Hematologic System
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| Pathophysiologic manifestations | |
| Hemoglobin | |
| Red blood cells | |
| Leukocytosis | |
| Leukopenia | |
| Thrombocytosis | |
| Disorders | |
| Aplastic anemias | |
| Iron deficiency anemia | |
| Pernicious anemia | |
| Sideroblastic anemias | |
| Thalassemia | |
| Disseminated intravascular coagulation | |
| Erythroblastosis fetalis | |
| Idiopathic thrombocytopenic purpura | |
| Polycythemia vera | |
| Secondary polycythemia | |
| Spurious polycythemia | |
| Thrombocytopenia | |
| Von Willebrand's disease |
B lood, although a fluid, is one of the body's major tissues. It continuously circulates through the heart and blood vessels, carrying vital elements to every part of the body.
Blood performs several vital functions through its special components: the liquid protein (plasma) and the formed constituents (erythrocytes, leukocytes, and thrombocytes) suspended in it. Erythrocytes (red blood cells) carry oxygen to the tissues and remove carbon dioxide. Leukocytes (white blood cells) 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.
Hematopoiesis, the process of blood formation, occurs primarily in the marrow. There primitive blood cells (stem cells) differentiate into the precursors of erythrocytes (normoblasts), leukocytes, and thrombocytes.
The average person has 5 to 6 L of circulating blood, which comprises 5% to 7% of body weight (as much as 10% in premature newborns). Blood is three to five times more viscous than water, has an arterial 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 level.
PATHOPHYSIOLOGIC MANIFESTATIONS
Bone marrow cells reproduce rapidly and have a short life span, and the storage of circulating cells in the marrow is minimal. Thus, bone marrow cells and their precursors are particularly vulnerable to physiologic changes that affect cell production. Disease can affect the structure or concentration of any hematologic cell.
Hemoglobin
The protein hemoglobin is the major component of the red blood cell. Hemoglobin consists of an iron-containing molecule (heme) bound to the protein globulin. Oxygen binds to the heme component and is transported throughout the body and released to the cells. The hemoglobin picks up carbon dioxide and hydrogen ions from the cells and delivers them to the lungs, where they are released.
A variety of mutations or abnormalities in the hemoglobin protein can cause abnormal oxygen transport.
Red blood cells
Red blood cell (RBC) disorders may be quantitative or qualitative. A deficiency of RBCs (anemia) can follow a condition that destroys or inhibits the formation of these cells. (See Erythropoiesis .)
Common factors leading to anemia include:
- drugs, toxins, ionizing radiation
- congenital or acquired defects that cause bone marrow to stop producing new RBCs cells (aplasia) and generally suppress production of all blood cells (hematopoiesis, aplastic anemia)
- metabolic abnormalities (sideroblastic anemia)
- deficiency of vitamins (vitamin B 12 deficiency, or pernicious anemia) or minerals (iron, folic acid, copper, and cobalt deficiency anemias) leading to inadequate erythropoiesis
- excessive chronic or acute blood loss (posthemorrhagic anemia)
- chronic illnesses, such as renal disease, cancer, and chronic infections
- intrinsically (sickle cell anemia) or extrinsically (hemolytic transfusion reaction) defective RBCs.
- abnormal proliferation of all bone marrow cells (polycythemia vera)
- abnormality of a single element (such as erythropoietin excess caused by hypoxemia or pulmonary disease).
Leukocytosis
Leukocytosis is an elevation in the number of white blood cells (WBCs). All types of WBCs may be increased, or only one type. (See WBC types and functions .) Leukocytosis is a normal physiologic response to infection or inflammation. Other factors, such as temperature changes, emotional disturbances, anesthesia, surgery, strenuous exercise, pregnancy, and some drugs, hormones, and toxins can also cause leukocytosis. Abnormal leukocytosis occurs in malignancies and bone marrow disorders.
Leukopenia
Leukopenia is a deficiency of WBCs ― all types or only one type. It can be caused by a number of conditions or diseases, such as human immunodeficiency virus (HIV) infection, prolonged stress, bone marrow disease or destruction, radiation or chemotherapy, lupus erythematosus, leukemia, thyroid disease, or Cushing syndrome. Because WBCs fight infection, leukopenia increases the risk of infectious illness.
Thrombocytosis
Thrombocytosis is an excess of circulating platelets to greater than 400,000/μl. Thrombocytosis may be primary or secondary.
In primary thrombocytosis, the number of platelet precursor cells, called megakaryocytes, is increased and the platelet count is greater than1 million/μl. The condition may result from an intrinsic abnormality of platelet function and increased platelet mass. It may accompany polycythemia vera or chronic granulocytic leukemia. In the presence of thrombocytosis, both hemorrhage and thrombosis may occur. This paradox occurs because accelerated clotting results in a generalized activation of prothrombin and a consequent excess of thrombin clots in the microcirculation. This process consumes exorbitant amounts of coagulation factors and thereby increases the risk of hemorrhage.
Secondary thrombocytosis is a result of an underlying cause, such as stress, exercise, hemorrhage, or hemolytic anemia. Stress and exercise release stored platelets from the spleen. Hemorrhage or hemolytic anemia signal the bone marrow to produce more megakaryocytes.
Thrombocytosis may also occur after a splenectomy. Because the spleen is the primary site of platelet storage and destruction, platelet count may rise after its removal until the bone marrow begins producing fewer platelets.
DISORDERS
Specific causes of hematologic disorders include trauma, chronic disease, surgery, malnutrition, drug, exposure to toxins or radiation, and genetic or congenital defects that disrupt production or function of blood cells.
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, leukopenia, and thrombocytopenia) and bone marrow hypoplasia. 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, especially when they're idiopathic or caused by chloramphenicol (Chloromycetin) use or infectious hepatitis. The death rate for severe aplastic anemia is 80% to 90%.
Possible causes of aplastic anemia are:
- radiation (about half of such anemias)
- drugs (antibiotics, anticonvulsants), or toxic agents (such as benzene or chloramphenicol [Chloromycetin])
- autioimmune reactions (unconfirmed), severe disease (especially hepatitis), or preleukemic and neoplastic infiltration of bone marrow
- congenital (idiopathic anemias): two identified forms of aplastic anemia are congenital ― hypoplastic or Blackfan-Diamond anemia (develops between ages 2 and 3 months); and Fanconi syndrome (develops between birth and 10 years of age).
Aplastic anemia usually develops when damaged or destroyed stem cells inhibit blood cell production. Less commonly, they develop when damaged bone marrow microvasculature creates an unfavorable environment for cell growth and maturation.
Signs and symptoms of aplastic anemia vary with the severity of pancytopenia, but develop insidiously in many cases. They may include:
- progressive weakness and fatigue, shortness of breath, headache, pallor, and ultimately tachycardia and heart failure due to hypoxia and increased venous return
- ecchymosis, petechiae, and hemorrhage, especially from the mucous membranes (nose, gums, rectum, vagina) or into the retina or central nervous system due to thrombocytopenia
- infection (fever, oral and rectal ulcers, sore throat) without characteristic inflammation due to neutropenia (neutrophil deficiency).
A possible complication of aplastic anemia is:
The following test results help diagnose aplastic anemia:
RBCs may be macrocytic (larger than normal) and anisocytotic (excessive variation in size), with:
- very low absolute reticulocyte count
- elevated serum iron (unless bleeding occurs), normal or slightly reduced total iron-binding capacity, presence of hemosiderin (a derivative of hemoglobin), and microscopically visible tissue iron storage
- decreased platelet, neutrophil, and lymphocyte counts
- abnormal coagulation test results (bleeding time) reflecting decreased platelet count
- “dry tap” (no cells) from bone marrow aspiration at several sites
- biopsy showing severely hypocellular or aplastic marrow, with varied amounts of fat, fibrous tissue, or gelatinous replacement; absence of tagged iron (because iron is deposited in the liver rather than bone marrow) and megakaryocytes (platelet precursors); and depression of RBCs and precursors (erythroid elements).
Differential diagnosis must rule out paroxysmal nocturnal hemoglobinuria and other diseases in which pancytopenia is common.
Effective treatment must eliminate an identifiable cause and provide vigorous supportive measures, including:
- packed RBC or platelet transfusion; experimental histocompatibility locus antigen-matched leukocyte transfusions
- bone marrow transplantation (treatment of choice for anemia due to severe aplasia and for patients who need constant RBC transfusions)
- for patients with leukopenia, special measures to prevent infection (avoidance of exposure to communicable diseases, diligent handwashing, etc.)
- specific antibiotics for infection (not given prophylactically because they encourage resistant strains of organisms)
- respiratory support with oxygen in addition to blood transfusions (for patients with low hemoglobin levels)
- corticosteroids to stimulate erythropoiesis; marrow-stimulating agents, such as androgens (controversial); antilymphocyte globulin (experimental); immunosuppressive agents (if the patient doesn't respond to other therapy); and colony-stimulating factors to encourage growth of specific cellular components.
Iron deficiency anemia
Iron deficiency anemia is a disorder of oxygen transport in which hemoglobin synthesis is deficient. A common disease worldwide, iron deficiency anemia affects 10% to 30% of the adult population of the United States. Iron deficiency anemia occurs most commonly in premenopausal women, infants (particularly premature or low-birth-weight infants), children, and adolescents (especially girls). The prognosis after replacement therapy is favorable.
Possible causes of iron deficiency anemia are:
- inadequate dietary intake of iron (less than 1 to 2 mg/day), as in prolonged nonsupplemented breast-feeding or bottle-feeding of infants or during periods of stress, such as rapid growth, in children and adolescents
- iron malabsorption, as in chronic diarrhea, partial or total gastrectomy, and malabsorption syndromes, such as celiac disease and pernicious anemia
- blood loss due to drug-induced GI bleeding (from anticoagulants, aspirin, steroids) or heavy menses, hemorrhage from trauma, peptic ulcers, cancer, or varices
- pregnancy, which diverts maternal iron to the fetus for erythropoiesis
- intravascular hemolysis-induced hemoglobinuria or paroxysmal nocturnal hemoglobinuria
- mechanical trauma to RBCs caused by a prosthetic heart valve or vena cava filters.
Iron deficiency anemia occurs when the supply of iron is inadequate for optimal formation of RBCs, resulting in smaller (microcytic) cells with less color (hypochromic) on staining. Body stores of iron, including plasma iron, become depleted, and the concentration of serum transferrin, which binds with and transports iron, decreases. Insufficient iron stores lead to a depleted RBC mass with subnormal hemoglobin concentration, and, in turn, subnormal oxygen-carrying capacity of the blood.
Because iron deficiency anemia progresses gradually, many patients exhibit only symptoms of an underlying condition. They tend not to seek medical treatment until anemia is severe.
At advanced stages, signs and symptoms include:
- dyspnea on exertion, fatigue, listlessness, pallor, inability to concentrate, irritability, headache, and a susceptibility to infection due to decreased oxygen-carrying capacity of the blood caused by decreased hemoglobin levels
- increased cardiac output and tachycardia due to decreased oxygen perfusion
- coarsely ridged, spoon-shaped (koilonchyia), brittle, and thin nails due to decreased capillary circulation
- sore, red, and burning tongue due to papillae atrophy
- sore, dry skin in the corners of the mouth due to epithelial changes.
Possible complications include:
- infection and pneumonia
- pica, compulsive eating of nonfood materials, such as starch or dirt
- bleeding
- overdosage of oral or IM iron supplements.
Blood studies (serum iron, total iron-binding capacity, ferritin levels) and iron stores in bone marrow may confirm iron deficiency anemia. However, the results of these tests can be misleading because of complicating factors, such as infection, pneumonia, blood transfusion, or iron supplements. Characteristic blood test results include:
- low hemoglobin (males, less than 12 g/dl; females, less than 10 g/dl)
- low hematocrit (males, less than 47; females, less than 42)
- low serum iron with high binding capacity
- low serum ferritin
- low RBC count, with microcytic and hypochromic cells (in early stages, RBC count may be normal, except in infants and children)
- decreased mean corpuscular hemoglobin in severe anemia
- depleted or absent iron stores (by specific staining) and hyperplasia of normal precursor cells (by bone marrow studies).
- exclusion of other causes of anemia, such as thalassemia minor, cancer, and chronic inflammatory, hepatic, or renal disease.
The first priority of treatment is to determine the underlying cause of anemia. Only then can iron replacement therapy begin. Possible treatments are:
- oral preparation of iron (treatment of choice) or a combination of iron and ascorbic acid (enhances iron absorption)
- parenteral iron (for patient noncompliant with oral dose, needing more iron than can be given orally, with malabsorption preventing adequate iron absorption, or for a maximum rate of hemoglobin regeneration).
Because total-dose I.V. infusion of supplemental iron is painless and requires fewer injections, it's usually preferred to IM administration. Considerations include:
- total-dose infusion of iron dextran (INFeD) in normal saline solution given over 1 to 8 hours (pregnant patients and geriatric patients with severe anemia)
- I.V. test dose of 0.5 ml given first (to minimize the risk for an allergic reaction).
Pernicious anemia
Pernicious anemia, the most common type of megaloblastic anemia, is caused by malabsorption of vitamin B 12 .
| AGE ALERT Onset typically occurs between the ages of 50 and 60 years, and incidence increases with age. It's rare in children. |
If not treated, pernicious anemia is fatal. Its manifestations subside with treatment, but some neurologic deficits may be permanent.
Pernicious anemia is characterized by decreased production of hydrochloric acid in the stomach, and a deficiency of intrinsic factor, which is normally secreted by the parietal cells of the gastric mucosa and is essential for vitamin B 12 absorption in the ileum. The resulting vitamin B 12 deficiency inhibits cell growth, particularly of RBCs, leading to production of few, deformed RBCs with poor oxygen-carrying capacity. It also causes neurologic damage by impairing myelin formation.
Possible causes of pernicious anemia include:
- genetic predisposition (suggested by familial incidence)
- immunologically related diseases, such as thyroiditis, myxedema, and Graves' disease (significantly higher incidence in these patients)
- partial gastrectomy (iatrogenic induction)
- older age (progressive loss of vitamin B 12 absorption).
| AGE ALERT The elderly often have a dietary deficiency of B 12 in addition to or instead of poor absorption. |
Characteristically, pernicious anemia has an insidious onset but eventually causes an unmistakable triad of symptoms:
- weakness due to tissue hypoxia
- sore tongue due to atrophy of the papillae
- numbness and tingling in the extremities as a result of interference with impulse transmission from demyelination.
Other common manifestations include:
- pale appearance of lips and gums
- faintly jaundiced sclera and pale to bright yellow skin due to hemolysis-induced hyperbilirubinemia
- high susceptibility to infection, especially of the genitourinary tract.
Pernicious anemia may also have gastrointestinal, neurologic, and cardiovascular effects.
Gastrointestinal symptoms include:
- nausea, vomiting, anorexia, weight loss, flatulence, diarrhea, and constipation from disturbed digestion due to gastric mucosal atrophy and decreased hydrochloric acid production
- gingival bleeding and tongue inflammation (may hinder eating and intensify anorexia).
- neuritis; weakness in extremities
- peripheral numbness and paresthesia
- disturbed position sense
- lack of coordination; ataxia; impaired fine finger movement
- positive Babinski and Romberg signs
- light-headedness
- altered vision (diplopia, blurred vision), taste, and hearing (tinnitus); optic muscle atrophy
- loss of bowel and bladder control; and, in males, impotence, due to demyelination (initially affects peripheral nerves but gradually extends to the spinal cord) caused by vitamin B 12 deficiency
- irritability, poor memory, headache, depression, and delirium (some symptoms are temporary, but irreversible central nervous system [CNS] changes may have occurred before treatment).
Cardiovascular symptoms include:
- low hemoglobin levels due to widespread destruction of RBCs caused by increasingly fragile cell membranes
- palpitations, wide pulse pressure, dyspnea, orthopnea, tachycardia, premature beats, and, eventually, heart failure due to compensatory increased cardiac output.
Possible complications include:
- hypokalemia (first week of treatment)
- permanent CNS symptoms (if the patient is not treated within 6 months of appearance of symptoms)
- gastric polyps
- stomach cancer.
Laboratory screening must rule out other anemias with similar symptoms but different treatments, such as:
- folic acid deficiency anemia
- vitamin B 12 deficiency resulting from malabsorption due to GI disorders, gastric surgery, radiation, or drug therapy.
Decreased hemoglobin levels by 1 to 2 g/dl in elderly men and slightly decreased hematocrit in both men and women reflect decreased bone marrow and hematopoiesis and, in men, decreased androgen levels; they aren't an indicator of pernicious anemia. Diagnosis of pernicious anemia is established by:
- positive family history
- hemoglobin 4 to 5 g/dl
- low RBC count
- mean corpuscular volume greater than 120 μl due to increased amounts of hemoglobin in larger-than-normal RBCs
- serum vitamin B 12 less than than 0.1 μg/ml
- bone marrow aspiration showing erythroid hyperplasia (crowded red bone marrow), with increased numbers of megaloblasts but few normally developing RBCs
- gastric analysis showing absence of free hydrochloric acid after histamine or pentagastrin injection
- Schilling test for excretion of radiolabeled vitamin B 12 (definitive test for pernicious anemia)
- serologic findings including intrinsic factor antibodies and antiparietal cell antibodies.
Treatment for pernicious anemia is:
- early parenteral vitamin B 12 replacement (can reverse pernicious anemia, minimize complications, and possibly prevent permanent neurologic damage)
- concomitant iron and folic acid replacement to prevent iron deficiency anemia (rapid cell regeneration increases the patient's iron and folate requirements)
- after initial response, decrease vitamin B 12 dosage to monthly self-administered maintenance dose (treatment must be given for life)
- bed rest for extreme fatigue until hemoglobin rises
- blood transfusions for dangerously low hemoglobin
- digoxin (Lanoxin), diuretic, low-sodium diet (if patient is in heart failure)
- antibiotics to combat infections.
Sideroblastic anemias
Sideroblastic anemias are a group of heterogenous disorders with a common defect: they fail to use iron in hemoglobin synthesis, despite the availability of adequate iron stores. These anemias may be hereditary or acquired. The acquired form can be primary or secondary. Hereditary sideroblastic anemia commonly responds to treatment with pyridoxine (vitamin B 6 ). The primary acquired (idiopathic) form, known as refractory anemia with ringed sideroblasts, resists treatment and is usually fatal within 10 years of the onset of complications or a concomitant disease. This form is most common in the elderly. It's commonly associated with thrombocytopenia or leukopenia as part of a myelodysplastic syndrome. Correction of the secondary acquired form depends on the cause.
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RINGED SIDEROBLAST
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Hereditary sideroblastic anemia appears to be transmitted by:
- X-linked inheritance, occurring mostly in young males (female carriers 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 drugs (such as isoniazid [Laniazid] and chloramphenicol [Chloromycetin])
- other diseases, such as rheumatoid arthritis, lupus erythematosus, multiple myeloma, tuberculosis, and severe infections.
In sideroblastic anemia, normoblasts fail to use iron to synthesize hemoglobin. As a result, iron is deposited in the mitochondria of normoblasts, which are then termed ringed sideroblasts. Iron toxicity can cause organ damage; untreated, it can damage the nuclei of RBC precursors.
Possible signs and symptoms of sideroblastic anemia include:
- anorexia, fatigue, weakness, dizziness, pale skin and mucous membranes, and, occasionally, enlarged lymph nodes due to iron toxicity
- dyspnea, exertional angina, slight jaundice, and hepatosplenomegaly due to heart and liver failure caused by excessive iron accumulation in these organs
- increased GI absorption of iron, causing signs of hemosiderosis (hereditary sideroblastic anemia)
- other symptoms depend on the underlying cause (secondary sideroblastic anemia).
- ringed sideroblasts on microscopic examination of bone marrow aspirate stained with Prussian blue or alizarin red dye. (See Ringed sideroblast .)
- hypochromic or normochromic and slightly macrocytic RBCs on microscopic examination; RBC precursors may be megaloblastic, with anisocytosis and poikilocytosis (abnormal variation in shape)
- low hemoglobin with high serum iron, transferrin, urobilinogen, and bilirubin levels due to RBC lysis
- normal platelet and leukocyte counts (occasional thrombocytopenia or leukopenia).
Treatment of sideroblastic anemias depends on the underlying cause and includes:
- several weeks of treatment with high doses of pyridoxine (vitamin B 6 )for hereditary form
- removal of the causative drug or toxin or treatment of the underlying condition (symptoms usually subside in acquired secondary form)
- folic acid supplements (may be beneficial when concomitant megaloblastic nuclear changes in RBC precursors are present)
- deferoxamine (Desferal) to treat chronic iron overload as needed
- blood transfusions (providing hemoglobin) or high doses of androgens (effective palliative measures for some patients with primary acquired form)
- phlebotomy to prevent hemochromatosis (the accumulation of iron in body tissues) increases the rate of erythropoiesis and uses up excess iron stores, reducing serum and total-body iron levels.
Thalassemia
Thalassemia, a hereditary group of hemolytic anemias, is characterized by defective synthesis in the polypeptide chains of the protein component of hemoglobin. Consequently, RBC synthesis is also impaired.
In b -thalassemia, the most common form of this disorder, synthesis of the beta polypeptide chain is defective. It occurs in three clinical forms: major, intermedia, and minor. The severity of the resulting anemia depends on whether the patient is homozygous or heterozygous for the thalassemic trait. The prognosis varies:
- thalassemia major: patients seldom survive to adulthood
- thalassemia intermedia: children develop normally into adulthood, although puberty is usually delayed
- thalassemia minor: normal life span.
- homozygous inheritance of the partially dominant autosomal gene (thalassemia major or thalassemia intermedia)
- heterozygous inheritance of the same gene (thalassemia minor).
Total or partial deficiency of beta polypeptide chain production impairs hemoglobin synthesis and results in continual production of fetal hemoglobin, lasting even past the neonatal period. Normally, immunoglobulin synthesis switches from gamma- to beta-polypeptides at the time of birth. This conversion doesn't happen in thalassemic infants. Their red cells are hypochromic and microcytic.
Possible signs and symptoms of thalassemia major (also known as Cooley's anemia, Mediterranean disease, and erythroblastic anemia) are:
- healthy infant at birth, during second 6 months if life develops severe anemia, bone abnormalities, failure to thrive, and life-threatening complications
- pallor and yellow skin and sclera in 3- to 6-month-old infants
- splenomegaly or hepatomegaly, with abdominal enlargement; frequent infections; bleeding tendencies (especially nose bleeds); anorexia
- small body, large head (characteristic features), and possible mental retardation
- possible features similar to Down syndrome in infants, due to thickened bone at the base of the nose from bone marrow hyperactivity.
Signs and symptoms of thalassemia intermedia are:
- some degree of anemia, jaundice, and splenomegaly
- possibly signs of hemosiderosis due to increased intestinal absorption of iron.
Signs of thalassemia minor are:
- mild anemia (usually produces no symptoms and is often overlooked; it should be differentiated from iron deficiency anemia).
Possible complications of thalassemia include:
- pathologic fractures due to expansion of the marrow cavities with thinning of the long bones
- cardiac arrhythmias
- heart failure.
Diagnosis of thalassemia major includes:
- low RBC and hemoglobin, microcytosis, and high reticulocyte count
- elevated bilirubin and urinary and fecal urobilinogen levels
- low serum folate reflects increased folate use by hypertrophied bone marrow
- peripheral blood smear showing target cells, microcytes, pale nucleated RBCs, and marked anisocytosis
- thinning and widening of the marrow space on skull and long bone X-rays due to overactive bone marrow
- granular appearance of bones of skull and vertebrae, areas of osteoporosis in long bones, deformed (rectangular or biconvex) phalanges
- significantly increased fetal hemoglobin and slightly increased hemoglobin A 2 quantitative hemoglobin studies
- excluding iron deficiency anemia (also produces hypochromic microcytic RBCs).
Diagnosis of thalassemia intermedia includes:
Diagnosis of thalassemia minor includes:
- hypochromic microcytic RBCs
- significantly increased hemoglobin A 2 and moderately increased fetal hemoglobin on quantitative hemoglobin studies.
Treatment of thalassemia major is essentially supportive and includes:
- prompt treatment with appropriate antibiotics for infections
- folic acid supplements to help maintain folic acid levels despite increased requirements
- transfusions of packed RBCs to increase hemoglobin levels (used judiciously to minimize iron overload)
- splenectomy and bone marrow transplantation (effectiveness has not been confirmed)
- no treatment for thalassemia intermedia and thalassemia minor
- no iron supplements (contraindicated in all forms of thalassemia).
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) occurs as a complication of diseases and conditions that accelerate clotting, causing small blood vessel occlusion, organ necrosis, depletion of circulating clotting factors and platelets, activation of the fibrinolytic system, and consequent severe hemorrhage. Clotting in the microcirculation usually affects the kidneys and extremities but may occur in the brain, lungs, pituitary and adrenal glands, and GI mucosa. DIC, also called consumption coagulopathy or defibrination syndrome, is generally an acute condition but may be chronic in cancer patients. Prognosis depends on early detection and treatment, the severity of the hemorrhage, and treatment of the underlying disease.
- infection, including gram-negative or gram-positive septicemia and viral, fungal, rickettsial, or protozoal infection
- obstetric complications, including abruption placentae, amniotic fluid embolism, retained dead fetus, septic abortion, eclampsia
- neoplastic disease, including acute leukemia, metastatic carcinoma, aplastic anemia
- disorders that produce necrosis, including extensive burns and trauma, brain tissue destruction, transplant rejection, hepatic necrosis
- other conditions, including heatstroke, shock, poisonous snakebite, cirrhosis, fat embolism, incompatible blood transfusion, cardiac arrest, surgery requiring cardiopulmonary bypass, giant hemangioma, severe venous thrombosis, and purpura fulminans.
It isn't clear why certain disorders lead to DIC or whether they use a common mechanism. In many patients, the triggering mechanisms may be the entrance of foreign protein into the circulation and vascular endothelial injury.
Regardless of how DIC begins, the typical accelerated clotting results in generalized activation of prothrombin and a consequent excess of thrombin. The thrombin converts fibrinogen to fibrin, producing fibrin clots in the microcirculation. This process uses huge amounts of coagulation factors (especially fibrinogen, prothrombin, platelets, and factors V and VIII), causing hypofibrinogenemia, hypoprothrombinemia, thrombocytopenia, and deficiencies in factors V and VIII. Circulating thrombin also activates the fibrinolytic system, which dissolves fibrin clots into fibrin degradation products. Hemorrhage may be mostly the result of the anticoagulant activity of fibrin degradation products as well as depletion of plasma coagulation factors.
Signs and symptoms of DIC caused by the anticoagulant activity of fibrin degradation products and depletion of plasma coagulation factors include:
- abnormal bleeding
- cutaneous oozing of serum
- petechiae or blood blisters
- bleeding from surgical or IV sites
- bleeding from the GI tract
- epistaxis
- hemoptysis.
- cyanotic, cold, mottled fingers and toes, due to fibrin clots in the microcirculation resulting in tissue ischemia
- severe muscle, back, abdominal, and chest pain from tissue hypoxia
- nausea and vomiting (may be a manifestation of GI bleeding)
- shock due to hemorrhage
- confusion, possibly due to cerebral thrombus and decreased cerebral perfusion
- dyspnea due to poor tissue perfusion and oxygenation
- oliguria due to decreased renal perfusion.
- decreased platelet count, usually less than 100,00/μl, because platelets are consumed during thrombosis
- fibrinogen less than150 mg/dl because fibrinogen is consumed in clot formation (levels may be normal if elevated by hepatitis or pregnancy)
- prothrombin time greater than15 seconds
- partial thromboplastin time greater than 60 seconds
- increased fibrin degradation products, often greater than 45 mcg/ml, due to excess fibrinolysis by plasmin
- D-dimer test (presence of an asymmetrical carbon compound fragment formed in the presence of fibrin split products) positive at less than 1:8 dilution
- positive fibrin monomers, diminished levels of factors V and VIII, fragmentation of RBCs, and hemoglobin less than 10 g/dl
- reduced urine output (less than 30 ml/hour), elevated blood urea nitrogen (greater than 25 mg/dl), and elevated serum creatinine (greater than 1.3mg/dl).
- blood, fresh frozen plasma, platelet, or packed RBC transfusions to support hemostasis in active bleeding
- heparin in early stages to prevent microclotting and as a last resort in hemorrhage (controversial in acute DIC after sepsis). (See Understanding DIC and its treatment .)
Erythroblastosis fetalis
Erythroblastosis fetalis, a hemolytic disease of the fetus and newborn, stems from an incompatibility of fetal and maternal blood; that is, mother and fetus have different ABO blood types or the fetus is Rh positive and the mother is Rh negative. The mother's immune system generates antibodies against fetal red cells.
The effects of hemolytic disease are more severe in Rh incompatibility than ABO incompatibility. ABO incompatibility may resolve after birth without life-threatening complications. ABO incompatibility occurs in about 25% of all pregnancies, but only 1 in 10 cases results in hemolytic disease. Rh incompatibility occurs in less than 10% of pregnancies and rarely causes hemolytic disease in the first pregnancy.
In severe, untreated erythroblastosis fetalis, the prognosis is poor, especially if brain and spinal cord become infiltrated with bilirubin (kernicterus). About 70% of these infants die, usually within the first week of life; survivors inevitably have severe neurologic damage, including sensory impairment, mental deficiencies, and cerebral palsy. Most fetuses with hydrops fetalis (the most severe form of this disorder, associated with profound anemia and edema) are stillborn; the few who are delivered alive rarely survive longer than a few hours.
Erythroblastosis fetalis is caused by:
The pathophysiologies of ABO and Rh incompatibility are different.
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UNDERSTANDING DIC AND ITS TREATMENT
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WHAT HAPPENS IN RH ISOIMMUNIZATION
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Signs and symptoms of erythroblastosis fetalis include:
- jaundice due to large amounts of unconjugated bilirubin released by hemolysis
- anemia due to hemolysis
- hepatosplenomegaly.
Complications of erythroblastosis fetalis include:
Diagnosis considers both prenatal and neonatal findings. Prenatal findings include:
- maternal history (for erythroblastotic stillbirths, abortions, previously affected children, previous anti-Rh titers)
- blood typing and screening (should be done frequently to determine changes in the degree of maternal immunization)
- paternal blood typing for ABO and Rh
- history of blood transfusion
- amniotic fluid analysis showing increased bilirubin and anti-Rh titers
- radiologic studies showing edema and, in hydrops fetalis, the halo sign (edematous, elevated, subcutaneous fat layers) and the Buddha position (fetus's legs are crossed).
Neonatal findings indicating erythroblastosis fetalis include:
- direct Coombs' test of umbilical cord blood to measure RBC (Rh-positive) antibodies in the newborn (positive only when the mother is Rh negative and the fetus is Rh positive)
- cord hemoglobin level less than 10 g, indicating severe disease
- many nucleated peripheral RBCs.
Treatment depends on the degree of maternal sensitization and the effects of hemolytic disease on the fetus or newborn. It may include:
- intrauterine-intraperitoneal transfusion (if amniotic fluid analysis suggests the fetus is severely affected and is not mature enough to deliver)
- planned delivery (usually 2 to 4 weeks before term date, depending on maternal history, serologic test results, and amniocentesis)
- exchange transfusion to remove antibody-coated RBCs and prevent hyperbilirubinemia by replacing the infant's blood with fresh group O, Rh-negative blood
- albumin infusion to bind bilirubin
- phototherapy (exposure to ultraviolet light to reduce bilirubin levels)
- gamma globulin containing anti-Rh antibody (Rh o [D]) to prevent Rh isoimmunization in Rh-negative females (ineffective if a previous pregnancy, abortion, or transfusion has already sensitized the mother).
Neonatal therapy for hydrops fetalis includes:
- intubation to maintain ventilation
- removal of excess fluid to relieve ascites and respiratory distress
- exchange transfusion
- maintaining body temperature.
Idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura (ITP) is a deficiency of platelets that occurs when the immune system destroys the body's own platelets. ITP may be acute, as in postviral thrombocytopenia, or chronic, as in essential thrombocytopenia or autoimmune thrombocytopenia.
| AGE ALERT Acute ITP usually affects children between the ages of 2 and 6 years; chronic ITP mainly affects adults younger than age 50, especially women between the ages of 20 and 40. |
The prognosis for acute ITP is excellent; nearly four of five patients recover without treatment. The prognosis for chronic ITP is good; remissions lasting weeks or years are common, especially among women.
ITP occurs when circulating immunoglobulin G (IgG) molecules react with host platelets, which are then destroyed in the spleen and, to a lesser degree, in the liver. Normally, the life span of platelets in circulation is 7 to 10 days. In ITP, platelets survive 1 to 3 days or less.
Signs and symptoms of ITP are caused by decreased levels of platelets and may include:
- nose bleeds
- oral bleeding
- hemorrhages into the skin, mucous membranes, and other tissues causing red discoloration of skin (purpura)
- small purplish hemorrhagic spots on skin (petechiae)
- excessive menstrual bleeding.
Possible complications of ITP are:
- platelet count less than 20,000 μl
- prolonged bleeding time
- abnormal size and appearance of platelets
- decreased hemoglobin level (if bleeding occurred)
- bone marrow studies showing abundant megakaryocytes (platelet precursor cells) and a circulating platelet survival time of only several hours to a few days
- humoral tests that measure platelet-associated IgG (may help establish the diagnosis; half the patients have elevated IgG).
Treatment for acute ITP includes:
- glucocorticoids to prevent further platelet destruction
- immunoglobulin to prevent platelet destruction
- plasmapheresis
- platelet pheresis.
Treatment for chronic ITP includes:
- corticosteroids to suppress phagocytic activity and enhance platelet production
- splenectomy (when splenomegaly accompanies the initial thrombocytopenia)
- blood and blood component transfusions and vitamin K to correct anemia and coagulation defects.
Alternative treatments include:
- immunosuppressants to help stop platelet destruction
- high-dose I.V. immunoglobulin
- immunoabsorption apheresis using staphylococcal protein-A columns.
Polycythemia vera
Polycythemia vera is a chronic disorder characterized by increased RBC mass, erythrocytosis, leukocytosis, thrombocytosis, and increased hemoglobin level, with normal or increased plasma volume. This disease is also known as primary polycythemia, erythremia, polycythemia rubra vera, splenomegalic polycythemia, or Vaquez-Osler disease. It usually occurs between the ages of 40 and 60, most commonly among Jewish males of European ancestry. It seldom affects children and doesn't appear to be familial.
The prognosis depends on age at diagnosis, the type of treatment used, and complications. Mortality is high if polycythemia is untreated, associated with leukemia, or associated with myeloid metaplasia (presence of marrow-like tissue and ectopic hematopoiesis in extramedullary sites, such as liver and spleen, and nucleated erythrocytes in blood).
The cause of polycythemia vera is unknown, but is probably related to:
In polycythemia vera, uncontrolled and rapid cellular reproduction and maturation cause proliferation or hyperplasia of all bone marrow cells (panmyelosis).
Increased RBC mass makes the blood abnormally viscous and inhibits blood flow to microcirculation. Diminished blood flow and thrombocytosis set the stage for intravascular thrombosis.
Possible signs and symptoms of polycythemia vera include:
- feeling of fullness in the head or headache due to altered hypervolemia and hyperviscosity
- dizziness due to hypervolemia and hyperviscosity
- ruddy cyanosis (plethora) of the nose and clubbing of the digits due to thrombosis in smaller vessels
- painful pruritus due to abnormally high concentrations of mast cells in the skin and their release of heparin and histamine.
Possible complications include:
The following test results help diagnose polycythemia vera:
- increased RBC mass
- normal arterial oxygen saturation in association with splenomegaly
- increased uric acid
- increased blood histamine
- decreased serum iron
- decreased or absent urinary erythropoietin
- bone marrow biopsy showing excess production of myeloid stem cells.
- phlebotomy to reduce RBC mass
- myelosuppressive therapy with radioactive phosphorus to suppress erythropoiesis (may increase the risk for leukemia).
Secondary polycythemia
Secondary polycythemia, also called reactive polycythemia, is excessive production of circulating RBCs due to hypoxia, tumor, or disease. It occurs in approximately 2 of every 100,000 people living at or near sea level; the incidence increases among those living at high altitudes.
Secondary polycythemia may be caused by:
Secondary polycythemia may result from increased production of the hormone erythropoietin ― which stimulates bone marrow to produce RBCs ― in a compensatory response to several conditions. These include hypoxemia caused by such conditions as chronic obstructive pulmonary disease, hemoglobin abnormalities (such as carboxyhemoglobinemia in heavy smokers), heart failure (causing a decreased ventilation-perfusion ratio), right-to-left shunting of blood in the heart (as in transposition of the great vessels), central or peripheral alveolar hypoventilation (as in barbiturate intoxication), and low oxygen content at high altitudes.
Increased production of erythropoietin may also be an inappropriate (pathologic) response to renal, central nervous system, or endocrine disorders or to certain neoplasms (such as renal tumors, uterine myoma, or cerebellar hemangiomas).
Possible signs and symptoms are:
- ruddy cyanotic skin, emphysema, and hypoxemia without hepatomegaly or hypertension (in the hypoxic patient)
- clubbing of the fingers (when the underlying cause is cardiovascular).
Diagnosis of secondary polycythemia is based on the following test results:
- high hematocrit and hemoglobin
- high mean corpuscular volume and mean corpuscular hemoglobin
- high urinary erythropoietin
- high blood histamine
- normal or low arterial oxygen saturation
- bone marrow biopsy showing hyperplasia or erythroid precursors.
The goal of treatment is to correct the underlying disease or environmental condition, and may include:
- phlebotomy or pheresis to reduce blood volume (to correct hazardous hyperviscosity or if the patient doesn't respond to treatment of the primary disease)
- continuous low-flow oxygen therapy to correct severe hypoxia.
Spurious polycythemia
Spurious polycythemia is characterized by an increased hematocrit and a normal or low RBC total mass. It results from diminished plasma volume and subsequent hemoconcentration. It is also known as relative polycythemia, stress erythrocytosis, stress polycythemia, benign polycythemia, Gaisb?ck's syndrome, or pseudopolycythemia. It usually affects middle-aged people and is more common in men than in women.
Causes of spurious polycythemia include:
- dehydration
- hemoconcentration due to stress
- high-normal RBC mass and low-normal plasma volume
- hypertension
- thromboembolic disease
- elevated serum cholesterol and uric acid
- familial tendency.
Conditions that promote severe fluid loss decrease plasma volume and lead to hemoconcentration. Such conditions include persistent vomiting or diarrhea, burns, adrenocortical insufficiency, aggressive diuretic therapy, decreased fluid intake, diabetic acidosis, and renal disease.
Nervous stress causes hemoconcentration by some unknown mechanism. This form of erythrocytosis (chronically elevated hematocrit) is particularly common in the middle-aged man who is a chronic smoker and has a type A personality (tense, hard driving, and anxious).
In many patients, an increased hematocrit merely reflects a normally high RBC mass and low plasma volume. This is particularly common in patients who don't smoke, aren't obese, and have no history of hypertension.
Signs and symptoms of spurious polycythemia may include:
- headaches or dizziness due to altered circulation secondary to hypervolemia and hyperviscosity
- ruddy appearance caused by cyanosis
- slight hypertension from increased blood volume
- tendency to hyperventilate when recumbent
- cardiac or pulmonary disease.
The following test results help diagnose spurious polycythemia:
- high hemoglobin and hematocrit
- high RBC count
- normal RBC mass
- normal arterial oxygen saturation
- normal bone marrow
- low or normal plasma volume
- possibly hyperlipidemia
- possibly uricosuria.
- appropriate fluids and electrolytes to correct dehydration
- measures to prevent further fluid loss, such as antidiarrheals if needed, avoiding dietary diuretics (e.g., caffeine), preventing excessive perspiration, remaining hydrated.
Thrombocytopenia
Thrombocytopenia, the most common cause of hemorrhagic disorders, is a deficiency of circulating platelets. It may be congenital or acquired; the acquired form is more common. Because platelets are needed for coagulation, this disease poses a serious threat to hemostasis. The prognosis is excellent in drug-induced thrombocytopenia if the offending drug ― usually carbamazepine (Tegretol) or heparin ― is withdrawn; in such cases, recovery may be immediate. In other types, the prognosis depends on the patient's response to treatment of the underlying cause.
Possible causes of thrombocytopenia include:
- decreased or defective platelet production in the bone marrow (as in leukemia, aplastic anemia, or drug toxicity)
- increased platelet destruction outside the marrow due to an underlying disorder (such as cirrhosis of the liver, disseminated intravascular coagulation, or severe infection)
- sequestration (increased amount of blood in a limited vascular area, such as the spleen)
- blood loss.
In thrombocytopenia, lack of platelets can cause inadequate hemostasis. Four mechanisms are responsible: decreased platelet production, decreased platelet survival, pooling of blood in the spleen, and intravascular dilution of circulating platelets. Megakaryocytes, giant cells in the bone marrow, produce platelets. Platelet production decreases when the number of megakaryocytes is reduced or when platelet production becomes dysfunctional. (See What happens in thrombocytopenia .)
Possible signs and symptoms of thrombocytopenia are:
- petechiae or blood blisters caused by bleeding into the skin
- bleeding into the mucous membrane
- malaise, fatigue, and general weakness
- large blood-filled blisters in the mouth (in adults).
The following tests help diagnose thrombocytopenia:
- platelet count usually less than 100,000/μl in adults
- prolonged bleeding time
- platelet antibody studies to help determine why the platelet count is low (also used to select treatment)
- platelet survival studies to help differentiate between ineffective platelet production and platelet destruction as causes of thrombocytopenia
- bone marrow studies to determine the number, size, and maturity of megakaryocytes in severe disease, helping identify ineffective platelet production as the cause and ruling out malignant disease.
Treatment of thrombocytopenia may include:
- withdrawing the offending drug or treating the underlying cause
- corticosteroids to increase platelet production
- lithium carbonate (Eskalith) or folate to stimulate bone marrow production
- I.V. gamma globulin (experimental use for severe or refractory thrombocytopenia)
- platelet transfusion to stop episodic abnormal bleeding due to low platelet count
- splenectomy to correct disease caused by platelet destruction (because the spleen is the primary site of platelet removal and antibody production).
Von Willebrand's disease
Von Willebrand's disease is a hereditary bleeding disorder, occurring more often in females and characterized by prolonged bleeding time, moderate deficiency of clotting factor VIII (antihemophilic factor), and impaired platelet function. This disease commonly causes bleeding from the skin or mucosal surfaces and, in females, excessive uterine bleeding. Bleeding may range from mild and asymptomatic to severe, potentially fatal, hemorrhage. The prognosis is usually good.
Von Willebrand's disease is caused by:
Recently, an acquired form has been identified in patients with cancer and immune disorders.
A possible mechanism is that mild to moderate deficiency of factor VIII and defective platelet adhesion prolong coagulation time. Specifically, this results from a deficiency of von Willebrand's factor (VWF), which stabilizes the factor VIII molecule and is needed for proper platelet function.
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WHAT HAPPENS IN THROMBOCYTOPENIA
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Defective platelet function is characterized in vivo by decreased agglutination and adhesion at the bleeding site and in vitro by reduced platelet retention when blood is filtered through a column of packed glass beads, and diminished ristocetin-induced platelet aggregation.
Prolonged coagulation time may cause:
- easy bruising
- epistaxis (nose bleed)
- bleeding from the gums
- petechiae (rarely)
- hemorrhage after laceration or surgery (in severe forms)
- menorrhagia (in severe forms)
- GI bleeding (in severe forms)
- excessive postpartum bleeding (uncommon)
- massive soft tissue hemorrhage and bleeding into joints (rare).
A complication of von Willebrand's disease is:
The following test results help diagnose von Willebrand's disease:
- prolonged bleeding time (greater than 6 minutes)
- slightly prolonged partial thromboplastin time (greater than 45 seconds)
- absent or low factor VIII
- absent or low factor VIII-related antigens
- low factor VIII activity
- ristocetin coagulation factor assay showing defective in vitro platelet aggregation
- normal platelet count and clot retraction.
