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This is the premature destruction of RBCs
When the marrow is unable to compensate for the premature destruction of RBCs, what results?
With chronic hemolysis, the marrow can increase RBC production up to ~5-8 times normal; with relatively low levels of hemolysis, the marrow is able to adjust and maintain a normal hemoglobin level. What is this called?
- Compensated Hemolysis
- This is rare -- there is usually some anemia present with a significant degree of hemolysis
To document hemolysis, signs of increased RBC production or destruction should be shown. How is increased RBC production documented? Destruction?
- Increase in reticulocyte count
- Increase in LDH, unconjugated bilirubin; decreased haptoglobin
One way to classify hemolytic anemias is to divide them into defects of the RBCs themselves (intrinsic) versus things that are external to the RBCs (extrinsic). Intrinsic hemolytic anemias are nearly always __________, whereas extrinsic hemolytic anemias are nearly always __________.
A second way to classify hemolytic anemias is into __________ hemolysis (the RBCs are destroyed within the circulation) versus ____________, which means phagocytosis of the RBCs by macrophages in the spleen and/or liver. Which is more severe? Which one is most common?
What are some of the causes of Intravascular Hemolysis?
- Immune: hemolytic transfusion reaction (immediate), cold agglutinin disease (severe), paroxysmal cold hemoglobinuria, drug-induced
- Mechanical: malfunctioning mechanical heart valve, thrombotic microangiopathy (TTP-HUS)
This is an IgM antibody against RBC antigens that binds to the RBC at cooler temperatures and then causes the RBCs to aggregate or agglutinate. This is commonly seen with Mycoplasma pneumonia, and occasionally with EBV infections; it also occurs in children with virus infections.
Cold Agglutinin Disease
What are these markers indicative of?
Hemoglobinemia --> red plasma
Hemoglobinuria --> red or dark brown urine
Hemosiderinuria --> chronic or previous hemolysis
A test for hemosiderin will be positive for what form of hemolysis? What form will it be negative for?
What are some forms of Extravascular Hemolysis?
- Immune: Delayed hemolytic transfusion reactions, most autoimmune hemolytic anemias, intrauterine -- erythroblastosis fetalis, drug-related
- RBC Membrane Defect (HS -- Hereditary Spherocytosis)
What does a hemoglobin electrophoresis evaluate for?
Inherited Hemolytic Anemias: Hemoglobinopathies
What is the osmotic fragility test used to diagnose?
Inherited Hemolytic Anemias: Hereditary Spherocytosis
What is the prime indicator (lab test wise) of an immune hemolysis?
A positive DAT (direct antiglobulin test)
What are two complications associated with chronic hemolysis?
- Bilirubin Gallstones
- Aplastic Crisis (RBC production shut off) -- caused by Parvovirus B19 infection, other infections, nutritional deficiency, or medications
What are the three major hemolytic anemias?
- Structural Hemoglobinopathies: Hemoglobin S (sickle), Hemoglobin C, etc
- RBC Enzyme Deficiencies
- RBC Membrane Abnormalities
What two things underlie the majority of inherited hemolytic anemias (most hemoglobinopathies, thalassemias, and G6PD deficiency)?
Mosquitoes & Malaria
What is the most common structural hemoglobinopathy in the world?
Hemoglobin S (Sickle)
What state related to hemoglobin S protects against falciparum malaria?
Heterozygous State or Sickle Trait
What is believed to be the fundamental pathophysiologic problem in sickle cell diseases?
Vascular occlusion by rigid, sticky, sickled RBCs
What is Homozygous Hb S (Hb SS; Hb alpha2 beta2S )
Sickle Cell Anemia
What refers to conditions in which the presence of a sickle hemoglobin gene is associated with significant clinical complications?
Sickle Cell Disease
What four clinical syndromes are associated with the Sickling Diseases?
- Acute Vasoocclusive (painful) Crises
- Sequestration Crisis -- splenic sequestration of blood with severe anemia & splenomegaly
- Acute Hemolytic Crisis
- Acute Aplastic Crisis -- parvovirus B19, other infections
What is the number one cause of death in Sickle Cell Diseases?
Infections -- special attention to salmonella osteomyelitis
What is the second most common hemoglobinopathy in the US (after Hemoglobin S)?
What are the three types of Hemoglobin C?
- Hb AC: clinically silent
- Hb CC: mild hemolytic anemia
- Hb SC: inheritance of genes for both S & C; sickling disease similar to homozygous sickle cell anemia
What do patients with Hb SC have a peculiar predisposition to? What do women with this disease have a predisposition to?
- Proliferative Retinopathy -- can cause blindness
- Acute Chest Syndrome -- during 3rd trimester of pregnancy
Identify the disease depicted below. Notice the rectangular crystals and numerous target cells.
Hb CC Disease
What is the 3rd most common hemoglobinopathy in the US (2nd worldwide)?
What are the three subsets of Hb E?
- Hb AE: clinically silent
- Hb EE: microcytosis, target cells; little or no anemia
- Hb E/beta-thalassemia: moderate to severe thalassemic state; may resemble beta-thalassemia major (Cooley's anemia)
What is the most common RBC enyzme defect? What is its mode of inheritence? Where does it occur?
- Glucose-6-Phosphate Dehydrogenase (G6PD)
- World-wide in areas of endemic malaria
This is an inability to maintain glutathione in its reduced state --> inability to detoxify H2O2. This causes an increased sensitivity to oxidant stress, which leads to the denaturation of hemoglobin with production of Heinz bodies, the denaturation of spectrin and other proteins, and the destruction of RBCs -- both intravascular and extravascular destruction.
Glucose-6-Phosphate Dehydrogenase Deficiency
The clinical severity of a G6PD deficiency is very variable, and in the majority of cases there is no hemolysis unless the patient is stressed (infections, drugs, etc). However, there is variability between ethnic groups. In African-Americans, the disease is usually ________, whereas in people of Mediterranean descent is is often ___________.
What difference in seen in the reticulocytes between these two variants?
- More Severe
- The African variant has reticulocytes with a normal G6PD Deficiency; the Mediterranean varient have severely decreased G6PD levels, even in reticulocytes
What is the most common cause of hemolytic episodes in people with G6PD deficiency?
What should be a consideration in any acute, non-immune hemolysis?
What phenomenon is shown in the blood smear below? What disease is revealed?
- Oxidant Hemolysis ("Bite Cells")
- G6PD Deficiency
What are the three primary RBC Membrane Defects?
- Hereditary Spherocytosis (HS)
- Hereditary Elliptocytosis (HE)
- Hereditary Pyropoikilocytosis (HPP)
What molecule forms the skeleton of RBCs? What molecule anchors the lipid bilayer to this cytoskeleton?
RBC Membrane Defects involve a defective attachment of the lipid bilayer to the spectrin cytoskeleton or deficient stability of the spectrin cytoskeleton. What is this called when the defect is in vertical attachment? What are defects in horizontal stability to the spectrin cytoskeleton called?
- Hereditary Spherocytosis
- Hereditary Elliptocytosis
What is the most common congenital hemolytic anemia in people of northern European descent? How are the majority of these inherited? What causes this?
- Hereditary Spherocytosis
- AD -- new mutations are common however
- Defect in ankyrin protein
What disease is revealed in the blood smear below?
Hereditary Spherocytosis -- spherocytes usually look small, dark, and solid (no central pallor)
What are the two steps to diagnose Hereditary Spherocytosis?
- Look for immune hemolysis with DAT
- Osmotic Fragility Test --> spheres cant swell --> explode
In Hereditary Spherocytosis, what condition needs to be managed in the neonatal period?
Hyperbilirubinemia --> may require exchange transfusions
This disease is usually due to a defect in spectrin, which leads to defective stability of the spectrin cytoskeleton. It is most common in African-Americans, and is an autosomal dominant inheritance pattern. Most cases are mild.
Hereditary Elliptocytosis (HE)
What disease is depicted in the blood smear below?
Hereditary Elliptocytosis (HE)
What disease is depicted below? This is a rare hereditary disease that is most common in African-Americans. It has a moderate to severe baseline hemolysis, and an autosomal recessive inheritance pattern.
Hereditary Pyropoikilocytosis (HPP)
Is direct complement-mediated hemolysis intravascular or extravascular? What anti-body is related to this mechanism of immune RBC destruction? What does the membrane attach complex do?
- IgG or IgM
- Punches holes in the membrane
Is phagocytosis by macrophages of the reticuloendothelial system intravascular or extravascular? What anti-body is related to this mechanism of immune RBC destruction? Where does this predominantly occur?
- Spleen and/or liver
What antibody is cold-reacting immune hemolysis related to? This antibody fixes to the RBC at cooler temperatures, fixes complement, and then may dissociate from the surface of the RBC. Examples include Cold Agglutinin Disease and Paroxysmal Cold Hemoglobinuria (PCH).
What antibody is warm-reacting immune hemolysis related to? Complement may or may not be involved in this. This may be idiopathic, secondary, or drug-related.
People with idiopathic cold agglutinin syndrome often have the most problems related to acrocyanosis. The fingers, tips of ears, and toes turn blue in cold temperatures. Why is this?
IgM antibody is big --> the RBCs tend to agglutiniate in cool temps and the aggregates tend to plug up capillaries
Cold-Reacting Immune Hemolysis can be intravascular, complement-mediated through membrane attack complex (C5b-9), or it may be extravascular, due to recognition of complement on RBCs by macrophages (predominantly in liver). Which is more common?
Identify the disease depicted in the blood smear below:
Cold Agglutination: IgM Antibodies to RBC Antigen
In treating cold-reacting immune hemolysis, treatment is primarily supportive. The infection-related subset is usually self-limited, and the goal is to treat the underlying condition when it is related to autoimmune disease or a lymphoproliferative disorder. Idiopathic Cold Agglutinin Syndrome may not require therapy except keeping warm. However, if further treatment is needed, what is generally prescribed?
Immunosuppressive Agents: Cyclophosphamide
This is generally a rare disease, although it is relatively frequent as a type of immune hemolysis in kids. It is due to a peculiar biphasic IgG antibody: the Donath-Lansteiner Antibody. This antibody reacts and fixes complement at cooler temperatures, and dissociates at warmer temps. The complement cascade goes to completion after rewarming. This is a type of intravascular hemolysis. What is it?
Paroxysmal Cold Hemoglobinuria (PCH)
What antibody is related to Paroxysmal Cold Hemoglobinuria? What is weird for this antibody in this disease? Is this disease an example of an intravascular or extravascular hemolysis?
- Biphasic IgG Antibody: Donath-Lansteiner Antibody
- Reacts and fixes to complement at cooler temps; dissociates at warmer temps
Paroxysmal Cold Hemoglobinuria primarily occurs in children after what? What is the usual treatment for this?
- After infection (usually viral) or vaccination
- Usually self-limited -- treatment primarily supportive
In warm-reacting immune hemolysis, is the hemolysis usually intravascular or extravascular? What are the three variants?
- Extravascular, primarily in spleen
- Primary (idiopathic), Secondary (to some underlying disease or condition), & Drug-related
Identify the slide below:
* Note: spherocytes, polychromasia, nucleated RBC
Warm Autoimmune Hemolytic Anemia
What is a characteristic finding on the blood smear in extravascular hemolysis?
In warm autoimmune hemolytic anemia, what is the antigen usually directed against?
Rh System: "Panagglutinin" -- present on all RBCs except rare Rh-null cells
The primary or idiopathic subset of warm-reactive hemolysis predominantly occurs in what subset of people? These tend to be chronic, and a low-titer ______ is present.
What is the standard treatment for Warm Autoimmune Hemolytic Anemia, beyond treating any underlying cause?
- Prednisone: most relapse when steroids tapered
- Splenectomy: do if relapse after steroids
- Transfusion as needed, but avoid if possible
What are the three mechanisms of Drug-Related Immune Hemolytic Anemia?
- Drug Absorption (Penicillin) Type
- Neoantigen (formerly immune complex) Type
- Autoimmune (Aldomet) Type
What mechanism of Drug-Related Immune Hemolytic Anemia generally occurs with very high doses of Penicillin? The drug binds tightly to the RBC surface, and the antibody to the drug reacts with the drug on the RBC surface. What type of hemolysis generally results? What is the severity?
- Drug Absorption Type
- Extravascular Hemolysis, primarily in spleen
- Not Severe
What mechanism of Drug-Related Immune Hemolytic Anemia occurs when a combination of drug is bound to the RBC antigen? The antibody fixes complement, and a complement cascade often proceeds to completion (MAC). This can occur with low doses of drug. What type of hemolysis is this? This mechanism can be sudden and severe -- what can result?
- Neoantigen Type
- Renal Failure -- shock, DIC, death
What drug class is most often associated with drug-related immune hemolytic anemia, especially the neoantigen type?
What mechanism of drug-related hemolytic anemia is a true autoimmune reaction: antibody is directed against RBC antigen, not the drug? The drug appears to induce T-cell dysfunction, causing this. What drug is primarily connected with this?
- Autoantibody Type
- Aldomet (alpha-methyldopa)
What organism produces lysolecithinase, which dissolves RBC membranes, causing infection-related hemolysis?
Clostridium perfringens sepsis
What organisms cause direct infection of RBCs, resulting in infection-related hemolysis?
- Babesia microti -- ticks
What are some common causes of Mechanical Intravascular Hemolysis?
- Malfunctioning Mechanical Heart Valve
- "March Hemoglobinuria"
- Microangiopathic Hemolysis -- thrombotic thrombocytopenic purpura (TTP); hemolytic uremic syndrome (HUS); DIC; Preeclampsia/eclampsia/HELLP syndrome; malignant hypertension
Identify the phenomenon shown in the slide below:
Schistocytes (fragments): Microangiopathic Hemolysis -- due to mechanical, intravascular trauma to RBCs
This is a rare form of hemolysis. It is an acquired defect that is intrinsic to the red cell. It is caused by a loss of the RBC complement-protective mechanisms; no antibodies are involved. It affects the hematopoietic stem cells or very early precursors; it affects all types of blood cells, not just red ones. The main problem in this is not hemolysis, however, it is actually thrombosis.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
What are the manifestations of Paroxysmal Nocturnal Hemoglobinuria (PNH)?
- Chronic Intravascular Hemolysis
- Thrombophilia: predominantly venous
- Association with Bone Marrow Failure: aplastic anemia; low-grade myelodysplasia (MDS)
Paroxysmal Nocturnal Hemolysis (PNH) is a relatively common cause of what, also known as Budd-Chiari Syndrome?
Hepatic Vein Thrombosis
Paroxysmal Nocturnal Hemolysis (PNH) is due to a deficiency of glycosylphosphatidylinositol (GPI) anchored proteins (membrane glycoproteins which anchors multiple proteins to cell surface). The critical factor in PNH is a loss of complement protective compounds _______ and _______. This causes an increased sensitivity to alternate pathway of complement activation.
Paroxysmal Nocturnal Hemolysis (PNH) is an acquired somatic mutation of PIG-A gene on what chromosome?
What are the most common symptoms of Paroxysmal Nocturnal Hemolysis (PNH)? What other symptoms are associated with this?
- Fatigue, malaise, & lethargy
- Difficulty swallowing or pain on swallowing; priapism in males; thromboembolic disease; gross hematuria in first morning urine
What is the key diagnostic test for Paroxysmal Nocturnal Hemolysis (PNH)?
Flow cytometry on peripheral blood -- absence of CD55, CD59, and other GPI-anchored proteins
What are the typical laboratory markers of Paroxysmal Nocturnal Hemolysis (PNH)?
- Increased LDH & total Bilirubin
- Decreased Haptoglobin
- Increased Reticulocyte Count
- Leukopenia &/or Thrombocytopenia
- Iron Deficiency
What is the primary treatment for Paroxysmal Nocturnal Hemolysis?
What recombinant antibody against the C5 complement component has been shown to decrease hemolysis and improve the quality of life in patients with PNH? (may also decrease the incidence of thromboembolic events)
- Correction of Iron Deficiency
- Eculizumab (Soliris)