lec 4 Hemolytic Anemia: Red cell enzymopathies and membrane disorders

hemolytic anemia

What disorder:

-RBCs are broken down/destroyed faster than body can replace them

-Intravascular or extravascular (or both)

-intrinsic vs extrinsic

intravascular hemolytic anemia

hemolysis of RBCs occurs as a result of mechanical trauma, infection, complement autoantibodies

-hemoglobinemia, hemoglobinuria, hemosiderinuria

extravascular hemolytic anemia

RBCs are destroyed as they pass thru liver, spleen, bone marrow, lymph nodes

-MACROPHAGES destroy structurally defective RBCs

hereditary spherocytosis

what disorder:

-intrinsic issue

-AD genetic defects in VERTICAL shape of cytoskeleton -> rigid, spherical shape

-SPECTRIN, ankyrin, band-3, band 4.2

-RBC has REDUCED deformity -> impairs passage; also get trapped in spleen

incidental finding of spherocytes on blood smear; any age, any severity

presentation of hereditary spherocytosis

inc MCHC and RDW

smear shows spherocytes w/o central pallow

increased osmotic fragility

lab findings of hereditary spherocytosis

-Flow cytometric of EMA BINDING: decreased fluorescence of spherocytes

-Osmotic fragility test: place RBC in hypotonic solution and record fraction of Hb released

confirmatory tests for hereditary spherocytosis

monitor, folic acid, transfusion, splenectomy

management and tx of hereditary spherocytosis

Hereditary elliptocytosis

what disorder:

-intrinsic issue

-AD genetic defect of membrane skeleton -> HORIZONTAL defects

-Proteins: spectrin, protein 4.1

-rare disorder affecting people of AFRICAN and MEDITERRANEAN ancestry

-presents similarly to spherocytosis

-blood smear shows eliptocytes

-increased osmotic fragility

lab findings of hereditary eliptocytosis

folic acid, transfusions, splenectomy

management/tx of hereditary eliptocytosis

G6PD deficiency

what disorder:

-intrinsic issue

-x linked impairment of pentose phosphate pathway

-NADPH NOT created -> not able to reduce GLUTATHIONE -> overwhelmed w/ OXIDATIVE stress -> Hb denatured -> HEINZ bodies

-common stressors: primaquine, dapsone, sulfa drugs, infections, FAVA beans

neonatal hyperbilirubinemia; adults asymptomatic until stressor

presentation of G6PD deficiency

Blood smear shows BITE cells, HEINZ bodies

G6PD activity decreased

labs seen with G6PD deficiency

presence of Heinz bodies, screen for G6PD qualitative/quantitative

diagnosis of G6PD deficiency

phototherapy or exchange transfusion for symptomatic neonates

-refrain from meds/stressors once diagnosis is known

management/tx of G6PD deficiency

pyruvate kinase deficiency

what disorder:

-intrinsic issue

-autosomal recessive defect in PK causes decreased ATP and rigid RBC → extravascular hemolysis

-can’t make ATP

-northern European ancestry

neonatal jaundice soon after birth, splenomegaly, anemia, cholelithiasis

presentation of pyruvate kinase deficiency

blood smear shows ECHINOCYTES, 2,3-BPG level increased

labs seen with pyruvate kinase deficiency

PK enzyme activity testing, genetic evidence

dx of pyruvate kinase deficiency

intrauterine blood transfusions, phototherapy, exchange transfusions, blood transfusions, folic acid

management/tx of pyruvate kinase deficiency

sickle cell anemia

what disorder:

-intrinsic issue

-autosomal recessive disorder of african ancestry causing abnormal shaped hemoglobin

-HbS caused from POINT mutation substitution VALINE for glutamic acid → sickling → intra- and extra-vascular hemolysis

MSK Pain, neuro deficits, chest pain, SOB, infarct, dactylitis

presentation of sickle cell anemia

blood smear shows sickle cells

labs seen in sickle cell anemia

NEWBORN screen, liquid chromatography, hemoglobin ELECTROPHORESIS

diagnosis of sickle cell anemia

Daily and prophylactic: folic acid, vaccines, HYDROXYUREA, penicillin until 5yo

Mild to mod symptoms: hydration, OXYGEN, analgesics, blood transfusions

Severe: transfusions, exchange transfusion, stem cell transplant

management/tx of sickle cell anemia

HbC disease

what disorder:

-intrinsic issue

-AR mutation of B globin gene

-mutation of glutamic acid for LYSINE -> more rigid RBC -> increasing viscosity of the blood -> shortened RBC survival -> EXTRAVASCULAR hemolysis

mild hemolytic anemia

presentation of HbC disease

smear shows intracellular crystals, target cells

labs seen with HbC disease

electrophoresis, liquid chromatography

dx of HbC disease

supportive care, folic acid

management/tx of HbC disease

Paroxysmal nocturnal hemoglobinuria

what disorder:

-off and on COMPLEMENT-mediated intravascular hemolysis causing organ dysfunction

-hematopoietic STEM CELL mutation → defect in SURFACE proteins

-reduced or absent GPI anchored proteins → loss of anchored complement INHIBITORS CD55 and CD59 → hemolysis

pink/RED urine in MORNING, abdominal pain, bone marrow suppression, ED

presentation of Paroxysmal nocturnal hemoglobinuria

1. Coombs negative hemolytic anemia

2. pancytopenia

3. venous thrombosis

triad of Paroxysmal nocturnal hemoglobinuria

-Associated w/ AML

-May have associated IRON deficiency as well

Coombs negative

Flow cytometry shows granulocytes and RBCs deficient in GPI linked CD55/CD59

Urine dip heme positive

normal to low WBC & Ferritin

labs associated with Paroxysmal nocturnal hemoglobinuria

FLOW cytometry shows reduction of loss of CD55/59

Bone marrow biopsy and exam (if leukopenia or thrombocytopenia occurs)

dx of Paroxysmal nocturnal hemoglobinuria

watchful waiting, complement inhibitor, transplant if needed

management/tx of of Paroxysmal nocturnal hemoglobinuria

HUS, TTP, DIC, HELLP

Microangiopathic hemolytic anemias (extrinsic)

hemolytic uremic syndrome (HUS)

What disorder:

-characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, HEMATURIA; often following bloody diarrhea

-Etiology: E. coli O157:H7 infection, SHIGA-like toxin

thrombotic thrombocytopenic purpura (TTP)

What disorder:

-characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neuro abnormalities, kidney dysfunction (classic pentad)

-etiology: decreased ADAMTS13

disseminated intravascular coagulopathy (DIC)

What disorder:

-Thrombocytopenia, microangiopathic hemolytic anemia, THROMBOSIS

-Etiology: inciting event (i.e. sepsis)

HELLP syndrome

What disorder:

-Thrombocytopenia, microangiopathic hemolytic anemia, elevated LIVER enzymes

-Etiology: eclampsia or preeclampsia

traumatic hemolytic anemia

What disorder:

-Causes: mechanical heart valves, calcified/stenotic heart valves

-Presentation: fatigue, jaundice, pallor, SOB

-Labs: decreased Hb, increased reticulocyte count, increased unconjugated bilirubin, increased LDH, decreased haptoglobin, normal platelet count

-Peripheral blood smear: SCHISTOCYTES

warm autoimmune hemolytic anemia

What disorder:

-IgG for Rh group antigens; seen in CLL and LUPUS; spherocytes and agglutinated RBCs

-Definitive: COOMBS positive

-Tx: immunosuppression

cold autoimmune hemolytic anemia

What disorder:

-COLD EXTREMITIES; mostly IgM binding to I antigen + COMPLEMENT; seen in CLL, mycoplasma pneumonia, MONO

-Definitive: COOMBS positive

Tx: avoid COLD, immunosuppression

splenectomy

may be performed theraputically to tx certain conditions

-Risk: Serious life-threatening INFECTIONS w/ ENCAPSULATED organisms (S. pneumoniae, HIB, N. meningitidis); recommended vaccines: pneumonia (PCV 15/20), HIB, meningitis (menactra, bexsero)

-Most children w/ anatomic or functional asplenia get DAILY ANTIBIOTICS until 5yo

-Most adults take abx ONE YEAR post-op

ABO incompatibility

What disorder:

Administration of antigenically incompatible red cells can cause an immediate hemolytic reaction

-If the recipient receives antigenically incompatible red cells, then the recipient’s IgM antibodies will cause complement fixation and intravascular lysis/hemolysis of transfused red blood cells.

-The clinical presentation of the patient depends on how much incorrect blood was given

• If small amount given, patient may develop fever, chills, sob, pain, hemoglobinuria

• If large amount given, patient can go into hypotensive shock and DIC. 

-Treatment: stop transfusion, have intravenous access in case need to support blood pressure

Rh incompatibility

If someone who is Rh Negative is exposed to blood that is Rh Positive than alloantibodies are created; these alloantibodies are only created after blood transfusions or pregnancy

-After the original exposure, alloantibodies are made and if the patient again receives the Rh antigen or Rh positive blood,  then an immune response will occur and hemolysis will ensue

-Indirect Coomb’s: Positive

antigen

blood type (A/B/AB/O) refers to the presence of that _____ on the surface of the blood cell

• A= A antigen; antibodies to B antigen

• B= B antigen; antibodies to A antigen

• AB = A antigen and B antigen; no antibodies → Universal Recipient

• O = O antigen; antibodies to A antigen and B antigen → Universal Donor

D antigen

Rh positive/negative refers to the presence or absence of __ ______ on the RBC surface; it is the most important antigen in transfusion

hemolytic disease of the fetus & newborn (erythroblastosis fetalis)

Mother who is Rh Negative has a child who is Rh Positive, and then mom makes alloantibodies to the Rh antigen

-While pregnant, leakage of fetal red cells across the placenta results in the mother making anti-D antibodies; however, the amount of anti-D antibodies made by the mother that crosses the placenta into the fetal circulation is too low to cause hemolysis

-With subsequent pregnancies, the mother mounts an immunologic response to D+ fetal  red cells, putting the new fetus/newborn at high risk of developing alloimmune hemolysis

-The newborn can develop severe anemia and kernicterus from the unconjugated bilirubin build up from hemolysis, generalized edema; if there are signs of fetal distress then intrauterine transfusion will prevent the development of hydrops and kernicterus

administration of RhoGam (anti-D immunoglobulin) to Rh- pregnant female at 28wks

-suppresses mother sensitization Rh D

treatment of hemolytic disease of the fetus & newborn (erythroblastosis fetalis)