Hemolytic Anemias (Inherited and Acquired)

G6PD Deficiency Mnemonic

"Stress makes me eat bites of Fava Beans with Heinz Ketchup" -Oxidative Stress -Bite Cells -Fava Beans -Heinz Bodies

Hereditary Spherocytosis Genetic Inheritance

-Autosomal Dominant (so positive family history) -WHITE PEOPLE!

Sickle Cell Disease Genetics and Phenotypes

-Autosomal recessive -No phenotype in newborns -Chronic hemolytic anemia -Vaso-occlusion -Pneumococcal infections and sepsis -Chronic inflammatory state -Organ damage

Sickle Cell Disease Common Phenotypes

-BLACK PEOPLE

Two Subtypes of G6PD Deficiency

-Congenital non-spherocytic hemolytic anemia -Occurs in the absence of oxidant stresses -patients have very low activity levels of G6PD -Acute, acquired hemolytic anemia -Precipitated by oxidant stresses-infection, drugs (sulfa), fava beans -G6PD-deficient hemolysis results in precipitation of denatured globin within the red cell (Heinz bodies)

Paroxysmal Nocturnal Hemoglobinuria (PNH)

-Coombs Negative -associated with a stem cell (bone marrow) abnormality in which abnormal clones of hematopoietic cells expand with deficient glycosylphosphatidylinositol (GPI) membrane anchors. -Two GPI-anchored proteins inhibit complement activation on red cells; their deficiency leads to excessive complement mediated hemolysis.

Mechanisms of Red Cell Fragmentation

-DIC: Fibrin Strands -TTP: Platelet Thrombi -Prosthetic Heart Valves: Abnormal Shear -Malignant Hypertension: Abnormal Shear

Case #2 -History: Rheumatic Mitral Stenosis, On Penicillin IV for S. viridans infection. After three weeks, develops... -Physical: Weakness, Pallor, Jaundice, Tachycardia -Labs: Down Hct, Up RC, Up Bilirubin -Diagnosis? Tests? Rx?

-Diagnosis: Drug Induced Warm Antibody -Tests: Indirect Bilirubin, Coombs Test -Rx: supportive, transfusion

Case #1 -History: Upper Respiratory Infection, Cough, 3 Weeks of Extreme Weakness and Dark Urine -Physical: Jaundice, Pallor, Tachycardia, Rales -Labs: Down Hct, Up RC, Up Bilirubin -Diagnosis? Tests? Rx?

-Diagnosis: Hemolysis (possibly Coagglutinin) -Tests: Indirect Bilirubin, Coombs Test -Rx: treat underlying cause and transfusion if needed

Case #4 -History: life long history of sporadic jaundice and anemia, OTHER FAMILY MEMBERS AFFECTED -Physical: Pallor, Jaundice, Tachycardia -Labs: Down Hct, Up RC, Up Bilirubin -Diagnosis? Tests? Rx?

-Diagnosis: Hereditary Spherocytosis (Family History) -Tests: Indirect Bilirubin, Coombs Test (negative), Osmotic Fragility -Rx: Splenectomy, Folic Acid

Case #3 -History: Migratory Arthralgias for 2 Years, ANA (Antinuclear Antibody, in systemic autoimmune disease), Rapid Onset Weakness -Physical: Pallor, Jaundice, Tachycardia -Labs: Down Hct, Up RC, Up Bilirubin -Diagnosis? Tests? Rx?

-Diagnosis: Lupus (Immune Hemolytic Anemia) -Tests: Indirect Bilirubin, Coombs Test -Rx: treat underlying cause, high dose steroids for lupus

Case #5 -History: anemia and jaundice starting ̴6 months after birth, other family members are affected -Physical: Pallor, Jaundice, Stunted Growth -Labs: Down Hct, Up RC, Up Bilirubin -Diagnosis? Tests? Rx?

-Diagnosis: Sickle Cell Anemia -Tests: Hb Electrophoresis -Rx: Hydroxyurea

Laboratory findings for Warm Agglutinin

-Direct Coombs' test positive for IgG, rarely positive for complement -Patient's serum will react in indirect Coombs' test with red cells coated with drug

Laboratory Test to diagnose PNH?

-Flow Cytometry of CD55 and CD59

Thalassemia Therapy

-Folate -Splenectomy -Transfusion -Iron chelation -Bone marrow transplantation

Treatment for Autoimmune Hemolytic Anemia

-Folic Acid -Prednisone -Splenectomy -IVIG -Rituximab -Immunosuppression

Thalassemia General Characteristics

-Globin chain imbalance leads to chronic hemolysis -Microcytic hypochromic anemia -Normal or increased iron stores -Kinetics-ineffective erythropoiesis -Splenomegaly -Cooley's anemia (β-thal-major) .....Transfusion dependent .....Transfusion-induced iron overload

Sickle Cell Disease Diagnosis and Treatment

-Hemoglobin Electrophoresis -Treatment with Hydroxyurea and Hydration

Two Types of Red Cell Hemoglobin Disorders that cause Hemolysis

-Hemoglobinopathies: qualitative disorders of hemoglobin -Thalassemias: quantitative disorders of hemoglobin

Two Anemias due to Cytoskeletal Defects

-Hereditary Spherocytosis -Hereditary Elliptocytosis

PNH Clinical Manifestations

-INTRAVASCULAR -Hemoglobinuria -Iron-deficiency anemia -Jaundice -Thrombosis -Abnormal bone marrow- leukopenia and thrombocytopenia may occur

Warm Agglutinin Autoimmune Hemolytic Anemia

-IgG antibodies (usually "warm") -Fc receptor mediated -EXTRAVASCULAR destruction -some IgG Ab's fix complement -"warm weather is Great" -Antibody-coated cells cleared by Fc- receptors (macrophages) -no agglutination, SPHEROCYTES and RETICULOCYTES INSTEAD!

Cold Agglutinin Autoimmune Hemolytic Anemia

-IgM antibodies (usually "cold") -INTRAVASCULAR destruction -complement fixing -"cold weather is MMMiserable" -reaction doesn't happen in vivo, but happens in blood smear due to being at room temperature.

Acquired Hemolysis Disorders

-Immune-related -auto-immune hemolysis -hemolytic disease of the newborn -transfusion reaction -Non-immune-related -infection (malaria, clostridia) -red cell fragmentation -TTP -HUS -DIC -prosthetic heart valve -Other disorders -PNH -severe liver disease -hypophosphatemia

Coomb's Negative Hemolytic Anemia (4 Types)

-Infection -Paroxysmal Nocturnal Hemoglobinuria (PNH) -Severe Liver Disease -Hypophosphatemia

PNH Therapy and Treatment

-Inhibit complement activation- eculizumab -Red cell transfusion -Thrombosis prophylaxis and treatment -Treat bone marrow failure, if present

Classifications of Immune Mediated Hemolytic Anemias

-Isoimmune (alloimmune) .....acute transfusion reaction .....delayed transfusion reaction .....isoimmune hemolytic disease of newborns (mothers are Rh-; fathers and infants are Rh+) -Autoimmune .....caused by cold-active antibodies .....caused by warm-active antibodies .....idiopathic .....drug-induced .....secondary to other diseases (lupus, lymphoma)

Hemolysis Phenotypes

-Jaundice (due to Bilirubin) -Red Plasma

3 Components Determining RBC Lifespan

-Membrane Cytoskeleton -ATP-Generating Pathway -Hemoglobin

Liver Disease and Anemia

-Mild-to-moderate liver disease causes target red cells -Severe liver disease is associated with acanthocytes (spur cells) -Hemolysis is mostly seen in severe liver disease due to increased red cell fragility.

Hereditary Spherocytosis Labs

-Osmotic Fragility Test! HS Cells will Hemolyze faster when incubated with Saline Dilutions

Common Red Cell Fragmentation Syndromes

-Prosthetic heart valves -Thrombotic thrombocytopenic purpura (TTP) -Hemolytic - uremic syndrome (HUS) -Malignant hypertension -Disseminated intravascular coagulation (DIC)

Microorganisms that cause Hemolysis

-Protozoa (Malaria, Babesiosis, Trypanosomiasis, Leishmaniasis) -Bacteria (Bartonella, Clostridium) -Spirochetes (Borrelia)

4 Basic Concepts of Hemolytic Anemias

-RBC Destruction is INCREASED -Bone Marrow Compensation Occurs (INCREASED RBC Production) -Bone Marrow RBC Production can INCREASE around 7 Fold -Some patients have Hemolysis WITHOUT Anemia

Inherited Hemolysis Disorders

-RBC membrane disorders -hereditary spherocytosis -hereditary elliptocytosis -RBC enzyme disorders -G6PD deficiency -PK deficiency -RBC hemoglobin disorders -sickle cell disease -thalassemia

Each day, ̴ 1% of the red cell mass dies and is replaced by...

-Reticulocytes

Red Cell Fragmentation Syndromes are characterized by...

-Shistocytes!

Laboratory Features of Hemolysis (2 Factors)

-Signs of RBC Destruction -Signs of Accelerated Erythropoiesis

Hereditary Spherocytosis Treatment

-Splenectomy -Folate

Hereditary Spherocytosis Clinical Features (3)

-Splenomegaly -Jaundice -Aplastic Episodes (Parvovirus B19)

Key Give-Away for Beta Thalassemia

-VERY INCREASED HbA2 and INCREASED HbF

G6PD Deficiency Genetics, Resistance, and Pathway

-X-Linked -relative resistance to Malaria -key enzyme in the Hexose Monophosphate Shunt

Thrombotic Thrombocytopenic Purpura (TTP) Diagnosis

-absent ADAMTS13. -Hemolysis due to Red Cell Fragmentation

Drugs Associated with Warm Agglutinin Autoimmune Hemolytic Anemia

-antibiotics (high dose Penicillin!)

Haptoglobin Function

-binds free Hemoglobin that is released into the blood stream as a result of Hemolysis. -thus, if Hemolysis is occuring, free Haptoglobin will be DECREASED on Lab Results

G6PD Deficiency Diagnosis

-blood smears shows RBCs with Heinz Bodies and Bite Cells

Hypophosphatemia and Hemolysis

-seen in patients receiving prolonged antacid therapy, parenteral nutrition without phosphorus supplementation, and starvation or alcoholism -Hypophosphatemia depletes red cell phosphorus and ATP, leading to rigid, non-deformable red cells

Alpha vs Beta Thalassemias

-α-thalassemias: decreased α-chain synthesis due to α-chain deletions -β-thalassemias: decreased β-chain synthesis due to multiple mutations (not exonic) -alpha is diagnosed usually through gene panel, beta is diagnosed with Hemoglobin Electrophoresis

Autoimmunity results from a loss of...

...self-tolerance leading to immune reactions to self-antigens

CLINICAL CONSEQUENCES OF VASO-OCCLUSION

Bone infarction Visceral infarction-stroke, abdominal pain , chest pain Asplenia Vision loss Leg ulcers Renal dysfunction Priapism

Triggers of Autoimmunity

genetic risks, infection (viral, bacterial), inflammation

Signs of RBC Destruction (5 Signs)

↑ indirect bilirubin ↑ LDH (Lactate Dehydrogenase) ↓ haptoglobin ↑ plasma hemoglobin ↑ urine hemoglobin

Signs of Accelerated Erythropoiesis (3 Signs)

↑ reticulocytes blood smear bone marrow erythroid hyperplasia