Hematological Disorders: Causes and Diagnostic Tests
Pernicious Anemia: Causes and Lab Findings
Pernicious anemia is a type of megaloblastic anemia caused by vitamin B12 deficiency, primarily due to autoimmune destruction of gastric parietal cells, leading to a lack of intrinsic factor (IF). Intrinsic factor is necessary for vitamin B12 absorption in the ileum. In addition to IF antibodies, some individuals produce antibodies against the B12-IF complex, further impairing B12 absorption. This results in defective DNA synthesis in erythroid precursor cells, leading to the production of abnormally large, immature red blood cells (megaloblasts). As a result, erythropoiesis is ineffective, and the red blood cells that do form are destroyed prematurely.
Lab findings include:
- Macrocytic anemia (elevated mean corpuscular volume, MCV)
- Hypersegmented neutrophils on the peripheral blood smear
- Low serum vitamin B12 level
- Elevated serum homocysteine and methylmalonic acid (MMA) levels
- Positive intrinsic factor antibody test
- A Schilling test (which assesses vitamin B12 absorption) can also aid in diagnosis
Diagnosing Bleeding Disorders
The diagnosis of bleeding disorders depends on the nature of the defect (platelet-related, clotting factor-related, or vascular). A complete blood count (CBC) with platelet count is performed first to check for thrombocytopenia (low platelet count), which may suggest platelet disorders.
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are essential tests for evaluating coagulation pathways. PT assesses the extrinsic and common pathways (Factors I, II, V, VII, and X), whereas aPTT assesses the intrinsic and common pathways (Factors I, II, V, VIII, IX, X, XI, and XII). A prolonged PT or aPTT suggests a clotting factor deficiency or a defect in the coagulation cascade.
Bleeding time, which measures platelet function, can be used to evaluate platelet disorders, though it is less commonly used due to variable results. Specific factor assays for clotting factors like Factor VIII (for hemophilia A) and Factor IX (for hemophilia B) are also conducted. Von Willebrand factor assays help in diagnosing von Willebrand disease, a common inherited bleeding disorder.
If disseminated intravascular coagulation (DIC) is suspected, fibrinogen levels and D-dimer are measured. Elevated D-dimer levels are indicative of fibrin degradation, which occurs in DIC.
Iron Deficiency Anemia: Causes and Lab Findings
Iron deficiency anemia is the most common cause of anemia worldwide. It occurs due to insufficient iron for the synthesis of hemoglobin, which is crucial for oxygen transport. The primary etiologies of iron deficiency anemia include inadequate dietary intake, chronic blood loss (e.g., gastrointestinal bleeding, heavy menstrual periods), and malabsorption (e.g., celiac disease, gastric surgery). Iron deficiency can also result from increased demand during pregnancy or growth spurts in children.
The pathophysiology involves a reduction in the iron stores (ferritin) and a decrease in the hemoglobin content of red blood cells, leading to microcytic and hypochromic red blood cells.
Lab findings include:
- Low hemoglobin level
- Low hematocrit
- Microcytic (low MCV) and hypochromic (low MCHC) red blood cell morphology
- Low serum ferritin (a direct indicator of iron stores)
- Decreased serum iron levels
- Elevated transferrin (the iron transport protein)
- Reduced transferrin saturation
- Elevated total iron-binding capacity (TIBC)
- Increased red blood cell distribution width (RDW) due to variability in red blood cell size
- A bone marrow biopsy can show decreased iron stores in severe cases
Qualitative Disorders of Leukocytes
Qualitative disorders of leukocytes refer to conditions where the function of white blood cells is impaired despite a normal or abnormal white blood cell count. These disorders can lead to an inability of leukocytes to effectively fight infections or perform other immune functions.
Examples include chronic granulomatous disease (CGD), where phagocytes fail to kill ingested microbes due to a defect in the NADPH oxidase enzyme, leading to recurrent infections, and leukocyte adhesion deficiency (LAD), where neutrophils cannot adhere to blood vessel walls to migrate to sites of infection.
In these disorders, laboratory findings typically include a normal or elevated white blood cell count, but function tests, such as the nitroblue tetrazolium (NBT) test (for CGD), or flow cytometry to assess adhesion molecules (for LAD), will show abnormal results. In CGD, the NBT test is negative (failure to reduce NBT dye), and in LAD, flow cytometry shows absence or reduced expression of adhesion molecules like CD18. Other qualitative disorders include hereditary neutrophil dysfunctions like Chediak-Higashi syndrome, which is characterized by defective lysosome function, leading to impaired phagocytosis.
Iron Deficiency Anemia: Classification and Lab Findings
Iron deficiency anemia is classified based on its etiology:
- Insufficient intake: Inadequate dietary intake of iron, particularly in infants, children, pregnant women, and individuals on restrictive diets.
- Increased iron loss: Commonly due to chronic blood loss, such as gastrointestinal bleeding (e.g., peptic ulcers, colon cancer), heavy menstruation, or hookworm infestations.
- Increased demand: Iron demand is increased during pregnancy, childhood growth, and periods of rapid cell division.
Lab findings include:
- Microcytic, hypochromic anemia with low hemoglobin levels
- Low serum iron
- Elevated transferrin
- High total iron-binding capacity (TIBC)
- Low ferritin levels
- Peripheral blood smear shows microcytic and hypochromic red blood cells
- RDW is usually elevated
- Bone marrow iron stores may be depleted in advanced cases
- Reticulocyte count is typically low in the absence of acute bleeding
Chronic Myeloid Leukemia: Pathogenesis and Diagnosis
Chronic myeloid leukemia (CML) is a type of leukemia characterized by the overproduction of myeloid cells. It is primarily caused by a chromosomal translocation known as the Philadelphia chromosome, which results from the fusion of the BCR gene on chromosome 22 with the ABL gene on chromosome 9. This translocation creates the BCR-ABL fusion gene, which encodes a constitutively active tyrosine kinase that promotes the uncontrolled proliferation of myeloid progenitor cells.
In CML, patients typically present with symptoms of chronic leukemia, such as fatigue, weight loss, splenomegaly, and bone pain.
Lab findings include:
- Elevated white blood cell counts with a left shift (presence of immature cells like myelocytes, metamyelocytes, and blasts in peripheral blood)
- Peripheral blood smear shows a “leukemoid reaction,” with an increased number of neutrophils and basophils
- A definitive diagnostic test is the identification of the Philadelphia chromosome through cytogenetic analysis or fluorescence in situ hybridization (FISH), which detects the BCR-ABL gene fusion
- The BCR-ABL fusion gene is also detectable by polymerase chain reaction (PCR)
- Bone marrow biopsy shows hypercellularity with an increase in myeloid cells
Megaloblastic Anemia: Causes, Features, and Diagnosis
Megaloblastic anemia is primarily caused by deficiencies of vitamin B12 or folate, both of which are necessary for DNA synthesis. The most common cause of vitamin B12 deficiency is pernicious anemia, while folate deficiency can result from inadequate dietary intake, malabsorption, or increased demand (as seen in pregnancy or hemolysis). The deficiency of these vitamins impairs DNA synthesis, leading to the formation of large, immature red blood cells called megaloblasts.
Clinically, patients with megaloblastic anemia present with symptoms related to anemia (fatigue, pallor, shortness of breath) and neurological symptoms in B12 deficiency (e.g., peripheral neuropathy, ataxia, memory loss).
Lab findings include:
- Macrocytic anemia (elevated MCV)
- Hypersegmented neutrophils on the peripheral blood smear
- Low reticulocyte count
- Vitamin B12 and folate levels are measured in the serum to confirm the deficiency
- Elevated levels of homocysteine and methylmalonic acid are commonly found
- Bone marrow examination reveals megaloblastic changes, with large, abnormal erythroid precursors
Thalassemia: Pathogenesis and Lab Investigations
Thalassemia is a group of inherited blood disorders characterized by reduced or absent production of one of the globin chains of hemoglobin, leading to ineffective erythropoiesis, hemolysis, and anemia. There are two major types of thalassemia: α-thalassemia (due to mutations in the α-globin gene) and β-thalassemia (due to mutations in the β-globin gene).
In α-thalassemia, the deletion or mutation of one or more of the α-globin genes leads to reduced α-chain production, causing an imbalance with β-globin chains, which form unstable tetramers that precipitate inside red blood cells, leading to cell destruction. In β-thalassemia, there is a reduced or absent synthesis of β-globin chains, leading to an excess of α-globin chains, which are toxic to red blood cell precursors. The result is microcytic hypochromic anemia.
Clinical features of thalassemia include anemia, splenomegaly, and hepatomegaly, along with bone deformities in severe cases.
Lab findings include:
- Microcytic, hypochromic anemia with elevated reticulocyte count
- Peripheral blood smear showing target cells, basophilic stippling, and nucleated red blood cells
- Hemoglobin electrophoresis can reveal abnormal hemoglobin patterns, such as the presence of hemoglobin F (fetal hemoglobin) in β-thalassemia
- Genetic testing and family history are essential for confirming the diagnosis and determining the type of thalassemia