Bone Marrow

Bone marrow is the soft spongy tissue that lies within the hollow interior of long bones. In adults, marrow in large bones produces new blood cells. Bone marrow forms around 4% of total body weight (around 2.6 kg in a healthy adult).

Types of bone marrow

There are two types of bone marrow:

• red marrow that is responsible for producing red blood cells, white blood cells and platelets
• yellow marrow consisting mainly of fat cells

There are a number of blood vessels and capillaries traversing through the marrow making it a very vascular organ.

At birth and in early childhood most of the marrow is red. As a person ages more and more of it is converted to the yellow type. About half of adult bone marrow is red.

Functions of bone marrow

Red blood cells (erythrocytes) carry oxygen to the tissues.

Platelets or thrombocytes (derived from megakaryocytes) help prevent bleeding and aid in clotting of blood.

Granulocytes (neutrophils, basophils and eosinophils) and macrophages (collectively known as myeloid cells) fight infections from bacteria, fungi, and other parasites. They also remove dead cells and remodel tissue and bones.

B-lymphocytes produce antibodies, while T-lymphocytes can directly kill or isolate invading cells.

RBC live for around 170 days and rest are shorter lived and need to be replenished continuously. An average human requires approximately one hundred billion new hematopoietic cells each day. This is performed by the Hematopoietic Stem Cells (HSCs).

Bone marrow and stem cells

Around the central bore of the bone or the central sinus lie the Mesenchymal stem cells. These cells have the capacity to form various cells of the body including osteoblasts (that form bones), chondrocytes (that form cartilage), myocytes (that form muscles) and other cells. Apart from this there are the endothelial stem cells that form blood vessels.

Bone marrow pathology and diagnosis

Certain diseases of the bone marrow like leukemia, multiple myeloma, myelodysplastic syndrome (MDS), pancytopenia, anemia etc. require examination of the bone marrow tissue. This is called bone marrow aspiration or bone marrow biopsy. A needle is used to withdraw samples of the marrow from within the bone. This is often a very painful process.

Bone marrow is suppressed with the use of cancer chemotherapy. This leads to severe drop in production of RBCs (leading to anemia), WBCs (leading to increased risk of life threatening infections) and platelets (leading to risk of bleeding tendencies).

With advent of medical science it is possible now to transplant the bone marrow in diseased individuals. This process has shown success in a number of cancer patients.

The bone marrow is a soft spongy tissue within the bones. It is the seat of production of hematopoietic cells. These cells include red blood cells or erythrocytes, white blood cells like granulocytes and myelocytes and platelets like thrombocytes.

The sites of bone marrow location include the sternum (middle of the chest), pelvis (hip bone), and femur (thigh bone).

Stem cells

The bone marrow contains stem cells that are primitive cells capable of turning into any desired cell in the body. As needed, the stem cells differentiate to become a particular kind of cell - a white blood cell, red blood cell, or platelet. From the bone marrow only the mature cells are released into the blood stream. Apart from the stem cells the bone marrow contains supporting fibrous tissues as well.

Main bone marrow problems

Diseases of the bone marrow may lead to an abnormality in the production of any of the mature blood cells, or their precurosor or predecessor immature cells. The main types of problems with the bone marrow include:

• increased production of one type of cell - this packs up the marrow with one type of cells and decreases the production of the other cell types
• increase in one cell line because the cells do not die at normal times
• producing immature cells that do not mature or function properly
• producing fragile cells that die easily or producing less number of cells
• increased growth of the supporting fibrous tissue network leading to formation of abnormal cells and decreased numbers of cells.
• lack of iron making RBC formation difficult
• spread of other diseases to the bone marrow

Diseases of the different cell types

Cell types and functions:

White blood cells (WBCs)

WBCs are of five different types:

• lymphocytes
• neutrophils (also called granulocytes)
• eosinophils
• basophils
• monocytes

These play different roles in infection prevention and protection of the body. For example, Neutrophils, basophils, and eosinophils kill and digest bacteria. Monocytes kill bacteria but also are produced more rapidly than the neutrophils and tend to be longer lived.

Lymphocytes are of two types B and T. T cells distinguish between own and foreign and B cells that circulate in the blood, produce antibodies - proteins that attach to specific antigens from the invading bacteria or viruses.

Red blood cells (RBCs)

RBCs are disc shaped small cells without a nucleus. They carry iron in a heme protein called hemoglobin. Hemoglobin allows RBCs to carry oxygen to tissues throughout the body.

Platelets or thrombocytes

These are small parts of large cells called megakaryocytes. Platelets circulate in blood and help in clotting process to plug holes in leaking blood vessels and to help activate other clotting factors.

Diseases and disorders of the bone marrow

The diseases and disorders of the bone marrow include Leukemia, Myelodysplastic Syndrome, Myeloproliferative disorders and so forth.

Leukemia

Leukemia is a cancer of the white blood cells that can affect any of the five WBC types. The cancer affects a line of cell that begins to replicate non-stop clogging the bone marrow and decreasing production of other cells.

The resulting leukemic cloned cells do not function normally. They do not fight infections.

Patients with leukemia may have frequent infections, anemia, bleeding, bruising, night sweats, and bone and joint pain.

The spleen that normally filters the blood and gets rid of old cells, may become enlarged. Lymph nodes that house the WBCs may also enlarge.

Blood picture shows immature cells from the bone marrow called blast cells. These are released due to excess production within the bone marrow.

Myelodysplastic Syndrome (MDS)

MDS is a group of diseases where there is abnormal bone marrow cell production. There are not enough normal blood cells being made. This leads to anemia, bleeding and risk of infections.

MDS syndromes are classified by how the cells in the bone marrow and blood smear look under the microscope. This includes anemias that are resistant to treatment, those that are inherited or genetic and a complex form of MDS. Over time, MDS tends to progress to acute myeloid leukemia.

Myeloproliferative disorders (MPD)

“Myelo” means bone marrow and MPD signifies proliferation of the bone marrow. These are a group of diseases.

There is overproduction of a precursor (immature form) of a marrow cell. This results in release of the immature forms of other precursors as well that are released in blood as blast forms when the body requires them.

The bone marrow in MPD shows a mixture of cells in various stages of maturity.

Aplastic anemia 

This is a condition where there is loss or suppression of production of RBCs. This may be due to a defect in the stem cell producing them or due to an injury to the bone marrow environment.

The injury may result from exposure to chemicals such as benzene, radiation, or certain drugs or may be genetic e.g. Fanconi's anemia or associated with a viral infection with parvo virus.

Iron deficiency anemias

Iron deficiency anemias lead to the formation of deformed and smaller RBCs released from the marrow. These are pale and small and are called microcytic RBCs.

Anemias may also be caused by deficiency or dysfunction of erythropoietin, a chemical produced by the kidneys that stimulates RBC production.

Other diseases and disorders of the bone marrow

Other diseases and disorders of the bone marrow include:

• Disorders of plasma cells or Plasma cell dyscrasia – There is overproduction of one clone of a B lymphocyte and its antibody protein.
• Lymphomas and other cancers that spread into the marrow and affect cell production.
• Thrombotic thrombocytopenic purpura – This results in the reduction of platelet production and bleeding tendencies.
• Unexplained cytopenia – This results in decrease in production of all cell types.
• Other causes include small cell tumors of childhood, Mast cell disease, Disseminated granulomatous disease, Primary amyloidosis, Metabolic bone disease etc.
• Bone marrow depression may be caused due to cancer chemotherapy, bone marrow transplantation and cancer radiation therapy.

Bone marrow consists of precursor or predecessor immature cells called stem cells. These are primitive cells that are capable of producing all types of cells.

Blood cells like RBCs, WBCs and platelets start out from young (immature) cells called hematopoietic stem cells. Stem cells mostly live in the bone marrow where they divide to make new blood cells. These cells mature into adult cells and then leave the marrow into the blood stream.

A small number of stem cells also get into the bloodstream. These are called peripheral blood stem cells.

What is a bone marrow transplant?

When the bone marrow has been destroyed by disease, chemotherapy or radiation, the stem cells may be transplanted and restored. Depending on the source of the stem cells this procedure may be called:

• Bone marrow transplant
• Peripheral blood stem cell transplant, OR
• Cord blood transplant.

These three types are called hematopoietic stem cell transplant. There are 3 possible sources of stem cells to use for transplants. This includes:

• bone marrow
• the bloodstream (peripheral blood)
• umbilical cord blood from newborns

History of bone marrow transplant

The first successful bone marrow transplant was done in 1968. After nearly two decades, stem cells taken from circulating (peripheral) blood were transplanted with success.

More recently, doctors have begun using cord blood from the placenta and umbilical cords of new born babies as another source of stem cells. Today nearly 50,000 new transplants are done each year.

When is a bone marrow transplant needed?

Stem cell transplants are used to replace bone marrow that has been destroyed by:

• disease
• leukemia
• aplastic anemia
• certain inherited blood diseases
• exposure to cancer chemotherapy
• cancer radiation therapy
• some diseases of the immune system

In these conditions the stem cells are unable to make adequate blood cells. A stem cell transplant may help correct these problems.

In some cancers, such as certain leukemias, multiple myeloma, and some lymphomas, a stem cell transplant can be an important part of treatment. In these patients high doses of chemotherapy or radiation therapy is a good therapy option but cannot be given due to its potential to cause bone marrow suppression. So once high doses are used a stem cell transplant is made to replenish the suppressed marrow.

Types of bone marrow transplant

Types of bone marrow transplant include:

1. Autologous BMT – Cells come from the patient’s own bone marrow
2. Allogeneic BMT – The cells come from a matched related or unrelated donor
3. Syngeneic BMT – the cells are derived from an identical twin.

Autologous stem cell transplant

In this type the patient’s own bone marrow cells are taken prior to the anti-cancer procedure. These stem cells are removed, or harvested, from either bone marrow or blood and then frozen.

After this a high dose of chemotherapy or radiation therapy is given. Once the bone marrow is suppressed the frozen cells are thawed and replaced back within the body.

Advantage of autologous stem cell transplant

The advantage is that the patient gets his or her own blood cells and thus there is a decreased risk of the body’s immune system not recognizing the cells and rejecting them or mounting an attack on them. This is called graft rejection and rejection makes allogenic transplants difficult.

Disadvantage of autologous stem cell transplant

The disadvantage of the process is the risk of the originally taken stem cells carrying cancer cells that are reintroduced in the body to. This may bring the cancer back.

What is autologous stem cell transplant used for?

This kind of transplant is mainly used to treat some leukemias and lymphomas, and multiple myeloma. It is sometimes used for other cancers, especially in children.

In a tandem transplant, a patient gets 2 courses of high-dose chemo, each followed by a transplant of their own stem cells. All of the stem cells needed are collected before the first high-dose chemo treatment, and half of them are used for each procedure.

Allogeneic stem cell transplant

In this type the stem cells do not come from the patient, but from a donor whose tissue type is matched with the patient. The donor may be a family member, usually a brother or sister.

The donor may be sought from a national registry as well. This may be called a MUD (matched unrelated donor) transplant.

Cord blood transplant is another method where blood is taken from the placenta and umbilical cord of new borns. This blood has a high number of stem cells. But the number of stem cells in a unit of cord blood is often too low for large adults, so this source of stem cells has so far been used more in children.

Advantage of allogenic stem cell transplant

The advantage of allogenic transplant is that the donor stem cells make their own immune cells, which may help destroy any cancer cells in the patient.

Disadvantage of allogenic stem cell transplant

The disadvantage is the risk of graft rejection that may require lifelong use of immunity suppressing agents.

What is allogenic stem cell transplant used for?

Allogeneic transplant is most often used to treat certain types of leukemia, lymphomas, and other bone marrow disorders such as myelodysplasia.

Many factors play a role in how the immune system knows the difference between “self” and “non-self.” The most important factor that is used in allogenic transplants is called human leukocyte antigen (HLA) system.

Human leukocyte antigens are proteins found on the surface of most cells. Each person has a number of pairs of HLA antigens (the best-known ones being A, B, C, DR, DQ, and DP). They inherit one of each of these antigens from each of their patents. Doctors try to match these antigens when finding a donor for a person getting a stem cell transplant. 

Syngeneic stem cell transplant

This is possible only between identical twins or triplets with similar genetic makeup. An advantage of syngeneic stem cell transplant is that graft-versus-host disease will not be a problem. There are no cancer cells in the transplant, either, as there would be from an autologous transplant.