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Leukopenia And Leukemia Risk Factors Biology Essay

A clinical condition, known as leukopenia occasionally occurs in which the bone marrow produces very few white blood cells, leaving the body unprotected against many bacteria and other agents that might invade the tissues.

Normally, the human body lives in symbiosis with many bacteria, because all the mucous membranes of the body are constantly exposed to large numbers of bacteria. The mouth almost always contains various spirochetal, pneumococcal, and streptococcal bacteria, and these same bacteria are present to a lesser extent in the entire respiratory tract. The distal gastrointestinal tract is especially loaded with colon bacilli. Furthermore, one can always find bacteria on the surfaces of the eyes, urethra, and vagina. Any decrease in the number of white blood cells immediately allows invasion of adjacent tissues by bacteria that are already present.

Within 2 days after the bone marrow stops producing white blood cells, ulcers may appear in the mouth and colon, or the person might develop some form of severe respiratory infection. Bacteria from the ulcers rapidly invade surrounding tissues and the blood.

Without treatment, death often ensues in less than a week after acute total leukopenia begins. Irradiation of the body by x-rays or gamma rays, or exposure to drugs and chemicals that contain benzene or anthracene nuclei, is likely to cause aplasia of the bone marrow. Indeed, some common drugs, such as chloramphenicol (an antibiotic), thiouracil (used to treat thyrotoxicosis), and even various barbiturate hypnotics, on very rare occasions cause leukopenia, thus setting off the entire infectious sequence of this malady.

After moderate irradiation injury to the bone marrow, some stem cells, myeloblasts, and hemocytoblasts may remain undestroyed in the marrow and are capable of regenerating the bone marrow, provided sufficient time is available. A patient properly treated with transfusions, plus antibiotics and other drugs to ward off infection, usually develops enough new bone marrow within weeks to months for blood cell concentrations to return to normal.

Leukemia

Leukemia is a cancer of one class of white blood cells in the bone marrow, which results in the proliferation of that cell type to the exclusion of other types. Leukemia appears to be a clonal disorder, meaning one abnormal cancerous cell proliferates without control, producing an abnormal group of daughter cells. These cells prevent other blood cells in the bone marrow from developing normally, causing them to accumulate in the marrow. Because of these factors, leukemia is called an accumulation and a clonal disorder. Eventually, leukemic cells take over the bone marrow. This reduces blood levels of all nonleukemic cells, causing the many generalized symptoms of leukemia.

Types of Leukemia

Leukemia is described as acute or chronic, depending on the suddenness of appearance and how well differentiated the cancerous cells are. The cells of acute leukemia are poorly differentiated, whereas those of chronic leukemia are usually well differentiated.

Leukemia is also described based on the proliferating cell type. For instance, acute lymphoblastic leukemia, the most common childhood leukemia, describes a cancer of a primitive lymphocyte cell line. Granulocytic leukemias are leukemias of the eosinophils, neutrophils, or basophils. Leukemia in adults is usually chronic lymphocytic or acute myeloblastic. Long-term survival rates for leukemia depend on the involved cell type, but range to more than 75% for childhood acute lymphocytic leukemia, which is a remarkable statistic for what was once a nearly always fatal disease.

Risk Factors for Developing Leukemia

Risk factors for leukemia include a genetic predisposition coupled with a known or unknown initiator (mutating) event. Siblings of children with leukemia are 2 to 4 times more likely to develop the disease than other children. Certain abnormal chromosomes are seen in a high percentage of patients with leukemia. Likewise, individuals with certain chromosomal abnormalities, including Down syndrome, have an increased risk of developing leukemia. Exposures to radiation, some drugs that depress the bone marrow, and various chemotherapeutic agents have been suggested to increase the risk of leukemia. Environmental agents such as pesticides and certain viral infections also have been implicated.

Previous illness with a variety of diseases associated with hematopoiesis (blood cell production) has been shown to increase the risk of leukemia. These diseases include Hodgkin lymphoma, multiple myeloma, polycythemia vera, sideroblastic anemia, and myelodysplastic syndromes. Chronic leukemia may sometimes transform into acute leukemia.

Clinical Manifestations

Acute leukemia has marked clinical manifestations. Chronic leukemia progresses slowly and may have few symptoms until advanced.

Pallor and fatigue from anemia.

Frequent infections caused by a decrease in white blood cells.

Bleeding and bruising caused by thrombocytopenia and coagulation disorders.

Bone pain caused by accumulation of cells in the marrow, which leads to increased pressure and cell death. Unlike growing pains, bone pain related to leukemia is usually progressive.

Weight loss caused by poor appetite and increased caloric consumption by neoplastic cells.

Lymphadenopathy, splenomegaly, and hepatomegaly caused by leukemic cell infiltration of these lymphoid organs may develop.

Central nervous system symptoms may occur.

Diagnostic Tools

Laboratory findings include alterations in specific blood cell counts, with overall elevation or deficiency in white blood cell count variable, depending on the type of cell affected.

Bone marrow tests demonstrate clonal proliferation and blood cell accumulation.

Cerebral spinal fluid is examined to rule out central nervous system involvement.

Complications

Children who survive leukemia have an increased risk of developing a new malignancy later on in life when compared to children who have never had leukemia, most likely related to the aggressiveness of chemotherapeutic (or radiological) regimens.

Treatment regimens, including bone marrow transplant, are associated with temporary bone marrow depression, and increase the risk of developing a severe infection that could lead to death.

Even with successful treatment and remission, leukemic cells may still persist, suggesting residual disease. Implications for prognosis and cure are unclear.

Treatment

Multiple drug chemotherapy.

Antibiotics to prevent infection.

Transfusions of red blood cells and platelets to reverse anemia and prevent bleeding.

Bone marrow transplant may successfully treat the disease. Blood products and broad spectrum antibiotics are provided during bone marrow transplant procedures to fight and prevent infection.

Immunotherapy, including interferons and other cytokines, is used to improve outcome.

Therapy may be more conservative for chronic leukemia.

The treatments described earlier may contribute to the symptoms by causing further bone marrow depression, nausea, and vomiting. Nausea and vomiting may be controlled or reduced by pharmacologic and behavioral intervention.

Anthocyanins (chemicals with known antioxidant and liver protecting properties) isolated from the plant Hibiscus sabdariffa are being studied as chemopreventive agents in that they cause cancer cell apoptosis (death) in human promyelocytic leukemia cells.

Anemia

Anemia is a condition in which there is a reduced number of red blood cells or decreased concentration of hemoglobin in those cells or both. Anemia is often a manifestation of some disease process or abnormality within the body. Although there are many causes of anemia, the actual mechanism by which the anemia results is generally due to (1) excess loss or destruction of red blood cells and (2) reduced or defective production of red blood cells.

Anemias may be classified according to cause or effect on red cell morphology

Size changes

Normocytic anemia

RBC size is unchanged

Example: Blood loss anemia

Macrocytic anemia

RBC size is increased

Example: B12/folic acid deficiency anemia

Microcytic anemia

RBC size is reduced

Example: Iron deficiency anemia

Color changes (due to altered hemoglobin content)

Normochromic

Normal hemoglobin concentration

Hypochromic

Reduced hemoglobin concentration

Example: Iron deficiency anemia may be classified as a microcytic, hypochromic anemia as both red blood cell size and hemoglobin content are reduced

General manifestations of anemia

A major feature of anemia is a reduced capacity for the transport of oxygen to tissues. This reduced oxygen delivery can result in the following:

Ischemia

Fatigability

Breathlessness upon exertion

Exercise intolerance

Pallor

Increased susceptibility to infection

Types of anemia

Hemolytic anemia

Anemia that results from excess destruction of red blood cells (hemolysis). Factors that may cause hemolysis include the following:

Autoimmune destruction of red blood cells

Certain drugs (example: quinine) or toxins

Cancers such as lymphoma and leukemia

Rheumatoid arthritis

Certain viral infections (parvovirus)

Parasitic infections (malaria)

Blood loss anemia

Anemia that results from acute blood loss. With acute loss of large amounts of blood, shock is the major concern. With chronic loss of smaller amounts of blood, iron deficiency is a chief concern. Causes of acute and chronic blood loss may include the following:

Trauma and hemorrhage

Malignancy

Peptic ulcers

Iron-deficiency anemia

Iron-deficiency anemia is a major cause of anemia worldwide. It can occur as a result of iron-deficient diets. Vegetarians are at particular risk for iron deficiency as are menstruating or pregnant women due to increased requirement for iron. Iron-deficiency anemia may also result from poor absorption of iron from the intestine or persistent blood loss (e.g., ulcers, neoplasia). Because iron is the functional component of hemoglobin, lack of available iron will result in a decreased hemoglobin synthesis and subsequent impairment of red blood cell oxygen-carrying capacity.

Cobalamin-deficiency or folate-deficiency anemia

Cobalamin (vitamin B 12) and folic acid are essential nutrients required for DNA synthesis and red cell maturation, respectively. Deficiency of these nutrients will lead to the formation of red blood cells that are of abnormal shape with shortened life spans due to weakened cell membranes. One important cause of vitamin B 12 deficiency is pernicious anemia that results from a lack of intrinsic factor production by the gastric mucosa. Intrinsic factor is required for normal absorption of vitamin B 12 from the intestine. Any intestinal abnormalities (e.g., neoplasia, inflammation) that interfere with the production of intrinsic factor can lead to vitamin B 12 deficiency. Folic acid deficiency most commonly results from poor diet, malnutrition or intestinal malabsorption.

Inherited anemia

Anemia may also result from genetic defects in red blood cell structure or function. Two common genetic disorders of erythrocytes are sickle cell anemia and thalassemia. Both of these disorders result from abnormal or absent genes for the production of hemoglobin.

Sickle cell disease

Sickle cell disease is a group of autosomal recessive disorders characterized by abnormal hemoglobin production. In the United States the highest prevalence of sickle cell disease is in blacks with a reported incidence of approximately 1 in 500 births. Sickle cell disease has several patterns of inheritance that determine the severity of the disease in afflicted individuals. In the homozygous form of the disease, most of the hemoglobin formed is defective and the clinical presentation is most severe. With the heterozygous form of the disease, less than half of the red cell hemoglobin is affected and the presentation is significantly milder. Individuals may also inherit the sickle cell trait and be carriers of the defective hemoglobin gene without significant clinical manifestations.

Manifestations of sickle cell disease: The abnormal hemoglobin formed in sickle cell disease results from a substitution mutation of a single amino acid. This mutation causes the deoxygenated hemoglobin to clump and become abnormally rigid. The rigidity of the defective hemoglobin deforms the pliable red blood cell membrane and causes erythrocytes to take on “sickled” or half-moon appearance. The degree of sickling that occurs is determined by the amount of abnormal hemoglobin within the red blood cell and only occurs when the abnormal hemoglobin is deoxygenated. As a result of their elongated shape and rigidity, affected blood cells do not pass easily through narrow blood vessels. Hemolysis of sickled red blood cells is also common. The spleen is a major site of red cell hemolysis since the blood vessels found within this organ are narrow and convoluted. As a result of the sluggish blood flow, many tissues and organs of the body are eventually affected by this disorder.

Specific manifestations may include the following:

Impaired oxygen-carrying capacity resulting in fatigue, pallor

Occlusion of blood vessels leading to ischemia, hypoxia, pain

Organ damage

Splenomegaly due to increased destruction of red blood cells in this organ

Jaundice as a result of increased amounts of hemoglobin released into circulation

Increased risk of infection and possible septicemia due to stagnation of blood

Thalassemia

Thalassemia is a genetic disorder characterized by absent or defective production of hemoglobin α or β chains. As with sickle cell anemia, afflicted individuals may be heterozygous for the trait and have a milder presentation of the disease or homozygous and have a more severe form of the disorder.

The β form of thalassemia (defective formation of β hemoglobin chains) is most common in individuals from Mediterranean populations, whereas the α form of thalassemia (defective formation of α hemoglobin chains) occurs mostly in Asians. Both the α and β forms of thalassemia are common in blacks.

Manifestations of thalassemia

In heterozygous individuals enough normal hemoglobin is usually synthesized to prevent significant anemia. In these individuals symptoms of anemia may appear only with exercise or physiologic stress. Homozygous individuals are often dependent on frequent transfusions to treat the resulting severe anemia. Children affected with the homozygous form may suffer severe growth retardation. The widespread hypoxia that can result from impaired oxygen-carrying capacity leads to erythropoietin-induced increases in hematopoiesis that can eventually affect the structure of the long bones. Severe anemia may also lead to congestive heart failure and marked hepatosplenomegaly. Excessive hemolysis of red blood cells may occur in severe forms of the disease due to overproduction of the normal hemoglobin subunit. Iron deposits from increased absorption and frequent transfusions may injure the liver and heart as well.

Treatment of sickle cell anemia and thalassemia

Individuals with inherited anemia should avoid physiologic stresses that might exacerbate hypoxia. Infections should be avoided and promptly treated if they occur to prevent a possible hypoxic crisis. Proper immunizations and vaccinations should be administered to lessen the chance of infection. Frequent transfusions of normal erythrocytes are commonly used in individuals with severe forms of inherited anemia during periods of crisis. These individuals are at risk for iron accumulation as well as contracting blood-borne pathogens such as hepatitis and HIV from improperly screened blood. Bone marrow transplant may be utilized effectively to cure patients with genetic anemias; however, the procedure carries considerable risk of its own.

Aplastic anemia

Aplastic anemia results from a lack of red blood cell production by the bone marrow. If erythrocyte stem cell precursors are lacking or destroyed, the process of erythropoiesis will be severely impaired. Aplastic anemia may result from a congenital defect in stem cell production or can be caused by exposure to agents that damage the bone marrow such as Chemicals (organic solvents, heavy metals), radiation, toxins, HIV infection, chemotherapeutic drugs and certain antibiotics (Chloramphenicol). Drug-induced aplastic anemia is usually a dose-dependent phenomenon.

The clinical manifestations of aplastic anemia will depend on the extent to which hematopoiesis is impaired. General symptoms of anemia such as pallor, fatigue and lethargy can occur initially. Bleeding in the skin and from the nose, mouth and body orifices may also occur from a lack of platelet production by the abnormal bone marrow. Increased susceptibility to infection is also seen as a result of diminished white blood cell production. The underlying cause of the aplastic anemia needs to be identified and further exposure prevented. Treatment should also include avoidance of physiologic stresses and infection. Transfusions are effective for temporarily improving oxygen-carrying capacity. In severe cases, bone marrow transplant may offer a cure.

Polycythemia

Polycythemia is a disorder in which the number of red blood cells in circulation is greatly increased. There are two categories of polycythemia: relative and primary. Relative polycythemia results from an increase in the concentration of red blood cells due to a loss of plasma volume. In contrast, primary polycythemia (polycythemia vera) is caused by excessive proliferation of bone marrow stem cells. Polycythemia vera is a rare neoplastic disorder that occurs in men between the ages of 40 and 60. A secondary form of polycythemia may occur from excess erythropoietin production as a physiologic response to hypoxia. Secondary polycythemia may be seen in individuals living at high altitudes, in chronic smokers or in people with chronic obstructive pulmonary disease.

Manifestations

Increased blood volume and viscosity

Increased risk of thrombus

Occlusion of small blood vessels

Hepatosplenomegaly from pooling of blood

Impaired blood flow to tissues (ischemia)

Treatment

Increasing fluid volume in relative polycythemia

Periodic removal of blood to reduce viscosity and volume in primary polycythemia

Chemotherapy or radiation to suppress activity of bone marrow stem cells in polycythemia vera

Thrombocytopenia (Purpura)

Thrombocytopenia represents a decrease in the number of circulating platelets (usually less than 100,000/mm3). It can result from decreased platelet production by the bone marrow, increased pooling of platelets in the spleen, or decreased platelet survival caused by immune or nonimmune mechanisms. Dilutional thrombocytopenia can result from massive transfusions because blood stored for more that 24 hours has virtually no platelets.

Decreased platelet production can result from suppression or failure of bone marrow function, such as occurs in aplastic anemia, or from replacement of bone marrow by malignant cells, such as occurs in leukemia. Infection with human immunodeficiency virus (HIV) suppresses the production of megakaryocytes. Radiation therapy and drugs such as those used in the treatment of cancer may suppress bone marrow function and reduce platelet production.

There may be normal production of platelets but excessive pooling of platelets in the spleen. The spleen normally sequesters approximately 30% to 40% of the platelets. However, as much as 80% of the platelets can be sequestered when the spleen is enlarged (splenomegaly). Splenomegaly occurs in cirrhosis with portal hypertension and in lymphomas.

Decreased platelet survival is an important cause of thrombocytopenia. In many cases, premature destruction of platelets is caused by antiplatelet antibodies or immune complexes. The antibodies can be directed against self-antigens (autoimmunity) or against nonself platelet antigens (from blood transfusions).

Autoimmune thrombocytopenias include idiopathic thrombocytopenic purpura and HIV-associated thrombocytopenias. Decreased platelet survival may also occur as the result of mechanical injury associated with prosthetic heart valves.

Drug-Induced Thrombocytopenia

Some drugs, such as quinine, quinidine, and certain sulfa-containing antibiotics, may induce thrombocytopenia. These drugs act as a hapten and induce antigen–antibody response and formation of immune complexes that cause platelet destruction by complement-mediated lysis. In persons with drug-associated thrombocytopenia, there is a rapid fall in platelet count within 2 to 3 days of resuming use of a drug or 7 or more days (i.e., the time needed to mount an immune response) after starting use of a drug for the first time. The platelet count rises rapidly after the drug use is discontinued.

The anticoagulant drug heparin has been increasingly implicated in thrombocytopenia and, paradoxically, in thrombosis. The complications typically occur 5 days after the start of therapy and result from production of heparin-dependent antiplatelet antibodies that cause aggregation of platelets and their removal from the circulation. The antibodies often bind to vessel walls, causing injury and thrombosis. The newer, low–molecular-weight heparin has been shown to be effective in reducing the incidence of heparin-induced complications compared with the older, high–molecular-weight form of the drug.

Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura, an autoimmune disorder, results in platelet antibody formation and excess destruction of platelets. The IgG antibody binds to two identified membrane glycoproteins while in the circulation. The platelets, which are made more susceptible to phagocytosis because of the antibody, are destroyed in the spleen.

Acute idiopathic thrombocytopenic purpura is more common in children and usually follows a viral infection. It is characterized by sudden onset of petechiae and purpura and is a self-limited disorder with no treatment. In contrast, the chronic form is usually seen in adults and seldom follows an infection. It is a disease of young people, with a peak incidence between the ages of 20 and 50 years, and is seen twice as often in women as in men. It may be associated with other immune disorders such as acquired immunodeficiency syndrome (AIDS) or systemic lupus erythematosus. The condition occasionally presents precipitously with signs of bleeding, often into the skin (i.e., purpura and petechiae) or oral mucosa. There is commonly a history of bruising, bleeding from gums, epistaxis (i.e., nosebleeds), and abnormal menstrual bleeding. Because the spleen is the site of platelet destruction, splenic enlargement may occur.

Diagnosis usually is based on severe thrombocytopenia (platelet counts <20,000/mL), and exclusion of other causes.

Treatment includes the initial use of corticosteroid drugs, often followed by splenectomy and the use of immunosuppressive agents.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TPP) is a combination of thrombocytopenia, hemolytic anemia, signs of vascular occlusion, fever, and neurologic abnormalities. The onset is abrupt, and the outcome may be fatal. Widespread vascular occlusions consist of thrombi in arterioles and capillaries of many organs, including the heart, brain, and kidneys. Erythrocytes become fragmented as they circulate through the partly occluded vessels and cause the hemolytic anemia. The clinical manifestations include purpura and petechiae and neurologic symptoms ranging from headache to seizures and altered consciousness.

Although TTP may have diverse causes, the initiating event seems to be widespread endothelial damage and activation of intravascular thrombosis. Toxins produced by certain strains of Escherichia coli (e.g., E. coli O157:H7) are a trigger for endothelial damage and an associated condition called the hemolytic-uremic syndrome.

Treatment for TTP includes plasmapheresis, a procedure that involves removal of plasma from withdrawn blood and replacement with fresh-frozen plasma. The treatment is continued until remission occurs. With plasmapheresis treatment, there is a complete recovery in 80% to 90% of cases.

Fibrinogen Deficiency

Factor I (or fibrinogen) deficiency is a very rare inherited disorder with complications that vary with the severity of the disorder. It is not well known, even among health professionals.

Discovery

Factor I deficiency was described for the first time in 1920 by Fritz Rabe and Eugene Salomon. These two German physicians are credited with discovering the disorder. They studied the case of a 9-year-old boy who presented unexplained bleeding problems from birth. Blood tests finally demonstrated the absence of fibrinogen in the child’s blood. His parents were first cousins, but they showed no bleeding problems. The two researchers established that it was an inherited disorder often found in subjects whose parents were blood relatives. Since then, knowledge about the condition has advanced considerably.

What is Fibrinogen?

Fibrinogen, also called Factor I, is a blood plasma protein produced by the liver that plays an important role in blood coagulation. Blood coagulation is a process in which several components of the blood form a clot. When blood escapes from a rupture in a blood vessel, coagulation is triggered. Several proteins, called coagulation factors, go into action to produce thrombin. The thrombin then converts fibrinogen to fibrin. Fibrin produced from fibrinogen is the main protein in a blood clot. It surrounds the cells in the blood and plasma and helps form the clot. The resulting clot, which is stabilized by Factor XIII, remains intact from 10 to 14 days, the time required for healing to take place. When there is a problem with fibrinogen, i.e., either it is missing or it does not function properly, the clot has difficulty forming. This can result in hemorrhaging or thrombosis.

The normal volume of fibrinogen in the blood is from 2 to 4 g/l (grams/litre). The amount of fibrinogen in blood can be measured from a blood sample. The following diagram was devised by a Toronto laboratory technician. It shows the stages in clot formation in a way that makes it easier to understand the theoretical notions explained above.

Types of Fibrinogen Deficiency

There are three types of deficiency:

Afibrinogenemia: (absence of fibrinogen)

In this type of factor I deficiency, there is a complete absence of fibrinogen. The fibrinogen level is <0.2 g/L of plasma. About 5 people out of 10 million are affected by it. Of the three types, this one causes the most serious bleeding.

Hypofibrinogenemia (lower than normal level)

Dysfibrinogenemia (improper functioning)

Transmission of Fibrinogen Deficiency

Fibrinogen deficiency is a very rare inherited bleeding disorder. It is transmitted from parent to child at conception. The disorder is caused by an abnormal gene. It affects both men and women, as well as people of all races and ethnic origins.

Every cell of the body contains chromosomes. A chromosome is a long chain of a substance called DNA. DNA is organized in 30,000 units: these are called genes. The genes determine physical characteristics, such as eye colour. In the case of fibrinogen deficiency, one of the genes involved is defective.

The defective gene in fibrinogen deficiency is located on a chromosome that is not responsible for the child’s sex (autosomal). As a result, both girls and boys can be affected equally.

Afibrinogenemia (absence of fibrinogen)

This is a recessive disorder, which means that both parents must be carriers. In order for a person to inherit fibrinogen deficiency, he must receive two defective genes, one from the mother and the other from the father. A carrier is a person who has only one of the two defective genes,

but is not affected by the disorder: the second gene enables just enough fibrinogen to be made for good coagulation. The fibrinogen level will be lower than normal, but there will be no symptoms of the disorder.

Hypofibrinogenemia and dysfibrinogenemia

These are inherited disorders that can be either dominant or recessive. Dominant means that a single parent can transmit the disorder if he or she is a carrier.

Recessive means that both parents must be carriers of the disorder in order to transmit it.

Symptoms

Afibrinogenemia (absence of fibrinogen)

In congenital afibrinogenemia (fibrinogen level <0.2 g/L), bleeding can vary, from slight to severe. Many patients have very long intervals between bleeding episodes. A diagnosis of afibrinogenemia is generally made postnatally, usually because of bleeding from the umbilical cord and/or a hemorrhage following circumcision.

Other types of bleeding have been described:

bruises

bleeding from the gums

epistaxis (nosebleeds)

gastrointestinal hemorrhage

genito-urinary hemorrhage

intra-cranial hemorrhage

rupture of the spleen and hemorrhage in the spleen

About 20% of those suffering from afibrinogenemia present hemarthroses (bleeding in the joints). Because of this particular feature, the disorder may be confused with hemophilia A or B.

Hypofibrinogenemia (lower than normal level)

Bleeding in hypofibrinogenemia is much like what is seen in afibrinogenemia. It can be more or less serious, depending on fibrinogen levels, which can vary from 0.2 to 0.8 g/L of plasma. The higher the fibrinogen level, the less bleeding. The lower the fibrinogen level, the more bleeding.

Dysfibrinogenemia (improper functioning)

In dysfibrinogenemia, the quantity of fibrinogen is normal, which means between 2 and 4 g/L. Bleeding can vary depending on how the fibrinogen is functioning. Bleeding may:

be absent (no symptoms)

show a tendency toward hemorrhage (as described in afibrinogenemia)

show a tendency toward thrombosis

How to Recognize Bleeding

It is strongly recommended that people who suffer from afibrinogenemia or severe hypofibrinogenemia learn to recognize the signs and symptoms of bleeding that could threaten their lives or the integrity of a limb, so they can react adequately and in a reasonable time.

The information below describes the main types of bleeding that may occur in someone with a coagulation disorder.

Bleeding that affects the head, neck, thorax (chest) or abdomen can be life-threatening and may require immediate medical attention. Bear in mind that this kind of bleeding can occur either following an injury or spontaneously (without injury).

Head

The brain, which is protected by the skull, controls all bodily functions that are essential to life. Bleeding in the brain is very serious.

Signs and symptoms:

Headache

Vision problems

Nausea and vomiting

Change of personality

Somnolence

Loss of balance*

Loss of the fine motor skills (clumsiness)*

Fainting*

Convulsions*

* These symptoms appear later in the event of serious injury to the head. If these symptoms appear, consult a physician immediately in order to receive treatment.

Neck

The tissue of the nose, mouth and throat are highly vascularized, which means that they contain many veins and arteries. The slightest lesion or infection can cause an accumulation of blood in this tissue. When the tissue swells with blood, it compresses the respiratory tract, making breathing difficult or even blocking it completely.

Signs and symptoms:

Pain in the neck or throat

Swelling

Difficulty swallowing

Difficulty breathing

Thorax (chest) Infrequent

The rib cage (thorax) contains the lungs and heart, as well as large blood vessels. If bleeding occurs in the lungs, the alveoli, which normally contain air, fill with blood, and breathing becomes difficult.

Signs and symptoms:

Chest pain

Difficulty breathing

Coughing, blood in sputum

Adomen (stomach)

The abdomen contains the stomach, spleen, liver and intestines, as well as other organs. An injury in this area can result in massive hemorrhaging of an organ or major blood vessel. If the hemorrhage is not treated, it can be fatal.

Signs and symptoms:

Pain in the abdomen or lower back

Nausea and vomiting

Blood in the urine

Blood in the stool or black stool

If one of these symptoms occurs, consult a physician immediately.

Other kinds of Bleeding

There are other kinds of bleeding that are not necessarily life-threatening, but for which treatment is necessary. These are described below.

Soft Tissue Bleeding

The signs and symptoms of bleeding of the soft tissue are as follows:

Redness in the affected area: Use a tape measure to check the size of the affected area regularly. If you don’t have a tape measure, you must check the area every hour to see if the redness is increasing.

Increase in the size of a bruise: Take a pen and draw a line around the bruise; this way you can see if it is spreading, shrinking or staying the same.

Pain: Note whether it gets stronger, and if you can pinpoint the source.

Bleeding in the Joints

The signs and symptoms of bleeding in the joints are as follows:

Pain during normal use of a joint or even at rest, especially if there is no bruise.

Swelling and heat in the joint, with or without bruising.

Reduced mobility of the joint.

Hesitation to move the joint - For example, a child who walks normally may suddenly start limping because of a hemorrhage in the ankle; a right-handed child can only use its left hand to grab objects because of bleeding in the elbow.

Agitation or crying when a child moves a joint. This behaviour may be caused by pain due to bleeding, especially in infants. Parents must learn to feel and assess joint movement; this is especially important for the knees, ankles and elbows.

Treatments

Many people who have hypofibrinogenemia or a dysfibrinogenemia do not need treatment

To control or prevent bleeding, all that’s required is to increase the fibrinogen level in the blood with blood products or substitutes. This kind of treatment is called factor replacement treatment. The aim of the treatment is to increase the fibrinogen level to 1 g/L when there is minor bleeding, and 2 g/L for serious bleeding or for surgery.

Fibrinogen concentrate can be administered by drip:

at the time of surgery

to the mother during childbirth or after delivery

after a trauma

before dental surgery

as prophylaxis (prevention) for subjects with afibrinogenemia to prevent bleeding

At the present time, the most frequently used treatment in Canada is fibrinogen concentrate. The concentrate is obtained from human plasma and contains fibrinogen only. The concentrate undergoes a viral inactivation process, which eliminates viruses such as HIV and hepatitis A, B and C.

It is impossible to completely eliminate the risk of transmitting infections that are currently unknown.

There are other options that can be considered for treatment:

plasma

cryoprecipitate

However, their use is not recommended much nowadays for various reasons, such as:

slight risk of viral transmission

possible serious allergic reactions because of the large number of different substances contained in these products in addition to fibrinogen.

Anticoagulants are sometimes used to reduce the risk of thrombosis among patients with dysfibrinogenemia.

Problems Specific to Women

Fibrinogen deficiency affects both men and women. However the impact is greater for women because of menstruation and conception. Amount of bleeding may vary depending on the type of deficiency.

Afibrinogenemia (absence of fibrinogen)

MENSTRUATION

In afibrinogenemia, menstrual bleeding can be very abundant (menorrhagia) or entirely normal. When bleeding is abundant, various treatments, such as oral contraceptives and/or Cyklokapron may be useful. Cyklokapron is an antifibrinolytic agent that helps stabilize the clot and better control bleeding. It is rare to have to use fibrinogen during menstruation.

PREGNANCY

The majority of pregnancies in women presenting afibrinogenemia end in miscarriage between the 5th and 8th week of pregnancy.

To avoid abortion, it is essential to increase the fibrinogen level to at least 1 g/L in the 4th week of pregnancy, and to maintain this level throughout the pregnancy. The fibrinogen level is increased by regular infusions of fibrinogen concentrate.

CHILDBIRTH

Detachment of the placenta is frequent at the start of labour. To prevent placental detachment it is necessary to keep the fibrinogen level between 1.5 g/L and 2 g/L, if possible.

AFTER CHILDBIRTH

Bleeding after childbirth (postpartum) is usually controlled fairly well with a lower dose of fibrinogen.

Hypofibrinogenemia (lower than normal level)

Menstrual problems and problems of pregnancy with hypofibrinogenemia are much like those observed in afibrinogenemia. They can be more or less serious, depending on the level of fibrinogen in blood.

The higher the fibrinogen level, the less abundant the menstrual bleeding and the fewer miscarriages.

The lower the fibrinogen level, the more likely menstrual bleeding will be abundant and the higher the rate of miscarriages. The treatment is the same as for afibrinogenemia.

Dysfibrinogenemia (improper functioning)

Menstrual problems and problems of pregnancy vary depending on the type of dysfibrinogenemia.

Treatment must be tailored to the situation. Many patients may give birth without bleeding, and fibrinogen concentrate is often not necessary.

Prevention

Never take aspirin. Aspirin is a drug that increases the risk of hemorrhage by inhibiting the functioning of platelets.

Prevent dental problems and gingivitis. Visit your dentist every six months. Your Hemophilia Centre can recommend a dentist who is familiar with coagulation problems.

Always contact your Hemophilia Centre if you have to have surgery or a tooth extraction in order to plan adequate preventive treatment.

Always wear a Medic-Alert type bracelet or a chain explaining your coagulation problem.

Wear protective equipment (e.g., a helmet) when you do certain physical activities. Contact sports such as boxing, soccer and hockey must be avoided due to the significant risk of bleeding they represent.

Vaccination

The Canadian Pediatrics Society has published several documents promoting the Canadian vaccination program. Children must receive their first vaccinations at a young age. However, it is important to take precautions in order to avoid bleeding at the injection site. The nurse at the hemophilia treatment centre will be able to tell you what precautions to take.

Special Precautions

Children with fibrinogen deficiency must receive their vaccines on a schedule set by their pediatrician or family physician. It is also recommended that anyone receiving human source coagulation factor concentrate be vaccinated against hepatitis A and B.

The hepatitis A virus is present in the stools of infected people. It can be transmitted from one person to another by:

food and water that have been in contact with an infected person;

sexual relations with an infected person;

contact with infected blood.

In the past, hepatitis B could be transmitted by blood factor concentrates. Nowadays, however, the concentrates pose no risk. This having been said, a person suffering from a coagulation disorder is more likely to need blood transfusions and these may transmit hepatitis B, albeit very rarely. That is why vaccination is recommended.

Hepatitis B is a disorder caused by a virus that attacks the liver. The liver helps to digest food and clean the blood. Some people infected by hepatitis B present no symptoms, but they can nevertheless transmit the disease to someone else. In other cases, hepatitis B makes people very sick. It can cause serious damage to the liver and an infection that lasts a very long time. There is no completely effective treatment for hepatitis B.

Hepatitis B is transmitted by contact with bodily fluids, including:

blood;

mother’s milk;

semen;

vaginal secretions.

Abnormal Haemoglobin

(Sickle cell disease and Thalassemia have been discussed under Anemia)

Heme is synthesized in a chain of eight reactions (!A). In addition to its incorporation into the hemoglobin of the erythroblasts (!p. 39), heme is synthesized in practically all organs and built into myoglobin, cytochrome P450, catalase, peroxidase, or the respiratory-chain cytochrome. Because these hemoproteins are indispensable, complete absence of heme synthesis is incompatible with life. Partial, usually heterozygous, defects of one of the participating enzymes have severe consequences.

Heme synthesis starts with the formation of "-amino-#-ketoadipate that is spontaneously transformed into $-aminolevulinate ($-amino-levulinic acid [$-ALA]). This step, which takes place in the mitochondria, is the rate limiting step of heme synthesis; it is catalyzed in the erythroblasts by $-ALA synthetase 2 (!A1) and in the liver by $-ALA -synthetase 1. The activity of both isoenzymes is reduced by heme, the end-product of the synthesis (negative feedback; !A, left). This happens in part through heme being bound in the cytosol to the heme-regulated element of the proenzyme and hindering the latter from passing into the mitochondria.

Effects of heme synthesis abnormalities differ depending on this feedback, depending on whether the substrate turnover of $-ALA-syn-thetase-2 or of one of the subsequent enzyme reactions is reduced. In the former case (!A1), the heme deficiency can only inadequately raise the activity of the deficient $-ALA–synthetase-2, so that a sideroblastic anemia will develop (!p. 36).

In deficiencies of the follow-on enzymes (!A2–8) a hugely increased availability of $-ALA (disinhibition of $-ALA-synthetase) develops due to the intact negative feedback. As a result, the concentrations of the substrates of all subsequent reactions are increased and thus the turnover is increased until enough heme has been produced. It is the high concentrations of the intermediary substances that lead to abnormalities (primary porphyrias;!A2–8). Depending on their solubility in water or lipids, the intermediary products are excreted in the urine ($-ALA, porphobilinogen[PBG]), uroporphyrin), or additionally via the bile in the stool (coproporphyrins, protoporphyrins), respectively. The porphyrins are produced fromthe respective porphinogens; theirexcretory pattern is of diagnostic significance.

The concentration of $-ALA is raised by a deficiency of $-ALA-dehydratase (= PBG synthetase) (!A2) as well as by a hypofunction of porphobilinogen deaminase (also called hydroxymethylbilane synthetase), the cause of acute intermittent porphyrias (!A3), in which the PBG concentration is also increased. This results in neurovisceral dysfunctions (tachycardia, nausea, vomiting, and constipation) and neuropsychogenic disorders (paralyses, seizures, coma, hallucinations). One of the causes of these dysfunctions may be the competition between $-ALA and the structurally similar neurotransmitter %-aminobutyrate (GABA).

In congenital erythropoietic porphyria (!A4) uroporphyrinogen will be formed nonenzymatically from hydroxymethylbilane, and converted enzymatically to coproporphyrinogen I (analogously to A5). Coproporphyrinogen I can no longer be used metabolically and, excreted in the urine, in infants it causes red stains on diapers and later on the teeth.Other effects are skin reactions to light and hemolytic anemia. In (the more frequent) porphyria cutanea tarda (!A5) the porphyrins cause damage to the skin (poorly healing blisters; !A, photograph) as a result of light absorption (especially at & = 440 nm). O2 radicals are involved in the generation of the skin lesions.

In hereditary coproporphyria (!A6), as also in porphyria variegata (!A7) (particularly common in South Africa [ca. three out of every 1000 whites]), $-ALA, PBG, and the coproporphyrins are all elevated, causing neuropsychogenic and dermatological symptoms in the affected children. In protoporphyria (increase of protoporphyrin; !A8) burns, itching, and pain in the skin due to photosensitivity are prominent after exposure to ultravioletrays.

Acquired porphyrias occur in lead poisoning (!A2,8; high $-ALA and PBG levels) and in hepatobiliary diseases, in which coproporphyrin excretion in bile is reduced.

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