Cell Biology and Treatment (ed.by S. thyroidism associated with stable untreated B. Murphy and J. R. Gilbert), pp. 31-51. myelofibrosis.. British Medial Journal. 286. Elsevier Biomedical. Amsterdam. 1316-1 317. MYERS.C.E.. CHABNERB..A.. DEVITA.V.T. &GRAL- STENMANS. &VAHERI.A. (1978)Distributionofa NIY, H.R. (1974)Bone marrow involvement in major connective tissue protein, fibronectin. in Hodgkin's disease: pathology and response to normal human tissues. Journal of Experimental MOPP chemotherapy. Blood. 44, 197-204. Medicine. 147, 1054-1064. O B ~ XD.J.E.LVENBEIS.G.J.. BRAYLAMR..C.. JONES. VELLENGA.E.. MULDER.N.H.. VAN ZA~TEN.A X . . J. 8- U ' E ~ E RR.S. (1983) The reversal of NEIWEGH. .O.8- M'OLDRING.M.G. ( 1 9 8 3 ) The myelofibrosis associated with chronic myelo- significance of the aminoterminal propeptides genous leukemia after allogeneicbone marrow of type III procollagen in paroxysmalnocturnal transplantation. Experimental Hematology. 11, haemoglobulinuria and myelofibrosis. Euro- 68 1-685. pean Journalof .Wuclear Medicine. 8. 499- 501. PEREZ-TAMARY.O(1. 978) Pathology of collagen M'AHL,S.M..M'AHL.L.M. & M ~ A R T HJT.B. .( 1978) degsadation. American jouml of Pathology, 92, Lymphocyte-mediated activation of fibroblast 509-566. proliferationand collagenproduction.Journalo/ PFITIT. J.E.. LEWIS. S.M.8- GOOLDEN.A.W.G. Immunology, 121, 942-946. (1978) Polycythaemia vera-transformation WEINBERGS..G.. LLIBIKA. ,. WIENER. S.N.. DEOXAS, to rnyelofibm~iasnd subsequent reversal. Scan- C.M.P..CHOESE. M.K.8- KOPELMAN.R.C. (1977) dirmvian Journal of Haematology. 20. 63-69. Myelofibrosisand renal osteodystrophy.Ameri- P m .J.E..LEWIS, S.M. Br NICHOLAS. A.W. (1979):, can Journal of Medicine. 63, 755-i64. Transitional myeloproliferative disorder. Bri- f.1 WOLF. J.L.. SPRUCE. W.E.. BEARMAN.R.M..FOR- tish journal ofHaematology. 43, 167-1 84. MAN. S.J.. SCOTT. E.P.. FAHEY.J.L.. F.~RBSTEIN. P ~ ~ L E HR. .& WALDROPF, .S. (1978) Silver M.J.R.APPAPORT.H. LC BLCMEI.;.(1982)Rever- impregnation methods for reticulum fibers and sal of acute ('malignant') myelosclerosis by reticulin: a reinvestigation of their origins and allogeneic bone marrow transplantation. specificity.Histochemistry. 57, 1 77-1 87. Blood. 59. 191-193. RAPPEPORT. J., PAFIKMARN...BELLI. J.. LEVEY.R.. YETGIK;S. . LC OZSOYLUS. . 19821Myeloid metaRWEs. F. 8: NATHAN. D. (1978)Reversibilityof plasia in vitamin D deficiency rickets. Scandina- Welofibrosis (MF) after bone marrow trans- vian Journal of Haematology. 28, 18C-185. Plantation (BMTTX). Blood. 52, Suppl. 1,2 71. ZUCKERMAN.K.S. & WICHAM. .S. ( 198 3 t Extracel- Abstract 589. lular matrix production by the adherent cellsof S1hCFRIED. M. ( 1892) Uber die chemischen Eigen- long-term bone marrow cultures. Blood, 61, =haften des reticulierten Gewebes.Brockhaus. 540-54 7 . -