See the related separate article on Aplastic Anaemia.
Bone marrow consists of a matrix of sinusoids lined with epithelial cells interspersed with islands of erythropoietic cells encapsulated by reticulin cells. The bone marrow is composed of red marrow and inactive adipose tissue (yellow marrow) in about equal quantity.
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.
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.
- 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 leukocytes, monocytes/macrophages and eosinophils.
Growth factors that determine this differentiation include erythropoietin and stem cell factor.
Bone marrow failure
Bone marrow failure can affect red blood cells (RBCs), white blood cells (WBCs), and platelets. Single line deficiencies or pancytopenia may occur. Causes include:
- Haemopoietic cell damage causing hypoplastic or aplastic anaemia. This may be:
- Maturation defects - eg, vitamin B12 or folate deficiency.
- Differentiation defects - eg, myelodysplasia.
- Bone marrow infiltration - eg, lymphoma, multiple myeloma, carcinoma, hairy cell leukaemia.
The annual incidences of paroxysmal nocturnal haemoglobinuria, aplastic anaemia and myelodysplastic syndrome are estimated to be 0.13, 0.2, and 7 per 100,000 population per year respectively. Bone marrow failure is also a frequent iatrogenic side-effect of radiotherapy and chemotherapy.
Whatever the cause, the 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 the 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.
- Other causes of anaemia.
- 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 positron emission tomography (PET) scans are sometimes used to look at bone marrow activity.
- Flow cytometry should be performed according to established guidelines to screen patients with suspected hematopoietic malignancies, including myelodysplastic syndrome.
- Molecular genetic studies are usually not performed in patients with mild chronic cytopenia unless there are signs of an occult underlying lymphoma. However, molecular genetic studies may become more widely used in the future.
The management will depend on the underlying cause and the degree of bone marrow failure.
- Transfusions with packed red cells and platelets may be required; severe cases may require bone marrow transplantation.
- Improvements in transplantation outcome are achievable with improved HLA tissue typing to identify better matched donors, improvements in the conditioning regimes, particularly fludarabine-based regimes, and improved supportive care.
- 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. A gold standard for severe aplastic anaemia, ineligible for allogenic transplant, is antithymocyte globulin and ciclosporin. 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.
Further reading and references
; National Cancer Institute
; British Committee for Standards in Haematology (Aug 2013)
; The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda). 2005 Oct20:349-56.
; Age-related marrow conversion and developing epiphysis in the proximal femur: evaluation with STIR MR imaging. J Huazhong Univ Sci Technolog Med Sci. 2007 Oct27(5):617-21.
; Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways. Cell Res. 2007 Sep17(9):746-58.
; Stem Cell Information US National Institutes of Health 2007
; Role of c-Kit and erythropoietin receptor in erythropoiesis. Crit Rev Oncol Hematol. 2005 Apr54(1):63-75.
; The differential diagnosis and bone marrow evaluation of new-onset pancytopenia. Am J Clin Pathol. 2013 Jan139(1):9-29. doi: 10.1309/AJCP50AEEYGREWUZ.
; Last marrow standing: bone marrow transplantation for acquired bone marrow failure conditions. Curr Hematol Malig Rep. 2012 Dec7(4):292-9. doi: 10.1007/s11899-012-0138-x.
; Low blood counts: immune mediated, idiopathic, or myelodysplasia. Hematology Am Soc Hematol Educ Program. 20122012:485-91. doi: 10.1182/asheducation-2012.1.485.
; Unrelated donor search and unrelated donor transplantation in the adult aplastic anaemia patient aged 18-40 years without an HLA-identical sibling and failing immunosuppression. Bone Marrow Transplant. 2013 Feb48(2):198-200. doi: 10.1038/bmt.2012.233. Epub 2012 Nov 26.
; Hematopoietic growth factors in aplastic anemia patients treated with Haematologica. 2009 May94(5):712-9. Epub 2009 Mar 31.
; ATG plus cyclosporine reduces all-cause mortality in patients with severe Acta Haematol. 2008120(4):237-43. Epub 2009 Feb 25.
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