Hematologic Disorders



Hematologic Disorders






INTRODUCTION

Blood, one of the body’s major fluid tissues, continuously circulates through the heart and blood vessels, carrying vital elements to every part of the body.


BLOOD BASICS

Blood performs several vital functions through its special components: the liquid portion (plasma) and the formed constituents (erythrocytes, leukocytes, and thrombocytes) that are suspended in it. Erythrocytes (red blood cells [RBCs]) carry oxygen to the tissues and remove carbon dioxide from them. Leukocytes (white blood cells [WBCs]) act in inflammatory and immune responses. Plasma (a clear, straw-colored fluid) carries antibodies and nutrients to tissues and carries waste away; plasma coagulation factors and thrombocytes (platelets) control clotting. (See Coagulation factors, page 456.)

Typically, the average person has 5 to 6 L of circulating blood, which constitute 5% to 7% of body weight (as much as 10% in premature neonates). Blood is three to five times more viscous than water, with an alkaline pH of 7.35 to 7.45, and is either bright red (arterial blood) or dark red (venous blood), depending on the degree of oxygen saturation and the hemoglobin (Hb) level.


FORMATION AND CHARACTERISTICS

Hematopoiesis, the process of blood formation, occurs primarily in the bone marrow of the femur, sternum, and vertebrae, where primitive blood cells (stem cells) produce the precursors of erythrocytes (normoblasts), leukocytes, and thrombocytes. During embryonic development, blood cells are derived from mesenchyma and form in the yolk sac. As the fetus matures, blood cells are produced in the liver, the spleen, and the thymus; by the fifth month of gestation, blood cells also begin to form in bone marrow. After birth, blood cells are usually produced only in the marrow.


BLOOD’S FUNCTION

The most important function of blood is to transport oxygen (bound to RBCs inside Hb) from the lungs to the body tissues and to return carbon dioxide from these tissues to the lungs. Blood also performs the following functions:



  • production and delivery of antibodies (by WBCs) formed by plasma cells and lymphocytes


  • transportation of granulocytes and monocytes to defend the body against pathogens by phagocytosis


  • immunity against viruses and cancer cells through sensitized lymphocytes


  • provision of complement, a group of immunologically important protein substances in plasma essential for immune and inflammatory responses

Blood’s other functions include control of hemostasis by platelets, plasma, and coagulation factors that repair tissue injuries and prevent or halt bleeding; acid-base and fluid balance; regulation of body temperature by carrying off excess heat generated by the internal organs for dissipation through the skin; and transportation of nutrients and regulatory hormones to body tissues and of metabolic wastes to the organs of excretion (kidneys, lungs, and skin).


BLOOD DYSFUNCTION

Because of the rapid reproduction of bone marrow cells and the short life span and minimal storage in the bone marrow of circulating cells, bone marrow cells and their precursors are particularly vulnerable to physiologic changes that can affect cell production, or hematopoiesis. Resulting blood disorders may be primary or secondary, quantitative or qualitative, or both; they may involve some or all blood components. Quantitative blood disorders result from increased or decreased cell production or cell destruction; qualitative blood disorders stem from intrinsic cell abnormalities or plasma component dysfunction. Specific causes of blood disorders include trauma, chronic disease, surgery, malnutrition, drugs, exposure to toxins and radiation, and genetic and congenital defects that disrupt production and function. For example, depressed bone marrow production or mechanical destruction of mature blood cells can reduce the number of RBCs, platelets, and granulocytes, resulting in pancytopenia (anemia, thrombocytopenia, and granulocytopenia). Increased production of multiple bone marrow components can follow myeloproliferative disorders.


ERYTHROPOIESIS

The tissues’ demand for oxygen and the blood cells’ ability to deliver it regulate RBC production, or erythropoiesis. Consequently, hypoxia (or tissue anoxia) stimulates RBC production by triggering the formation and release of erythropoietin, a hormone (produced by the kidneys) that activates bone marrow to produce RBCs. Erythropoiesis may also be stimulated by androgens (which accounts for the higher RBC counts in men). RBCs have a life span of approximately 120 days.









Coagulation factors










































Factor


Synonym


Factor I


Fibrinogen


Factor II


Prothrombin


Factor III


Tissue thromboplastin


Factor IV


Calcium ion


Factor V


Labile factor


Factor VII


Stable factor


Factor VIII


Antihemophilic globulin or antihemophilic factor A


Factor IX


Plasma thromboplastin component, Christmas factor


Factor X


Stuart-Prower factor


Factor XI


Plasma thromboplastin antecedent


Factor XII


Hageman factor


Factor XIII


Fibrin stabilizing factor


The actual formation of an erythrocyte begins with an uncommitted stem cell that may eventually develop into an RBC or a WBC. Such formation requires certain vitamins—B12 and folic acid—and minerals, such as copper, cobalt, and especially iron, which is vital to hemoglobin’s oxygen-carrying capacity. Iron is obtained from various foods and is absorbed in the duodenum and upper jejunum, leaving the excess for temporary storage in reticuloendothelial cells, especially those in the liver. Iron excess is stored as ferritin and hemosiderin until it’s released for use in the bone marrow to form new RBCs.



RBC DISORDERS

RBC disorders include quantitative and qualitative abnormalities. Deficiency of RBCs (anemia) can follow any condition that destroys or inhibits the formation of these cells. Common factors leading to this deficiency include:



  • chronic illnesses, such as renal disease, cancer, and chronic infections


  • congenital or acquired defects that cause bone marrow aplasia and suppress general hematopoiesis (aplastic anemia) or erythropoiesis


  • deficiencies of vitamins (vitamin B12 deficiency or pernicious anemia) or minerals (iron, folic acid, copper, and cobalt deficiency anemias) that cause inadequate RBC production


  • drugs, toxins, and ionizing radiation


  • excessive chronic or acute blood loss (posthemorrhagic anemia)


  • intrinsically or extrinsically defective RBCs (sickle cell anemia and hemolytic transfusion reaction)


  • metabolic abnormalities (sideroblastic anemia)

Comparatively few conditions lead to excessive numbers of RBCs:



  • abnormal proliferation of all bone marrow elements (polycythemia vera), especially RBC mass


  • a single-element abnormality (for instance, an increase in RBCs that results from erythropoietin excess, which in turn results from hypoxemia, hypertension, or pulmonary disease)


  • decreased plasma cell volume, which produces a corresponding relative increase in RBC concentration (such as through the use of drugs)


FUNCTION OF WBCS

WBCs, or leukocytes, protect the body against harmful bacteria and infection and are classified as granular leukocytes (basophils, neutrophils, and eosinophils) or nongranular leukocytes (lymphocytes, monocytes, and plasma cells). (See Two types of leukocytes.) Usually, WBCs are produced in bone marrow; lymphocytes and plasma cells are produced in lymphoid tissue as well. Neutrophils have a circulating half-life of less than 6 hours; some lymphocytes may survive for weeks or months. Normally, WBCs number between 5,000 and 10,000/µl.

There are six types of WBCs:



  • Neutrophils, the predominant form of granulocyte, make up about 60% of WBCs; they help devour invading organisms by phagocytosis.


  • Eosinophils, minor granulocytes, may defend against parasites and lung and skin infections and act in allergic reactions. They account for 1% to 5% of the total WBC count.


  • Basophils, minor granulocytes, may release heparin and histamine into the blood and participate in delayed hypersensitivity reactions. They account for 0% to 1% of the total WBC count.


  • Monocytes, along with neutrophils, help devour invading organisms by phagocytosis. They help process antigens for lymphocytes and form macrophages in the tissues; they account for 1% to 6% of the total WBC count.



  • Lymphocytes occur as B cells and T cells. B cells aid antibody synthesis; T cells regulate cell-mediated immunity. They account for 20% to 40% of the total WBC count.


  • Plasma cells develop from lymphocytes, reside in the tissue, and produce antibodies. Plasma cells do not normally circulate in the blood.


A temporary increase in production and release of mature WBCs (leukemic reaction) is a normal response to infection. However, an excessive number of immature WBC precursors and their accumulation in bone marrow or lymphoid tissue is characteristic of leukemia. These nonfunctioning WBCs (blasts) provide no protection against infection; crowd out RBCs, platelets, and mature WBCs; and spill into the bloodstream, sometimes infiltrating organs and impairing function.

WBC deficiencies may reflect inadequate cell production, drug reactions, ionizing radiation, infiltrated bone marrow (cancer), congenital defects, aplastic anemia, folic acid deficiency, or hypersplenism. The major WBC deficiencies are granulocytopenia, lymphocytopenia, and monocytopenia.



PLATELETS, PLASMA, AND CLOTTING

Platelets are small (2 to 4 microns in diameter), colorless, disk-shaped cytoplasmic fragments split from cells in bone marrow called megakaryocytes. The normal platelet concentration is 150,000 to 400,000/µl. These fragments, which have a life span of approximately 10 days, perform three vital functions:



  • initiate vasoconstriction of damaged blood vessels to minimize blood loss


  • form hemostatic plugs in injured blood vessels


  • with plasma, provide materials that accelerate blood coagulation—notably platelet factor 3

Plasma consists mainly of proteins (chiefly albumin, globulin, and fibrinogen) held in aqueous suspension. Other components of plasma include glucose, lipids, amino acids, electrolytes, pigments, hormones, respiratory gases (oxygen and carbon dioxide), and products of metabolism, such as urea, uric acid, creatinine, and lactic acid. Its fluid characteristics— including osmotic pressure, viscosity, and suspension qualities—depend on its protein content. Plasma components regulate acid-base balance and immune responses and mediate coagulation and nutrition.

In a complex process called hemostasis, platelets, plasma, and coagulation factors interact to control bleeding.


HEMOSTASIS AND THE CLOTTING MECHANISM

Hemostasis is the complex process by which the body controls bleeding. When a blood vessel ruptures, local vasoconstriction and platelet clumping (aggregation) at the injury site initially help prevent hemorrhage. This activation of the coagulation system, called extrinsic cascade, requires release of tissue thromboplastin from the damaged cells. However, formation of a more stable clot requires initiation of the complex clotting mechanism known as the intrinsic cascade system. When endothelial vessel injury or a foreign body in the bloodstream activates this system, activating factor XII triggers clotting. In the final common pathway, prothrombin is converted to thrombin. Thrombin acts on fibrinogen to form fibrin, the basis of a clot.


THERAPY WITH BLOOD COMPONENTS

Because of improved methods of collection, component separation, and storage, blood transfusions are being used more effectively than ever. Separating blood into components permits a single unit of blood to benefit several patients with different hematologic abnormalities. Component therapy allows replacement of a specific blood component without risking reactions from other components.

Blood typing, crossmatching, and human leukocyte antigen (HLA) typing are compatibility tests used to ensure safe, effective replacement therapy and minimize the risk of transfusion reactions. Blood typing determines the antigens present in the patient’s RBCs by reaction with standardized sera. (Critical antigen groups are those of ABO and Rh factor.) Crossmatching the patient’s blood with transfusion blood provides some assurance that the patient doesn’t have antibodies against donor red cells. HLA typing may be helpful for the patient who needs long-term transfusion therapy or frequent platelet transfusions, but usually, only family members can provide an appropriate match because antigenic properties are genetically determined.


BONE MARROW TRANSPLANTATION

Bone marrow transplantation is used to treat acute leukemia, aplastic anemia, severe combined immunodeficiency disease, Nezelof syndrome, and Wiskott-Aldrich syndrome. In this procedure, marrow from a twin or another HLAidentical donor (usually a sibling) is transfused in an attempt to repopulate the recipient’s bone marrow with normal cells.

A hematologic disorder can affect nearly every aspect of the patient’s life, perhaps resulting in life-threatening emergencies that require prompt medical treatment. This is particularly true of patients with such diseases as hemophilia and thalassemia major, diseases for which no cure is available. Astute, sensitive care founded on a firm understanding of hematologic basics can help the patient survive such illnesses. In situations with poor prognoses, the patient may need to make many adjustments to maintain an optimal quality of life.


ANEMIAS


Pernicious anemia

Pernicious anemia, also known as vitamin B,12 deficiency, is a type of megaloblastic anemia characterized by decreased gastric production
of hydrochloric acid and deficiency of intrinsic factor (IF), a substance normally secreted by the parietal cells of the gastric mucosa that’s essential for vitamin B12 absorption in the ileum. The resulting deficiency of vitamin B12 causes serious neurologic, gastric, and intestinal abnormalities. Untreated pernicious anemia may lead to permanent neurologic disability and death. (See Peripheral blood smear in pernicious anemia.)



CAUSES AND INCIDENCE

Familial incidence of pernicious anemia suggests a genetic predisposition. (It may involve an inherited single dominant autosomal factor.) Significantly higher incidence in patients with immunologically related endocrine diseases, such as thyroiditis, myxedema, and Graves’ disease, seems to support a widely held theory that an inherited autoimmune response causes gastric mucosal atrophy and, therefore, deficiency of hydrochloric acid and IF. IF deficiency impairs vitamin B12 absorption. The resultant vitamin B12 deficiency inhibits cell growth, particularly of red blood cells (RBCs), leading to insufficient and deformed RBCs with poor oxygen-carrying capacity. It also impairs myelin formation, causing neurologic damage. Iatrogenic induction can follow partial gastrectomy.




Pernicious anemia primarily affects people of northern European ancestry. It’s rare in children and infants. Onset typically occurs after age 35, and incidence increases with age. It affects about 2% of people older than age 60.



SIGNS AND SYMPTOMS

Characteristically, pernicious anemia has an insidious onset but eventually causes an unmistakable triad of symptoms: weakness, sore tongue, and numbness and tingling in the extremities. The lips, gums, and tongue appear markedly bloodless. Hemolysis-induced hyperbilirubinemia may cause faintly jaundiced sclera and pale to bright yellow skin. In addition, the patient may become highly susceptible to infection, especially of the genitourinary tract.

Other systemic symptoms of pernicious anemia include the following:



  • GI—Gastric mucosal atrophy and decreased hydrochloric acid production disturb digestion and lead to nausea, vomiting, anorexia, weight loss, flatulence, diarrhea, and constipation. Gingival bleeding and tongue inflammation may hinder eating and intensify anorexia.


  • Central nervous system (CNS)—Demyelination caused by vitamin B12 deficiency initially affects the peripheral nerves but gradually extends to the spinal cord. Consequently, the neurologic effects of pernicious anemia may include neuritis; weakness in extremities; peripheral numbness and paresthesia; disturbed position sense; lack of coordination; ataxia; impaired fine finger movement; positive Babinski’s and Romberg’s signs; light-headedness; altered vision (diplopia and blurred vision), taste, and hearing (tinnitus); optic muscle atrophy; loss of bowel and bladder control; and, in males, impotence. Its effects on the nervous system may also produce irritability, poor memory, headache, depression, and delirium. Although some of these symptoms are temporary, irreversible CNS changes may have occurred before treatment.


  • Cardiovascular—Increasingly fragile cell membranes induce widespread destruction of RBCs, resulting in low Hb levels. The impaired oxygen-carrying capacity of the blood secondary to lowered Hb leads to weakness, fatigue, and light-headedness. Compensatory increased cardiac output results in palpitations, wide pulse pressure, dyspnea, orthopnea, tachycardia, premature beats and, eventually, heart failure.


  • Musculoskeletal—Scissors gait can also occur as a late sign of untreated anemia.





Folic acid deficiency anemia

Folic acid is a water-soluble vitamin that is rapidly excreted; body stores are limited to a few weeks. It is therefore relatively easy to develop a folic acid deficiency.

Folic acid deficiency anemia is a common, slowly progressive, megaloblastic anemia. It usually occurs in infants, adolescents, pregnant and lactating females, alcoholics, elderly people, and people with malignant or intestinal diseases.


CAUSES AND INCIDENCE

Folic acid deficiency anemia may result from:



  • alcohol abuse (alcohol may suppress metabolic effects of folate)


  • poor diet (common in alcoholics, elderly people living alone, and infants, especially those with infections or diarrhea)


  • impaired absorption (due to intestinal dysfunction from disorders such as celiac disease, tropical sprue, regional jejunitis, or bowel resection)


  • bacteria competing for available folic acid


  • excessive cooking, which can destroy a high percentage of folic acids in foods (See Preventing folic acid deficiency anemia.)



  • limited storage capacity in infants


  • prolonged drug therapy (anticonvulsants and estrogens)


  • increased folic acid requirements during pregnancy; during rapid growth in infancy (common because of recent increase in survival of premature infants); during childhood and adolescence (because of general use of folatepoor cow’s milk); and in patients with neoplastic diseases and some skin diseases (chronic exfoliative dermatitis)

It’s estimated that 10% of the United States population has low folate stores.


SIGNS AND SYMPTOMS

Folic acid deficiency anemia gradually produces clinical features characteristic of other megaloblastic anemias, without the neurologic manifestations: progressive fatigue, shortness of breath, palpitations, weakness, glossitis, mouth ulcers, nausea, anorexia, headache, fainting, irritability, forgetfulness, pallor, and slight jaundice. Folic acid deficiency anemia doesn’t cause neurologic impairment unless it’s associated with vitamin B12 deficiency, as in pernicious anemia.





Aplastic anemias

Aplastic, or hypoplastic, anemias result from injury to or destruction of stem cells in bone marrow or the bone marrow matrix, causing pancytopenia (anemia, granulocytopenia, and thrombocytopenia) and bone marrow hypoplasia. (See Peripheral blood smear in aplastic anemia.) Although commonly used interchangeably with other terms for bone marrow failure, aplastic anemia properly refers to pancytopenia resulting from the decreased functional capacity of a hypoplastic, fatty bone marrow. These disorders generally produce fatal bleeding or infection, particularly when they’re idiopathic or stem from chloramphenicol or from infectious hepatitis. Mortality for aplastic anemias with severe pancytopenia is 80% to 90%.


CAUSES AND INCIDENCE

Aplastic anemias usually develop when damaged or destroyed stem cells (which develop into red blood cells [RBCs], white blood cells, and platelets) inhibit RBC production. Less commonly, they develop when damaged bone marrow microvasculature creates an unfavorable environment for cell growth and maturation. About one-half of such anemias result from drugs (antibiotics, anticonvulsants, anti-inflammatory drugs, antineoplastics, diuretics, phenothiazines, antidiabetics, and antithyroid drugs), toxic agents (such as benzene and chloramphenicol), or radiation. The rest may result from immunologic factors (unconfirmed), severe disease (especially hepatitis), viral infection (especially in
children), or preleukemic and neoplastic infiltration of bone marrow.

Idiopathic anemias may be congenital. Two such forms of aplastic anemia have been identified: Congenital hypoplastic anemia (Blackfan-Diamond anemia) develops between ages 2 and 3 months; Fanconi’s syndrome, between birth and age 10. In Fanconi’s syndrome, chromosomal abnormalities are usually associated with multiple congenital anomalies, such as dwarfism, and hypoplasia of the kidneys and spleen. In the absence of a consistent familial or genetic history of aplastic anemia, researchers suspect that these congenital abnormalities result from an induced change in the fetus’ development.

Incidence is 0.6 to 6.1 cases per 1 million people in the United States. There is no racial predilection.



SIGNS AND SYMPTOMS

Clinical features of aplastic anemias vary with the severity of pancytopenia but develop insidiously in many cases. Anemic symptoms include progressive weakness and fatigue, shortness of breath, headache, pallor and, ultimately, tachycardia and heart failure. Thrombocytopenia leads to ecchymosis, petechiae, and hemorrhage, especially from the mucous membranes (nose, gums, rectum, and vagina) or into the retina or central nervous system. Neutropenia may lead to infection (fever, oral and rectal ulcers, and sore throat) but without characteristic inflammation.





Sideroblastic anemias

Sideroblastic anemias are a group of heterogenous disorders with a common defect; they fail to use iron in hemoglobin (Hb) synthesis, despite the availability of adequate iron stores. These anemias may be hereditary or acquired; the acquired form, in turn, can be primary or secondary. Hereditary sideroblastic anemia may respond to treatment with pyridoxine. Correction of the secondary acquired form depends on the causative disorder; the primary acquired (idiopathic) form, however, resists treatment and usually proves fatal within 10 years after onset of complications or a concomitant disease.


CAUSES AND INCIDENCE

Hereditary sideroblastic anemia appears to be transmitted by X-linked inheritance, occurring mostly in young males; females are carriers and usually show no signs of this disorder.

The acquired form may be secondary to ingestion of or exposure to toxins, such as alcohol and lead, or to certain drugs, such as isoniazid used to treat tuberculosis. It can also occur as a complication of other diseases, such as rheumatoid arthritis, lupus erythematosus, multiple myeloma, tuberculosis, and severe infections.

The primary acquired form, known as refractory anemia with ringed sideroblasts, is most common in elderly people. It’s commonly associated with thrombocytopenia or leukopenia as part of a myelodysplastic syndrome.

In sideroblastic anemia, normoblasts fail to use iron to synthesize Hb. As a result, iron is deposited in the mitochondria of normoblasts, which are then termed ringed sideroblasts. (See Ringed sideroblast, page 468.)

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Aug 27, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hematologic Disorders
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