Chapter 29: Alterations of the Hematologic System

Anemia

• Reduction in:

           ➢ Number of erythrocytes, or

           ➢ Decreased quality or quantity of hemoglobin

• From

          ➢ Impaired erythrocyte production

          ➢ Acute or chronic blood loss

          ➢ Increased erythrocyte destruction

          ➢ Combination of the above

-polycythemia: when you see an increase in erythrocyte number or the volume is excessive

Anemia

• Classifications

          ➢ Etiologic factor (cause), cell size and hemoglobin (“-cytic”/”-chromic”)

             • Anemias of blood loss

                ~Normocytic-normochromic

                   – Post-hemorrhagic anemia

             • Anemias of diminished erythropoiesis

                ~Macrocytic (megablastic)

                   – Pernicious anemia

                   – Folate deficiency anemia

                ~Microcytic hypochromic

                  – Iron deficiency anemia

                ~Anemia of chronic disease

                ~Aplastic anemia

                ~Hemolytic anemia

1. Classification by Etiologic Factor & Morphology

Anemia can be categorized based on the cause and RBC morphology, which includes cell size (-cytic) and hemoglobin content (-chromic).

A. Anemias of Blood Loss

• Normocytic-Normochromic Anemia (Normal RBC size and hemoglobin concentration)

  • Post-hemorrhagic anemia:

    • Caused by acute or chronic blood loss (e.g., trauma, surgery, gastrointestinal bleeding).

    • Initially, RBCs remain normal in size and hemoglobin content.

    • If bleeding persists, iron deficiency may develop, leading to microcytic hypochromic anemia.

B. Anemias of Diminished Erythropoiesis

(Impaired RBC production due to nutritional deficiencies, bone marrow dysfunction, or chronic disease)

• Macrocytic (Megaloblastic) Anemia (Large RBCs due to impaired DNA synthesis)

  • Pernicious anemia:

    • Vitamin B12 deficiency due to lack of intrinsic factor (often caused by autoimmune gastritis).

    • Leads to neurological symptoms and impaired DNA synthesis.

  • Folate deficiency anemia:

    • Due to low folic acid levels, often caused by malnutrition, alcoholism, or pregnancy.

    • Similar to B12 deficiency but without neurological symptoms.

• Microcytic Hypochromic Anemia (Small RBCs with low hemoglobin content)

  • Iron deficiency anemia:

    • Most common anemia worldwide, caused by chronic blood loss (e.g., heavy menstruation, GI bleeding) or insufficient iron intake.

    • Results in pale, small RBCs (hypochromic, microcytic).

• Anemia of Chronic Disease (ACD)

  • Associated with chronic infections, inflammation, or cancer.

  • Impaired iron utilization despite normal or increased iron stores.

  • Usually normocytic or microcytic with low iron availability.

• Aplastic Anemia

  • Bone marrow failure leading to decreased production of RBCs, WBCs, and platelets (pancytopenia).

  • Causes: Autoimmune damage, radiation, toxins, or viral infections.

• Hemolytic Anemia (Increased RBC destruction)

  • Caused by genetic defects, autoimmune disorders, infections, or toxins.

  • Examples: Sickle cell anemia, hereditary spherocytosis, G6PD deficiency.

  • RBCs break down prematurely, leading to jaundice and splenomegaly.

Summary

• Normocytic-Normochromic Anemia: Blood loss or chronic disease.

• Macrocytic Anemia: B12 or folate deficiency.

• Microcytic Hypochromic Anemia: Iron deficiency.

• Aplastic Anemia: Bone marrow failure.

• Hemolytic Anemia: Increased RBC destruction.

-Isocytosis is a medical term that refers to a condition where red blood cells (erythrocytes) are of equal size. 

-It is the opposite of anisocytosis, where red blood cells vary in size. 

-Poikilocytosis refers to an increase in abnormal red blood cells of any shape that makes up 10% or more of the total population. Poikilocytes can be flat, elongated, teardrop-shaped, crescent-shaped, sickle-shaped, or can have pointy or thorn-like projections, or may have other abnormal features.

Anemia

• Clinical manifestations

         ➢ Reduced oxygen-carrying capacity: hypoxia

         ➢ Reduced oxygen levels in the blood: hypoxemia

         ➢ Dyspnea, palpitations, dizziness, fatigue, pallor(pale)

         ➢ Neurological and GI changes(late manifestations)

• Treatment

         ➢ Transfusions, dietary correction, and administration of supplemental vitamins or iron

         ➢ Correction of the underlying condition(if you can correct the underlying condition thats going to reverse the anemia)

Clinical Manifestations of Anemia

1. Reduced Oxygen-Carrying Capacity → Hypoxia

   • Insufficient oxygen delivery to tissues leads to fatigue, weakness, and shortness of breath.

2. Reduced Oxygen Levels in Blood → Hypoxemia

   • Decreased hemoglobin concentration results in lower oxygen saturation in the blood.

3. General Symptoms:

   • Dyspnea (shortness of breath) – Due to oxygen deprivation in tissues.

   • Palpitations & Tachycardia – The heart compensates for low oxygen by increasing cardiac output.

   • Dizziness & Fatigue – Due to inadequate oxygen supply to the brain and muscles.

   • Pallor (pale skin and mucous membranes) – Reduced hemoglobin leads to decreased blood color.

4. Neurological and Gastrointestinal Symptoms (Seen in B12 Deficiency Anemia):

   • Neurological: Numbness, tingling, memory issues (seen in pernicious anemia due to B12 deficiency).

   • Gastrointestinal: Loss of appetite, weight loss, abdominal discomfort.

Treatment of Anemia

1. Blood Transfusions

   • Used for severe anemia or acute blood loss.

   • Provides immediate relief by increasing RBC count and oxygen-carrying capacity.

2. Dietary Correction & Supplements

   • Iron supplementation (for iron deficiency anemia).

   • Vitamin B12 injections or folic acid supplements (for megaloblastic anemia).

   • Improved diet with iron-rich foods (red meat, spinach, legumes).

3. Correction of the Underlying Condition

   • Treating chronic diseases (kidney disease, inflammatory conditions).

   • Stopping blood loss (e.g., treating ulcers, heavy menstruation).

   • Managing bone marrow disorders (e.g., aplastic anemia may require immunosuppressive therapy or bone marrow transplant).

Anemia

1. Etiologic Events

   • Decreased erythropoiesis (reduced RBC production due to bone marrow dysfunction, nutritional deficiencies, or chronic disease).

   • Increased RBC destruction (hemolysis or excessive blood loss).

2. Primary Consequences of Anemia

   • ↓ RBCs and hemoglobin → ↓ oxygen transport (hypoxemia).

   • Tissue hypoxia due to inadequate oxygen supply.

Clinical Manifestations of Tissue Hypoxia

• Ischemia (reduced blood flow to tissues)

  • Muscle claudication (pain due to low oxygen in muscles).

  • Weakness and fatigue from inadequate oxygenation of muscles.

  • Pallor (pale skin and mucous membranes) due to decreased hemoglobin.

• Cardiovascular Effects

  • Heart (angina/chest pain) due to increased oxygen demand.

  • Increased heart rate (tachycardia) and stroke volume (SV) to compensate for low oxygen levels.

  • Erythropoietin production increases to stimulate bone marrow to produce more RBCs.

• Respiratory System

  • Increased respiratory rate and depth to compensate for reduced oxygen.

  • Exertional dyspnea (shortness of breath with activity) due to oxygen deprivation.

• Central Nervous System Effects

  • Dizziness, fainting, and lethargy due to reduced oxygen to the brain.

• Liver and Organ Damage

  • Fatty changes in the liver, heart, and kidneys due to hypoxia-induced metabolic alterations.

Compensatory Mechanisms (To Maintain Oxygen Supply)

1. Cardiovascular System

   • ↑ Heart rate and stroke volume to enhance oxygen delivery.

   • Hyperdynamic circulation (increased blood flow due to low viscosity).

   • Can lead to cardiac murmurs and high-output cardiac failure if severe.

2. Renal System

   • Capillary dilation for better blood distribution.

   • Renin-aldosterone system activation → Salt and water retention → ↑ Blood volume.

3. Increased 2,3-BPG in RBCs

   • Shifts the oxygen-hemoglobin dissociation curve, facilitating oxygen release from hemoglobin to tissues.

Normocytic-Normochromic Anemias

• Posthemorrhagic anemia

-red blood cells are a normal size, they are a normal red color, you just have less of them and you have less of them because of bleeding

-decrease number of red blood cells

-due to acute blood loss from the vasculature

-major cause of post hemorrhagic anemia is going to be trauma

-physical manifestation that you see are going to depend on the site of the blood loss and the severity of the blood loss 

-treat post hemorrhagic anemia would be through intravenous administration 

Megaloblastic (Macrocytic) Anemias

• aka megocytic anemias

• RBCs are unusually large

         ➢ Die prematurely (eryptosis)

• DNA synthesis is defective.

         ➢ Vitamin B12 or folate (B9) deficiency

• Types

        ➢ Pernicious anemia(Vitamin B12 Deficiency)

        ➢ Folate deficiency anemia(Vitamin B9 Deficiency)(scaliness around the corners of mouth, mouth inflmamantion, painful lacerations in the mouth, GI distress)(Neural tube defects in fetuses (important for pregnant women to take folic acid)

-a dietary deficiency can lead to macrocytic anemia(B vitamins)

Megaloblastic Anemias

• Pernicious anemia

-most common macrocytic anemia

-caused by vitamin B 12 deficiency and its going to lack the intrinsic factor from the gastric parietal cells that is required for that V12 absorption(caused by malabsorption of B12)

-proton pump inhibitors dealing with ulcers can also be a common space for pernicious anemia

Image A (Left Side)

• Shows macrocytic (enlarged) red blood cells (RBCs).

• RBCs appear larger than normal and more oval-shaped instead of the typical round shape.

• Suggests ineffective erythropoiesis, a hallmark of megaloblastic anemia.

Image C (Right Side)

• Displays a hypersegmented neutrophil—a characteristic finding in megaloblastic anemia.

• Normal neutrophils typically have 3–5 lobes, but in megaloblastic anemia, they develop 6 or more lobes due to defective DNA synthesis.

• The presence of hypersegmented neutrophils is a diagnostic clue for vitamin B12 or folate deficiency.

Key Takeaways

• Pernicious anemia is caused by vitamin B12 deficiency, often due to intrinsic factor deficiency.

• The combination of macrocytosis (large RBCs) and hypersegmented neutrophils is a classic finding in megaloblastic anemia.

• This condition leads to ineffective hematopoiesis, resulting in symptoms like fatigue, pallor, glossitis, and neurological issues.

Megaloblastic Anemias

• Pernicious anemia bone marrow aspirate

Megaloblastic Anemias are a group of disorders characterized by defective DNA synthesis, usually due to vitamin B12 or folate deficiency. This defect leads to the production of large, abnormal, immature red blood cells known as megaloblasts in the bone marrow, and macrocytic anemia in the peripheral blood.

🧬Pernicious Anemia– Overview:

• A specific type of megaloblastic anemia caused by vitamin B12 deficiency.

• Most commonly due to autoimmune destruction of gastric parietal cells, leading to intrinsic factor deficiencyand poor B12 absorption.

• Frequently seen in older adults and has associations with other autoimmune disorders.

🦴Bone Marrow Aspirate in Pernicious Anemia:

In pernicious anemia, the bone marrow findings are typically hypercellular due to compensatory erythropoiesis, with striking abnormalities:

📌Key Features on Bone Marrow Aspirate:

1. Megaloblasts: Large erythroid precursors with immature, open (fine) nuclear chromatin and mature cytoplasm—due to impaired DNA synthesis.

2. Nuclear-cytoplasmic asynchrony: The cytoplasm matures normally (due to unaffected RNA synthesis), but the nucleus lags behind.

3. Hypersegmented neutrophils: Granulocyte precursors show increased nuclear lobulation (≥5 lobes).

4. Giant metamyelocytes: Enlarged white cell precursors.

5. Abnormal megakaryocytes: May be increased in number, often with bizarre nuclear morphology.

6. Ineffective erythropoiesis: Despite a hypercellular marrow, there's low reticulocyte count and anemia—suggesting that red blood cell production is defective and cells are being destroyed before maturing.

7. 🔍 Diagnostic Support:

• Serum B12: Low

• Anti-intrinsic factor antibodies: Positive in many cases

• Elevated homocysteine and methylmalonic acid levels

• Peripheral smear: Macrocytic anemia, anisopoikilocytosis, hypersegmented neutrophils

Megaloblastic Anemias

• Pernicious anemia clinical manifestations

• Weakness, fatigue

• Paresthesias(Paresthesia is the feeling of tingling, numbness or “pins and needles.”) of the feet and fingers, difficulty walking(affects limb function)

• Loss of appetite, abdominal pains, weight loss

• Sore tongue that is smooth and beefy red, secondary to atrophic glossitis

• “Lemon yellow” (sallow) skin as a result of a combination of pallor and icterus

• Hepatomegaly(enlarged liver), splenomegaly(enlarged spleen)

• Neurologic symptoms from nerve demyelination

       ~Not reversible, even with treatment

    ➢ Is often unrecognizable in older adults because of its subtle, slow onset and presentation

-treatment is b12 injections and those are going to occur on a regular basis and they will be high doses

Megaloblastic Anemias

• Folate (folic acid) deficiency anemia

 ➢ Clinical manifestations

           • Severe cheilosis: scales and fissures of the lips and corners of the mouth

           • Stomatitis: mouth inflammation

           • Painful ulcerations of the buccal mucosa and tongue; characteristic of burning mouth syndrome

          • Dysphagia (difficulty swallowing), flatulence, and watery diarrhea

          • Neurologic symptoms: usually not seen

 ➢ Treatment

         • Oral dose of folate is administered daily until normal blood levels are obtained.

         • Lifelong treatment is not necessary

Megaloblastic Anemias

• Folate deficiency anemia

🌿 Folate Deficiency Anemia

A megaloblastic anemia caused by inadequate folate (vitamin B9), which is essential for DNA synthesis, especially in rapidly dividing cells like those in the bone marrow.

🔍 Causes of Folate Deficiency:

1. Inadequate intake – Poor diet (common in alcoholics, elderly, or malnourished individuals)

2. Increased requirement – Pregnancy, hemolytic anemia, cancer, rapid growth

3. Malabsorption – Celiac disease, inflammatory bowel disease

4. Drugs – Methotrexate, phenytoin, trimethoprim (interfere with folate metabolism)

5. Alcoholism – Impairs absorption and metabolism

🧬 Pathophysiology:

• Folate is needed for thymidine synthesis, a DNA building block.

• Deficiency results in impaired DNA synthesis, causing ineffective hematopoiesis and megaloblastic changes.

💉 Clinical Features:

• Fatigue, pallor, weakness

• Glossitis (smooth, red tongue)

• Irritability, poor concentration

• No neurologic symptoms (unlike B12 deficiency)

🩸 Peripheral Blood Smear:

• Macrocytic anemia (high MCV)

• Oval macrocytes

• Hypersegmented neutrophils

• Anisopoikilocytosis (variation in cell size and shape)

🦴 Bone Marrow Findings (similar to other megaloblastic anemias):

• Hypercellular marrow

• Megaloblastic changes: nuclear-cytoplasmic asynchrony

• Giant metamyelocytes

• Increased mitotic activity but ineffective

🔬 Lab Findings:

• ↓ Serum folate

• Normal or ↓ RBC folate

• ↑ Homocysteine

• Normal methylmalonic acid (important for differentiating from B12 deficiency)

💊 Treatment:

• Oral folic acid supplementation

• Address underlying cause (diet, alcohol use, medication)

Question 1: A person with a gastrectomy is seen in the clinic for generalized weakness, fatigue, difficulty walking, and abdominal pain. You suspect this

individual has

1. folate deficiency anemia.

2. eryptosis anemia.

3. polycythemia anemia.

4. pernicious anemia.

Explanation ANS: 4
Pernicious anemia is caused by inadequate or absent production of intrinsic factor (IF) by gastric parietal cells. Complete or partial removal of the stomach (gastrectomy) causes IF deficiency.
Folate deficiency anemia produces scales and fissures of the lips and mouth, stomatitis, buccal and tongue ulcers, dysphagia, flatulence, and watery diarrhea and is from a lack of folate.
2. Premature death of damaged erythrocytes, eryptosis, is a common mechanism of cellular loss in individuals with anemias secondary to deficiencies of iron, infections (e.g., malaria, mycoplasma), chronic diseases (e.g., diabetes, renal disease), genetic diseases (e.g., beta-thalassemia, glucose-6-phosphate dehydrogenase [G6PD] deficiency, sickle-cell trait), and myelodytsplastic syndrome.
3. Polycythemias are conditions in which erythrocyte numbers or volume is excessive.

Microcytic-Hypochromic Anemias

• RBCs are abnormally small, have reduced hemoglobin

• Causes

        ➢ Disorders of iron metabolism

        ➢ Disorders of porphyrin and heme synthesis

        ➢ Disorders of globin synthesis

Microcytic-Hypochromic Anemias

• Iron deficiency anemia

    ➢ Most common type of anemia worldwide

    ➢ Causes

            • Dietary lack of iron and eating disorders(most common cause)

            • Impaired absorption

            • Increased requirement

            • Chronic blood loss

            • Medications (that cause GI bleeding)(ibuprofen)

            • Some surgeries

Microcytic-Hypochromic Anemias

• Iron deficiency anemia

-dead red blood cells that are unable to carry any oxygen

-theyre not producing the right amound of hemoglobin to allow for efficient oxygen carrying capacity in the blood

Microcytic-Hypochromic Anemias

• Iron deficiency anemia

-clinical manifestations: pallor of the mucous membranes and skin, yellowing of the skin, tongue dryness and soreness, fatigue and weakness, earlobes and palms are very very pale, conjunctiva in the eyes is also very pale, fingernails are sunk in (spoon shape, concave shape)

-treatment: replace the iron or get more iron into the body

Anemia of Chronic Disease

• Mild-to-moderate anemia from decreased erythropoiesis

        ➢ Chronic systemic disease or inflammation: infections, cancer, inflammatory or autoimmune diseases

• Pathologic mechanisms

           • Decreased erythrocyte life span(affected by chemotherapies)

           • Suppressed production of erythropoietin

           • Ineffective bone marrow response to erythropoietin

           • Altered iron metabolism

-clinical manifestations of anemia of chronic disease look just like iron deficiency anemia

Anemia of Chronic Disease

Anemia of Chronic Disease (ACD), showing how chronic inflammation or infection alters iron metabolism and leads to normocytic-normochromic anemia. Here's a breakdown of what’s going on:

🔵Blue Arrows – Normal Iron Metabolism:

1. Iron ingestion and absorption:

   • Iron (Fe++) is ingested from food, absorbed by the GI system, and bound to gastroferrin for transport.

2. Transport and storage:

   • Fe++ can be:

     • Stored as ferritin or hemosiderin.

     • Carried in the plasma by transferrin (TrFe).

     • Delivered to the bone marrow for erythropoiesis (production of red blood cells).

3. Erythrocytes are produced and circulate normally.

🔴Red Arrows – Abnormal Mechanisms in Chronic Disease:

1. Chronic inflammation/infection activates macrophages.

2. Activated macrophages:

   • Release cytokines, which:

     • Decrease erythropoiesis (less RBC production).

     • Increase destruction of existing RBCs.

     • Contribute to anemia.

3. Iron is trapped inside macrophages as they increase production of apoferritin and lactoferrin—proteins that bind iron, making it less available for transferrin transport and erythropoiesis.

4. This leads to less iron in circulation, even though total body iron stores may be adequate or increased.

5. The Mononuclear Phagocyte System (MPS) removes iron and contributes to this iron withholding, reinforcing the cycle.

🩸 Final Result:

These processes lead to normocytic-normochromic anemia—anemia where red blood cells are normal in size and hemoglobin content but reduced in number due to:

• Decreased RBC production

• Increased RBC destruction

• Iron sequestration (functional iron deficiency)

Question 2: Anemia of chronic disease is caused by:

1. immunoglobulin G (IgG) binding to erythrocytes at normal body temperatures.

2. autoantibodies against erythrocyte surface antigens.

3. reduced response to erythropoietin.

4. paroxysmal nocturnal hemoglobinuria.

Explanation ANS: 3
ACD results from a combination of (1) decreased erythrocyte life span, (2) suppressed production of erythropoietin, (3) ineffective bone marrow erythroid progenitor response to erythropoietin, and (4) altered iron metabolism and iron sequestration in macrophages.
1. Warm autoimmune hemolytic anemia is caused by IgG that binds optimally to erythrocytes at normal body temperature (98.6°F, 37°C).
2. Autoimmune hemolytic anemias (AIHAs) are acquired disorders caused by autoantibodies against antigens normally on the surface of erythrocytes.
4. Paroxysmal nocturnal hemoglobinuria may be congenital or acquired secondarily to acquired aplastic anemia. The disease results from a mutation in the X-linked gene for phosphatidylinositol glycan—class A (PIG-A), which results in a defect in expression of glycosylphosphatidylinositol (GPI) in hematologic stem cells.

Aplastic Anemia

• Pancytopenia(reduction or absence of all the types of blood cells)

• Most are autoimmune disorders

        ➢ Chemicals, drugs, physical agents, unpredictable exposures; inherited or idiosyncratic(pathology isn’t known).

• Types

        ➢ Pure RBC aplasia(only red blood cells being affected)

        ➢ Fanconi anemia(rare genetic anemia that results from defects in DNA repair and so that leads to the decreased production of all of the types of blood cells)

• Hypocellular bone marrow replaced with fat

• Manifests with hypoxemia(decreased oxygen in the blood), pallor, weakness, fever, dyspnea(shortness of breath or difficulty breathing)

• Treated by bone marrow or stem cell transplants, immunosuppression

Aplastic Anemia

1. Top Half (Healthy Gut & Normal Hematopoiesis)

   • Dietary fiber supports microbial diversity, leading to the production of short-chain fatty acids (SCFAs).

   • SCFAs promote healthy hematopoietic stem cells (HSCs) in the bone marrow, allowing normal differentiation into erythroid, myeloid, and lymphoid cells.

   • This represents a balanced immune system and proper bone marrow function.

2. Bottom Half (Dysbiosis & Bone Marrow Failure in Aplastic Anemia)

   • Dysbiosis (disruption of gut microbiota) leads to increased levels of lipopolysaccharides (LPS) and pathogen-associated molecular patterns (PAMPs).

   • These activate toll-like receptors (TLRs) on monocytes, which trigger the release of TNF-α (tumor necrosis factor-alpha).

   • TNF-α inhibits HSCs, leading to bone marrow failure, characteristic of aplastic anemia.

Key Takeaways from the Image

✅ The gut microbiome plays a crucial role in regulating the immune system and bone marrow function.
✅ Dysbiosis contributes to autoimmunity by triggering inflammatory responses that destroy HSCs.
✅ TNF-α is a major factor in bone marrow suppression in aplastic anemia.

Clinical Implications

🔹 Potential treatments could include gut microbiota modulation (probiotics, prebiotics, fecal microbiota transplantation) to reduce immune activation in aplastic anemia.
🔹 Anti-inflammatory therapies (TNF-α inhibitors, immunosuppressive drugs) could protect HSCs.

Question 3: A person is admitted with an autoimmune disease directed against the hematopoietic stem cells. You know this will produce:

1. aplastic anemia.

2. iron deficiency anemia.

3. sideroblastic anemia.

4. fanconi anemia.

Explanation ANS: 1
Aplastic anemia is the result of bone marrow suppression or failure caused by an autoimmune disease directed against the hematopoietic stem cells that produces pancytopenia.
Iron Deficiency Anemia can arise from one of two different etiologies or a combination of both; inadequate dietary intake or excessive blood loss.
Sideroblastic anemias (SAs) are a heterogeneous group of disorders characterized by anemia of varying severity caused by a defect in mitochondrial heme synthesis.
Fanconi anemia is a rare genetic anemia characterized by pancytopenia resulting from defects in DNA repair. This anemia develops early in life and is accompanied by multiple congenital anomalies.

Hemolytic Anemia

• Accelerated destruction of RBCs

• Types

        ➢ Paroxysmal nocturnal hemoglobinuria(releasing hemoglobin into your urine during the night)

        ➢ Autoimmune hemolytic anemias

           • Warm autoimmune hemolytic

           • Cold agglutinin autoimmune hemolytic

           • Cold hemolysin autoimmune hemolytic

           • Drug-induced hemolytic anemia

Hemolytic anemia is characterized by accelerated destruction of red blood cells (RBCs), leading to anemia and increased reticulocyte production as the bone marrow attempts to compensate.

Types of Hemolytic Anemia:

1. Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Cause: A mutation in the PIGA gene, leading to a deficiency in CD55 and CD59, which protect RBCs from complement-mediated destruction.

• Symptoms:

  • Hemoglobinuria (dark urine, especially in the morning)

  • Fatigue, pallor, dyspnea

  • Increased risk of thrombosis (major cause of death in PNH)

• Diagnosis: Flow cytometry for CD55/CD59 deficiency

• Treatment: Eculizumab (a complement inhibitor), bone marrow transplant

2. Autoimmune Hemolytic Anemias (AIHA)

These are caused by autoantibodies attacking RBCs, leading to hemolysis.

a) Warm Autoimmune Hemolytic Anemia (WAHA)

• Cause: IgG antibodies bind RBCs at normal body temperature (37°C)

• Associated with: Lupus (SLE), CLL, lymphomas, drugs (penicillin, cephalosporins)

• Diagnosis: Positive Direct Coombs Test (DAT)

• Treatment: Corticosteroids, rituximab, splenectomy

b) Cold Agglutinin Disease (CAD)

• Cause: IgM antibodies bind RBCs at cold temperatures (<30°C)

• Associated with: Mycoplasma pneumoniae, EBV infections

• Symptoms: Acrocyanosis (bluish discoloration of fingers), hemolysis in cold exposure

• Diagnosis: Cold agglutinin test, positive Coombs Test

• Treatment: Avoid cold, rituximab

c) Cold Hemolysin Disease (Paroxysmal Cold Hemoglobinuria - PCH)

• Cause: IgG antibodies (Donath-Landsteiner antibodies) bind RBCs at cold temperatures but lyse them when warmed.

• Associated with: Viral infections (children post-infection)

• Symptoms: Sudden hemoglobinuria after cold exposure

• Diagnosis: Donath-Landsteiner test

• Treatment: Self-limited, supportive care

d) Drug-Induced Hemolytic Anemia

• Cause: Drugs trigger immune-mediated destruction of RBCs

• Mechanisms:

  • Hapten-mediated (Penicillin) → Drug binds RBC, leading to immune attack

  • Immune complex-mediated (Quinidine) → Drug-RBC complex triggers complement

  • Autoantibody production (Methyldopa) → Drug alters RBC antigens

• Treatment: Stop the drug

Hemolytic Anemia

• Drug-induced hemolytic anemia

  ➢ Result of an allergic reaction against foreign antigens

  ➢ Penicillin, cephalosporins (more than 90%), hydrocortisone

🩸 Hemolytic Anemia Overview:

• Hemolytic anemia occurs when red blood cells (RBCs are destroyed (hemolyzed) faster than they can be produced.

• This leads to anemia (low RBC count), fatigue, pallor, jaundice (from increased bilirubin), and sometimes splenomegaly (enlarged spleen).

💊 Drug-Induced Hemolytic Anemia:

This is a type of immune hemolytic anemia that happens when a drug triggers the immune system to destroy red blood cells.

✅ Mechanism:

• It’s usually the result of an allergic-like immune reaction.

• The drug or its metabolite acts as a hapten—it binds to RBCs and triggers the immune system to target them.

🛑 Types of Immune Reactions:

1. Hapten-mediated (most common):

   • The drug binds to the surface of RBCs.

   • The immune system produces IgG antibodies that attack the RBC-drug complex.

   • RBCs are then removed by macrophages in the spleen.

2. Immune complex formation:

   • The drug forms complexes with antibodies in the plasma.

   • These complexes attach to RBCs and activate complement, leading to cell lysis.

3. Autoimmune induction:

   • The drug induces production of autoantibodies against RBC antigens, even after the drug is stopped.

🚨 Common Drugs That Cause It:

• Penicillin (especially at high doses)

• Cephalosporins (responsible for >90% of drug-induced cases)

• Hydrocortisone (less common, but can be involved in immune modulation)

📋 Clinical Features:

• Sudden onset fatigue, pallor, dark urine (from hemoglobinuria), jaundice.

• Positive Coombs test (direct antiglobulin test).

• Elevated LDH, bilirubin, and reticulocyte count.

• Decreased haptoglobin.

Hemolytic Anemia

• Clinical manifestations

       ➢ May be asymptomatic

       ➢ Jaundice (icterus)

       ➢ Aplastic crisis

       ➢ Splenomegaly

• Evaluation

       ➢ Bone marrow: abnormally increased numbers of erythrocyte stem cells (erythroid hyperplasia)

       ➢ Clinical manifestations

       ➢ Blood tests

• Treatment

       ➢ Acquired: remove cause or treat underlying disorder

       ➢ First line: corticosteroids

       ➢ Second line: splenectomy and rituximab (monoclonal antibody)

       ➢ Paroxysmal nocturnal hemoglobinuria: eculizumab

🩺 Clinical Manifestations:

• May be asymptomatic, especially if hemolysis is mild or slow.

• Jaundice (icterus): From elevated unconjugated bilirubin due to RBC breakdown.

• Aplastic crisis: Sudden halt in RBC production (can be triggered by infections like parvovirus B19).

• Splenomegaly: Enlarged spleen due to increased removal of damaged RBCs.

🧪 Evaluation:

• Bone marrow biopsy: Shows erythroid hyperplasia, meaning increased production of RBC precursors as a compensatory response.

• Blood tests:

  • Low hemoglobin and hematocrit

  • Elevated reticulocyte count (body trying to replace lost RBCs)

  • High LDH and bilirubin

  • Low haptoglobin

  • Positive Coombs test (in immune-mediated cases)

• Evaluate based on clinical presentation (e.g., fatigue, jaundice, dark urine).

💊 Treatment:✅ Acquired Hemolytic Anemia:

• Remove the trigger (e.g., stop the offending drug or treat the infection).

🔹 First-Line Treatment:

• Corticosteroids (e.g., prednisone): Suppress the immune response if it's autoimmune.

🔸 Second-Line Treatment:

• Splenectomy: Reduces RBC destruction in the spleen.

• Rituximab: A monoclonal antibody that targets B-cells producing harmful antibodies.

🧬 Specific Case – Paroxysmal Nocturnal Hemoglobinuria (PNH):

• Caused by a complement-mediated hemolysis due to PIGA gene mutation.

• Treatment: Eculizumab: A monoclonal antibody that inhibits complement protein C5.

Myeloproliferative Red Blood Cell Disorders

• Polycythemia(overproduction of the red blood cells)

       ➢ Overproduction of RBCs occurs.

• Relative polycythemia

       ➢ Is a result of dehydration

       ➢ Fluid loss results in relative increases of RBC counts and hemoglobin and hematocrit values.

      ➢ Resolves with fluid intake

• Iron overload(blood cells are carrying too much oxygen in the blood)

Myeloproliferative Red Blood Cell Disorders

• Absolute polycythemia→Primary→ Abnormal regulation of the multipotent hematopoietic stem cells→Polycythemia vera

• Absolute polycythemia→Secondary→Increase in erythropoietin as a normal response to chronic hypoxia→Inappropriate response to erythropoietin-secreting tumors→Most common

Primary Absolute Polycythemia (Polycythemia Vera - PV)

• Caused by abnormal regulation of hematopoietic stem cells.

• Characterized by an increase in red blood cell mass, independent of erythropoietin levels.

• Often associated with JAK2 mutations, leading to uncontrolled RBC production.

• Can cause increased blood viscosity, leading to a higher risk of thrombosis and cardiovascular complications.

Secondary Absolute Polycythemia

• Occurs due to an increase in erythropoietin (EPO) levels as a compensatory or inappropriate response.

• Compensatory Causes (Chronic Hypoxia-Driven)

  • High altitude exposure

  • Chronic lung disease (e.g., COPD, sleep apnea)

  • Congenital heart disease (right-to-left shunts)

  • Smoking (carboxyhemoglobin-induced hypoxia)

• Inappropriate Causes (EPO-Secreting Tumors)

  • Renal cell carcinoma

  • Hepatocellular carcinoma

  • Pheochromocytoma

  • Hemangioblastoma

• Most common form of absolute polycythemia since it is often secondary to underlying conditions.

Myeloproliferative Red Blood Cell Disorders

• Polycythemia vera

        ➢ Chronic neoplastic, nonmalignant condition

        ➢ acquired mutation in Janus kinase 2 (JAK2)

        ➢ Overproduction of RBCs (frequently with increased levels of WBCs [leukocytosis] and platelets [thrombocytosis])

        ➢ Splenomegaly

Polycythemia Vera (PV) Overview

• Chronic neoplastic, nonmalignant condition

  • A myeloproliferative disorder characterized by excessive red blood cell production.

  • Not considered a malignant cancer but can progress to acute myeloid leukemia in some cases.

• Pathophysiology

  • Acquired mutation in Janus kinase 2 (JAK2) gene (JAK2 V617F mutation in ~95% of cases).

  • Mutation leads to constitutive activation of JAK-STAT signaling, causing uncontrolled erythropoiesis independent of erythropoietin (EPO) regulation.

• Clinical Features

  • Overproduction of RBCs → Polycythemia (↑ hemoglobin & hematocrit).

  • Leukocytosis (increased WBCs) → Can lead to inflammation and increased infection risk.

  • Thrombocytosis (increased platelets) → Heightened risk of thrombosis (stroke, deep vein thrombosis, myocardial infarction).

  • Splenomegaly (enlarged spleen) → Due to excessive RBC turnover.

  • -increased blood pressure

• Symptoms

  • Hyperviscosity syndrome → Headaches, dizziness, blurred vision.

  • Thrombotic complications → Increased risk of blood clots.

  • Aquagenic pruritus (itching after warm showers). (intense itching)

  • Ruddy complexion (plethora due to increased RBC mass).

MyeloMyeloproliferative Red Blood Cell Disorders

• Polycythemia vera

-treatments are going to include: phlebotomy(just withdraw the blood cells), low dose aspirin, interferon alpha?, hydroxyurea(increase oxygen carrying capacity of hemoglobin molecules by altering the hemoglobin molecules themselves)

-clinical presentation: increaed numbers of red blood cells, which leads to redding of the skin, often associated with edema(swelling)

Question 4: A person arrives in the clinic reporting 4 days of nausea, vomiting, and diarrhea. The hematocrit is 61%. You suspect:

1. primary polycythemia.

2. secondary polycythemia.

3. relative polycythemia.

4. absolute polycythemia.

Explanation ANS: 3
This term indicates that the elevated hematocrit is due to a reduction in fluid volume or dehydration with subsequent hemoconcentration. Relative polycythemia results from hemoconcentration of the blood associated with dehydration that may be caused by decreased water intake, diarrhea, excessive vomiting, or increased use of diuretics.
1. Polycythemia vera (PV) (also known as primary polycythemia) is one of several disorders collectively known as chronic myeloproliferative disorders. Primary polycythemia occurs in response to abnormal regulation of the hematopoietic stem cells.
2. Secondary polycythemia results from chronic hypoxemia, which stimulates release of erythropoietin.
4. Absolute polycythemia describes an increase in erythrocytes that is not related to volume state and includes both primary and secondary polycythemia.

The patient has nausea, vomiting, and diarrhea for 4 days, which suggests dehydration. Relative polycythemia occurs when plasma volume decreases due to fluid loss (e.g., dehydration), leading to an artificially elevated hematocrit without an actual increase in RBC mass.

In contrast:

• Primary polycythemia (Polycythemia Vera) (Option 1) would typically involve a JAK2 mutation and be a chronic condition, not an acute presentation.

• Secondary polycythemia (Option 2) (due to hypoxia or EPO-producing tumors) usually does not present suddenly with gastrointestinal symptoms.

• Absolute polycythemia (Option 4) refers to a real increase in RBC mass rather than a plasma volume contraction.

Myeloproliferative Red Blood Cell Disorders

• Iron overload

        ➢ Hereditary hemochromatosis(common inherited autosomal recessive disorder of iron metabolism, you’re not able to metabolize the iron and you end up with excessive iron deposits in the liver which ends up causing tissue damage, and in the liver it can cause fatty liver)

-some symptoms would be abdominal pain, joint pain, stopping of menstruation, and or impotense

-hepatomegaly, diabetes, abnormal liver enzymes, cardiomegaly

1. Left Side: Image Comparison of Hands

   • Shows a normal hand (left) versus a hand with hyperpigmentation (right), a characteristic sign of iron overload.

   • Bronzed or darkened skin is a hallmark of hemochromatosis, often referred to as “bronze diabetes” when associated with diabetes.

2. Right Side: Diagram of Genetic Hemochromatosis Pathophysiology

   • Key points:

     • Genetic mutation in HFE gene → leads to decreased hepcidin production (hepcidin is the key regulator of iron homeostasis).

     • Low hepcidin → increased iron absorption in the intestines.

     • Excess iron storage in organs (liver, pancreas, heart) → leads to complications like cirrhosis, diabetes, cardiomyopathy.

Clinical Relevance

• Symptoms:

  • Fatigue, joint pain, abdominal pain.

  • Skin hyperpigmentation.

  • Liver dysfunction (cirrhosis, hepatocellular carcinoma risk).

  • Diabetes mellitus (due to iron deposition in the pancreas).

• Diagnosis:

  • Elevated serum ferritin & transferrin saturation.

  • Genetic testing for HFE mutations (C282Y mutation is most common).

• Treatment:

  • Phlebotomy (removal of excess iron through blood withdrawal).

  • Iron chelation therapy in some cases.

Alterations of Platelets and Coagulation

• Platelet disorders

        ➢ Thrombocytopenia(too low of a platelet count)

           • ITP

           • TTP

        ➢ Thombocythemia(too high of a platelet count)

           • ET

        ➢ Qualitative alterations

• Coagulation disorders

        ➢ Disseminated intravascular coagulation

        ➢ Thromboembolic disease

        ➢ Acquired hypercoagulability

Platelet Disorders

Platelets (thrombocytes) are small cell fragments that play a crucial role in blood clotting. Disorders of platelets can involve either too few, too many, or dysfunctional platelets.

Thrombocytopenia (Low Platelet Count)

A platelet count below 150,000/μL can lead to excessive bleeding. Causes include immune disorders, infections, and certain medications.

• Immune Thrombocytopenic Purpura (ITP):

  • An autoimmune disorder where the immune system destroys platelets.

  • Can be acute (common in children) or chronic (more common in adults).

  • Symptoms: Easy bruising, petechiae (small red spots on the skin), nosebleeds, and heavy menstrual bleeding.

• Thrombotic Thrombocytopenic Purpura (TTP):

  • A rare but life-threatening condition caused by abnormal blood clot formation leading to low platelet levels.

  • Associated with ADAMTS13 enzyme deficiency, which prevents proper breakdown of von Willebrand factor.

  • Symptoms: Fever, neurological symptoms, kidney damage, and purpura.

Thrombocythemia (High Platelet Count)

A platelet count above 450,000/μL can increase the risk of clotting or bleeding.

• Essential Thrombocythemia (ET):

  • A rare bone marrow disorder leading to excessive platelet production.

  • Can be caused by mutations in the JAK2, CALR, or MPL genes.

  • Symptoms: Blood clots, headaches, dizziness, tingling in hands/feet, and increased risk of stroke or heart attack.

Qualitative Platelet Disorders

In these disorders, the platelet count is normal, but platelet function is impaired.

• Causes include genetic defects (e.g., Glanzmann thrombasthenia), medications (e.g., aspirin), or systemic diseases (e.g., uremia from kidney failure).

• Symptoms: Prolonged bleeding, bruising, and difficulty clotting.

Coagulation Disorders

Coagulation disorders affect the blood’s ability to clot properly, either leading to excessive clotting or bleeding.

Disseminated Intravascular Coagulation (DIC)

• A serious condition where widespread clotting occurs throughout the body, depleting clotting factors and platelets, leading to excessive bleeding.

• Causes: Sepsis, trauma, cancer, obstetric complications (e.g., placental abruption).

• Symptoms: Uncontrolled bleeding, organ failure, and small blood clots.

Thromboembolic Disease

• A group of conditions where abnormal blood clots form in the veins or arteries, potentially leading to life-threatening complications.

• Includes Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE).

• Risk factors: Prolonged immobility, surgery, cancer, genetic clotting disorders (e.g., Factor V Leiden mutation).

• Symptoms: Swelling, pain, redness in the affected limb (DVT), shortness of breath, and chest pain (PE).

Acquired Hypercoagulability

• A condition where blood is prone to clotting due to external factors.

• Causes:

  • Cancer

  • Pregnancy

  • Oral contraceptives or hormone replacement therapy

  • Antiphospholipid syndrome (autoimmune disorder that increases clot risk)

• Symptoms: Increased risk of thrombosis, miscarriages in pregnancy, and complications such as stroke or heart attack.

Disorders of Platelets

• Thrombocytopenia(low platelet count)(100,000/mm3-450,000 (normal range))(with thrombocytopenia you’re going to have problems with hemostasis, youre going to have problem controlling bleeding and thats becasue you have too few platelets creating platelet plugs for clotting)

        ➢ Platelet count <100,000/mm3

           • <50,000/mm3: hemorrhage from minor trauma

           • <15,000/mm3: spontaneous bleeding

           • <10,000/mm3: severe bleeding that can be fatal

        ➢ Immune thrombocytopenic purpura (ITP)

           • autoimmune condition where you have developed IgG antibodies against platelet glycoproteins (post-viral acute and chronic forms)

        ➢ Thrombotic thrombocytopenic purpura (TTP) → the platelets are going to aggregate and cause occlusion of the arterials and the capillaries causing the blood to back up and then the blood can bleed out into the tissues

           • Thrombotic microangiopathy

           • Familial and acquired idiopathic types

Causes of Thrombocytopenia

Thrombocytopenia can result from decreased platelet production, increased platelet destruction, or sequestration (trapping of platelets in the spleen).

1. Immune Thrombocytopenic Purpura (ITP)

• Cause: Autoimmune disorder in which the immune system produces IgG antibodies that attack platelet glycoproteins, leading to platelet destruction in the spleen.

• Forms:

  • Acute ITP → Often follows a viral infection (more common in children).

  • Chronic ITP → Can persist long-term (more common in adults, especially women).

• Symptoms:

  • Easy bruising (purpura)

  • Small, pinpoint hemorrhages (petechiae)

  • Nosebleeds (epistaxis)

  • Bleeding gums and prolonged bleeding from cuts

• Treatment:

  • Corticosteroids (reduce immune response)

  • Intravenous immunoglobulin (IVIG)

  • In severe cases, splenectomy (removal of the spleen) may be required.

2. Thrombotic Thrombocytopenic Purpura (TTP)

A rare but life-threatening condition that leads to thrombotic microangiopathy (widespread clotting in small blood vessels).

• Cause:

  • Deficiency or inhibition of ADAMTS13, an enzyme that cleaves von Willebrand factor (vWF).

  • Without ADAMTS13, vWF accumulates, causing excessive platelet aggregation and clot formation.

• Types:

  • Familial (genetic) → Rare, inherited mutation.

  • Acquired (idiopathic) → Autoimmune, often due to antibodies against ADAMTS13.

• Symptoms (Pentad of TTP):

  • Thrombocytopenia (low platelets → bleeding, petechiae).

  • Microangiopathic hemolytic anemia (destruction of red blood cells → jaundice, fatigue).

  • Neurologic symptoms (confusion, headaches, stroke-like symptoms).

  • Kidney dysfunction (proteinuria, renal failure).

  • Fever (systemic inflammation).

• Treatment:

  • Plasma exchange (removes autoantibodies and replenishes ADAMTS13).

  • Immunosuppressive therapy (e.g., corticosteroids).

Disorders of Platelets

• TTP 

• Familial form is often seen in children and the idiopathic is in adults (highest in women in their 30s)

• Extreme thrombocytopenia(a very low platelet numbers, intravascular hemolytic anemia(due to the production of malformed red blood cells), memory disturbances, behavior irregularities, headaches or coma, kidney failure, fever

Thrombotic Thrombocytopenic Purpura (TTP)

TTP is a rare but serious blood disorder characterized by excessive clotting in small blood vessels, leading to low platelet counts (thrombocytopenia) and red blood cell destruction (hemolysis).

Healthy State (Left Panel - "A")

In a normal, healthy bloodstream:

• Endothelial cells (cells lining blood vessels) maintain smooth blood flow.

• Von Willebrand Factor (vWF) is a protein that helps platelets stick together and form clots when necessary (e.g., during injury).

• ADAMTS13 enzyme breaks down large vWF multimers into smaller, soluble fragments, preventing unnecessary platelet clumping.

• Platelets remain in a balanced state, only activating when needed.

• Red blood cells (RBCs) move freely without damage.

TTP Condition (Right Panel - "B")

When a person has TTP:

1. Deficiency or inhibition of ADAMTS13

   • This enzyme normally prevents the buildup of large vWF multimers.

   • In TTP, there’s either a genetic mutation (congenital TTP) or autoantibodies inhibiting ADAMTS13 (acquired TTP).

2. Excessive von Willebrand Factor (vWF) multimers

   • Without ADAMTS13, ultralarge vWF multimers accumulate and remain uncleaved.

   • These multimers cause excessive platelet activation, leading to unwanted clot formation.

3. Formation of Microthrombi (Small Clots)

   • The clots block small blood vessels, reducing blood flow to organs (e.g., brain, kidneys, heart).

   • This can lead to organ failure, strokes, or other serious complications.

4. Red Blood Cell Destruction (Schistocytes)

   • As blood squeezes past clots, red blood cells get shredded into fragments called schistocytes.

   • This results in hemolysis (destruction of RBCs), leading to anemia and jaundice.

5. Severe Thrombocytopenia (Low Platelet Count)

   • Since platelets are being used up to form unnecessary clots, fewer are available in circulation.

   • This leads to easy bruising, prolonged bleeding, and petechiae (small red/purple spots on the skin due to bleeding under the skin).

Key Symptoms of TTP

• Neurological Symptoms (confusion, headaches, seizures, strokes)

• Kidney Damage (due to microthrombi blocking blood flow)

• Fever

• Fatigue and Pallor (due to anemia)

• Petechiae, Bruising, or Nosebleeds (due to low platelets)

Disorders of Platelets

• Thrombotic thrombocytopenic purpura (TTP)

       ➢ “Pathognomonic pentad”

         • Extreme thrombocytopenia

         • Intravascular hemolytic anemia

         • Ischemic signs and symptoms most often involving the CNS (approximately 65% exhibit memory disturbances, behavioral irregularities, headaches, or coma)

         • Kidney failure

         • Fever

       ➢ Treatment

         • Untreated acute TTP: mortality rate of 90%, reduced to 10%–20% with prompt treatment

         • Plasma exchange with fresh frozen plasma

         • Steroids

         • Splenectomy: performed if no response to treatment (most severe treatment)

         • Caplacizumab: anti-vWF; platelet-protective effect

Caplacizumab is a monoclonal antibody that targets von Willebrand Factor (vWF) and has a platelet-protective effect in Thrombotic Thrombocytopenic Purpura (TTP).

Mechanism of Action:

1. Binds to vWF – Caplacizumab specifically binds to the A1 domain of vWF, preventing it from interacting with platelets.

2. Prevents Platelet Aggregation – By blocking vWF, it reduces the formation of platelet-rich microthrombi.

3. Protects Platelets from Consumption – Since fewer platelets are being trapped in microthrombi, platelet levels recover faster.

4. Reduces Organ Damage – By limiting clot formation, caplacizumab helps restore normal blood flow, preventing ischemia in organs like the brain, kidneys, and heart.

Disorders of Platelets (Cont.)

• Thrombocythemia

       ➢ aka thrombocytosis

       ➢ Platelet counts: >450,000/mm3 more than

       ➢ Cause: accelerated platelet production in the bone marrow

       ➢ Types: primary or secondary (reactive=increasing the production of platelets)

       ➢ Causes intravascular clot formation (thrombosis), hemorrhage, or other abnormalities

Thrombocythemia, also called thrombocytosis, is a disorder characterized by excessively high platelet counts (above 450,000/mm³). This condition can lead to abnormal clotting (thrombosis) or, paradoxically, bleeding (hemorrhage)due to dysfunctional platelets.

Types of Thrombocythemia

1. Primary (Essential Thrombocythemia, ET)

   • A bone marrow disorder caused by mutations in genes like JAK2, CALR, or MPL.

   • Results in uncontrolled megakaryocyte (platelet precursor) production.

   • Platelets are often dysfunctional, increasing the risk of both clotting and bleeding.

2. Secondary (Reactive Thrombocytosis)

   • Occurs in response to another underlying condition.

   • Causes include:

     • Inflammation (chronic diseases like rheumatoid arthritis, infections)

     • Iron deficiency anemia

     • Cancer

     • Surgery or trauma

     • Splenectomy (removal of the spleen) – The spleen normally helps regulate platelet levels.

Complications of Thrombocythemia

• Thrombosis (Blood Clots)

  • Excess platelets can cause clots in arteries or veins, leading to:

    • Stroke

    • Heart attack

    • Deep vein thrombosis (DVT)

    • Pulmonary embolism

• Hemorrhage (Bleeding)

  • Despite high platelet counts, platelet dysfunction can cause abnormal bleeding:

    • Easy bruising

    • Nosebleeds

    • Gastrointestinal bleeding

Disorders of Platelets

• Essential (primary) thrombocythemia (ET) (congenital)

       ➢ Chronic myeloproliferative disorder

          • Excessive platelet production from defective megakaryocyte progenitors

          • Rare hereditary type of: familial ET (FET)

       ➢ Clinical manifestations: microvascular thrombosis, erythromyalgia, possible bleeding

       ➢ Treatment: interferon, hydroxyurea, anagrelide, aspirin; prevent clots or bleeding

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by excessive platelet production due to defective megakaryocyte progenitors in the bone marrow. Unlike secondary thrombocytosis, ET occurs without an obvious underlying cause and can lead to both thrombosis (clotting) and bleeding complications.

Causes & Pathophysiology

• ET results from mutations in genes regulating blood cell production, mainly:

  • JAK2 mutation (found in ~50-60% of cases)

  • CALR mutation (in ~20-30%)

  • MPL mutation (less common)

• These genetic mutations cause uncontrolled proliferation of megakaryocytes, leading to excess platelet production.

• In rare hereditary cases, familial ET (FET) occurs due to inherited genetic mutations.

Clinical Manifestations

1. Microvascular Thrombosis (Clots in Small Vessels)

   • Leads to symptoms like:

     • Headaches

     • Dizziness

     • Visual disturbances

2. Erythromelalgia (Burning Pain & Redness in Hands/Feet)

   • Due to clotting in small arteries, causing pain, warmth, and redness in extremities.

3. Bleeding Tendency (Paradoxical Effect)

   • Despite high platelet counts, platelets may be dysfunctional, leading to:

     • Nosebleeds

     • Easy bruising

     • Gastrointestinal bleeding

4. Increased Risk of Major Thrombotic Events

   • Stroke (brain blood clot)

   • Heart attack (myocardial infarction)

   • Deep vein thrombosis (DVT)

   • Pulmonary embolism (PE)

Disorders of Platelets

• ET

1. Flowchart Explaining the Pathophysiology of ET

• JAK2 mutation & other MPN (myeloproliferative neoplasm) changes lead to cell activation.

• Platelets become hyperactive, producing thromboxane and other platelet products, which contribute to inflammation and clot formation (coagulative activation).

• Leukocytes also contribute by releasing cytokines and pro-inflammatory products, further worsening inflammation and endothelial dysfunction.

• This cycle increases the risk of thrombosis and vascular complications.

2. Histological Images (Right Side)

• Top Image (Bone Marrow Biopsy, Marked with Arrows)

  • Shows megakaryocyte hyperplasia, which is a hallmark of ET.

  • Large abnormal megakaryocytes (platelet precursors) are indicated by arrows.

  • This confirms excessive platelet production in the bone marrow.

• Bottom Image (Peripheral Blood Smear)

  • Displays numerous platelets, often in clusters.

  • Some platelets appear enlarged and abnormally shaped, indicating platelet dysfunction.

Alterations of Platelet Function

• Qualitative alterations

       ➢ Increased bleeding with normal platelet count

       ➢ Congenital: platelet-vascular wall adhesion, platelet- platelet interactions, platelet degranulation, arachadonic acid pathways, membrane phospholipid regulation

      ➢ Acquired: drug effects, systemic inflammatory conditions, hematologic conditions

      ➢ Clinical manifestations

         • Petechiae; purpura; bleeding (pulmonary mucosa, gingival, GU, GI, and gum)

Qualitative platelet disorders refer to functional defects in platelets despite a normal platelet count, leading to increased bleeding tendencies. These disorders can be congenital (inherited) or acquired.

1. Congenital (Inherited) Qualitative Platelet Disorders

These are genetic defects affecting different aspects of platelet function, including:

• Platelet-Vascular Wall Adhesion

  • Example: Bernard-Soulier Syndrome (defect in GPIb receptor, preventing platelet binding to von Willebrand factor).

• Platelet-Platelet Interactions (Aggregation Defects)

  • Example: Glanzmann Thrombasthenia (defect in GPIIb/IIIa receptor, preventing platelet aggregation).

• Platelet Degranulation (Defective Release of Granules)

  • Platelets fail to release critical clotting factors, affecting clot formation.

• Arachidonic Acid Pathway Defects

  • Example: Cyclooxygenase (COX) pathway defects, leading to impaired thromboxane A2 (TXA2) production, which is crucial for platelet activation.

• Membrane Phospholipid Regulation Defects

  • Affects the surface expression of phospholipids, leading to impaired clotting factor activation.

2. Acquired Qualitative Platelet Disorders

These are caused by external factors affecting platelet function.

• Drug-Induced Platelet Dysfunction

  • Aspirin, NSAIDs – Inhibit COX-1, reducing TXA2 production and impairing platelet activation.

  • Clopidogrel, Ticagrelor – Block P2Y12 ADP receptors, reducing platelet aggregation.

• Systemic Inflammatory Conditions

  • Sepsis, autoimmune diseases (e.g., lupus, rheumatoid arthritis) – Cause platelet dysfunction due to inflammatory mediators.

• Hematologic Conditions

  • Leukemias, myelodysplastic syndromes (MDS) – Produce defective platelets.

  • Uremia (chronic kidney disease) – Leads to platelet dysfunction due to toxin buildup.

3. Clinical Manifestations

Patients with qualitative platelet disorders experience mucocutaneous bleeding, including:

• Petechiae – Small pinpoint hemorrhages in the skin.

• Purpura – Larger areas of skin bleeding.

• Mucosal Bleeding – Nosebleeds (epistaxis), gum bleeding (gingival bleeding).

• Gastrointestinal (GI) Bleeding – Can lead to melena (black stools) or hematochezia (fresh blood in stool).

• Genitourinary (GU) Bleeding – Blood in urine (hematuria).

• Pulmonary Bleeding – Hemoptysis (coughing up blood) in severe cases.

Alterations of Platelet Function

This image illustrates the mechanism of platelet activation and inhibition with a focus on agonist-induced platelet activation and the effects of different antiplatelet drugs.

1. Platelet Activation Pathway

• Platelets are activated by stimuli such as:

  • Collagen, thrombin, ADP, TXA₂ (thromboxane A₂), and shear stress.

• These stimuli bind to receptors (R) on the platelet membrane, triggering intracellular signaling.

• Arachidonic acid is converted into TXA₂, which further enhances platelet activation through the TXA₂ receptor (TXR).

• Activation leads to inside-out signaling, resulting in the expression of αIIbβ3 (GPIIb/IIIa), which is critical for platelet aggregation.

2. Sites of Drug Action (Antiplatelet Therapies)

A. P2Y12 Inhibitors (Block ADP-Mediated Platelet Activation) - Blue & Purple Boxes

• Drugs:

  • Ticagrelor, Cangrelor, Elinogrel (direct inhibitors).

  • Prasugrel, Clopidogrel, Ticlopidine (prodrugs that require metabolism).

• Mechanism:

  • These drugs inhibit the P2Y12 receptor, preventing ADP from stimulating platelet activation.

  • Result: Reduced platelet aggregation and clot formation.

B. Aspirin (ASA) – Green Box

• Mechanism:

  • Inhibits cyclooxygenase-1 (COX-1), blocking thromboxane A₂ (TXA₂) synthesis.

  • Result: Prevents platelet activation and aggregation.

C. GPIIb/IIIa Inhibitors (Prevent Platelet Aggregation) – Orange & Blue Boxes

• Drugs:

  • Abciximab, Eptifibatide, Tirofiban.

• Mechanism:

  • Block αIIbβ3 (GPIIb/IIIa) integrin receptors, which are required for platelet cross-linking by fibrinogen.

  • Result: Inhibits final step of platelet aggregation.

3. Summary of Drug Effects on Platelet Function

• Aspirin (ASA): Blocks TXA₂ production, reducing platelet activation.

• P2Y12 Inhibitors (Clopidogrel, Ticagrelor, etc.): Block ADP signaling, preventing further activation.

• GPIIb/IIIa Inhibitors (Abciximab, etc.): Block platelet aggregation by preventing fibrinogen binding.

Clinical Implications

• These antiplatelet agents are used in cardiovascular diseases (e.g., heart attack, stroke, stent placement) to prevent thrombosis.

• Aspirin is widely used for primary and secondary prevention of cardiovascular events.

• P2Y12 inhibitors and GPIIb/IIIa inhibitors are used in acute coronary syndromes and percutaneous coronary interventions (PCI).

Disorders of Coagulation

• Causes: defects or deficiencies of clotting factors

       ➢ Vitamin K deficiency

       ➢ Liver disease

       ➢ Cardiovascular abnormalities

       ➢ Vasculitis

       ➢ Impaired hemostasis

• Types

       ➢ Disseminated intravascular coagulation

       ➢ Thromboembolic disease

       ➢ Hereditary thrombophilias(associated with lipids, triglycerides)

       ➢ Acquired hypercoagulability

Coagulation disorders arise from defects or deficiencies in clotting factors, leading to abnormal bleeding or clotting. These disorders can be due to genetic conditions, acquired diseases, or external factors affecting coagulation.

1. Causes of Coagulation Disorders

✅ Vitamin K Deficiency:

• Vitamin K is essential for synthesizing clotting factors II (prothrombin), VII, IX, and X.

• Deficiency leads to excessive bleeding and prolonged clotting times.

✅ Liver Disease:

• The liver produces most clotting factors; damage leads to impaired hemostasis and coagulopathy.

• Common in cirrhosis, hepatitis, or liver failure.

✅ Cardiovascular Abnormalities:

• Turbulent blood flow in conditions like heart valve disease or atrial fibrillation can promote clot formation (thrombosis).

✅ Vasculitis:

• Inflammation of blood vessels can damage the endothelium, triggering abnormal clotting or bleeding.

✅ Impaired Hemostasis:

• Dysfunction of platelets or clotting factors can lead to excessive bleeding or thrombosis.

2. Types of Coagulation Disorders

🔹 Disseminated Intravascular Coagulation (DIC)

• A life-threatening condition with widespread clot formation followed by excessive bleeding due to clotting factor depletion.

• Causes: Sepsis, trauma, malignancy, pregnancy complications.

🔹 Thromboembolic Disease

• Formation of abnormal blood clots (thrombosis) that can travel and block vessels (embolism).

• Examples: Deep vein thrombosis (DVT), pulmonary embolism (PE), stroke.

🔹 Hereditary Thrombophilias

• Genetic conditions causing excessive clotting tendency.

• Examples: Factor V Leiden mutation, Prothrombin gene mutation, Antithrombin III deficiency.

🔹 Acquired Hypercoagulability

• Increased clotting risk due to medical conditions, medications, or lifestyle factors.

• Causes: Cancer, pregnancy, obesity, smoking, prolonged immobility, oral contraceptives.

Clinical Implications

• Bleeding disorders (e.g., hemophilia, liver disease) lead to easy bruising, prolonged bleeding, and spontaneous hemorrhages.

• Hypercoagulable states (e.g., thrombophilias, DIC) increase the risk of stroke, heart attack, and organ damage due to clot formation

Disseminated Intravascular Coagulation

• Complex, acquired disorder: clotting and hemorrhage occur simultaneously

        ➢ Characterized by a cycle of intravascular clotting, followed by active bleeding

• Cause: conditions that release tissue factor

• Clinical manifestations are widely variable

• Treatment: eliminate underlying pathology, control thrombosis, maintain organ function, administer replacement therapy, replace anticoagulants

Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulation (DIC) — a serious, often life-threatening disorder where the body's normal blood clotting process becomes overactive and chaotic.

🔁 Overview of the DIC Process:

1. Triggers (Top Row)

DIC can be triggered by several conditions:

• Trauma

• Sepsis (infection-related inflammation)

• Cancer

• Products of conception (e.g., amniotic fluid embolism)

• Injury of endothelium (blood vessel lining)

🔽 Main Cascade of Events:

2. Endothelium damage & tissue factor release

These triggers lead to:

• Damage to blood vessels

• Inflammatory response

• Release of tissue factor (a key initiator of coagulation)

3. Activation of the clotting cascade

• The coagulation system is massively activated.

• This results in widespread clot formation in small vessels (microvascular thrombosis).

4. Vascular occlusion & complications

• Microthrombi block blood vessels → leading to:

  • Ischemic tissue damage (from lack of oxygen)

  • Hemolytic anemia (RBCs get damaged in narrowed vessels)

5. Platelet & clotting factor consumption

• Massive clotting uses up platelets and coagulation factors, leaving the body unable to clot normally.

• This leads to bleeding, often spontaneous or severe.

🔁 Simultaneous Fibrinolytic Pathway (Right Side):

As the body tries to break down the clots:

• Platelet aggregation and plasmin activation occur.

• Fibrinolysis breaks down fibrin clots.

• This produces:

  • Fibrin split products (which further inhibit clotting)

  • Lysis of clotting factors

  • Inhibition of thrombin and platelets

⚠ Final Outcome:

A paradox:

• Clotting + Bleeding at the same time:

  • Microvascular thrombosis causes organ damage.

  • Consumption and degradation of clotting components cause uncontrolled bleeding.

🧠 Key Concepts:

• DIC is not a primary disease — it's a secondary complication of other critical illnesses.

• It's a delicate imbalance between coagulation and fibrinolysis.

• Both clotting (thrombosis) and bleeding (hemorrhage) occur, often simultaneously.

Question 5: An individual has disseminated intravascular coagulation (DIC). Which pathophysiologic mechanism is occurring?

1. Platelet consumption results in thrombocytosis.

2. Tissue factor is decreased.

3. Clotting is abnormally widespread and ongoing.

4. Natural anticoagulants are greatly increased.

Explanation ANS: 3
DIC results from abnormally widespread and ongoing activation of clotting .
1. Platelet consumption exceeds production, resulting in a thrombocytopenia that increases bleeding.
2. The common pathway for DIC appears to be excessive and widespread exposure of Tissue factor.
4. Not only is the clotting system extensively activated in DIC, but the predominant natural anticoagulants (tissue factor inhibitor, antithrombin III [AT III], protein C) are also greatly diminished.

Thromboembolic Disease

• Results from a fixed (thrombus) or moving (embolus) clot that blocks flow within a vessel

        ➢ Arterial thrombi: defects in proteins involved in hemostasis

        ➢ Venous thrombi: variety of clinical disorders or conditions

• Treatment: anti-coagulants, thrombolytics

• Virchow triad

        ➢ Injury to the blood vessel endothelium

     ➢ Abnormalities of blood flow

     ➢ Hypercoagulability (thrombophilia) of the blood

Thromboembolic disease occurs when a blood clot (thrombus or embolus) forms and obstructs blood flow in arteries or veins. This condition can cause life-threatening complications, such as stroke, pulmonary embolism (PE), or deep vein thrombosis (DVT).

1. Types of Thromboembolic Events

🔹 Arterial Thrombi

• Form in arteries due to defects in proteins involved in hemostasis.

• Composed mainly of platelets and fibrin (white thrombi).

• Common in conditions like:

  • Atherosclerosis (fatty plaque buildup)

  • Atrial fibrillation (irregular heart rhythm leading to clot formation)

  • Heart valve disease or prosthetic valves

• Complications: Stroke, myocardial infarction (heart attack), limb ischemia.

🔹 Venous Thrombi

• Form in veins due to a variety of conditions.

• Composed mainly of red blood cells and fibrin (red thrombi).

• Common in:

  • Deep vein thrombosis (DVT) – clot in deep veins, usually in the legs.

  • Pulmonary embolism (PE) – clot dislodges and moves to the lungs, causing life-threatening blockage.

• Risk Factors: Immobility (bed rest, long flights), pregnancy, obesity, cancer, clotting disorders.

2. Virchow's Triad – Three Main Causes of Clot Formation

Virchow's Triad explains the pathophysiology of thrombosis, highlighting three major factors that contribute to clot formation:

1⃣ Endothelial Injury

• Damage to blood vessel walls triggers clotting.

• Causes: Hypertension, surgery, trauma, smoking, infections, diabetes.

2⃣ Abnormal Blood Flow

• Stasis (slow blood flow): Occurs in immobility (e.g., long hospital stays, paralysis).

• Turbulent flow: Seen in heart valve disease or aneurysms.

3⃣ Hypercoagulability (Thrombophilia)

• Increased tendency to clot, either hereditary or acquired.

• Causes:

  • Genetic: Factor V Leiden, Prothrombin mutation, Protein C/S deficiency.

  • Acquired: Cancer, pregnancy, oral contraceptives, autoimmune diseases (e.g., lupus anticoagulant).

Treatments

✅ Anticoagulants (Prevent Clot Growth & Formation)

• Heparin (IV/subcutaneous) – Immediate action, prevents clot propagation.

• Warfarin (Coumadin) – Long-term use, monitored via INR/PT.

• Direct oral anticoagulants (DOACs):

  • Apixaban, Rivaroxaban, Dabigatran (preferred for many patients due to convenience).

✅ Thrombolytics (Clot Busters – Used in Emergencies)

• Tissue plasminogen activator (tPA) – Used in acute stroke, massive PE, or myocardial infarction (MI).

• High bleeding risk, so only used in life-threatening situations.

✅ Supportive Measures

• Compression stockings – Prevent DVT.

• Early ambulation – After surgery to reduce clot risk.

• Lifestyle changes – Stop smoking, maintain healthy weight, stay active.

Arterial clots → Due to platelet dysfunction & vascular injury (linked to stroke & heart attack).

Venous clots → Due to stasis & hypercoagulability (linked to DVT & PE).

Virchow’s Triad (Endothelial injury, Blood flow abnormalities, Hypercoagulability) explains clot formation.

Anticoagulants (warfarin, heparin, DOACs) prevent clot growth, while thrombolytics (tPA) dissolve existing clots in emergencies.

Hereditary Thrombophilias

• Inherited conditions increase risk for thrombosis.

• Most are autosomal dominant.

Acquired Hypercoagulability

• Deficiencies in protein S and C and AT III

• Antiphospholipid syndrome

Hereditary Thrombophilias & Acquired Hypercoagulability

Thrombophilias refer to conditions that increase the risk of blood clot formation (thrombosis). These can be hereditary (genetic) or acquired and often lead to deep vein thrombosis (DVT), pulmonary embolism (PE), or stroke.

1. Hereditary Thrombophilias

• Genetic conditions that increase clotting risk.

• Most are autosomal dominant, meaning an affected person has a 50% chance of passing it to their children.

• Common hereditary thrombophilias:

✅ Factor V Leiden Mutation (Most Common)

• Mutation in Factor V makes it resistant to Protein C, increasing clot risk.

• Found in 5% of Caucasians but rare in other populations.

• Leads to DVT, PE, and pregnancy complications (miscarriages, preeclampsia).

✅ Prothrombin Gene Mutation (G20210A)

• Causes increased prothrombin (Factor II) levels → promotes clot formation.

• Increased risk of DVT & PE.

✅ Protein C & Protein S Deficiencies

• Protein C & S help break down clots; deficiency leads to uncontrolled clotting.

• Can cause life-threatening clots in veins (purpura fulminans in newborns).

✅ Antithrombin III (AT III) Deficiency

• Antithrombin III prevents excessive clot formation; deficiency leads to hypercoagulability.

• Resistant to heparin therapy, making treatment more difficult.

✅ Hyperhomocysteinemia

• High homocysteine levels damage blood vessels and promote clotting.

• Linked to stroke, DVT, and heart disease.

2. Acquired Hypercoagulability

• Develops due to medical conditions, lifestyle factors, or medications.

• Often linked to inflammation, immune disorders, and metabolic diseases.

✅ Antiphospholipid Syndrome (APS)

• Autoimmune disorder where the body makes antibodies against phospholipids, increasing clot risk.

• Can cause:

  • Recurrent miscarriages

  • Stroke, DVT, PE

  • Livedo reticularis (mottled skin)

• Diagnosed by lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein-I antibodies.

✅ Deficiencies in Protein S, Protein C, and AT III

• Can be inherited or acquired (e.g., due to liver disease, kidney disease, infections, or pregnancy).

• Increased clot formation, leading to DVT, PE, and strokes.

✅ Other Acquired Causes

• Cancer (procoagulant state from tumors)

• Pregnancy (increased clotting factors, reduced venous flow)

• Obesity, smoking, prolonged immobility, oral contraceptives

3. Diagnosis & Treatment

🔍 Diagnostic Tests

• D-dimer (clot breakdown marker)

• Genetic testing for Factor V Leiden, Prothrombin mutation

• Antiphospholipid antibody panel (for APS)

• Protein C, Protein S, AT III levels

• Homocysteine levels

💊 Treatment Options

• Anticoagulants (Warfarin, Heparin, DOACs - Apixaban, Rivaroxaban)

• Lifestyle changes (Exercise, quitting smoking, weight control)

• Avoid estrogen-containing contraceptives in high-risk individuals

Key Takeaways

✅ Hereditary thrombophilias (Factor V Leiden, Prothrombin mutation, Protein C/S, AT III deficiency) → Genetic risk for clotting.
✅ Acquired hypercoagulability (APS, Protein C/S/AT III deficiencies, cancer, pregnancy, obesity) → Develops over time.
✅ Diagnosis involves genetic testing, antibody panels, and clotting factor levels.
✅ Anticoagulants and lifestyle changes are the main treatments.

Acquired Hypercoagulability, which is a condition where the blood has an increased tendency to clot due to external or non-genetic factors.

🔹 Top Section: Key Causes of Acquired Hypercoagulability

1. Deficiencies in Natural Anticoagulants:

   • Protein S and Protein C: These normally help prevent excessive clotting. Deficiencies → higher clot risk.

   • Antithrombin III (AT III): Another anticoagulant that inhibits thrombin. A deficiency allows unregulated clot formation.

2. Antiphospholipid Syndrome (APS):

   • An autoimmune disorder where the body makes antibodies against phospholipids in blood vessels.

   • This increases clot formation, especially in veins and arteries, and can lead to miscarriages, strokes, or DVTs.

🔹 Bottom Left Image: Clinical Presentation

• Image of a foot with skin necrosis, bruising, and discoloration:

  • Likely showing a venous thromboembolism or skin infarction due to impaired blood flow.

  • This could be caused by APS or other hypercoagulable states leading to vascular occlusion (blocked blood vessels).

🔹 Bottom Right Flowchart: Trauma-Induced Coagulopathy

This diagram explains how trauma and bleeding can lead to coagulopathy (a bleeding/clotting disorder), which is tied to both bleeding risk and clotting risk.

Process Breakdown:

1. Trauma → Tissue Damage

   • Causes cytokine and hormone release (inflammatory response)

   • Leads to inflammation and fibrinolysis activation

   • Simultaneously stimulates coagulation via hemostasis and endothelial activation

2. Blood Loss → Shock

   • Uses up clotting factors

   • Requires resuscitation with fluids/blood

3. Complications from Resuscitation:

   • Dilution of clotting factors

   • Hypothermia from transfusion

   • Leads to traumatic coagulopathy — body is unable to clot properly

4. Tissue Hypoxia and Acidosis:

   • Worsen coagulopathy by impairing normal cell and enzyme function

5. Preexisting Factors Worsen It:

   • Age, genetics, comorbidities (like diabetes or heart disease), or medications

🧠 Summary:

• Acquired hypercoagulability is not inherited but develops from conditions like protein C/S or AT III deficiency, autoimmune syndromes, or severe trauma.

• Trauma can push the body into a vicious cycle of clotting AND bleeding, especially in critically ill patients.

• Understanding this is key in ICU and emergency settings where managing the balance between bleeding and clotting is lifesaving.

Anemia is defined as a reduction in the total circulating red cell mass or a decrease in the quality or quantity of hemoglobin. Polycythemias are excessive levels or volumes of RBCs.

Anemias can result from blood loss, impaired erythrocyte production, increased erythrocyte destruction, and a combination of these factors.

Total circulating red blood cell mass is reflected by changes in plasma volume caused by dehydration and fluid retention.

Anemias can be classified in several ways and a useful way is by the main underlying mechanism.

Clinical manifestations of anemia may be demonstrated in all organs and tissues (tissue hypoxia) throughout the body. Decreased oxygen delivery to tissues causes fatigue, dyspnea, syncope, angina, compensatory tachycardia, and organ dysfunction

Posthemorrhagic anemia is a normocytic-normochromic anemia caused by acute blood loss. A major cause of acute blood loss is trauma, a rising global problem.

Anemia from chronic blood loss occurs if the loss is greater than the replacement capacity of the bone marrow. If iron stores are depleted, iron deficiency anemia can occur.

Macrocytic (megaloblastic) anemias are characterized by larger than normal erythroid precursors (megaloblasts) in the bone marrow that mature into large erythrocytes. They most commonly are caused by deficiency of vitamin B12 or folate.

PA results from inadequate vitamin B12 absorption because autoimmune gastritis impairs the production of IF, which is required for vitamin B12 uptake from the gut. Folate deficiency anemia is caused by inadequate dietary intake of folate. Both anemias respond to replacement therapy.

Microcytic-hypochromic anemias are characterized by abnormally small erythrocytes with insufficient hemoglobin content. The anemias result from disorders of (a) iron metabolism (IDA), (b) porphyrin and heme synthesis (SAs), or (c) globin synthesis (thalassemia).

IDA is the most common type of nutritional disorder worldwide. It is usually a result of dietary deficiency. Other major causes are impaired absorption, increased requirement, and chronic blood loss. IDA usually develops slowly, with a gradual insidious onset of symptoms, which include fatigue, weakness, dyspnea, alteration of various epithelial tissues, and vague neuromuscular complaints result.

Individuals at highest risk for developing IDA include older adults, women, infants, teenagers eating poor diets, and those living in poverty. Once the source of blood loss is identified and corrected, oral iron replacement therapy can be initiated.

ACD, also called anemia of inflammation, results from decreased erythropoiesis and impaired iron utilization in people with chronic systemic disease or inflammation. ACD is common among hospitalized individuals.

Examples of mechanisms associated with ACD include (1) decreased erythrocyte life span, (2) reduced production of erythropoietin, (3) ineffective bone marrow response to erythropoietin, and (4) iron sequestration in macrophages. In particular, the proinflammatory cytokine IL-6 increases hepatocyte release of hepcidin which suppresses ferroportin transport of iron out of macrophages.

AA is a critical condition characterized by a reduction or absence of all three blood cell types (pancytopenia). Unless the cause is determined, bone marrow aplasia results in death.

 Hemolytic anemia is a result of excessive destruction of erythrocytes and may be acquired or hereditary. Common, acquired forms are autoimmune reaction (immunohemolytic) and drug-induced hemolysis.

AIHAs include (a) warm reactive antibody type, (b) cold agglutinin type, and (c) cold hemolysin type (paroxysmal cold hemoglobinuria)

Examples of mechanisms associated with ACD include (a) decreased erythrocyte life span, (b) reduced production of erythropoietin, (c) ineffective bone marrow response to erythropoietin, and (d) iron sequestration in macrophages. In particular, the proinflammatory cytokine IL-6 increases hepatocyte release of hepcidin, which suppresses ferroportin transport of iron out of macrophages.

Polycythemia vera is a myeloproliferative disorder characterized by excessive proliferation of erythrocyte precursors, frequently with increased levels of white blood cells and platelets, in the bone marrow and splenomegaly. Signs and symptoms result directly from increased blood volume and viscosity and a predisposition to thrombosis.

Therapeutic phlebotomy to remove excessive blood volume and the use of hydroxyurea have been helpful in decreasing the excessive erythrocyte population.

Thrombocytopenia is characterized by a platelet count less than 150,000/mm3 of blood; a count less than 50,000/mm3 increases the potential for hemorrhage associated with minor trauma.

Thrombocytopenia may be congenital or acquired and primary or secondary to other acquired or congenital conditions. Acquired thrombocytopenia is associated with autoimmune diseases, viral infections, nutritional deficiencies, chronic renal failure, bone marrow hypoplasia, radiation therapy, and bone marrow infiltration by cancer. Most common forms of thrombocytopenia are the result of increased platelet consumption

Heparin-induced thrombocytopenia develops in approximately 4% of individuals receiving unfractionated heparin.

Immune thrombocytopenic purpura (ITP) is a major cause of platelet destruction, often affecting females, and results in hemorrhaging that ranges from petechiae to bleeding from mucosal sites.

Thrombotic thrombocytopenic purpura (TTP) causes platelet aggregation leading to microcirculatory occlusion.

Thrombocythemia is characterized by a platelet count more than 450,000/mm3 of blood and is symptomatic when the count exceeds 1 million/mm3, which increases the risk for intravascular clotting (thrombosis).

Essential or primary thrombocythemia is caused by excessive platelet production in the bone marrow secondary to increased plasma thrombopoietin levels resulting from defects in the thrombopoietin receptor.

 Qualitative alterations in normal platelet adherence or aggregation prevent platelet plug formation and may result in prolonged bleeding times.

Prolonged bleeding can result from alterations in platelet function, including adhesion between platelets and the vessel wall, platelet-platelet adhesion, platelet granule secretion, arachidonic acid pathway activity, and membrane phospholipid regulation.

Disorders of coagulation are usually caused by defects or deficiencies of clotting factors.

Coagulation is impaired when there is a deficiency of vitamin K because of insufficient production of prothrombin and synthesis of clotting factors II, VII, IX, and X, often associated with liver diseases.

DIC is a complex syndrome that results from a variety of clinical conditions that release tissue factor, causing an increase in fibrin and thrombin activity in the blood and producing augmented clot formation and accelerated fibrinolysis. Sepsis is often associated with DIC.

DIC is characterized by a cycle of intravascular clotting followed by active bleeding caused by the initial consumption of coagulation factors and platelets and diffuse fibrinolysis.

Diagnosis of DIC is based on dysfunctional coagulation activity. Treatment is complex, nonstandardized, and focused on removing the primary cause, restoring hemostasis, and preventing further organ damage.

Thromboembolic disease results from a fixed (thrombus) or moving (embolus) clot that blocks flow within a vessel, denying nutrients to tissues distal to the occlusion; death can result when clots obstruct blood flow to the heart, brain, or lungs.

Hypercoagulability is the result of deficient anticoagulation proteins. Secondary causes are conditions that promote venous stasis.

The term Virchow triad refers to three factors that can cause thrombus formation: (1) vessel wall injury, (2) blood flow abnormalities, and (3) altered blood constituents leading to hypercoagulability.

Autoantibodies against phospholipids result in a state of acquired hypercoagulability, an increased risk for venous or arterial thrombosis, and a higher incidence of pregnancy complications.