Bone Marrow and Bone Marrow Failure

See related separate article Aplastic Anaemia.

Bone marrow consists of a matrix of sinusoids lined with epithelial cells interspersed with islands of erythropoietic cells encapsulated by reticulin cells.¹ The bone marrow weighs about 3000 g in an average adult male. It is composed of red marrow and inactive adipose tissue (yellow marrow) in about equal quantity. Half of the red marrow is itself adipose tissue, so active red marrow is a only a quarter of the total bone marrow mass.²

Bone marrow is mainly found in the pelvis, ribs and ends of the long bones of the axial skeleton. At birth, 100% of marrow is of the active red type, and this is gradually replaced by adipose tissue as an individual ages.³

Some erythropoietic cells are stem cells. Pluripotent stem cells are able both to renew themselves and to differentiate into various cell types, depending upon the growth factors acting upon them:

• They first differentiate into either lymphoid stem cells or myeloid stem cells.⁴
• Lymphoid stem cells can only develop into B, T or NK lymphocytes.
• Myeloid stem cells undergo a series of stages as progenitor and precursor cells to form erythrocytes, platelets (via megakaryocytes), basophils, polymorphonuclear leucocytes, monocytes/macrophages and eosinophils.⁵

Growth factors that determine this differentiation include erythropoietin and granulocyte colony-stimulating factor.⁶

Bone marrow failure can affect red blood cells (RBCs), white blood cells (WBCs), and platelets. Single line deficiencies or pancytopenia may occur. Causes include:

• Haemopoetic cell damage causing hypoplastic or aplastic anaemia. This may be:
  • Congenital, with inherited gene mutations, e.g. Fanconi's anaemia, Diamond-Blackfan anaemia
  • Acquired - viruses (hepatitis B virus, Epstein-Barr virus, parvovirus B19), autoimmunity, ionising radiation, antineoplastic agents, poisons (e.g. benzene), drugs
• Maturation defects , e.g. vitamin B12 or folate deficiency
• Differentiation defects, e.g. myelodysplasia
• Bone marrow infiltration, e.g. lymphoma, multiple myeloma, carcinoma, hairy cell leukaemia

Aplastic anaemia is rare in Europe (~2/million population) but bone marrow failure with leukaemia (~30/million population) or myelodysplasia (~50/million population) is far more common. Bone marrow failure is also a frequent iatrogenic side-effect of radiotherapy and chemotherapy.

Whatever the cause, patient presents with signs and symptoms of:

• Anaemia - tiredness, weakness, pallor, breathlessness, tachycardia
• Neutropenia - recurrent or severe bacterial infections
• Thrombocytopenia - easy bruising, petechiae, bleeding from nose and/or gums

Presence of hepatomegaly, splenomegaly or lymphadenopathy suggests a diagnosis of leukaemia.

• Systemic lupus erythematosus and hypersplenism - can cause pancytopenia with a normal bone marrow
• Leukaemia
• Other causes of anaemia
• Paroxysmal nocturnal haemoglobinuria

• Full blood count - normocytic, normochromic anaemia with low reticulocyte count in aplastic anaemia and myelodysplasia.
• WBC count - indicates whether leukaemia or megaloblastic anaemia is the cause.
• Bone marrow aspiration and biopsy - hypoplastic in non-leukaemic cause, histology may give indication of cause of failure.
• Imaging - radionucleotide scans, MRI or PET scans are sometimes used to look at bone marrow activity.

Non-drug

• Transfusions with packed red cells and platelets may be required; severe cases may require bone marrow transplantation.⁸
• Children with severe aplastic anaemia are now being treated with matched-related donor stem cell transplantation (or unrelated, if no family match is possible).⁹

Drugs

• Febrile neutropenia is a medical emergency and aggressive antibiotic treatment may be required.
• Where transplant is not an option, intensive immunosuppressive therapy is used, sometimes in conjunction with haemopoietic growth factors, although the benefit of these is debated.¹⁰ A gold standard for severe aplastic anaemia, ineligible for allogenic transplant, is antithymocyte globulin and ciclosporin.¹¹ In aplastic anaemia, haematologic remission rates of 70-80% can be achieved.
• Myelodysplasia can be treated with supportive transfusion and treatment of infection whilst a search is made for an allogeneic stem cell donor. Intensive chemotherapy regimes are not usually successful.

1. Kopp HG, Avecilla ST, Hooper AT, et al; The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda). 2005 Oct;20:349-56. [abstract]
2. Dass, C Parker J; Joint Program in Nuclear Medicine Bone Marrow Scintigraphy Harvard Medical School 1997
3. Ricci C, Cova M, Kang YS, et al; Normal age-related patterns of cellular and fatty bone marrow distribution in the axial skeleton: MR imaging study. Radiology. 1990 Oct;177(1):83-8. [abstract]
4. Reya T; Regulation of hematopoietic stem cell self-renewal. Recent Prog Horm Res. 2003;58:283-95. [abstract]
5. Stem Cell Basics; Stem Cell Information US National Institutes of Health 2007
6. Olweus J, Terstappen LW, Thompson PA, et al; Expression and function of receptors for stem cell factor and erythropoietin during lineage commitment of human hematopoietic progenitor cells. Blood. 1996 Sep 1;88(5):1594-607. [abstract]
7. Besa E, Woermann, U; Bone Marrow Failure eMedicine.com, Jan 2008.
8. Vassiliou GS, Webb DK, Pamphilon D, et al; Improved outcome of alternative donor bone marrow transplantation in children with severe aplastic anaemia using a conditioning regimen containing low-dose total body irradiation, cyclophosphamide and Campath. Br J Haematol. 2001 Sep;114(3):701-5. [abstract]
9. Kennedy-Nasser AA, Leung KS, Mahajan A, et al; Comparable outcomes of matched-related and alternative donor stem cell transplantation for pediatric severe aplastic anemia. Biol Blood Marrow Transplant. 2006 Dec;12(12):1277-84. [abstract]
10. Gurion R, Gafter-Gvili A, Paul M, et al; Hematopoietic growth factors in aplastic anemia patients treated with Haematologica. 2009 May;94(5):712-9. Epub 2009 Mar 31. [abstract]
11. Gafter-Gvili A, Ram R, Gurion R, et al; ATG plus cyclosporine reduces all-cause mortality in patients with severe Acta Haematol. 2008;120(4):237-43. Epub 2009 Feb 25. [abstract]

• National Cancer Institute Inherited bone marrow failure syndromes; American government funded site
• Dokal I, Vulliamy T; Inherited aplastic anaemias/bone marrow failure syndromes. Blood Rev. 2008 May;22(3):141-53. Epub 2007 Dec 31. [abstract]