Can plasma fibrinogen level predict bone marrow fibrosis?
Year 2023,
, 80 - 86, 31.01.2023
Yildiz Ipek
Ayse Nilgun Kul
Abstract
Objective: We aimed to assess the possible relationship between plasma fibrinogen level and bone marrow fibrosis (BMF) grades in
patients who had undergone bone marrow (BM) biopsy for any reason.
Patients and Method: This retrospective cohort study included 106 participants aged 18 years and over who had undergone
simultaneous BM biopsy and circulatory fibrinogen level measurement during 2020 and 2021 at our center. BMF grade was measured
by the modified Bauermeister grading system (MBGS). Participants were divided into two groups according to MBGS as those without
BMF and those with BMF.
Results: Fifty-eight male were included in our study, and the median age of the patients was 63 (range: 19-97) years. Fibrinogen
(p=0.004) and lactate dehydrogenase (LDH) (p=0.030) levels were significantly higher in the fibrosis group. Multiple regression
revealed that high fibrinogen (≥359) and high LDH (≥238) were independently associated with a higher likelihood of fibrosis presence
(adjusted for age and sex); however, diagnostic analyses revealed low accuracy.
Conclusion: High plasma fibrinogen and LDH levels were found to be independently associated with the presence of BMF. However,
it was also evident that neither of these parameters could be used for diagnostic purposes.
References
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myelosuppression due to progressive bone marrow fibrosis in
a patient with acute promyelocytic leukemia. Case Reports in
Hematol 2019; 2019: 1616237. doi: 10.1155/2019/1616237.
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role of extracellular matrix stiffness in megakaryocyte and
platelet development and function. Am J Hematol 2018; 93:
430-41. doi: 10.1002/ajh.25008.
- Rizvi H, Butler T, Calaminici M, et al. United Kingdom
immune thrombocytopenia registry: retrospective evaluation
of bone marrow fibrosis in adult patients with primary immune
thrombocytopenia and correlation with clinical findings. Br J
Haematol 2015; 169: 590-4. doi: 10.1111/bjh.13330.
- Narang NC, Rusia U, Sikka M, Kotru M. Morphological
changes in bone marrow post imatinib therapy in chronic
phase CML: a follow up study on sequential bone marrow
aspirates and biopsies. J Clin Diagn Res 2017; 11: EC25-9. doi:
10.7860/JCDR/2017/25173.9650.
- Della Porta MG, Malcovati L, Boveri E, et al. Clinical relevance
of bone marrow fibrosis and CD34-positive cell clusters in
primary myelodysplastic syndromes. J Clin Oncol 2009; 27:
754-62. doi: 10.1200/JCO.2008.18.2246.
- Tu M, Hu S, Lou Z. A high value of fibrinogen in
immunoglobulin A nephropathy patients is associated with a
worse renal tubular atrophy/interstitial fibrosis score. J Clin
Lab Anal 2022; 36: e24120. doi: 10.1002/jcla.24120.
- Sörensen I, Susnik N, Inhester T, et al. Fibrinogen, acting
as a mitogen for tubulointerstitial fibroblasts, promotes
renal fibrosis. Kidney Int 2011; 80: 1035-44. doi: 10.1038/
ki.2011.214.
- De Giorgio-Miller A, Bottoms S, Laurent G, Carmeliet P,
Herrick S. Fibrin-induced skin fibrosis in mice deficient in
tissue plasminogen activator. Am J Pathol 2005; 167: 721-32.
doi: 10.1016/s0002-9440(10)62046-9.
- Ahmed HH, Amer MS, Salem NA, Abou El-Fadl HM.
Therapeutic implications of bone marrow mesenchymal stem
cells in experimental liver fibrosis. World J Pharm Res 2013;
2: 1971-98.
- Masamune A, Kikuta K, Watanabe T, et al. Fibrinogen induces
cytokine and collagen production in pancreatic stellate cells.
Gut 2009; 58: 550-9. doi: 10.1136/gut.2008.154401.
- Vidal B, Serrano AL, Tjwa M, et al. Fibrinogen drives
dystrophic muscle fibrosis via a TGFbeta/alternative
macrophage activation pathway. Genes Dev 2008; 22: 1747-
52. doi: 10.1101/gad.465908.
- Li FJ, Surolia R, Singh P, et al. Fibrinogen mediates cadmiuminduced
macrophage activation and serves as a predictor of
cadmium exposure in chronic obstructive pulmonary disease.
Am J Physiol Lung Cell Mol Physiol 2022; 322: L593-l606. doi:
10.1152/ajplung.00475.2021.
- Reshma VJ, Anwar AS, Mufeed A, Roshni A. Estimation of
plasma fibrinogen degradation products in oral submucous
fibrosis: A clinico-pathological study. J Int Soc Prev
Community Dent 2015; 5: 309-13. doi: 10.4103/2231-
0762.161760.
- Zhang Y, Xin Q, Wu Z, et al. Application of isobaric tags
for relative and absolute quantification (iTRAQ) coupled
with two-dimensional liquid chromatography/tandem mass
spectrometry in quantitative proteomic analysis for discovery
of serum biomarkers for idiopathic pulmonary fibrosis. Med
Sci Monit 2018; 24: 4146-53. doi: 10.12659/MSM.908702.
- Sogawa K, Noda K, Umemura H, et al. Serum fibrinogen alpha
C‐chain 5.9 k D a fragment as a biomarker for early detection
of hepatic fibrosis related to hepatitis C virus. Proteomics Clin
Appl 2013; 7: 424-31. doi: 10.1002/prca.201200094.
- Yu X, Hu F, Yao Q, Li C, Zhang H, Xue Y. Serum fibrinogen
levels are positively correlated with advanced tumor stage
and poor survival in patients with gastric cancer undergoing
gastrectomy: a large cohort retrospective study. BMC Cancer
2016; 16: 480. doi: 10.1186/s12885.016.2510-z.
- Bauermeister DE. Quantitation of bone marrow reticulin—a
normal range. Am J Clin Pathol 1971; 56: 24-31. doi: 10.1093/
ajcp/56.1.24.
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marrow fibrosis: pathophysiology and clinical significance of
increased bone marrow stromal fibres. Br J Haematol 2007;
139: 351-62. doi: 10.1111/j.1365-2141.2007.06807.x.
- Thiele J, Grashof K, Fisher R. Follow-up study on bone
marrow reticulin fibrosis in AML. Anal Cell Pathol 1991; 3:
225-31. PMID: 1883746
- Thiele J, Kvasnicka HM, Facchetti F, Franco V, Van Der Walt
J, Orazi A. European consensus on grading bone marrow
fibrosis and assessment of cellularity. Haematologica 2005; 90:
1128-32. PMID: 16079113
- O’malley DP, Sen J, Juliar BE, Orazi A. Evaluation of stroma in
human immunodeficiency virus/acquired immunodeficiency
syndrome–affected bone marrows and correlation with
CD4 counts. Arch Pathol Lab Med 2005; 129: 1137-40. doi:
10.5858/2005.129.1137-EOSIHI.
- Bain BJ, Clark DM, Wilkins BS. Bone marrow pathology: John
Wiley & Sons, 2019.
- Tefferi A. Pathogenesis of myelofibrosis with myeloid
metaplasia. J Clin Oncol 2005; 23: 8520-30. doi: 10.1200/
JCO.2004.00.9316.
- Buesche G, Ganser A, Schlegelberger B, et al. Marrow fibrosis
and its relevance during imatinib treatment of chronic
myeloid leukemia. Leukemia 2007; 21: 2420-7. doi: 10.1038/
sj.leu.2404917.
- Tadmor T, Shvidel L, Aviv A, et al. Significance of bone
marrow reticulin fibrosis in chronic lymphocytic leukemia at
diagnosis: a study of 176 patients with prognostic implications.
Cancer 2013; 119: 1853-9. doi: 10.1002/cncr.27930.
- Liu B, Limback J, Kendall M, et al. Safety of CT-Guided
Bone Marrow Biopsy in Thrombocytopenic Patients: A
Retrospective Review. J Vasc Interv Radiol 2017; 28: 1727-31.
doi: 10.1016/j.jvir.2017.08.009.
- Lowenthal RM, Taylor BV, Jones R, Beasley A. Severe
persistent sciatic pain and weakness due to a gluteal artery
pseudoaneurysm as a complication of bone marrow biopsy. J
Clin Neurosci 2006; 13: 384-5. doi: 10.1016/j.jocn.2005.03.027.
- Shehata M, Schwarzmeier JD, Hilgarth M, Hubmann R,
Duechler M, Gisslinger H. TGF-β1 induces bone marrow
reticulin fibrosis in hairy cell leukemia. J Clin Invest 2004; 113:
676-85. doi: 10.1172/JCI19540.
- Hasselbalch H, Junker P, Lisse I, Bentsen KD. Serum
procollagen III peptide in chronic myeloproliferative
disorders. Scand J Haematol 1985; 35: 550-7. doi: 10.1111/
j.1600-0609.1985.tb02827.x.
- Abou Zahr A, Salama ME, Carreau N, et al. Bone marrow
fibrosis in myelofibrosis: pathogenesis, prognosis and targeted
strategies. Haematologica 2016; 101: 660-71. doi: 10.3324/
haematol.2015.141283.
- Cattoretti G, Schiró R, Orazi A, Soligo D, Colombo MP. Bone
marrow stroma in humans: anti-nerve growth factor receptor
antibodies selectively stain reticular cells in vivo and in vitro.
Blood 1993; 81: 1726-38. PMID: 7681701
- Hasselbalch HC. The role of cytokines in the initiation and
progression of myelofibrosis. Cytokine Growth Factor Rev
2013; 24: 133-45. doi: 10.1016/j.cytogfr.2013.01.004.
- Castro-Malaspina H, Rabellino EM, Yen A, Nachman RL,
Moore M. Human megakaryocyte stimulation of proliferation
of bone marrow fibroblasts 1981; 57: 781-7. PMID: 7470627
- Breton-Gorius J, Bizet M, Reyes F, et al. Myelofibrosis and
acute megakaryoblastic leukemia in a child: topographic
relationship between fibroblasts and megakaryocytes with an
α-granule defect. Leuk Res 1982; 6: 97-110. doi: 10.1016/0145-
2126(82)90048-0.
- Schmitt A, Jouault H, Guichard J, Wendling F, Drouin A,
Cramer EM. Pathologic interaction between megakaryocytes
and polymorphonuclear leukocytes in myelofibrosis. Blood
2000; 96: 1342-7. PMID: 10942376
- Schepers K, Pietras EM, Reynaud D, et al. Myeloproliferative
neoplasia remodels the endosteal bone marrow niche into a
self-reinforcing leukemic niche. Cell Stem Cell 2013; 13: 285-
99. doi: 10.1016/j.stem.2013.06.009.
- Kikuchi T, Shimizu T, Toyama T, Abe R, Okamoto S. Successful
treatment of TAFRO syndrome with tocilizumab, prednisone,
and cyclophosphamide. Intern Med 2017: 8522-16.
- Herrick S, Blanc-Brude O, Gray A, Laurent G. Fibrinogen.
Int J Biochem Cell Biol 1999; 31: 741-6. doi: 10.1016/s1357-
2725(99)00032-1.
- Greiling D, Clark RA. Fibronectin provides a conduit for
fibroblast transmigration from collagenous stroma into fibrin
clot provisional matrix. J Cell Sci 1997; 110 ( Pt 7): 861-70. doi:
10.1242/jcs.110.7.861.
- Héron A, Lévesque JP, Hatzfeld A, et al. Mitogenic effect of
fibrinogen on hematopoietic cells: involvement of two distinct
specific receptors, MFR and ICAM-1. Biochem Biophys Res
Commun 1998; 246: 231-7. doi: 10.1006/bbrc.1998.8583.
- Wilberding JA, Ploplis VA, Mclennan L, et al. Development
of pulmonary fibrosis in fibrinogen-deficient mice. Ann N
Y Acad Sci 2001; 936: 542-8. doi: 10.1111/j.1749-6632.2001.
tb03542.x.
- Ploplis VA, Wilberding J, Mclennan L, et al. A total fibrinogen
deficiency is compatible with the development of pulmonary
fibrosis in mice. Am J Pathol 2000; 157: 703-8. doi: 10.1016/
s0002-9440(10)64582-8.
Year 2023,
, 80 - 86, 31.01.2023
Yildiz Ipek
Ayse Nilgun Kul
References
- Inagawa Y, Komeno Y, Saito S, et al. Prolonged
myelosuppression due to progressive bone marrow fibrosis in
a patient with acute promyelocytic leukemia. Case Reports in
Hematol 2019; 2019: 1616237. doi: 10.1155/2019/1616237.
- Leiva O, Leon C, Kah Ng S, Mangin P, Gachet C, Ravid K. The
role of extracellular matrix stiffness in megakaryocyte and
platelet development and function. Am J Hematol 2018; 93:
430-41. doi: 10.1002/ajh.25008.
- Rizvi H, Butler T, Calaminici M, et al. United Kingdom
immune thrombocytopenia registry: retrospective evaluation
of bone marrow fibrosis in adult patients with primary immune
thrombocytopenia and correlation with clinical findings. Br J
Haematol 2015; 169: 590-4. doi: 10.1111/bjh.13330.
- Narang NC, Rusia U, Sikka M, Kotru M. Morphological
changes in bone marrow post imatinib therapy in chronic
phase CML: a follow up study on sequential bone marrow
aspirates and biopsies. J Clin Diagn Res 2017; 11: EC25-9. doi:
10.7860/JCDR/2017/25173.9650.
- Della Porta MG, Malcovati L, Boveri E, et al. Clinical relevance
of bone marrow fibrosis and CD34-positive cell clusters in
primary myelodysplastic syndromes. J Clin Oncol 2009; 27:
754-62. doi: 10.1200/JCO.2008.18.2246.
- Tu M, Hu S, Lou Z. A high value of fibrinogen in
immunoglobulin A nephropathy patients is associated with a
worse renal tubular atrophy/interstitial fibrosis score. J Clin
Lab Anal 2022; 36: e24120. doi: 10.1002/jcla.24120.
- Sörensen I, Susnik N, Inhester T, et al. Fibrinogen, acting
as a mitogen for tubulointerstitial fibroblasts, promotes
renal fibrosis. Kidney Int 2011; 80: 1035-44. doi: 10.1038/
ki.2011.214.
- De Giorgio-Miller A, Bottoms S, Laurent G, Carmeliet P,
Herrick S. Fibrin-induced skin fibrosis in mice deficient in
tissue plasminogen activator. Am J Pathol 2005; 167: 721-32.
doi: 10.1016/s0002-9440(10)62046-9.
- Ahmed HH, Amer MS, Salem NA, Abou El-Fadl HM.
Therapeutic implications of bone marrow mesenchymal stem
cells in experimental liver fibrosis. World J Pharm Res 2013;
2: 1971-98.
- Masamune A, Kikuta K, Watanabe T, et al. Fibrinogen induces
cytokine and collagen production in pancreatic stellate cells.
Gut 2009; 58: 550-9. doi: 10.1136/gut.2008.154401.
- Vidal B, Serrano AL, Tjwa M, et al. Fibrinogen drives
dystrophic muscle fibrosis via a TGFbeta/alternative
macrophage activation pathway. Genes Dev 2008; 22: 1747-
52. doi: 10.1101/gad.465908.
- Li FJ, Surolia R, Singh P, et al. Fibrinogen mediates cadmiuminduced
macrophage activation and serves as a predictor of
cadmium exposure in chronic obstructive pulmonary disease.
Am J Physiol Lung Cell Mol Physiol 2022; 322: L593-l606. doi:
10.1152/ajplung.00475.2021.
- Reshma VJ, Anwar AS, Mufeed A, Roshni A. Estimation of
plasma fibrinogen degradation products in oral submucous
fibrosis: A clinico-pathological study. J Int Soc Prev
Community Dent 2015; 5: 309-13. doi: 10.4103/2231-
0762.161760.
- Zhang Y, Xin Q, Wu Z, et al. Application of isobaric tags
for relative and absolute quantification (iTRAQ) coupled
with two-dimensional liquid chromatography/tandem mass
spectrometry in quantitative proteomic analysis for discovery
of serum biomarkers for idiopathic pulmonary fibrosis. Med
Sci Monit 2018; 24: 4146-53. doi: 10.12659/MSM.908702.
- Sogawa K, Noda K, Umemura H, et al. Serum fibrinogen alpha
C‐chain 5.9 k D a fragment as a biomarker for early detection
of hepatic fibrosis related to hepatitis C virus. Proteomics Clin
Appl 2013; 7: 424-31. doi: 10.1002/prca.201200094.
- Yu X, Hu F, Yao Q, Li C, Zhang H, Xue Y. Serum fibrinogen
levels are positively correlated with advanced tumor stage
and poor survival in patients with gastric cancer undergoing
gastrectomy: a large cohort retrospective study. BMC Cancer
2016; 16: 480. doi: 10.1186/s12885.016.2510-z.
- Bauermeister DE. Quantitation of bone marrow reticulin—a
normal range. Am J Clin Pathol 1971; 56: 24-31. doi: 10.1093/
ajcp/56.1.24.
- Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone
marrow fibrosis: pathophysiology and clinical significance of
increased bone marrow stromal fibres. Br J Haematol 2007;
139: 351-62. doi: 10.1111/j.1365-2141.2007.06807.x.
- Thiele J, Grashof K, Fisher R. Follow-up study on bone
marrow reticulin fibrosis in AML. Anal Cell Pathol 1991; 3:
225-31. PMID: 1883746
- Thiele J, Kvasnicka HM, Facchetti F, Franco V, Van Der Walt
J, Orazi A. European consensus on grading bone marrow
fibrosis and assessment of cellularity. Haematologica 2005; 90:
1128-32. PMID: 16079113
- O’malley DP, Sen J, Juliar BE, Orazi A. Evaluation of stroma in
human immunodeficiency virus/acquired immunodeficiency
syndrome–affected bone marrows and correlation with
CD4 counts. Arch Pathol Lab Med 2005; 129: 1137-40. doi:
10.5858/2005.129.1137-EOSIHI.
- Bain BJ, Clark DM, Wilkins BS. Bone marrow pathology: John
Wiley & Sons, 2019.
- Tefferi A. Pathogenesis of myelofibrosis with myeloid
metaplasia. J Clin Oncol 2005; 23: 8520-30. doi: 10.1200/
JCO.2004.00.9316.
- Buesche G, Ganser A, Schlegelberger B, et al. Marrow fibrosis
and its relevance during imatinib treatment of chronic
myeloid leukemia. Leukemia 2007; 21: 2420-7. doi: 10.1038/
sj.leu.2404917.
- Tadmor T, Shvidel L, Aviv A, et al. Significance of bone
marrow reticulin fibrosis in chronic lymphocytic leukemia at
diagnosis: a study of 176 patients with prognostic implications.
Cancer 2013; 119: 1853-9. doi: 10.1002/cncr.27930.
- Liu B, Limback J, Kendall M, et al. Safety of CT-Guided
Bone Marrow Biopsy in Thrombocytopenic Patients: A
Retrospective Review. J Vasc Interv Radiol 2017; 28: 1727-31.
doi: 10.1016/j.jvir.2017.08.009.
- Lowenthal RM, Taylor BV, Jones R, Beasley A. Severe
persistent sciatic pain and weakness due to a gluteal artery
pseudoaneurysm as a complication of bone marrow biopsy. J
Clin Neurosci 2006; 13: 384-5. doi: 10.1016/j.jocn.2005.03.027.
- Shehata M, Schwarzmeier JD, Hilgarth M, Hubmann R,
Duechler M, Gisslinger H. TGF-β1 induces bone marrow
reticulin fibrosis in hairy cell leukemia. J Clin Invest 2004; 113:
676-85. doi: 10.1172/JCI19540.
- Hasselbalch H, Junker P, Lisse I, Bentsen KD. Serum
procollagen III peptide in chronic myeloproliferative
disorders. Scand J Haematol 1985; 35: 550-7. doi: 10.1111/
j.1600-0609.1985.tb02827.x.
- Abou Zahr A, Salama ME, Carreau N, et al. Bone marrow
fibrosis in myelofibrosis: pathogenesis, prognosis and targeted
strategies. Haematologica 2016; 101: 660-71. doi: 10.3324/
haematol.2015.141283.
- Cattoretti G, Schiró R, Orazi A, Soligo D, Colombo MP. Bone
marrow stroma in humans: anti-nerve growth factor receptor
antibodies selectively stain reticular cells in vivo and in vitro.
Blood 1993; 81: 1726-38. PMID: 7681701
- Hasselbalch HC. The role of cytokines in the initiation and
progression of myelofibrosis. Cytokine Growth Factor Rev
2013; 24: 133-45. doi: 10.1016/j.cytogfr.2013.01.004.
- Castro-Malaspina H, Rabellino EM, Yen A, Nachman RL,
Moore M. Human megakaryocyte stimulation of proliferation
of bone marrow fibroblasts 1981; 57: 781-7. PMID: 7470627
- Breton-Gorius J, Bizet M, Reyes F, et al. Myelofibrosis and
acute megakaryoblastic leukemia in a child: topographic
relationship between fibroblasts and megakaryocytes with an
α-granule defect. Leuk Res 1982; 6: 97-110. doi: 10.1016/0145-
2126(82)90048-0.
- Schmitt A, Jouault H, Guichard J, Wendling F, Drouin A,
Cramer EM. Pathologic interaction between megakaryocytes
and polymorphonuclear leukocytes in myelofibrosis. Blood
2000; 96: 1342-7. PMID: 10942376
- Schepers K, Pietras EM, Reynaud D, et al. Myeloproliferative
neoplasia remodels the endosteal bone marrow niche into a
self-reinforcing leukemic niche. Cell Stem Cell 2013; 13: 285-
99. doi: 10.1016/j.stem.2013.06.009.
- Kikuchi T, Shimizu T, Toyama T, Abe R, Okamoto S. Successful
treatment of TAFRO syndrome with tocilizumab, prednisone,
and cyclophosphamide. Intern Med 2017: 8522-16.
- Herrick S, Blanc-Brude O, Gray A, Laurent G. Fibrinogen.
Int J Biochem Cell Biol 1999; 31: 741-6. doi: 10.1016/s1357-
2725(99)00032-1.
- Greiling D, Clark RA. Fibronectin provides a conduit for
fibroblast transmigration from collagenous stroma into fibrin
clot provisional matrix. J Cell Sci 1997; 110 ( Pt 7): 861-70. doi:
10.1242/jcs.110.7.861.
- Héron A, Lévesque JP, Hatzfeld A, et al. Mitogenic effect of
fibrinogen on hematopoietic cells: involvement of two distinct
specific receptors, MFR and ICAM-1. Biochem Biophys Res
Commun 1998; 246: 231-7. doi: 10.1006/bbrc.1998.8583.
- Wilberding JA, Ploplis VA, Mclennan L, et al. Development
of pulmonary fibrosis in fibrinogen-deficient mice. Ann N
Y Acad Sci 2001; 936: 542-8. doi: 10.1111/j.1749-6632.2001.
tb03542.x.
- Ploplis VA, Wilberding J, Mclennan L, et al. A total fibrinogen
deficiency is compatible with the development of pulmonary
fibrosis in mice. Am J Pathol 2000; 157: 703-8. doi: 10.1016/
s0002-9440(10)64582-8.