Hematology pathophysiology

ERYTHROCYTES DISORDERS

ANEMIAS

Introduction
 Any condition in which the number of red blood cells per mm 3, the amount of hemoglobin in
100 ml of blood, and/or the volume of packed red blood cells per 100 ml of blood are less
than normal

Etiological classification
1. Hemolytic anemia; any anemia resulting from an increased rate of erythrocyte destruction
2. Hemorrhagic anemia; anemia resulting directly from loss of blood.
3. Aplastic anemia; anemia characterized by a greatly decreased formation of erythrocytes and
hemoglobin, usually associated with pronounced granulocytopenia and thrombocytopenia, as
a result of hypoplastic or aplastic bone marrow.

Morphological classification
1. Microcytic anemia; suggest altered heme or globin synthesis e.g. iron [Fe] deficiency,
thalassemia and related Hb-synthesis defects, anemia of chronic disease
2. Normocytic anemia; suggests a hypoproliferative or hypoplastic mechanism, hemolysis,
marrow suppression, CRF
3. Macrocytic anemia; (large RBCs i.e. MCV  95fL/cell), which suggest a defect in DNA
synthesis. These anemias are usually caused by defective vitamin B12 or folic acid
metabolism or by an interference with DNA synthesis by chemotherapeutic cytoreductive
drugs. Macrocytic changes are common in myelodysplasia [An abnormality in development of
the spinal cord]

Poikilocytosis
 variation in shape of red cells
 A red blood cell of irregular shape.

Anisocytosis
 variations in red blood cell size
 Considerable variation in the size of cells that are normally uniform

Iron-Deficiency Anemia

 The primary mechanism for Fe deficiency, the most common cause of anemia, must always
be considered to be blood loss
 Fe deficiency may also be caused by increased Fe requirement, diminished Fe
absorption, or both.
 Fe deficiency is likely during the first 2 yr of life if dietary Fe is inadequate for rapid growth.
 Adolescent girls may become Fe deficient from inadequate dietary Fe, increased growth
requirements, and menstruation.
 Other bases for anemia may be decreased Fe absorption after gastrectomy, upper small-
bowel malabsorption syndromes, and occasionally some forms of pica (primarily clay)
 Additional loss by menstruation (mean, 0.5 mg/day), pregnancy (0.5 to 0.8 mg/day),
lactation (0.4 mg/day), and blood loss (from disease, accident, or phlebotomy) readily leads
to Fe deficiency, which occurs in stages, culminating in depletion.

Pernicious anemia

 Also Anemia Caused by Vitamin B12 Deficiency

 Pernicious anemia is a megaloblastic anemia caused by B12 malabsorption.
 In this condition, atrophy of the gastric glands is severe, with loss of parietal cells and an
inability to secrete intrinsic factor, a necessary cofactor in B 12 absorption.
 Several findings point to an immunologic or inherited basis for this disease.
 In pernicious anemia, 90% of patients have antibodies to parietal cells and their components,
including antibodies to intrinsic factor and the proton pump H +, K+-ATPase.
 Vitamin B12 cannot be absorbed in the terminal ileum without intrinsic factor (a secretion of
the parietal cells of the gastric mucosa).
 CAUSES:Atrophic gastric mucosa, Intrinsic factor deficiency, Probable autoimmunity against
gastric parietal cells, Autoimmunity against intrinsic factor

Sickle cell anemia

 Sickle and normal adult hemoglobin differ solely in the substitution of a neutral amino acid
(valine) for an acidic one (glutamic) in the sixth position from the N-terminal end of the -
globin chain
 The amino acid substitution replaces a hydrophilic amino acid with a hydrophobic one, a
change that alters the physical properties of the molecule, making it unstable, susceptible to
oxidation, and predisposed to polymerization upon deoxygenation.
 The filaments and fibers of polymerized deoxyhemoglobin S that form produce a rigid red cell
distorted into the characteristic sickle shape.
 The rigid sickle cell is easily damaged by mechanical stress during its passage through the
vasculature.
 The result is a chronic hemolytic anemia with a rate of red cell destruction two to eight times
normal.
 Because of its decreased deformability, the sickle erythrocyte is susceptible to
entanglement and sequestration wherever blood flow is sluggish.
 Such rigid, misshapen cells also increase blood viscosity and compromise blood flow,
often to the extent of producing local ischemia, thrombosis, vaso-occlusion, and infarction.
 Enhanced adherence of sickle red cells to vascular endothelium is thought to be an important
initiating factor in vaso-occlusive events.
 Laboratory evaluation include examination of the peripheral blood smear; a complete blood
count with red cell indices; reticulocyte count; hemoglobin electrophoresis on cellulose
acetate (pH 8.6) and citrate agar (pH 6.2); hemoglobin solubility testing; and quantitative
determinations of hemoglobins A, S, A2, and F, or other variant hemoglobins.

WHITE BLOOD CELL DISORDERS

NEUTROPHILIA

 Neutrophilia may be defined as an increase in circulating neutrophils to more than 8.0 x

109/L.
 "Physiologic" causes of neutrophilia include stress, physical exercise, and pregnancy.
 The neutrophilia observed with stress reflects elevated blood levels of catecholamines and
glucocorticosteroids.
 neutrophilia is more frequently encountered as a reaction to an underlying disease process
 The three major classes of disorders associated with neutrophilia are (1) infections and
inflammatory diseases; (2) tissue destruction, as in myocardial or pulmonary infarction, major
surgery, or shock; and (3) malignant disease.
 Other miscellaneous causes include hemorrhage, hemolysis, diabetic ketoacidosis, thyroid
storm, eclampsia, or the administration of drugs such as lithium or glucocorticosteroids.
 Bacterial infection is the most common cause of a neutrophilic leukocytosis, but neutrophilia
may also be seen in fungal, viral, and parasitic infections.
NEUTROPENIA

 It is a reduction in the blood neutrophil (granulocyte) count, often leading to increased

susceptibility to bacterial and fungal infections.
 Neutropenia exists when the neutrophil count falls below 1500/L.
 Drugs are one of the most common causes of neutropenia.
 Cytotoxic chemotherapy induces neutropenia because of the high proliferative rate of
neutrophil precursors and the rapid turnover of blood neutrophils.
 Diminished neutrophil production is a frequent and often early feature of megaloblastic
anemias caused by vitamin B12 or folate deficiency, although it is usually accompanied by
macrocytic anemia and sometimes by mild thrombocytopenia.
 Impaired neutrophil production can occur when leukemia, myeloma, lymphoma, or metastatic
solid tumors (e.g. breast, prostate) infiltrate and replace the bone marrow.
 Tumor-induced myelofibrosis may further extenuate neutropenia.
 Neutropenia can also result from bone marrow failure
 Neutropenia is also a prominent feature of myelodysplasia and is accompanied by
megaloblastoid features in the bone marrow
 Splenomegaly of any cause can lead to moderate neutropenia, thrombocytopenia, and
anemia.
 Transient neutropenia often accompanies viral infections (e.g. early-stage infectious
mononucleosis), and sepsis is a particularly serious cause of neutropenia.
 Chronic neutropenia often accompanies HIV infection, the result of impaired production of
neutrophils and accelerated destruction of neutrophils by antibodies
 A variety of bone marrow disorders and nonmarrow conditions may cause neutropenia
 All the causes of aplastic anemia and pancytopenia may cause neutropenia.
 The clinical manifestations of neutropenia result from an increased susceptibility to infection

EOSINOPHILIA

 Eosinophilia is diagnosed when the absolute blood eosinophil count is in excess of 0.5 x
109/L.
 The function of eosinophils is not well understood, but they are known to play a role in host
defense against certain parasitic infestations and also to interact with immune complexes
 The most common cause for mild eosinophilia in hospitalized patients is drug allergy.
 Hypereosinophilic syndromes are associated with the most marked elevations of eosinophil
counts.

BASOPHILIA

 Basophilia is rarely encountered. Its presence may be helpful in diagnosing a primary

myeloproliferative disorder such as chronic myelogenous leukemia, polycythemia vera, or
myelofibrosis.

LYMPHOCYTOSIS

 It is distinguished between absolute and relative lymphocytosis.

 Absolute lymphocytosis may be defined as an increase in blood lymphocytes above 4.0 x
109/L.
 Relative lymphocytosis occurs when there is an increased percentage of circulating
lymphocytes, but the absolute number does not exceed 4.0 x 10 9/L.
 An example of relative lymphocytosis occurs in patients with neutropenia, when the
decreased granulocyte count produces leukopenia and most remaining cells are
lymphocytes.
 The absolute number of lymphocytes, however, remains normal.
 Lymphocytosis has been described in association with certain endocrine disorders, especially
thyrotoxicosis and adrenal insufficiency.
 An absolute lymphocytosis in childhood is associated with acute or chronic viral infections,
pertussis, syphilis, tuberculosis, and hyperthyroidism.

LYMPHOPENIA

 It is a reduction, relative or absolute, in the number of lymphocytes in the circulating blood.

 Lymphopenia may be present in patients with AIDS or lymphangiectasia.

PLATELET DISORDERS

THROMBOCYTOSIS

 Thrombocytosis is defined as a platelet count exceeding 450,000/(micro)L.

 Most thrombocytosis probably results from an increased rate of platelet production.
 Common causes of secondary or reactive thrombocytosis are malignant tumors, iron
deficiency, hemorrhage, inflammatory diseases, and connective-tissue disorders.
 Essential thrombocytosis is a myeloproliferative disorder that accounts for most cases in
which platelet counts exceed 1 million/uL.
 Essential thrombocytosis is an uncommon myeloproliferative disorder of unknown cause in
which marked proliferation of the megakaryocytes in the bone marrow leads to elevation of
the platelet count.

THROMBOCYTOPENIA

 It’s a quantity of platelets below the normal range of 140,000 to 440,000/L.

 Thrombocytopenia may stem from failed platelet production, splenic sequestration of
platelets, increased platelet destruction or use, or dilution of platelets
 These can be broadly divided into three categories on the basis of platelet kinetics.
 Thrombocytopenia may be caused by (1) impaired production of platelets by the bone
marrow, (2) platelet sequestration from splenomegaly, or (3) increased destruction of
platelets in the peripheral circulation that exceeds the approximately eightfold capacity of the
bone marrow to compensate by accelerated production.
 In patients receiving large volumes of rapidly administered platelet-poor blood products,
thrombocytopenia may also develop on a dilutional basis.

IDIOPATHIC THROMBOCYTOPENIC PURPURA

 Is an autoimmune disorder in which an IgG autoantibody is formed that binds to platelets.

 Although the antiplatelet antibody may bind complement, platelets are not destroyed by direct
lysis.
 Rather, destruction takes place in the spleen, where splenic macrophages with Fc receptors
bind to antibody-coated platelets.

THROMBOTIC THROMBOCYTOPENIC PURPURA

 Is an uncommon syndrome with microangiopathic hemolytic anemia, thrombocytopenia, and

a markedly elevated serum LDH.
 Thrombotic microangiopathy is thrombosis within small blood vessels, as in thrombotic
thrombocytopenic purpura.

CONGENITAL QUALITATIVE PLATELET DISORDERS

Introduction
 Bleeding disorders characterized by prolonged bleeding times despite a normal platelet count
are called qualitative platelet disorders.
 The disorders may be classified as (1) von Willebrand's disease, a congenital disorder of a
plasma protein necessary for platelet adhesion; and (2) congenital disorders intrinsic to the
platelet

1. VON WILLEBRAND'S DISEASE

 It is a group of disorders characterized by deficient or defective von Willebrand factor (vWF),

a protein that mediates platelet adhesion.
 Adhesion is a process separate from platelet aggregation.
 Platelets adhere to the subendothelium via vWF, which is bound to a specific receptor on the
platelet composed of glycoprotein Ib (and missing in Bernard-Soulier syndrome).
 Platelets aggregate via fibrinogen, which binds to a different receptor composed of
glycoproteins IIb and IIIa (deficient in Glanzmann's thrombasthenia)

2. DISORDERS INTRINSIC TO THE PLATELETS

Glanzmann's Thrombasthenia
 This is a rare autosomal recessive intrinsic platelet disorder causing bleeding.
 Platelets are unable to aggregate because of lack of receptors (containing glycoproteins IIb
and IIa) for fibrinogen, which form the bridges between platelets during aggregation.

Bernard-Soulier Syndrome
 This is a rare autosomal recessive intrinsic platelet disorder causing bleeding.
 Platelets cannot adhere to subendothelium because they lack receptors (composed of
glycoprotein Ib) for von Willebrand factor, which mediates platelet adhesion.

Storage Pool Disease

 This is a group of mild bleeding disorders characterized by defective secretion of platelet
granule contents (especially ADP) that stimulate platelet aggregation.

ACQUIRED QUALITATIVE PLATELET DISORDERS

Uremia
 Uremia causes abnormal platelet function
 The severity of the bleeding tendency is roughly proportionate to the degree of renal
insufficiency.

Myeloproliferative Disorders
 All the myeloproliferative disorders can produce abnormalities in platelet function.
 A number of biochemical abnormalities are present in these platelets

Other Disorders
 Aspirin causes a mild bleeding tendency by irreversibly acetylating cyclooxygenase, an
enzyme that participates in platelet aggregation.

DISSEMINATED INTRAVASCULAR COAGULATION (DIC)

 Disseminated intravascular coagulation (DIC) is a pathologic condition associated with

inappropriate activation of coagulation and fibrinolytic systems.
 It should be considered a secondary phenomenon resulting from an underlying disease state.
 DIC occurs as a secondary event in a wide variety of illnesses associated with excess
production of circulating thrombin
 The pathophysiologic factors responsible for inappropriate activation of the clotting
mechanism include endothelial cell injury, liberation of thromboplastin from injured tissue, and
release of phospholipid from red cell or platelet injury.
 All these mechanisms may contribute to development of a bleeding diathesis resulting from
increased thrombin activity.
 Additionally, widespread DIC will cause increased platelet aggregation, consumption of
coagulation factors, secondary activation of the fibrinolytic system, and deposition of fibrin
into multiple organ sites, which can result in ischemic tissue damage.
 The associated thrombocytopenia and presence of fibrin split products will impair satisfactory
hemostasis.
 Disseminated intravascular coagulation can be thought of as the consequence of the
presence of circulating thrombin (normally confined to a localized area).
 Disseminated intravascular coagulation can be caused by a number of serious illnesses,
including sepsis (especially with gram-negative bacteria but possible with any widespread
bacterial or fungal infection), severe tissue injury (especially burns and head injury), obstetric
complications (amniotic fluid embolus, septic abortion, retained fetus), cancer (acute
promyelocytic leukemia, mucinous adenocarcinomas), and major hemolytic transfusion
reactions.