DISEASES OF HEMATOLYMPHOID SYSTEM

Manar hajeer, MD

RED CELL DISORDERS

Anemia is a reduction in the oxygen-transporting capacity of blood, which usually stems from a reduction of the total circulating red cell mass to below-normal amounts.

Anemia can result from excessive bleeding, increased red cell destruction, or decreased red cell production.

BLOOD LOSS (HEMORRHAGE):

Acute: trauma Chronic: lesions of gastrointestinal tract,

gynecologic disturbances.

INCREASED DESTRUCTION (HEMOLYTIC ANEMIAS)

Intrinsic (intracorpuscular) abnormalities   Hereditary   Membrane abnormlities   spherocytosis.  Enzyme deficiencies : glucose-6-phosphate

dehydrogenase.   Disorders of hemoglobin synthesis       Deficient globin synthesis: thalassemia syndromes       Structurally abnormal globin synthesis

(hemoglobinopathies): sickle cell anemia,  

Extrinsic (extracorpuscular)   Antibody mediated   Mechanical trauma to red cells  Infections: malaria

IMPAIRED RED CELL PRODUCTION

Disturbance of proliferation and differentiation of stem cells: aplastic anemia, pure red cell aplasia, anemia of renal failure,

Disturbance of proliferation and maturation of erythroblasts

  Defective DNA synthesis: deficiency or impaired utilization of vitamin B12 and folic acid (megaloblastic anemias)

 Defective hemoglobin synthesis     Deficient heme synthesis: iron deficiency     Deficient globin synthesis: thalassemias     Anemia of renal failure

1. ANEMIA OF BLOOD LOSS(HEMORRHAGE)

With acute blood loss, the immediate threat to

the patient is hypovolemia (shock) rather than anemia.

- Is characterized by normocytic and normochromic RBCs- Recovery from acute blood loss anemia is enhanced by a rise

in the erythropoeitin levels, which stimulates increased red cell production within several days.

- With chronic blood loss, iron stores are gradually depleted and the result is iron defficiency anemia.

2. THE HEMOLYTIC ANEMIAS

- Are associated with accelerated destruction of red cells - Normal life span of RBCs is 120 days.- Destruction can be:a. Intrinsic inherited red cell defects., b. External acquired factors.

General features of all hemolytic anemias 1. Increase in erythropoiesis and reticulocytosis. 2. Retention of iron .3. In severe cases, extramedullary hematopoesis often develop in

spleen, liver, and lymph nodes.

Intravascular versus extravascular hemolysis.

INTRAVASCULAR HEMOLYSIS

Causes of intravascular hemolysis :1. Trauma (defective heart valve) 2. Biochemical or physical agents that damage the red cell

membranes

Intravascular hemolysis leads to:a. Hemoglobinemia & Hemoglobinuria.b. Hemosiderinuria .c. Conversion of the heme pigment to bilirubin can result in

jaundice. d. Renal acute tubular necrosis.

EXTRAVASCULAR HEMOLYSIS- Is more common than intravascular and takes place

within the macrophages of the spleen and liver.- Because extreme alterations of shape are necessary for

red cells to successfully navigate the splenic sinusoids, any reduction in red cell deformability makes this passage difficult and leads to splenic sequestration, followed by phagocytosis.

Extravascular hemolysis :a. No hemoglobinemia or hemoglobinuria .b. Produces jaundice and pigmented gallstones. c. There is splenomegaly .d. In chronic forms, iron accumulates, giving rise to

systemic hemosiderosis .

I. HEREDITATORY SPHEROCYTOSIS (HS)

Characterized by an inherited (Intrinsic) defect in red cell membrane that makes the cell spheroidal, less deformable, and vulnerable to splenic destruction.

Because of limited deformability, spherocytes are destroyed by macrophages of spleen and the role of the spleen is illustrated by the beneficial effect of splenectomy and although the spherocytes persist, the anemia is corrected .

The characteristic clinical features are anemia, splenomegaly and jaundice .

II. SICKLE CELL ANEMIAS The hemoglobinopathies are a group of

hereditary disorders that are defined by the presence of structurally abnormal hemoglobins.

The most common hemoglobinopathy is caused by mutation in the B-globin chain gene that creates sickle hemoglobin (HbS)

Upon deoxygenation , HbS molecules undergo polymerization, and these polymers distort the red cell, which assumes a crescentic , or sickle in shape .

- Sickling of red cells is initially reversible upon reoxygenation. However, membrane damage occurs with each episode of sickling, and eventually the cells become irreversibly sickled .

VARIABLES INFLUENCE SICKLING OF RED CELLS

a. The presence of hemoglobins other than HbS. The presence of HbA and HbF slows the rate of polymerization greatly. That’s why sickle cell disease usually becomes apparent after the sixth month of life.

b. The concentration of HbS in the cell. red cell dehydration, which increases the Hb concentration, greatly facilitates sickling and can trigger occlusion of small blood vessels

c. The length of time that red cells are exposed to low oxygen tension. sickling is confined to microvascular beds where blood flow is sluggish. This is normally the case in the spleen and the bone marrow, which are prominently affected by sickle cell disease.

d. Inflammation and infection causes slowing of blood flow and this enhance significant sickling.

TWO MAJOR CONSEQUENCES STEM FROM THE SICKLING OF RED CELLS

1. repeated episodes of deoxygenation cause membrane damage and dehydration of red cells, which become rigid and irreversibly sickled. producing a chronic extravascular hemolytic anemia. Overall, the mean life span of red cells in sickle cell anemia patients averages only 20 days.

2. widespread microvascular obstructions, which result in ischemic tissue damage and pain crises. appears to result from factors, such as infection, inflammation, dehydration, and acidosis.

CLINICAL FEATURES:

1- Severe chronic hemolytic anemia

2- Increased breakdown of heme pigments, which are processed into bilirubin with resultant jaundice

3- Microvascular obstruction, which provokes tissue ischemia and infarction and can affect any organ.

4- extramedullary hematopoesis

5- prominent cheekbones and changes in the skull .

6- splenomegaly and autosplenectomy.

7- hemosiderosis and gallstones are common.

COMPLICATIONS

1- acute chest syndrome, which can be triggered by pulmonary infections or fat emboli from necrotic marrow that secondarily involve the lung.

2- central nervous system stroke,3- Vaso-occlusive or pain crises, affects the bone marrow.2. The aplastic crisis is a sudden but temporary cessation

of erythropoiesis, triggered by parvovirus B19 infection of erythroblasts.

III. THALASSEMIAS A group of inherited disorders caused by mutations that

decrease the rate of synthesis of alpha or beta -globin chains and as a consequence there is a deficiency of hemoglobin, with secondary red cell abnormalities caused by relative excess of the other unaffected globin chain.

Adult hemoglobin, or HbA, is a tetramer composed of two α chains and two β chains

B-THALASSEMIA:

types of mutationsa. B0 : no B-globin chains are producedb. B+: reduced but detectable B-globin synthesis:

• Thalassemia major: both chains mutated.• Thalassemia minor or thalassemia trait, only one

mutation, which is asymptomatic microcytic anemia or mild microcytosis without anemia .

Unpaired alpha chains form aggregates that precipitate

within the red cells , causing severe membrane damage to provoke extravascular hemolysis .

Microcytic hypochromic anemia.

Clinical course: B-thalassemia major manifests itself postnatally as HbF

synthesis is decreased and affected children fail to develop normally, with growth retardation shortly after birth.

Skeletal deformities, splenomegaly, hepatomegaly, cachexia.

- They are sustained only by repeated blood transfusions, which improve the anemia and reduce the skeletal deformities

- With transfusion alone survival into the-- second or third decade is possible.

- Hemochromatosis results from iron overload from transfused red cells and unless the patients are treated with iron chelators , cardiac failure causes death in the second or third decade of life

IV. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

The red cells are vulnerable to injury by oxidants and free radicals, which are normally inactivated by the reduced form of glutathione (GSH)

Abnormalities affecting the enzymes required for GSH production reduce the ability of red cells to be protected from oxidative injury, lead to hemolytic anemias.

Regeneration of GSH is impaired in G6PD-deficient cells

o It is an x-linked recessive disorder.o Intravascular and extravascular hemolysis.

o It produces no symptoms until the patient is exposed to an environmental factor mostly infections and drugs (antimalarial primaquine and sulfonamides), that results in oxidant stress.

o Also might be triggered by oxidants in certain foods like Fava beans.

3-ANEMIAS OF DIMINISHED ERYTHROPOIESIS

A- Iron Deficiency Anemia:Is the most common form of anemia of nutritional

deficiency. Normally, serum iron levels is 120 μg/dL in men and 100

μg/dL in women. Causes:1. In non developed countries, low intake and vegetarian

diets are an important cause of iron deficiency2. Malabsorption such as celiac disease.3. Increased demands during pregnancy and infancy. 4. Chronic blood loss is the most important cause of iron

deficiency anemia in the western world and it may occur from , peptic ulcers, intestinal ulcers, colonic cancer, hemorrhoids) or the female genital tract (e.g., menstruation, cancers).

CLINICAL COURSE

a. In most instances ,it is asymptomatic. b. Nonspecific manifestations, such as weakness,

listlessness, and pallor,c. With severe anemia, flattening, and "spooning" of the

fingernails appears.d. A curious neuro-behavioral complication is pica, the

tendency to consume non-foodstuffs such as dirt or clay.e. Anemia is microcytic hypochromic. impaired work and cognitive performance No extramedullary hematopoesis.

B- Folate (Folic Acid) Deficiency AnemiaMegaloblastic anemia secondary to folate deficiency is not

common .The risk of clinically significant folate deficiency is high

with poor diet or increased needs (pregnant women).

Folate is widely prevalent in nearly all foods but is readily destroyed by 10 to 15 minutes of cooking. so the best sources of are fresh uncooked vegetables and fruits.

Causes of folate deficiency anemia:a. Decreased absorption by acidic foods and substances found

in beans b. Phenytoin (Dilantin) inhibit absorption and methotrexate inhibit

metabolism.c. The site of intestinal absorption is the small intestine; thus,

malabsorptive disorders such as celiac disease and tropical sprue, can impair folate uptake .

Clinical features:- Weakness and easy fatigability. - sore tongue and cheilosis- It should be stressed that, unlike in vitamin B12 deficiency,

neurologic abnormalities do not occur

C . Vitamin B12 Deficiency:

long-standing malabsorption is the most common and important cause.

- Vitamin B12 is abundant in all animal foods, including eggs and dairy products, and is resistant to cooking and boiling..

- As a result, deficiencies due to diet are rare and are virtually confined to strict vegeterians because vit B12 is stored in the liver, which normally contains reserves that are sufficient to support bodily needs for 5 to 20 years.

Until proved otherwise, a deficiency of vitamin B12 (in the western world) is caused by pernicious anemia and this disease seems to stem from an autoimmune reaction against parietal cells and intrinsic factor itself, which produces gastric mucosal atrophy .

Chronic vitamin B12 malabsorption is seen following gastrectomy or resection of ileum and in disorders that involve the distal ileum (Crohn disease)

Clinical Features 1. Pallor, easy fatigability, and, in severe cases, dyspnea and

heart failure. 2. The principal neurologic lesions associated with vitamin B12

deficiency are symmetric numbness, tingling, and burning in feet or hands, followed by unsteadiness of gait .

Although the anemia responds dramatically to parenteral vitamin

B12, the neurologic manifestations often fail to resolve

Uncommonly, the neurologic disease occurs in the absence of overt anemia

D- APLASTIC ANEMIA

- Characterized by marrow failure and pancytopenia Etiology and Pathogenesis a. In more than ½ of cases, it is idiopathic.b. In the remainder, an exposure to drugs or chemicals, such as

chloramphenicol c. certain viral infections, most often community-acquired viral

hepatitis,

Slowly progressive anemia causes the insidious development of weakness, pallor, and dyspnea.

Thrombocytopenia often presents with petechiae and ecchymoses.

Granulocytopenia may be manifested only by frequent and persistent minor infections or by the sudden onset of chills and fever.

Splenomegaly is characteristically absent.

THROMBOCYTOPENIA :

Thrombocytopenia is characterized by spontaneous bleeding, a prolonged bleeding time, and a normal PT and PTT

- A platelet count of 100000 cells/µL considered to constitute thrombocytopenia

- Platelet count in the range of 20,000 to 50,000 cells/µL are associated with an increased risk of post-traumatic bleeding,

- Spontaneous bleeding becomes evident - when count falls below 20,000 cells/µL

CLINICAL FEATURES:

- Most bleeding tends to occur from superficial blood vessels and produce petechiae or large ecchymosis in the skin, the mucous membranes of gastrointestinal and urinary tracts.

- Larger hemorrhages into the central nervous system are a major hazard in patients with markedly decreased platelet counts

IMMUNE THROMBOCYTOPENIC PURPURA (ITP)

- Called idiopathic thrombocytopenic purpura- It can be Primary or idiopathic (in the absence of any

known risk factors) or Secondary .

- There are two main types of primary ITP1. Chronic primary ITP: A common disorder that tends to

affect adult females between ages of 20 and 40 years2. Acute primary ITP: A self-limited form that is most

commonly seen in children due to viral infections

The spleen is usually normal in size and thus splenic enlargement or lymphadenopathy should lead one to consider other possible diagnoses

The importance of the spleen in this disorder is confirmed by the clinical benefits produced by splenectomy,

- The bone marrow usually contains increased numbers of megakaryocytes, a finding common to all forms of thrombocytopenia caused by accelerated platelet destruction

- A marrow examination is helpful in excluding marrow failure