Hemonc Flashcards
G6PD deficiency
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- the first and rate limiting step in HMP pathway, it converts glucose-6-phosphate to 6-phosphogluconate
- NADPH is necessary to keep glutathione reduced
- Oxidizing agents (e.g. fava beans, sulfonamides, primaquine, anti-tuberculosis
- X-linked recessive disorder in some; more prevalent among blacks, may provide malarial resistance due to increased H2O2 in RBCs
-Heinz bodies – oxidized Hemoglobin precipitated within RBCs.
-Bite cells- result from the phagocytic removal of Heinz bodies
by splenic macrophages.
drugs) oxidize Hb, NADPH via GSH reduces Hb
THINK: “BITE into some HEINZ ketchup.”
Heinz Bodies- Oxidization of iron from ferrous to ferric form. Seen in G6PD deficiency or with certain drugs
Erythrocytes and precursors
Carries O2 to tissues and CO2 to lungs
- Anucleate and biconcave
- Life span of 120 days
- 90% of glucose used in glycolysis, 10% in HMP shunt
- Reticulocyte = immature erythrocyte, marker of erythroid proliferation, bluish color on Wright-Giemsa stain (ribosomes)
- Anisocytosis = varying sizes
- Poikilocytosis = varying shapes
- Erythrocytosis =polycythemia= incr. hematocrit
A 30-year-old, previously healthy man passes dark brown urine several days after starting the prophylactic antimalarial drug primaquine. On physical examination, he appears pale and is afebrile. There is no organomegaly. Laboratory studies show that his serum haptoglobin level is decreased (sign of intravascular hemolysis). Which of the following is the most likely explanation of these findings?
A. Mechanical fragmentation of RBCs
B. Increased susceptibility to lysis by complement
C. Nuclear maturation defects resulting from impaired DNA synthesis
D. Impaired globin synthesis
E. Hemolysis of antibody-coated cells
F. Oxidative injury to hemoglobin
G. Reduced deformability of the RBC membrane
- oxidative injury to hemoglobin
- this patient has glucose-6-phosphate dehydrogenase deficiency. A drug that leads to oxidative injury to the RBCs such as primaquine can induce hemolysis. Oxidant injury to hemoglobin produces inclusion of denatured hemoglobin within RBCs. The inclusions damage the cell membrane directly, giving rise to intravascular hemolysis. These cells have reduced membrane deformability and they are removed from the circulation by the spleen
A. Mechanical fragmentation of RBCs
B. Increased susceptibility to lysis by complement
C. Nuclear maturation defects resulting from impaired DNA synthesis
D. Impaired globin synthesis
E. Hemolysis of antibody-coated cells
F. Oxidative injury to hemoglobin
G. Reduced deformability of the RBC membrane
Platelet
Platelet (thrombocyte)
-Small cytoplasmic fragment derived from megakaryocytes -Contains dense granules (ADP, calcium) and α granules (vWF,
fibrinogen, fibronectin)
-Approximately 1/3 of platelet pool is stored in spleen
-Petechiae (< 3mm) if platelets low
White blood cell differentiation
Blood Cell Differentiation
-WBC differential
Neutrophils (60%)
Lymphocytes (30%) - around the size of RBCs
Monocytes (5%)
Eosinophils (2%)
Basophils (1%)
-the last three are unlikely to be seen in peripheral smear unless abnormlality.
Neutrophils Like Making Everything Better
What are normals of leukocytes: Divided into granulocytes (neutrophil, eosinophil, basophil) and mononuclear cells (monocytes, lymphocytes).
4000-11,000 cells/mm^3 or microliter
Neutrophil
- Acute inflammatory response cell. Increased in bacterial infections. Phagocytic. Multi-lobed nucleus. PMN -Small more numerous specific granules contain leukocyte alkaline phosphatase (LAP), collagenase, lysozyme, and lactoferrin,
- Larger, less numerous azurophilic granules (lysosomes) contain acid phosphatase, myeloperoxidase, and β-glucuronidase
- Hypersegmented polys (6 or more lobes) are seen in vitamin B12/folate deficiency
- Band forms seen in CML and infection
- PMN chemotactic factors: IL-8, LTB4, C5a, PAF
Respiratory burst and CGD
Respiratory Burst (Oxidative Burst) -Involves the activation of the phagocyte NADPH oxidase complex - end product is HClO radical aka bleach which is formed from myeloperoxidase converting H2o2 into bleach -the NADPH will prevent escaped H2O2 from killing the PMN by converting it into water -Note that NADPH plays a role in both the creation (O2 radical via NADPH oxidase( deficiency leads to chronic granulomatous disease) and neutralization (via GSH) of ROS Myeloperoxidase contains a blue-green heme- containing pigment that gives sputum its color.
[CGD]
Phagocytes of patients with chronic granulomatous disease (CGD) who lack NADPH oxidase can still utilize H2O2 generated by invading organisms and convert it to ROS. However CGD patients are at increased risk for infection by catalase positive species (S. aureus, Aspergillus which breakdown H2O2) - all organisms generate H2O2 to kill related organisms so they can have prominence. If you are invaded by a catalase positive species which gets rid of hydrogen peroxide by themselves and also no H2O2 are generated so these patients are more vulnerable
Eosinophils and Basophils
Eosinophil -Defends against helminthic infections (major basic protein). Bilobed nucleus.
-Produces histaminase (helps limit reaction following mast cell degranulation) (limiting basophils) and major basic protein (MBP, a helminthotoxin) which kills helminths
Loves to eat antigen-antibody complex
Causes of eosinophilia (elevated eosinophils= NAACP Neoplastic Asthma Allergic processes Chronic adrenal insufficiency Parasites (invasive)
Basophil
- Mediates allergic reaction
- basophil granules containing heparin (anticoagulant), histamine (vasodilator) and leukotrienes.
- Elevated in CML
Mast cell
- Mediates allergic reaction in local tissues. Resembles basophils with basophilic granules
- Can bind the Fc portion of IgE to membrane. IgE cross-links upon antigen binding
- **Cromolyn sodium prevents mast cell degranulation (used for asthma prophylaxis) ‘
- Degranulation leads to release of histamine, heparin, tryptase, leukotrienes and eosinophil chemotactic factors.
Basophils & Mast Cells are similar but arise from different lines
Easy- A 10-year-old male patient is diagnosed with an acute bacterial infection. His blood leukocyte count was 38,000 cells per µL (reference range: 4,000 to 11,000 per µL). The predominant cell type found in increased numbers in this patient’s blood is
A. Eosinophils B. Neutrophils C. Monocytes D. B cells E. Dendritic cells
Neutrophils - could have lots of lobes or could look like what? Bands. All band is is that sausage thing, neutrophil that is pushed out early before its lobes are formed.
VitK
Vitamin K Function: Reduced vitamin K catalyzes γ-carboxylation of glutamic acid. Necessary for the synthesis of clotting factors II, VII, IX, X and proteins C, S and Z. Warfarin – vitamin K antagonist
Deficiency: Vitamin K not found in breast milk. So neonates are given a vitamin K injection at birth to prevent hemorrhage. VitK comes from gut bacteria which babies don’t have- no food yet. Vit. K deficiency can also occur after prolonged use of broad-spectrum antibiotics because no gut bacteria are present to synthesize vitamin K.
A 63 year old man with adenocarcinoma of the colon presents with a 1 month history of widespread eccymoses. On PE he appears cachetic and pale. Laboratory studies show hemoglobin 8.5 g/dL (normal 11-15); platelet count, 15,000/ mm3 (normal 150-440K); WBC count, 9000/mm3 (normal 4-11K); prothrombin time, 30 seconds (normal 11-15); partial thromboplastin time, 55 seconds (normal 25-40); very elevated FDP and D-dimer levels; and very low fibrinogen levels. What is the best explanation for the patient’s condition?
A. Thrombocytopenia due to a bone marrow defect B. Vitamin K deficiency due to broad spectrum antibiotic use C. Disseminated intravascular coagulation caused by a mucin- containing procoagulant D. Chronic blood loss from colon cancer
DIC caused by mucin-containing procoagulant - all the clots - hemoglobic anemia.
A: Prothombin time and PTT are both off and they shouldn’t
B: he may have defect in PT and PPT: shouldn’t have problem with platelets
D: he would have anemia but not problem with platelets
Procoagulants from the adenocarcinoma activate non-specific coagulation throughout the body consuming coagulation factors and platelets. Cancers usually cause a chronic type of DIC as described here. Acute causes of DIC include sepsis, burns and obstetric complications
Which of the following is a vitamin K–dependent factor that is activated by thrombin and limits coagulation by cleaving activated factors V and VIII.
A. Protein C B. Protein S C. Antithrombin III (ATIII) D. Plasminogen E. Prekallikrein
Protein C:
thrombin activates factors 8 and 5 to enhance coagulation. Thrombin also activates protein C which in turn degrades factors VIII and V to limit coagulation. This is important feedback loop
A 5-year-old boy has had a history of easy bruising and blood in his urine since infancy. The is a bleeding history in the family. He has several ecchymoses of the skin on the lower extremities. Laboratory studies show hemoglobin, 13.1 g/dL (normal) platelet count, 287,600/mm3 (normal); WBC count, 6830/mm3 (normal); prothrombin time, 13 seconds (normal 11-15); activated partial thromboplastin time, 54 seconds (normal 25-40). If he does not receive appropriate treatment, which of the following manifestations of this illness is most likely to ensue?
A) Splenomegaly B) Petechiae C) Hemolysis D) Hemochromatosis E) Hemarthroses
E) Hemarthroses
The patient likely has hemophilia A. With low factor VIII activity, there is severe disease and joint hemorrhages are common, leading to severe joint deformity and ankylosis
There is blood in the urine, bleeding history in the family, why do you think intrinsic instead of extrinsic? APTT is abnormal, the PT is normal so it can’t be extrinsic. Deep bleeding.
Prothrombin Time (PT) measures the integrity of the extrinsic system as well as factors common to both pathways. The international normalized ratio (INR) is a derivative of PT. Activated Partial Thromboplastin Time (aPTT), which measures the integrity of the intrinsic system and the common components. Thrombin time (TT) is rarely used
A 23-year-old woman has had a history of bleeding problems all of her life, primarily heavy menstruation and bleeding gums. A sister and an uncle also have bleeding problems. Physical examination shows several bruises. Laboratory studies show hemoglobin, 9.5 g/dL (normal 11-15); platelet count, 229,300/mm3 (normal 150-440K); WBC count, 7185/mm3 (normal 4-11K); prothrombin time, 12 seconds (normal 11-15); and partial thromboplastin time, 46 seconds (normal 25-40). Ristocetin-dependent platelet aggregation in patient plasma is markedly reduced. Ristocetin acts as a denuded blood vessel wall. Which of the following responses should the physician use when advising the patient of potential consequences of this disease?
A) You might need allogeneic bone marrow transplantation B) Expect increasing difficulty with joint mobility C) Anticoagulation is needed to prevent deep venous thrombosis
D) You could experience excessive bleeding after oral surgery
E) A splenectomy might be necessary to control the disease
The answer is D. An inherited bleeding disorder with normal platelet count suggests a common bleeding disorder, von Willebrand disease. In most cases it is inherited as an autosomal dominant trait. A reduction in the quantity of vWF impairs platelet adhesion to damaged walls and hemostasis is compromised. Because vWF acts as a carrier for Factor VIII the level of this procoagulant protein is diminished and the apttt is elevated.
Why is it not B? Hemearthroses
Ristocetin is a factor that mimics a blood vessel wall and shows you if patient blood and VWF works
70-year-old male presents to his primary care physician for complaints of fatigue. The patient reports feeling tired during the day over the past 6 months. Past medical history is significant for moderately controlled type II diabetes. Family history is unremarkable. Thyroid stimulating hormone and testosterone levels are within normal limits. Complete blood cell count reveals the following: WBC 5.0K, hemoglobin 9.0, hematocrit 28%, and platelets 350K. Mean corpuscular volume is 76. Iron studies demonstrate a ferritin of 15 ng/ml (nl 30-300). Of the following, which is the next best step?
A. Bone marrow biopsy B. Blood transfusion C. Gel electrophoresis D. Coombs test E. Colonoscopy
Colonoscopy - the most likely anemia in general is iron deficiency anemia. In a patient of this age, blood loss from colorectal cancer should be suspected so a colonoscopy would be the next best step.
A 37-year-old woman presents to her primary care physician with a 6-month history of fatigue. She denies any recent history of fevers, chills or headaches. She does not smoke or drink alcohol. A complete blood count demonstrates a normocytic anemia. Iron studies are ordered and demonstrate the following: Reticulocyte production index (RPI) = 1.4 Serum iron: 41 µg/dL (normal 50–170 µg/dL) TIBC: 230 µg/dL (normal 250–370 µg/dL) Transferrin saturation: 18% (normal 15–50%) Serum ferritin: 180 µg/L (normal 15-150 µg/L)
Which of the following is a likely cause of this patient’s iron studies findings?
A. Lead poisoning B. Dysfunctional uterine bleeding C. Splenic sequestration of RBCs D. Rheumatoid arthritis E. RBC enzyme deficiency
Rheumatoid arthritis
Anemia of chronic disease
What is the WHO definition of anemia
and normal hematocrit values
The World Health Organization (WHO) defines anemia as a hemoglobin level
- < 13 g/dL in men
- <12 g/dL in non-pregnant women.
During pregnancy, women hemoglobin would be lower.
Hematocrit - if you have 100% of your blood volume, what percent is packed red blood cells
The mean hematocrit value for
adult males is 47% (normal, 40-54)
for adult females is 42% (normal, 37-47). Hematocrit is a less reliable indicator of anemia than hemoglobin due to changes in plasma volume and hemoglobin concentrations.
Anemia - hematocrit = 30%
Polycythemia - hematocrit = 70%
Dehydration - hematocrit = 70%
Hematocrit is really dependent on hydration status.
Y/N
- More reticulocytes should be found in patient with anemia?
- Young reticulocytes should last longer in the blood than old reticulocytes?
- Reticulocytes should be increased no matter the cause of anemia?
- yes
- yes
- yes
What are two corrections for reticulocyte count?
Correction #1 for Anemia: Produces the corrected reticulocyte count.
In a person whose reticulocyte count is 10%, hemoglobin 7.5 g/dL, and hematocrit 23%, the absolute reticulocyte count = 10 × (7.5/15) [or × (23/45)] = 5% (adequate response to anemia)
Correction #2 for Longer Life of Prematurely Released Reticulocytes in the Blood: Produces the Reticulocyte Production Index (RPI).
In the same person, the RPI is the corrected reticulocyte count divided by 2, which reflects the increased life expectancy of prematurely released reticulocytes RPI= 5/2= 2.5
-reticulocytes that are young will last longer, you have to divide by approximate lifespan of reticulocytes. 5% divided 2 > RPI = 2.5. That number we will use to determine if the response of the marrow is good. In the end that is the number that is the bar where we decide if marrow is good or not. 2.5 or greater regardless of degree of anemia there is GOOD production from the marrow
A healthy 19-year-old woman suffered blunt abdominal trauma in a motor vehicle accident. On admission to the hospital, her initial hematocrit was 33%, but over the next hour, it decreased to 28%. A paracentesis yielded serosanguineous fluid. She was taken to surgery, where a liver laceration was repaired, and 1 L of bloody fluid was removed from the peritoneal cavity. She remained stable. A CBC performed 5 days later is most likely to show which of the following morphologic findings in RBCs in the peripheral blood?
A) Reticulocytosis B) Basophilic stippling C) Hypochromia D) Schistocytes
The acute blood loss in this case probably intraperitoneal hemorrhage results in reticulocytosis from marrow stimulation by anemia
Schistocytes: are not sickle cells, they are little shitty cells. Here I am, I am a pudgy RBCs, if there is narrowing in vascularity, I get fragmented. Like in DIC - blood vessels lined by clots, if these cells go through them they get fragmented.
What are the size values in anemia in femptoLiters
Microcytic <80fL
Normocytic 80-100fL
Macrocytic >100fL
- Microcytes are associated with poor cytoplasmic maturation- no Hb
- Macrocytes are associated with poor nuclear maturation - form more hemoglobin during this time and grow larger
Pathologic RBC forms
Acanthocyte Basophilic Stippling Dacrocyte (tear drop cell) Bite cell Burr cell Hereditary elliptocytosis Macro-ovalocyte Ringed Sideroblast Schistocyte Spherocytosis Target Cell Heinz bodies Howell-jolly bodies
- Acanthocyte: Liver disease, cholesterol dysregulation
- Basophilic Stippling: Myelodysplastic syndromes, sideroblastic anemias, Lead poisoning (subset of sideroblastic)
- Dacrocyte: (teardrop cell) Myelofibrosis [shed a tear]
- Bite cell: G6PD deficiency - removing oxidized hemoglobin
- Burr cell: ESRD, PK deficiency Energy trouble in cells, more uniform projections versus acanthocyte
- Hereditary elliptocytosis: asymptomatic, caused by mutation in genes encoding RBC membrane proteins (spectrin)
- Macro-ovalocyte: Megaloblastic anemia (also hypersegmented PMNs), marrow failure
- Ringed Sideroblast: Sideroblastic anemia. Excess iron in mitochondria=pathologic - seen when stained for iron, incorporated in mitochondria in the last step, when iron isn’t incorporated you see it heavily staining in the mitochondria
- Schistocyte DIC, TTP/HUS, mechanical hemolysis (e.g. heart valve prosthesis)
- Spherocytosis Hereditary, autoimmune hemolytic anemia - not as flexible - loss of plasma membrane.
- Target Cell Asplenia, Liver disease, Thalassemia - looks opposite from the normal central pallor- dark middle and ring, why? Spleen should filter out crappy RBCs,
- Heinz bodies Oxidation of iron from ferrous to ferric form. Seen in G6PD deficiency. SH to S-S. Leads to bite cells
- Howell-Jolly bodies (nuclear remnants) Normally removed from RBCs by splenic macrophages. Seen in patients with functional hyposplenia or asplenia
Microcytic, hypochromic (MCV< 80 fL) anemia
Iron deficiency-most common
Decreased iron due to chronic bleeding (GI loss, menorrhagia), malnutrition, gastrectomy (acids promotes Fe2+ form which is more readily absorbed) increased demand (pregnancy), hookworm (developing world)
Findings: decreased iron and ferritin, and increased TIBC. Fatigue, conjunctival pallor, pica (consumption of nonfood substances), spoon nails (koilonychia)
May manifest as Plummer-Vinson syndrome (triad of 1. iron deficiency anemia, 2. esophageal webs, and 3. atrophic glossitis)
Central pallor > 1/3 of RBC diameter is a marker of hypochromia
How do each of these change? Serum iron TIBC Ferritin - storage form) % transferrin sat
in
Iron deficiency
ACD
Hemochromatosis
Pregnancy/Contraceptive use
Iron deficiency: Serum iron - decreases TIBC - increases Ferritin - storage form) - decreases % transferrin sat - really decreases
ACD
Serum iron - decreases
TIBC - decreases
Ferritin - storage form) - increases
% transferrin sat - normal (not iron deficiency)
-inflammation of the liver, IL stimulate the liver to make hepsiden - blocks ferroportin which means iron can’t get out of the enterocyte, sloughs and lose in the stool. You block ability of iron to get in. Hepsiden also blocks transport of liver outside. You have iron trapped in these organs. TIBC reciprocal is low
Hemochromatosis Serum iron - increases TIBC - decreases Ferritin - storage form) - increases % transferrin sat - really increases -high iron, very high ferritin, high saturation. You can set off the metal detector.
Pregnancy Serum iron TIBC - increases Ferritin - storage form) - N/A % transferrin sat -decreases
Iron deficiency has low iron stores (ferritin) with a compensatory increase in TIBC
• Anemia of chronic disease (ACD) due to inflammation has ferritin trapped in cells and a low TIBC.
Alpha-thalassemia
α-thalassemia
Two genes on each chromosome 16, four genes total
α -globin gene deletions > decreased α-globin synthesis.
Cis deletion prevalent in Asian populations; trans deletion prevalent in African populations.
1 allele deletion no anemia
2 allele deletion- mild microcytic anemia
3 allele deletion – HbH disease. Very little α-globin. Excess β-globin forms β4 (HBH) - microcytic anemia
4 allele deletion- No α-globin. Excess γ-globin forms γ4 (causes fatal hydrops fetalis). More likely in Asians
beta-thalassemia
β -thalassemia
One beta gene on each chromosome 11, two total. β+ mutant, β0 absent
Prevalent in Mediterranean and AA populations
β-thalassemia minor (heterozygote): β/β+ Diagnosis confirmed by increased HbA2 (alpha2delta2)>2.5% ) and/or HbF (α2γ2, >1.0%) on Hb electrophoresis
β-thalassemia major (homozygote): β0/β0 (β chain is absent, >95% HbF); β+/β+ (>70% HbF) - means if both are mutated as opposed to both absent
Severe anemia with target cells requiring blood transfusion. Marrow expansion (crew cut on skull x-ray). Chipmunk facies. Increased risk of parvovirus B19-induced aplastic crisis - it wipes out this hyperplastic bone marrow. HbF is protective in the infant and disease only becomes symptomatic after 6 months.
(something important I realized, in alpha thal you can still make tetramers of beta and make RBCs, in beta thal major, alpha globins can’t make tetramers, you make precipitates, and its toxic killing RBC precursors. This is why you have the associated target cell (low hemoglobin), extramedullary hematopoiesis, and aplastic crisis due to PARVO
Sideroblastic anemia
Sideroblastic anemia Defect in heme synthesis: in forming the protoporphyrin ring (the first step)
most common cause alcohol (acquired), myelodysplastic syndrome, genetic X-linked defect in δ-ALA synthase, vitamin B6 deficiency, copper deficiency
Findings: high serum iron (not used), high ferritin, low TIBC, high saturation, basophilic stippling (retained rRNA)
Treatment: Pyridoxine (B6, cofactor for delta ALA synthase) - minor enzymatic defect may respond
Lead poisoning
Lead inhibits *ferrochelatase and δ-ALA dehydratase, ringed sideroblast and basophilic stippling
Symptoms: (LEAD)
Lead Lines on gingivae (Burton Lines) and long bones.
Encephalopathy and Erythrocyte basophilic stippling.
Abdominal colic and sideroblastic anemia.
Drops- wrist and foot drop.
(these are severe chronic lead poisoning and are not that useful) - usually just have suspicion and test positive for lead
Treatment: Chelation with dimercaprol and EDTA
A 73-year-old man has been healthy all his life. He takes no medications and has had no major illnesses or surgeries. For the past year, he has become increasingly tired and listless, and he appears pale. Physical examination shows no hepatosplenomegaly and no deformities. CBC shows hemoglobin, 9.7 g/dL (nl 13-17); hematocrit, 29.9% (nl 40-54); MCV, 69 mm3; platelet count, 331,000/mm3 (nl 150-400K); and WBC count, 5500/mm3 (nl 4.5-11K). Which of the following is the most likely underlying condition causing this patient’s findings?
(A) Occult malignancy (B) Autoimmune hemolytic anemia (C) β-Thalassemia major (D) Chronic alcoholism (E) Vitamin B12 deficiency (F) Hemophilia A
A) malignancy
This patient has microcytic anemia - MCV is low
first thing to think about is blood loss > occult malignancy in the colon.
this patient has microcytic anemia which is typical of iron deficiency. Iron deficiency is the most common form of anemia worldwide. The lack of iron impairs heme synthesis. The marrow response is to downsize the RBCs eventually resulting in a microcytic and hypochromic anemia. At this patient’s age, bleeding from an occult malignancy should be strongly suspected as the cause of iron deficiency.
A 32-year-old woman from Saigon, Vietnam, gives birth at 34 weeks’ gestation to a hydropic stillborn male infant. Autopsy findings include hepatosplenomegaly and cardiomegaly, serous effusions in all body cavities, and generalized hydrops. No congenital anomalies are noted. There is marked extramedullary hematopoiesis in visceral organs. Which of the following findings is most likely to be present on hemoglobin electrophoresis of the fetal RBCs?
(A) Hemoglobin A1 (B) Hemoglobin A2 (C) Hemoglobin Bart’s (D) Hemoglobin C (E) Hemoglobin E (F) Hemoglobin F (G) Hemoglobin H
C)
The infant had alpha- thalassemia major, which is most likely to occur in individuals of Southeast Asian ancestry, each of whose parents could have two abnormal alpha-globin genes on chromosome 16. A complete lack of alpha-globin chains precludes formation of hemoglobins Alpha1, Alpha 2 and F. ONly a tetramer of gamma chains (bart’s hemoglobin can be made leading to severe fetal anemia, Inheritance of three abnormal alpha globin chains leads to hemoglobin H disease with tetramers of beta chains;survival to adult hood is possible. Hemoglobin C and E produce mild hemolytic anemias
Anemia of chronic disease
Inflammation > increased hepcidin from the liver > inhibits iron transport > decreased release of iron from macrophages and decreased iron absorption from gut.
Associated with conditions such as rheumatoid arthritis, SLE, neoplastic disorders and chronic kidney disease
Decreased serum iron and TIBC; increased ferritin
Can become microcytic like iron deficiency anemia. Iron can’t reach the bone marrow where it is needed to make erythrocytes
Treatment: EPO (chronic kidney disease only)
Aplastic anemia
Aplastic Anemia Caused by destruction of myeloid stem cells due to:
- radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites),
- viruses (parvovirus B19, EBV, HIV, HCV),
- Fanconi anemia (DNA repair defect),
- idiopathic primary stem cell defect
Pancytopenia: all cell types are down, RBC, WBC, platelets. Normal cell morphology, but hypocellular bone marrow with fatty infiltration (dry bone marrow tap)
Symptoms: Fatigue, malaise, pallor, purpura (low platelets-bleeding), mucosal bleeding, petechiae, infection
Treatment: immunosuppressives, allogenic bone marrow transplantation, RBC and platelet transfusion, bone marrow stimulation with colony stimulating factors. You can’t transfuse WBC as they have MHC class 1.
What is the classic and other viruses that cause aplastic anemia
*Parvovirus B19, EBV, HIV, HCV
Intravascular vs extravascular hemolysis
Intravascular hemolysis Findings: decrease haptoglobin, increased LDH and some increase in unconjugated bilirubin, hemoglobinuria, and hemosiderinuria,
Causes: paroxysmal nocturnal hemoglobinuria, G6PD deficiency, micro/macro angiopathic anemia, malaria
Extravascular hemolysis Findings: macrophage in spleen clears RBCs - outside the blood circulation. Increased LDH plus large (breakdown if much more effective) increase in unconjugated bilirubin (from heme breakdown in macrophages), which causes jaundice but NO hemoglobinuria/hemosiderinuria. (most of the breakdown goes right into the blood)
Causes: RBC membrane defect, RBC enzyme defect, hemoglobinopathies (S and C), autoimmune
How do each of these differ in intravascular and extravascular hemolysis
Serum Haptoglobin urine hemoglobin urine hemosiderin Unconjugated bilirubin Serum LDH
Intravascular: Serum Haptoglobin- absent urine hemoglobin - present urine hemosiderin - present Unconjugated bilirubin - elevated Serum LDH - elevated
Extravascular: Serum Haptoglobin - mildly reduced - minimal spilling of heme urine hemoglobin - absent urine hemosiderin - absent Unconjugated bilirubin - very elevated Serum LDH - elevated
INTRINSIC hemolytic anemia
4 kinds
- Hereditary spherocytosis: Defect in proteins interacting with RBC membrane skeleton and plasma membrane causes premature removal of RBCs by spleen. - vertical posts interact with spectrin allows an RBC to be biconcave. Spherocyte exposed to macrophage chews on it, gets some cell membrane off forming a spherocyte. - spleen is taking this out, its extravascular predominantly but intrinsic defect.
Findings: Splenomegaly, aplastic crisis (parvovirus B19) Labs: Osmotic fragility test Treatment: Splenectomy which resolves hemolysis but Howell-Jolly bodies appear - G6PD deficiency: Most common enzymatic disorder of RBCs. X-linked recessive so disease of males. Increased RBC susceptibility to oxidant stress (no reduced glutathione) when exposed to sulfa drugs, anti-malarials, infections, fava beans. Heinz bodies and bite cells - from splenic macrophages .
- Pyruvate kinase deficiency: Defect in pyruvate kinase > decreased ATP > rigid RBCs > extravascular hemolysis. Newborn hemolytic anemia - it only uses glycolysis - terminal enzyme is pyruvate kinase. RBC can’t form the biconcave shape, taken out vascularly.
- HbC:Glutamic acid-to-lysine mutation in β-globin. Patients with HbSC (1 of each mutant gene) have milder disease than have HbSS patients Labs (homozygotes) target cells
- valine is uncharged allowing hemoglobin to stick together. glutamic acid is negative charge but this is why hemoglobin sickles when sticking together .IN contrast, glutamic acid is negative, lysine is positive. You’ve changed a negative to positive. You get target cells with HbC.
Sickle Cell anemia
Sickle Cells Anemia: HbS point mutation (substitution of glutamic acid with valine) at position 6. 8% of African Americans carry the HbS trait. Low O2, dehydration or acidosis precipitates sickling > anemia, and vaso-occlusive disease. This gives the Hb a new ability to polymerase when deoxygenated
HbS/β-thalassemia heterozygote: mild to moderate sickle cell disease depending on amount of β-globin - sickle trait has one normal beta and one sickle. Sickle beta thal would have even less beta. More likely to sickle.
Findings: Newborns are initially asymptomatic because of increased HbF and decreased HbS. “Crew Cut” on skull x-ray due to marrow expansion from increased erythropoiesis (also in thalassemias). Sickle cells on smear. Crew cut: Bone marrow expansion in the calvara. Anytime bone marrow is hyperactive is going to produce an aplastic crisis by effecting the stem cells.
Complications:
-Aplastic crisis
(Parvovirus B19),
-Autosplenectomy (Howell-Jolly bodies)> increased risk of infection with encapsulated organisms (common cause of death in children),
-Salmonella osteomyelitis,
-Extramedullary hematopoiesis,
-Dactylitism (swollen fingers from vaso- occlusion),
-Acute chest syndrome (common cause of death in adults),
-Renal papillary necrosis (due to low O2 in papilla.
Treatment: hydroxyurea (increased HbF) and hydration
Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal Nocturnal Hemoglobinuria
Acquired mutation in a hematopoietic stem cells. Increased complement- mediated RBC lysis (impaired synthesis of GPI anchor for decay accelerating factor that protects RBC membrane from complement). Mild respiratory acidosis at night triggers hemolysis. 10% of patients > acute leukemia.
Triad: Coombs (-) hemolytic anemia, pancytopenia, and venous thrombosis (cause of death)
Labs: CD55/59 (-) RBCs on flow cytometry, low or no haptoglobulin.
Treatment: Eculizumab (complement pathway inhibitor)
Only pure cause of intravascular hemolysis due to an intrinsic RBC defect.
4 kinds of extrinsic hemolytic normocytic anemia
Autoimmune hemolytic anemia (AIHA)
Warm agglutinin (IgG)- chronic anemia seen in SLE (most common), CLL, α-methyldopa, pencillin.
Cold agglutinin (IgM)- acute anemia triggered by cold; seen in CLL, Mycoplasma and Mononucleosis. RBCs agglutinate and may cause painful, blue fingers and toes with cold exposure.
Many warm and cold AIHA are idiopathic but most are Coombs (+)
Microangiopathic anemia: RBCs are damaged when passing through obstructed or narrowed vessel lumina. DIC, TTP-HUS, SLE, and malignant hypertension. Schistocytes (helmet cells) due to mechanical destruction of RBCs
Macroangiopathic anemia: Prosthetic heart valves and aortic stenosis may also cause hemolytic anemia secondary to mechanical destruction. Schistocytes on peripheral blood smear
Infections:
Malaria, Babesia invade RBCs and cause lysis
A 17-year-old boy reports passage of dark urine to his physician. He has a history of multiple bacterial infections and venous thromboses for the past 10 years, including portal vein thrombosis in the previous year. On physical examination, his right leg is swollen and tender. CBC shows hemoglobin, 9.8 g/dL; hematocrit, 29.9%; MCV, 92 µm3; platelet count, 150,000/mm3; and WBC count, 3800/mm3 with 24% segmented neutrophils, 1% bands, 64% lymphocytes, 10% monocytes, and 1% eosinophils. He has a reticulocytosis, and his serum haptoglobin level is very low. A mutation affecting which of the following gene products is most likely to give rise to this clinical condition?
(A) Spectrin (B) Glucose-6-phosphate dehydrogenase (C) Phosphatidylinositol glycan A (PIGA) (D) β-Globin chain (E) Factor V (F) Prothrombin G20210A
C)
portal vein thromboses is odd.
WBC count: low
Paroxysmal nocturnal hemoglobinuria is an acquired disorder in the myeloid stem cell membrane produced by a mutation in the PIGA gene. Mutation in this gene prevents the membrane expression of certain proteins that require a glycolipid anchor. These include proteins that protect cells from lysis by spontaneously activated complement. As a result, RBCs, granulocytes, and platelets are exquisitely sensitive to the lytic activity of complement. The RBC lysis is intravascular, patients can have hemoglobinuria (dark urine. Defects in platelet function are believed to be responsible for venous thrombosis
