Anemia

Aplastic anemia

• Pancytopenia • Empty marrow (no megakaryocytes or precursors) • Most are idiopathic Causes • Idiopathic • Drugs • Viruses • Pregnancy • Fanconi anemia Clinical findings • Pallor, dizziness, fatigue (anemia) • Recurrent infection (leukopenia) • Bleeding, bruising (thrombocytopenia) Morphology • Blood: empty • Bone marrow: empty Treatment • Avoid further exposure • Give blood products • Drugs: G-CSF, prednisone, ATG • Bone marrow transplant as last resort • 3-year survival: 70%

Morphology of CAHA

• Red cell agglutinates • Rare spherocytes

Morphology of sickle cell anemia

• Sickle cells (detected in homozygous individuals following traumatic events) • Post-splenectomy blood picture o nucleated red blood cells- no spleen quality control o targets o Howell-Jolly bodies- fragments of DNA that remain in RBC, usually removed by spleen o Pappenheimer bodies- granules of iron retained in RBC o INCREASED platelet count- (these usually reside in spleen) Pappenheimer- think of pounding an IRON HAMMER- retained iron in RBC

G6PD clinical findings

• Some patients asymptomatic • Others have episodic hemolysis • Triggers: broad beans (favism), drugs (antibiotics, aspirin) • Spontaneous resolution • Highest incidence of G6PD in areas where malaria is endemic o ?provide inhospitable environment in RBC • Jaundiced sclera

Hemoglobinopathies

• Structurally abnormal hemoglobin- may or may not have clinical presentation depending on how effected structure is by mutation o Usually point mutation on beta chain • Lab test: hemoglobin electrophoresis • Most important hemoglobinopathies: sickle cell anemia

To diagnose sickle cell anemia

• Val-->Glu point mutation in beta chain of HbS changes charge - this will effect the position of the Hb on gel • If pt has sickle cell trait (1 abnormal, 1 normal) then there will be 2 bands on gel- HbS and HbA

Morphology of G6PD deficiency

• Without exposure, no anemia • After exposure, get acute hemolysis o Bite cells, fragments Heinz bodies

Anemia of liver disease

• Anemia is frequent in liver disease • Multiple causes • "Uncomplicated" cases are rare • May see acanthocytes, targets "Uncomplicated" anemia of liver disease: • RBC survival and impaired marrow response Other factors can complicate the picture: • Folate deficiency • Iron deficiency from frequent hemorrhages Morphology -"Uncomplicated" cases: o Mild anemia o Usually normocytic; sometimes macrocytic o Poikilocytosis (targets, acanthocytes) -"Complicated" cases: o Megaloblastosis (from folate deficiency) o Microcytosis (from iron deficiency) Clinical findings • 3/4 of patients with liver disease are anemic! • Most cases are "complicated" • Alcohol abusers may get hemolytic episodes (which resolve with withdrawal of alcohol)

Sickle cell anemia clinical findings

• Blacks (8% are heterozygous) • Severity of disease is variable • Chronic hemolysis • Vaso-occlusive disease • increased infections-->(autosplenectomy)- periods of bleeding/aggregation, infarction, and fibrosis lead to spleen atrophy, decreased function of spleen, increased risk for infection (especially with encapsulated organisms)

Anemia of blood loss

• Cause: traumatic, acute blood loss • At first, hemoglobin is normal! (ratio normal secondary to fluid loss) • After 2-3 days, see increased reticulocytes to fill lost blood • Chronic blood loss is different (it causes iron deficiency anemia).

G6PD deficiency characteristics and pathophysiology

• DECREASED G6PD → INCREASED peroxides → INCREASED cell lysis • Oxidant exposure • Bite cells (removal of Heinz bodies) • Self-limiting RBC death: • W/o glutathione, they can't reduce nasties free radicals • Nasties attack hemoglobin bonds • Heme breaks away from globin • Globin denatures, sticks to red cell membrane ("Heinz body") • Spleen bites out Heinz bodies (Heinz ketchup bodies get eaten by macrophages in spleen--> bite cells)

IDA bone marrow histology

• Erythroid hypoplasia • Decreased iron stores (blue iron stores in normal marrow with special stain)

B12/folate deficiency

• Etiology: o Anemia-- Vitamin B12 and folate are needed for DNA synthesis deoxyuridate to thymidylate- including RBC precursors o Deficiency -B12 - Dietary intake (rare), decreased gastric secretion of intrinsic factor (PA), malabsorption- can have neurologic sequelae • Subacute combined degeneration of the dorsal and lateral spinal columns -Folate-- Poor dietary intake EtOH, malabsorption, increased demand (pregnancy, hemolytic anemias) • Diagnosis o Smear -Macrocytic (High MCV) RBCs, +/- hypersegmented neutrophils, +/- modest neutropenia o B12 -Low serum B12, elevated serum methylmalonic acid levels -Anti-IF Abs, Schilling test (?), PA accounts for 75% o Folate -Serum folate level-- can normalize with a single good meal • Treatment o B12 deficiency: B12 1 mg/month IM, or 1-2 mg/day po o Folate deficiency: Improved diet, folate 1 mg/day -Monitor for a response to therapy. o Pernicious Anemia - monitor for gi cancers.

Sideroblastic anemias

• Heterogenous grouping of anemias defined by presence of ringed sideroblasts in the BM • Etiologies: Hereditary (rare), type of porphyria, Myelodysplasia, EtOH, Drugs (INH, Chloramphenicol) • May need bone marrow to definitively diagnose

Hemoglobin chain development

• HgF- fetal hemoglobin • At birth- Hgb A- alpha2beta2 • Adult= Hgb A- alpha2beta2 o Alpha chain form of thalassemia more severe than beta

Pathophysiology and morphology of CAHA

• IgM, complement coat red cells, falls off in warm body parts • IgM pentamer bridges red cells --> agglutination • Complement STAYS STUCK and may lyse red cells (in blood) but usually just opsonizes them (and macrophages in spleen eat them) • Pathogenesis can be intravascular (IgM) or extravascular (spleen) hemolysis Morphology • Red cell agglutinates • Rare spherocytes

Anemia of chronic disease

• Infections, inflammation, malignancy • Iron metabolism disturbed • Normochromic, normocytic anemia • Anemia usually mild • LOOK NORMAL! Pathogenesis: Disturbed iron metabolism o absorption is okay o ...but release is screwed up o can't get iron into hemoglobin o hepcidin over-produced • Shortened RBC survival • Impaired marrow response to anemia Labs: DECREASED serum iron, DECREASED/nl TIBC (total iron binding capacity decreased secondary to decreased transferrin production over time), INCREASED ferritin, INCREASED marrow storage iron

Direct antiglobulin test

• Looks for antibody on RBC surface • Positive result means it's an autoimmune hemolytic anemia

Blood morphology of megaloblastic anemia

• Macrocytic anemia (based on MCV) • Oval macrocytes • Hypersegmented neutrophils

Bone marrow morphology of megaloblastic anemia

• Megaloblastic erythroblasts • Megaloblastic neutrophils and precursors o Big cells and young nuclei

Anemia of chronic disease pathogenesis

• Normocytic (normal red cell size) • You need a chronic disease (usually inflammatory or infectious) • Microcytic or normocytic anemia • Decreased serum Iron • Decreased serum TIBC (decreased production from liver) • Normal Fe/TIBC ratio (LOW in Iron deficiency) • Normal or increased ferritin

Severe thalassemias

o Make marrow in other areas like the skull in attempt to overcome shortage of hemoglobin o Hair on end pattern of bone marrow on X-ray of skull o Not specific for but also occurs in __________

Clinical findings of beta thalassemia

o Mediterraneans, Blacks, Asians o Thal minor: usually asymptomatic o Thal major: variable severity, usually presents in infancy

Morphology of iron deficiency anemia

Hypochromatic, microcytic anemia-->larger zone of pallor. Not enough hemoglobin Anisocytosis- large range of sizes of cells Poikilocytosis- funny shaped red cells Decreased reticulocytes, increased platelets (reactive thrombocytosis) Elliptocytes (cigar cells)

Post-splenectomy blood picture in SS anemia

o nucleated red blood cells- no spleen quality control o targets o Howell-Jolly bodies- fragments of DNA that remain in RBC, usually removed by spleen o Pappenheimer bodies- granules of iron retained in RBC o INCREASED platelet count- (these usually reside in spleen)

B12/folate and megaloblastic anemia

slowed DNA synthesis and unimpaired RNA synthesis --> immature nucleus and mature cytoplasm

Megaloblastic anemia

-Defective DNA synthesis -Nuclear/cytoplasmic asynchrony -B12/folate -Macrocytic anemia with oval macrocytes and hypersegmented neutrophils

Hereditary spherocytosis

-Tons of spherocytes -Spectrin defect -Splenectomy is curative Clinical triad: ANEMIA, JAUNDICE, SPLENOMEGALY more common aneia (1/5,000) variable age of onset and severity Can have parvovirus induced crises Pathogenesis -Abnormal RBC cytoskeleton (spectrin, actin) -Loss of surface area -Spleen removes spheres Treatment: RBC transfusions, splenectomy if severe (but then more susceptible to encapsulated bacteria like Haemophilus)

Symptoms of anemia

Anemia= reduction below normal in hemoglobin or red blood cell number Usually asymptomatic. Symptoms only occur after persistently prolonged, significantly lower, or very rapid loss of hemoglobin

Pathogenesis and clinical presentation of WAHA

IgG coats red cells (opsonization) Macrophages either: o wolf red cells down whole o nibble at red cells Clinical: • Any age, sex • Variable severity • Splenomegaly

Warm Autoimmune hemolytic anemias (WAHA)

IgG or IgM Spherocytes Destruction happens in the spleen Causes: primary, or secondary cross reactivity from leukemia, AI, infections, drugs

Autoimmune hemolytic anemias (AIHA)

IgG or IgM Spherocytes Destruction happens in the spleen (and/or intravascularly in CAHA) CAN be warm or cold based on when Ig attatches to RNC

Schistocyte formation associated with microangiopathic hemolytic anemia

Associated with what anemia?

Cold Autoimmune hemolytic anemias (CAHA)

IgM, complement Destruction mostly in spleen Some intravascular destruction Agglutination causes: primary, or secondary (infections, lymphoproliferative diseases) Clinical • Chronic hemolysis aggravated by cold • Pallor, cyanosis in cold body parts

Genes in alpha and beta thalassemia

In BETA Problem: defective transcription, translation, or processing of mRNA of -chain gene Severity of defect: • B gene: normal gene • B+ gene: produces some chains • B0 gene: produces NO chains severity minor-->intermediae-->major In ALPHA- chain genes are absent leading to silent --> deadly disease presentation

Reticulocyte counts

Increased reticulocytes (greater than 2-3% or 100,000/mm3 total) are seen in blood loss and hemolytic processes (although up to 25% of hemolytic anemia will present with a normal reticulocyte count due to immune destruction of red cell precursors) Reticulocyte counts are most helpful if extremely low (<0.1%) or greater than 3% (100,000/mm3 total).

Causes of iron deficiency in iron deficiency anemia

Decreased iron intake • bad diet- not common, sometimes in babies • bad absorption- s/p colon resection Increased iron loss • GI bleed- occult bleeding • heavy menses (menorrhagia) • chronic blood loss Increased iron requirement: pregnancy -PREMENOPAUSAL? MENORRHAGIA -ANYONE ELSE? GI BLOOD LOSS

Microcytic anemia

Etiologies • Increased iron requirements o Blood loss o GI disorders o Excessive/prolonged menstruation o Chronic blood donations o Rapid growth in body size between 2 and 36 mo o Pregnancy and lactation • Inadequate supply o Poor nutritional intake in children o Malabsorption. s/p surgery obesity, celiac o Achlorhydria from gastritis or drug therapy Lab testing • Decreased hemoglobin • Microcytic MCV • Decreased serum iron • Increased or normal TIBC (total iron binding capacity) • Decreased iron saturation (Serum Fe/TIBC ratio)

Sickle cell anemia pathophysiology

From point mutation HgS. Ok when bound to O2 but when oxygen dissociates HgS becomes sickle shaped and aggregates/ polymerizes- clog vessels and are fragile

RBC labs

Hemoglobin: how many hemogloblin molecules you have by weight per unit volume (g/dL). Anemic or not? Normal usually 12-15 g/dL RDW (red cell distribution width): how different the cells are from each other in size MCV (mean cell volume): how big the red cells are on average. Normal 80-100 femtoliters • Smaller than average= microcytic • Larger than average= macrocytic

• G6PD deficiency- no glutathione • W/o glutathione, they can't reduce nasties free radicals • Nasties attack hemoglobin bonds • Heme breaks away from globin • Globin denatures, sticks to red cell membrane ("Heinz body") • Spleen bites out Heinz bodies (Heinz ketchup bodies get eaten by macrophages in spleen bite cells)

How does this occur?

IDA blood cell morphology

Hypochromatic, microcytic anemia-->larger zone of pallor. Not enough hemoglobin Anisocytosis- large range of sizes of cells Poikilocytosis- funny shaped red cells Decreased reticulocytes, increased platelets (reactive thrombocytosis) Elliptocytes (cigar cells)

Iron deficiency anemia key points

LABS DECREASED ferritin (storage form of iron)- THIS IS DIAGNOSTIC of iron deficiency. If it is not low it could still be IDA since ferritin is an acute phase reactant and could be elevated secondary to stress INCREASED total iron-binding capacity (transferrin has more empty binding sites secondary to low iron) DECREASED serum iron To treat: find etiology, supplement oral iron

B12 deficiency causes

Lack of IF- pernicious anemia (AI destruction of IF) Pancreatic damage Ileal damage/ resection decreasing absorption Tapeworm

MCV

MCV> 100 macrocytic • B12, Folic acid deficiency (ham and eggs) • Drugs that impair DNA synthesis (AZT, chemotherapy, chronic alcohol use, azathioprine) MCV 80-100 normocytic • Anemia of chronic disease • Mixed deficiencies • Renal failure •Hypothyroidism MCV < 80 microcytic • Iron deficiency • Thalassemia trait • Anemia of chronic disease (30-40%) • Sideroblastic anemias

Morphology of HS (hereditary spherocytosis)

Mild normochromic, normocytic anemia Numerous spherocytes

Iron deficiency anemia signs/symptoms

Most common microcytic anemia Symptoms- fatigue, dizziness. Or asymptomatic Signs- pale, spoon nails, smooth tongue Pica- craving for dirt, ice, windex

Morphology of hemolytic anemia

Normochromic, normocytic red cells Spherocytes- smaller, less membraned RBC, no central pallor Other poikilocytes: • targets • sickles • fragmented red cells

Microangiopathic hemolytic anemia

Physical trauma to red cells Schistocytes Find out why! Etiology: • Things that trigger the clotting system o Malignancy o Obstetric complications o Sepsis o Trauma Also artificial heart valve

To diagnose hemolytic anemia

Signs of increased RBC destruction • serum bilirubin • LDH- lactate dehydrogenase • free haptoglobin- (carries around free hemoglobin) • Hemoglobinemia/-uria - free hemoglobin in the blood or urine Signs of increased RBC production • Reticulocytosis- increased early red cells • Nucleated red cells in blood

MAHA - more severe, err on the side of caution

Similar presentations, if unsure diagnose which?

Microangiopathic hemolytic anemia

Specific to what anemia?

WAHA morphology

Spherocytosis Differentiate from hereditary spherocytosis from DAT- look identical under blood smear

WAHA vs HS

Spherocytosis Differentiate from hereditary spherocytosis from DAT- look identical under blood smear

Uses of B12 in the body

Subacute combined degeneration of the spinal cord- motor and sensory problems Re B12 and anemia: in a patient with macrocytosis, ALWAYS check for B12 deficiency. (Even if folate is low!)

Causes of MAHA

This is associated with ____ Know: Physical trauma to red cells Schistocytes Find out why! Causes of this include triggers of clotting systems (MOST common things that trigger clotting systems). Red cells are getting physically ripped apart o Malignancy o Obstetric complications o Sepsis o Trauma

Anemia of renal disease

To know • End-stage renal failure • Cause: lack of erythropoietin • May see echinocytes Clinical features • End-stage renal failure • Anemia severity roughly correlates with degree of renal failure Management • If mild, need not treat. • If severe, replace erythropoietin.

Morphology of thalassemia

o Hypochromic, microcytic anemia o May be anisocytosis (variation in size) and poikilocytosis (weird shaped cells) (depends on severity of defect) degree of anisocytosis by RDW determines ID from thalassemia • RDW increased- IDA • RDW low- mild thalassemia Also may see: o Target cells o Basophilic stippling

triangulocyte

Which one is specific to o microangiopathic hemolytic anemia?

Schistocytes are associated with forms of hemolytic anemia like microangiopathic hemolytic anemia and G6PD

characteristics: pointy and zone of central pallor associated with which disease?

Autosplenectomy

increased infections in SS patient leads to this finding characterized by periods of bleeding/aggregation, infarction, and fibrosis lead to spleen atrophy, decreased function of spleen, increased risk for infection (especially with encapsulated organisms)

Thalassemia

microcytic anemia (low MCV)- inherited quantitative hemoglobin defect- can't make enough of alpha or beta chains

Clinical findings of alpha thalassemia

o Asians, blacks o Carrier state and thal trait: asymptomatic o HbH disease: moderate to severe disease o Hydrops fetalis: fatal in utero

Types of hemolytic anemia

o Chronic (usually congenital) Well-compensated Sometimes have crises o Acute (usually acquired) Back, abdominal, limb pain Headache, malaise, fever Jaundice, pallor, tachycardia o Inherited Membrane defects Enzyme deficiencies Globin defects o Acquired Autoimmune hemolytic anemia Microangiopathic hemolytic anemia Infection-related Drug-related