Bone Marrow and Bone Marrow Failure

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 active red marrow 50% and inactive adipose tissue (yellow marrow) 50%. Half of the red marrow is itself adipose tissue, so the total amount of active red marrow in the body is 25% of the total mass.²

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

Some erythropoietic cells are stem cells. Pluripotent stem cells are able to both renew themselves and differentiate into various cell types, depending upon the growth factors acting upon them. They first differentiate into either lymphoid stem cells or a 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 either affect red blood cells (RBCs,) white blood cells (WBCs ) and platelets (in which case the condition is termed pancytopenia) or single cell line deficiencies can occur.

Pancytopaenia

Bone marrow problems causing this include:

• Aplastic anaemia - initially may not involve all three types of blood cells, occurs from stem cell dysfunction that is either:
  • Congenital - e.g. Fanconi's anaemia
  • Acquired - damage by viruses (hepatitis B virus, Epstein-Barr virus, parvovirus), autoimmunity, ionising radiation, antineoplastic agents, poisons (e.g. benzene), drugs (e.g. chloramphenicol)⁸

Single cell line deficiencies are rare. They include:

• Myelodysplasia due to a defect of differentiation of precursors
• Acute myeloid or lymphoblastic leukaemia
• Infiltration of marrow e.g. lymphoma, multiple myeloma, carcinoma, hairy cell leukaemia
• Megaloblastic anaemia (vitamin B12 or folate deficiency)
• Myelofibrosis - fibrosis of bone marrow associated with radiotherapy, Hodgkin's disease, polycythaemia vera and malignant transformation

Aplastic anaemia is rare in Europe (~2/million population) but bone marrow failure from leukaemia (~30/million population) or myelodysplasia (~50/million population) is far more common. Bone marrow failure is also a frequent side effect of radiotherapy and chemotherapy.⁹

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
• Various types of leukaemia (e.g. giant hairy cell, myelogenous)
• Other causes of anaemia
• Paroxysmal nocturnal haemoglobinuria

• Full blood count - normocytic, normochromic anaemia with low reticulocyte count in aplastic anaemia and myelodysplasia.
• White cell count - indicates whether leukaemia or megaloblastic anaemia is cause
• Bone marrow aspiration and biopsy - hypoplastic in non-leukaemic cause, histology may give indication of cause of failure

Non-drug

• Transfusions with packed red cells and platelets may be required, severe cases may require bone marrow transplantation.¹⁰
• Children with severe aplastic anaemia are now being treated with matched-related donor stem cell transplantation (or unrelated, if no family match is possible).¹¹

• Antibiotics may be needed if there is infection.
• Antithymocyte globulin and antilymphocyte globulin with oxymethalone and high dose IV methylprednisolone is a beneficial regime for a significant number of aplastic anaemia patients.¹²
• Other drugs used which have been used in aplastic anaemia with haemopoietic growth factors, and antithymocyte globulin include danazol and ciclosporin.¹³
• 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.