Untitled

• Disorders of the blood can be categorized into three main types: red cell disorders, white cell disorders, and clotting disorders.
• Clotting disorders include issues with platelets and factors.

Roadmap of Topics

• The following topics regarding blood related disorders will be covered
• Red cell disease
• Morphology of RBC and Lab tests, including blood loss
• Hemolytic disease
• White blood cell disease
• Blood cancers
• Bleeding disorders

Red Cell Disease: Types and Characteristics

• There are three ways to develop red cell issues
• Loosing RBCs
• Hemolysis
• Decreased production of RBCs
• Anemia leads to shortness of breath, organ failure, and shock.
• Chronic anemia leads to pallor, fatigue, presyncope/syncope and can result in growth retardation and bone deformities.

RBC Morphology and Blood Tests

• Erythropoietin (EPO) is the growth factor responsible for making new RBCs.
• Red cells measured with Hgb/Hematocrit both measure the Hg directly.
• Mean Corpuscular Volume (MCV) helps distinguish the size type of disease.
• The reticulocyte count measures the young cells
• Helps distinguish between hemolytic and agenerative anemia.
• Iron is measured by testing iron level, iron binding capacity, and ferritin.
• Bilirubin is measured in conjugated and unconjugated forms
• Helpful in differentiating hemolytic anemia
• Folate and B12 can show Macrocytic anemia
• Hemoglobin electrophoresis distinguishes between hemoglobin abnormalities.
• The Coombs test detects anti-body mediated hemolytic anemia.
• Measure the change of hemoglobin, because anemia is relative
• "anemia relates to blood-holder"
• When anemia onset is slow
• O2 deficit leads to increased cardiac output, respiratory rate
• Red cell 2,3-diphosphoglycerate (DPG) enhances the release of 02 from hemoglobin, which helps compensate for chronic anemia.
• More than 20% blood loss often leads to shock and is often fatal.
• At first hemoglobin reads are normal
• Over the next few days, hemodilution begins and the full effect of anemia shows up, similar once IV fluids are given to a trauma patient.

Chronic Blood Loss and Iron Levels

• Chronic blood loss gradually depletes iron stores.
• Proper Hgb cannot be made without iron
• A chronic anemia of underproduction occurs
• Chronic bleed is indicated by:
• Low serum iron, because the body doesn't have iron
• High TIBC, because the body attempts to grab more iron
• Low ferritin, because this is the body’s major storage protein for iron
• High ferritin, think anemia of chronic disease

Hemolysis: Lab Evaluation and Pathophysiology

• RBCs live 120 days - in RBC destruction, lifespan is shortened
• In hemolysis, RBCs are lysed when they die
• Leads to the release of unconjugated bilirubin
• Unable to be conjugated through normal delivery to the liver
• Hemolysis causes low 02, increased EPO, and increased production of reticulocytes.
• To confirm, check the reticulocyte count.

Hemolysis

• Hemolysis can be classified by cause: intravascular or extravascular.
• Extravascular Hemolysis:
• Defects destroy the RBCs with phagocytes - a spleen issue
• Spleen needs cells be able to change shape to move through it.
• Otherwise cells are stuck, known as "sequestration"
• The macrophages ingest cells that do not have optimal deformability
• Extravascular Hemolysis has additional findings:
• Hyperbilirubinemia and jaundice occur
• Late-stage causes gallstones and cholelithiasis
• Leads to Splenomegaly
• Pathway: RBC houses Hgb, which inside the cell breaks releasing bili as a byproduct + disease causes RBC to not be pliant | RBCs stuck in spleen spleen houses macrophages for such purpose lets unconjugated bili into bloodstream jaundice and gallstones, as can splenomegaly

Intravascular Hemolysis

• Intravascular occurs with direct insult to a RBC that bursts it directly in the blood stream.
• Examples include turbulence from defective heart valve, complement destruction, and toxins
• Hemoglobin is released into the blood and passes into the urine
• Some Hg is processed into hemosiderin which builds in the kidney and then lost in urine
• Both intravascular and extravascular hemolysis have:
• Increased unconjugated bilirubin
• Decreased haptoglobin - This is a plasma protein that binds free hemoglobin and removes it from circulation

Hereditary Spherocytosis

• This is an autosomal dominant trait
• Leads to intrinsic defect in RBC membrane leading to spherical, non-deformable cell.
• This results in sequestration and destruction in the spleen
• Mutations in ankyrin or spectrin proteins, both structural cell membrane proteins
• Causes blebs to form at the membrane surface which are then shed
• Bit by bit, cytoplasm bits are released which decreases surface to volume ratio forming a sphere
• These spherical RBCs are destroyed by macrophages in the spleen
• Clinical features are anemia, splenomegaly, and jaundice.
• Moderate anemia, can cause aplastic crisis from parvovirus B19
• Treatment is splenectomy, which improves the anemia.

Hemoglobinopathies Overview

• Hemoglobinopathies are disorders of hemoglobin.
• Types include Sickle Cell, Alpha and Beta Thalassemia

Sickle Cell Anemia

• Results from Single amino acid substitution replacing glutamate with valine at 6th amino acid position on the beta hemoglobin
• This causes all HgA (Hg"Adult") to be turned to HgS (Hg "Sickled”) in homozygotes
• Only half of protein mutated in heterozygotes
• Under hypoxic conditions, cells with this mutation undergo sickled structural change and is irreversible.
• Each sickle-forming episode leads to influx of calcium, resulting in loss of K and H20 and damages the membrane skeleton
• Sickled cells hemolyze easily and get stuck in the microvasculature.
• Fetal hemoglobin has a combination of gamma-globin and alpha-globin
• Adult hemoglobin combines alpha-globin and beta-globin.
• Six months after birth, gamma-globin is gradually replaced with beta-globin.

Sickel Cell Anemia cont.

• HgF protects in womb so the blood stream contains HgA (adult)
• HgF persists in the blood stream until 6 months of age
• Symptoms include splenomegaly; vasoocclusive crises characterized by body pain; hand-foot syndrome:
• Infarct in bones
• Other symptoms: acute chest syndrome with sluggish blood flow to inflamed lung hypoxia; stroke; proliferative retinopathy
• 2nd to vasoocclusions, impairs vision.

Thalassemias: Types and Pathophysiology

• Diseases are associated with an imbalance in the production of alpha or beta globin.
• This causes the formation of hemoglobin molecules with an abnormal number of alpha or beta globins
• Hemoglobins do not bind oxygen efficiently, possibly lethal
• Alpha thalassemia has reduced or absent synthesis of alpha globin
• A most common cause is deletion(s) of one or both alpha globin genes
• There are two different genes for alpha globin, thus 4 alleles
• Beta thalassemia is reduced or absent synthesis of beta globin
• Happens from single-base pair substitutions that result in proteins that have either reduced activity, altered activity, or no activity at all
• There is one gene with two alleles

Alpha Thalassemia Details

• Alpha Thalassemia is the result of destruction of 1,2,3, or 4 alleles that code for alpha-globin.
• When three or more alpha-globin chains are lost, the cell experiences a vitally low amount of alpha-globin
• This means the remaining beta-globin pairs will form a tetramer
• This tetramer is beta-4 in adults, and gamma-4 in infants.
• Infants build up tetramers of gamma-globin until 6 months of age.
• Both tetramers have high affinity for oxygen, so they won't let go
• Hb H (4) disease
• Moderately severe hemolytic anemia develops due to gradual precipitation of Hg H inside erythrocyte.
• This forms inclusions in the mature red blood cell, and removal of these inclusions by the spleen damages the cells.
• Hydrops fetalis or Hb Bart's (4)
• Infants suffer from severe intrauterine hypoxia
• Massive generalized fluid accumulation causes infant death

Beta Thalassemia Details

• Can either be heterozygous or homozygous.
• There is Decreased -globin production, leads to imbalance in globin synthesis and preciipitation of excess chains
• Alpha chains don't form their own tetramers, which leads to accumulation in the cell forming Heinz bodies
• The Heinz bodies will damage the red cell membrane
• Patients suffer from iron overload, which cannot be accommodated by functional RBCs
• Carriers of one -thalassemia allele are clinically well and have thalassemia minor
• Hypochromic or microcytic red blood cells
• May have a slight anemia that can be misdiagnosed as iron deficiency
• In malaria common areas
• Individuals may be homozygous recessive or compound heterozygotes and have thalassemia major
• Major is characterized by severe anemia and needs lifelong medical management
• Signs include Prominent cheekbones and protrusion of upper jaw
• From expansion of marrow cavity in bones of skull and face

G6PD Overview

• This deficiency is an X-linked recessive mutation of the G6PD gene
• G6PD is an enzyme that processes glucose and results in NADPH
• NADPH protects red blood cells from the harmful effects of reactive oxygen species
• G6PD deficiency produces no symptoms until patients are exposed to environmental factors that increase oxidant stress (e.g., infectious agents, certain drugs and food, severe stress)
• Deficiency causes Hemolytic anemia and usually affects 1 in 10 Black males

G6PD Details

• Drugs causing deficiency:
• Chlorpropamide – anti-diabetic
• Dapsone – antibiotic with anti-inflammatory properties
• Fluoroquinolones – “floxacins” antibiotics and Nitrofurantoin – antibiotic
• Antimalarial – “quines”
• Chemicals and foods that cause deficiency: -Fava beans; Henna; Naphthalene
• After 3-5 days following exposure, blood smear shows RBC with precipitates of denatured globin (Heinz bodies)
• Splenic macrophages have "bite cells”

Overview of Anemia of Decreased Production

• Diminished erythropoiesis can arise from:
• Iron Deficiency Anemia
• Anemia of Chronic Inflammation
• Megaloblastic Anemia
• Aplastic Anemia

Iron Deficiency Anemia Details

• This type of anemia is the most often seen
• Inadequate intake (or loss) of iron leads to insufficient hemoglobin synthesis
• Caused mainly by nutritional deficiency in developing countries
• Western World anemia is mainly from blood loss (e.g., ulcers, colon cancer, hemorrhoids, menorrhagia)
• To diagnose, look for:
• Hypochromic and microcytic red cells; Iron levels are low and Transferrin saturation is low
• Elevated total iron-binding capacity, and low Ferritin Levels
• Can be asymptomatic - with weaknesses, pallor, and listlessness in severe cases
• In chronic cases: spooning of the nails or pica

Anemia of Chronic Disease

• This kind of anemia is ofter seen in hospitalized patients, caused by Chronic microbial infections, Chronic immune disorders, and Neoplasms
• Inflammatory cytokines increases hepatic hepcidin.
• Hepcidin blocks iron for use in RBCs
• Chronic inflammation also blunts EPO synthesis.
• Iron is being stored away and not put into RBC's.
• This means Ferritin will be high.
• The cause is unclear - inhibits the growth of iron-dependent organisms
• Iron is actually being stored so ferritin is high
• Iron is not desired so TIBC is low
• MCV remains normal and the cells are not hypochromic
• EPO is a treatment but underlying disease must be cured

Megaloblastic Anemia

• Nucleotides ACTG are building blocks of DNA
• Note T = thiamine
• Thiamine is from Thymidine (a ribose sugar) is then converted to thiamine
• Thiamine needs folate and B12
• When compounds of Thiamine and DNA is poor, then red blood cell precursor cells increase greatly called megaloblasts.
• Folate Deficiency is cause of inadequate diet, and folate gets destroyed 10-15 cooking minutes
• if DNA levels are low, replication can’t happen
• Happens in those with poor nutrition and pregnant women, it is diagnosed with MCV, blood smear, and folate level.
• B12 is "Cobalamin" released by gastric juices from food
• Intrinsic factor secreted from parietal cells in the mucosa of gastric fundus binds to B12 in the stomach and passes to the distal ilium
• There is absorbed into enterocytes and distributed to liver, enough for 5 years

Megaloblastic Anemia Specifics

• 2 Main causes of B12 deficiency, Consuming enough B12 or Pernicious Anemia.
• The secondary cause is Gl disorders effects, where B absorption happens
• Gl disorders that can cause: Chron’s, gastritis, or pepsin suppression
• Clinical symptoms are Fatigue and Beefy red tongue.
• spinal cord disease - B12 anemia exhibits by neurologic symptoms
• This involves DNA synthesis and macrocytic anemia
• Anemia can be improved with folate but neurologic symptoms worsen. Th

Aplastic Anemia Details

• Suppressed cells trigger bone marrow failure and pancytopenia.
• 1/2 come from idiopathic reasons, the other is from toxins, radiation, or medication
• A sign includes fat replacement in bone marrow
• Autoreactive T causes marrow failure
• Leads to Anemia, thrombocytopenia, and neutropenia
• Progresses weakness and pallor

Polycythemia Overview

• Is the increased quantity of red blood cells
• Primary: proliferation of myeloid stem cells
• Secondary: increase from lung/heart disease
• Primary polycythemia (polycythemia vera)
• Clonal proliferation of myeloid stem cells
• Uncontrolled cells that increase total mass
• Secondary polycythemia
• Volume comes from erythroid from bone marrow
• Causes hypoxia through, and increases the the EPO hormone produced from altitude or congenital disease.
• Can occur due to renal carcinoma

Polycythemia Symptoms

• Look for hypertension, red face, and headaches as symptoms.
• Could also involve puritis and visual or neurologic problems.
• This can also cause splenomegaly and hypercellular bone marrow
• Deep Vein Thrombosis DVT and heart attack can then follow, raising rates for stroke and leukemia

Leukocyte Disorders

There are two types of leukocyte disorders:

• Technically Benign disorders
• Often secondary to other causes
  • Leukopenia - WBC count below normal
  • Leukocytosis - WBC above normal
• Malignant disorders
  • Leukemia - White precursor in bone marrow -Lymphoid Stem -Myeloid
  • Lymphoma
    • White cells in linmpy
  • Myeloma
    • Malig plasma

Leukopenia

Is a reduction in WBC counts.

• Likely seen from from sepsis
• Cause from chemotherapy or in spleen

More Details on Leukocytosis

• Leukocytosis - Often due to inflammatory response
• Infection
• Slight rise is due to catecholamine or some other factor. -High cell quantity means leukemia

Infectious Mononucleosis

• It is an infection due to Epstein–Barr Virus
• Symptoms include fever, inflamed limbs, swollen spleen, swollen throats
• In this disease Lymphocytes are activated in the T cells

Cat-Scratch Disease

• Due to hensel causing inflamation and lumps
• Most patients are under 18, with growth of tissue.
• More frequently seen on underarms.

Overview of Neoplastic Proliferations

• Abnormal multiplication of tissues
• Include lymphomas and multiple Mylomas

Leukemias

• Leads to Malig. cells -Expansion of bone marrow -- Maturing is harder -Suppression of bone occurs
• Blood count increases for young blood cell
• Can cause Anemia and uncontrollable bleeding

Myeloblast Vs Lymphoblast

• Myeloblast can create myelocytes for granulocytes such as base,esoin, or nutrio.
• Lymphoblast are for lymphocytes: -B -T

Subtypes of Leukemias

• AML is acute with blast cells
• Due to nuetrio probs or blood cancer
• Looking for "blast"
• Immature cells grow quickly
• ALL similar but with lymph cells and is treatable in Kids
• CML: The cells mature well but are now chronic
• It is from nuetrio cells and has a lot of WBC -Causes Phillychromo: where B breaks

Hodgkins

Cause Reed cells to grow which affect cells and tissues The spread is quick with B signs that make it hard to move More growth with B symptoms

Non-Hodgkins Lymphoma

With lymph spread this means less B signs, which makes it hared to reed

Hodgkin's vs Non-Hodgkin's Lymphoma

• Hodgkin
• Single axial with nodes and it is often linked with the first axis group
• It spreads rapidly and is rarely involved
• There are common outgrowths but it is rare here.
• Non-Hodgkin
• Much higher chance of mult growing at outgrowths commonly It just affects the peripheral nodes

Bleeding Disorders

• The topic here is regarding any of 4, DIC with all I T problems
• The causes are with tissue functions
• In this syndrome the coagulation leads to
• Common factors, trauma, and sepsing
• ITP caused from tissues attacking tissues
• Med problems can attack the antigens HUR and HUR can happen due to this

Thrombotic Problems Details

• Caused by low cells, or something with vW
• This makes the platelets use up very fast.
• Then HURE is something with comp protein affecting cells This the platelet activate and the cells fail
• Both cell functions can make the bones fail or have more fever

Willebrand Dis

• Dominant problem causes from mutations from WP
• Causes problems with WP or the platelets
• causes Mild bleeding
• Often mistaken for plate problems

Hemophilia: Types and Causes

• Two types affect joints with tissue failure
• A is herded with VIIII affecting men
• B same but has IX.