Unit 3 Flashcards
Anemia is considered to be present if:
- the Hb concentration of the RBCs or the Hct is below the lower limit of the reference range for the individual’s age, gender, and geographical location.
Define anemia
A decrease in the ability of RBCs to carry oxygen to the tissues resulting in hypoxia
Anemia may be a sign of an underlying disorder such as:
- liver disease
- alcohol toxicity
- hypothryroidism
- myelodysplasia
What is the development of anemia related to?
- normal erythrocyte kinetics
Describe how anemia is related to normal erythrocyte kinetics
- the total RBC mass in a daily steady state is the balancing of the number of new erythrocytes produced each day to replace the RBCs that have reached the end of the their life span of 120 days
What can the clinical signs and symptoms of anemia result from?
- Diminished delivery of oxygen to the tissues
- related to the lowered Hb concentration
- clinical signs reflect the rate of reduction of Hb and blood volume
What are common signs and symptoms of anemia
?
- fatigue
- shortness of breath
- skin pallor
- not as common: vertigo, faintness, headache, and heart palpitations
How are anemias classified based on red cell morphology?
- categorizes anemias by the size of the erythrocyte
- Macrocytic, microcytic, normocytic
How are anemia classified based on pathophyslogically?
- Impaired RBC production: insufficient or ineffective erythropoiesis
- Increased RBC destruction: hemolysis
- Blood loss (acute or chronic)
Describe factors that impact HSC or development issues
- aplastic anemia
- myelodysplastic anemia
- malignant metastases
- Acquired—> acute hemorrhage
- inherited —> chronic hemorrhaging
Describe what causes bone marrow damage
- chemicals, radiation
- some drugs
- iron deficiency and thalassemia
Blood loss: RBC membrane defect or enzyme deficiency
Describe infiltration of bone marrow
- Neoplasms
- abnormal Hb molecule
Describe nuclear defect of impaired red cells
- megaloblastic anemia
- blood loss: Antibody reaction, infectious microorganisms, chemical/ drug reaction, and traumatic cell injury
Describe semiquantitative grading of erythrocyte morphology
- erythrocyte changes are commonly reported using the following:
—> descriptive terms, such as few, moderate, or marked
—> grades on a numerical scale such as: 1+, 2+, 3+ …
—> 1+ = slight to few
—> 2+ = moderate
—> 3+/4+ = marked
Describe laboratory assessment of Anemia
- Clinical signs and symptoms
- CBC wire differential, RBC indices and morphology, reticulocyte count
- Hb decreased: males = <13.0 g/dL and females <12 g/dL
- Classification by RBC indices
What would it mean if the patient has low MCV, low MCHC, is microcytic and hypochromic?
- typical of matural defects:
- iron deficiency anemia
- Thalassemia
- Sideroblastic anemia
What would it mean if the patient has Normal MCH, normal MCHC, is normocytic and normochromic?
- typical of hypoproliferation
- Bone marrow disorder
- iron deficiency anemia
- autoimmune disease
What would it mean if the patient had High MCV or macrocytic?
- typical of maturation defects
- Vitamin B12 deficiency
- folate deficiency
- excessive alcohol ingestion
- hypothyroidism
What are additional assessments of anemia?
- RBC indices
- The red cell histogram
- Red cell distribution width (RDW) or red cell morphology index (RCMI)
- PB smear evaluation
- Reticulocyte count
- BM examination
What is the supplementary testing for Normal MCH and MCHC?
- serum iron
- Total iron-binding capacity (TIBC)
- Ferritin
What supplementary testing is performed on decrease MCV and MCHC?
- Serum ion
- total-iron binding capacity (TIBC)
- ferritin
What supplementary testing is performed when MCV is increased?
- serum vitamin B12
- Serum folic acid
Describe bone marrow examination for anemias
- may be performed if properly indicated and may reveal an abnormal ratio of leukocytes to erythrocytes using the myeloid:erythroid (M:E) ratio
Describe Hb F concentration testing of anemia
To evaluate possible hemoglobinopathies and thalassemias
Describe thick and thin smear assessment for anemia
- to evaluate the presence of possible material or Babesial parasites
Describe platelet count for assessment of anemia
To evaluate healing sufficiency after trauma
Describe reticulocyte count of anemia assessment
To evaluate red cell production in the bone marrow (can help ID pathophysioloic mechanisms of anemia)
Describe Sickle Cell testing for anemia assessment
- to screen for sickling hemoglobinopathies
Describe G6PD assay of anemia assessment
To screen for enzyme deficiencies in G6PD enzyme activity
Describe hemoglobin electrophoresis
- to separate out Hb protein fractions to identify possible hemoglobinopathies and thalassemias
What tests are performed in other parts of the lab that could be useful?`
- antibody screening and ID tests
- Direct antiglobulin (AHG) test
- Measurements of bilirubin levels
- Folic acid or vitamin B12 assays
What is the purpose of antibody screening and ID tests?
- to identify immune causes of RBC destruction
What is the purpose of the Direct antiglobulin (AHG) test?
To screen for immune causes of RBC destruction
What is the purpose of measuring bilirubin levels?
To help identify RBC destruction (either intracvacular or extravascular)
What is the purpose of folic acid or vitamin B12 assays?
To help identify megaloblastic anemia due to nutritional deficiencies in folate and B12 vitamins
What is the purpose of haptoglobulin level testing?
- to help identify intravascular hemolysis
What is the purpose of lactic dehydrogenase (LDH) determination ?
To help identify intravascular hemolysis
What is the purpose of Serum iron and total binding capacity?
- to measure circulating iron in the serum and transferrins binding capacity for iron
What is the purpose of occult blood testing?
To identify GI bleeds as a source of chronic blood loss
What is the purpose of Urbilinogen screening ?
To identify hemolysis in general, does not distinguish between intravascular and extra vascular
What are indications for a bone marrow evaluation?
- microcytic anemia where iron storage assessment with Prussian blue stain may be a value in anemias of chronic disorders or the presence of sideroblasts in sideroblastic anemia
- normocytic or macrocytic anemia without increased retic production to evaluate or myelodysplasia
- Neutropenia, thrombocytopenia or pancytopenia without an explaination
- immunoglobulin disorders such as multiple myeloma
- Neoplasms such as acute leukemia or lymphomas for diagnosis and/or staging purposes
What occurs if the survival time of RBCs is decreased?
- bone marrow must increase production to maintain balance of the RBC mass (homeostasis)
What does increased erythropoiesis depend on?
Demonstrated by an increase retic. Count which is dependent on available iron and protein
What is absolute iron deficiency?
Inadequate utilization of iron stores
What is functional iron deficiency?
A condition where the total body iron is adequate, but it cannot be mobilized fast enough for needed increase in erythropoiesis
What is the limitation of classifying anemias?
Within each classification, the various subdivisions are not completely inclusive
Which mechanism for classifying anemia has more merit? Why?
Physiological system because it describes the basic mechanism or probable mechanism responsible for the anemia
What is the limitation of morphological classification?
- it tells nothing about they etiology or reason for the anemia
What conditions are associated with Macrocytic anemia
- seen in maturational defects and non-megaloblastic anemia
- Alcoholism
- Liver disease
- aplastic anemia
- Myelodysplastic syndrome
What is disorders are associated with accelerated erythropoiesis of nonmegaloblastic macrocytic anemias.
- hemolytic anemia
- posthemorrhagic anemia
What disorders are associated with pathological megaloblastic anemia?
- pernicious anemia
- folic acid deficiency
- myelodysplasia
- erythroleukemia
- some drugs
What is most likely cause of macrocytosis?
Folic acid deficiency
Describe hypoproliferative anemias
- have normal RBC size
- demonstrate a hypocellular bone marrow with a normal or increased myeloid:erythroid (M:E) ratio
How are normocytic anemia separated?
Based on erythrocyte response of bone marrow
Describe intrinsic hemolytic anemias
- increased Retic. Count
- membrane defects
- Hemoglobinopathies
- enzyme deficiencies
Describe extrinsic hemolytic anemia
- increased Retic. Count
- can be caused by immune reactions or non immune red blood injury such as infectious agents, drugs, chemicals, venoms, and severe burns
What are microcytic anemias associated with?
- defective hemoglobin synthesis
- include late stage iron deficiency anemia, anemia of chronic disorders, sideroblatic anemia, thalassemia and HbE disease trait
What is Hb and Hct measurements affected by ?
- altered plasma volumes
- chronic oxygenation status
- hemoglobin variations
- abnormal hemoglobins
The laboratory based definition of anemia is a reduced concenconcentration of of ______ compared to a reference value
- Hb or parked erythrocytes
What is a significant laboratory finding in anemia?
Decreased Hb
The reference range for MCV is?
80-96 fL
What is the reference range for MCH?
27-33 pg
What is the reference range for MCHC?
33-36%
Describe the etiology of blood loss anemia
- the acute loss of blood is usually associated with traumatic condtions such as an accident or severe injury
- occasionally acute blood loss may occur during or fate surgery
Describe physiology of acute blood loss anemia
- acute blood loss does not produce an immediate anemia
- a severe hemorrhage or rapid blood loss amounting to more than 20% of the circulating blood volume reduces an individual’s total blood volume and produces a condition of shock and related cardiovascular problems
- in acute blood loss, the body itself adjusts to the situation by expanding the circulatory volume, which produces the subsequent anemia
What is the etiology of acute vs chronic blood loss anemia?
Acute —> trauma
Chronic —> GI tract
Is there blood loss disruption in acute vs chronic blood loss anemia?
Acute—> yes
Chronic —> no
Is there iron deficiency in acute vs chronic blood loss anemia?
Acute —> no
Chronic —> yes
What is the Hct levels in acute vs chronic blood loss anemia?
Acute —> normal
Chronic —> decreased
What is the WBC count of acute vs chronic blood loss anemia?
Acute —> increased
Chronic —> Normal
What is the platelet levels of acute vs. chronic blood loss anemia?
Acute —> increased
Chronic —> Normal
What is the Reticulocyte levels of acute vs chronic blood loss anemia?
Acute —> Normal
Chronic —> Increased
Describe physiological adaptions to acute blood loss
- increased respiratory rate
- increased heart rate and cardiac output
- redirected blood flow from the periphery of the body to the vital body core, for example, heart and brain
Describe physiological adaptions to chronic blood loss
- increased erythropoietin production
- increased 2,3-DPG (BPG) production
- decreased hemoglobin-oxygen affinity
What is the earliest hematological change in acute blood loss?
- transient all in the platelet count, which may rise to elevated levels within 1 hour (inflammatory reaction)
After the fall in platelet count, what is the next hematological change in acute blood loss?
The development of neutrophilic leukocytosis (10-34 x 10^9/L) with a shift to to the left
Describe the Hb and Hct levels during acute blood loss anemia
- do not fall immediately but fall as tissue fluid moves into the blood circulation.
- It can be 48-72 hours after the hemorrhage until the full extent of the red cell loss is apparent
Describe the peripheral blood film of acute blood loss anemia at 24 hours
- NC/NC
- normal MCV, MCH, MCHC
Describe the peripheral blood film of acute blood loss anemia after 5 days
- increased reticulocyte which develops macrocytosis
- takes place 3-5 days after the blood loss and reaches a maximum at 10 days later
How long does it take the blood to recover from anemia such as WBC count, morphological picture, and red cell profile?
- it takes 2-4 days after blood loss for WBC count to return to normal
- about 2 weeks for morphology to disappear
- the return of red cell profile to previous values takes longer than 2 weeks
Describe when 500-1000 mL of blood loss occurs
- 10-20% blood volume
- few or no symptoms
Describe when 1,000-1,500 mL of blood loss occurs
- 20-30% blood volume
- symptoms: asymptomatic, light-headedness, hypotension, tachycardia
Describe when 1,500-2,000 mL of blood loss occurs
- 30-40 % blood volume
- thirst
- shortness of breath
- clouding or loss of consciousness
- blood pressure
- cardiac output
- venous pressure decrease
- pulse usually becomes rapid
- cold extremities
- clammy
- pale
Describe when 2,000-2,500 mL of blood loss occurs
- 40-50% blood volume
- lactic acidosis
- shock
- irreversible shock
- death
Describe etiology of chronic blood loss anemia
- frequently associated with disorders such as the following:
—> GI tract
—> Heacy menstruation in women
—> urinary tract abnormalities
Describe the bleed of chronic blood loss anemia
- blood loss of small amounts occurs over an extended period, usually months
- does not disrupt blood volume
Describe blood lost in seal amount over an extended period of time
-both the clinical and hematological features seen in acute bleeding are absent
- regeneration of RBCs occurs at slower rate
- the reticulocyte count may be normal or slightly increased
describe laboratory findings of Chronic blood loss anemia
- a noticeable anemia does not usually develop until after storage iron is depleted
- gradually, chronic bleeding results in an iron deficiency, and the newly formed cells are morphologically hypochromic and microcytic
- the WBC count is normal or slightly decreased
- Platelets are commonly increased, and only later, in severe iron deficiency, are they likely to be decreased
What is aplastic anemia
- one of a group of disorders, known as hypoproliferative disorder, that are characterized by reduced growth or production of blood cells
- unusual disease of bone marrow failure
What are diseases easily confused with aplastic anemia?
- fanconi’s anemia
- dyskeratosis congentia
- acquired
- aleukemic leukemia
- large granular lymphocytosis
- myelodysplasia
- myelofibrosis
- paroxysmal nocturnal hemoglobinemia
What are characteristics of fanconi’s anemia?
Expressed in young patients, physical anomalies
What are characteristics of dyskeratosis congenita?
Expressed in young patients, physical anomalties
What are the characteristics of aleukemic leukemia?
Very young or very old patients, blasts in Buffy coat and bone marrow spicules
What are characteristics of large granular lymphocytosis?
Older patients, neutropenia
What are characteristics of myelodysplasia?
Older patients, bone marrow has normal cellularity or hypercellular
What are characteristics of myelofibrosis
Heptaosplenomegaly, leuko-erythroblasts appearance on peripheral blood smear
What are the characteristics of Paroxysmal nocturnal hemoglobinemia (PNH)?
RBC hemolysis
What does cytopenia with hypocellular marrow impact?
- all three cell lines, resulting in pancytopenia as in constitutional aplastic anemia
- two cell lines such as PNH
- a single RBC, WBC, or PLT cell line such as Diamond-Blackfan anemia (DBA)
- can be due to premalignant conditions or myelofibrosis
What are laboratory findings in Bone marrow syndromes?
- wide range or mild to severe cytopenias
- macrocytosis can be seen and in some situation may be the only finding
—> some situations may be masked by an underlying iron deficiency or thalassemia - elevated Hb F is common
- dysplastic changes in cells of the marrow
What are the three types of aplastic anemia?
- Idiopathic aplastic anemia (major form)
- Iatrogenic aplastic anemia
- Constitutional aplastic anemia
Describe idiopathic aplastic anemia
- major form
- occurs in patients with no established history of chemical or drug exposure or viral infection
Describe constitutional aplastic anemia
- designates a congenital or genetic predisposition to bone marrow failure
What are iatrogenic agents?
- benzene and benzene derivatives
- trinitrotoluene
- insecticide’s and weed killers
- inorganic arsenic
- anti-metabolites
- antibiotics`
What are immune mediated causes of aplastic anemia?
- Iatrogenic agents
- transfusion-associated graft versus host disease
- eosinophilic fasciitis
- Hepatitis- associated disease
- pregnancy
- intermediate metabolites of some common drugs
- idiopathic aplastic anemia
Describe immune-mediated pathophysiology of aplastic anemia
- activated type 1 cytotoxic T cells implicated
- telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways
- cellular immune suppression may occur transiently with certain viral infections, such as parvovirus virus or certain medications
Describe Hematopoietic failure pathophysiology of aplastic anemia
- insufficient or defective pluripotent stem cells, progenitor stem cells, or committed stem cells
- the microenvironment may be unable to provide for the normal development of hematopoietic cells
- absence of humoral or cellular cytokines (stimulators)
- excessive suppression of hematopoiesis by resident T lymphocytes or macrophages
What are signs and symptoms that depend on the degree of the deficiencies?
- bleeding from thrombocytopenia
- infection from neutropenia
- signs and symptoms of anemia
- splenomegaly and lymphadenopathy are absent
What are the phases of Aplastic Anemia?
- Onset of disease
- recovery
- late disease
What infections are responsible for causing aquired cases of APA?
- HBV
- HCV
- measles
- EBV
- cytomegalovirus
Define Iatrogenic
- relation to illness cause by medical examination or treatment (side effects that can lead to conditions)
What are examples of Iatrogenic agents?
- Benzene and benzene derivatives
- Trinitrotoluene
- Insecticides and weed killers
- Inorganic arsenic
- Antimetabolites
- Antibiotics
What is APA caused by?
- damage or destruction of the hemopoietic tissue of the bone marrow that results in deficient production of blood cells.
What is it called when all cell lines are affected?
Pancytopenia
When is a diagnosis of APA made?
When at least 2 of the 3 PB values fall below critical levels
Describe what the peripheral blood smear would look like in APA
- NC/NC
- varying degrees of anisocytosis and poik with normal RDW in most cases
Describe genetic influence of APA
TERT or TERC (5-10% of patients) teleomerase mutations found
Describe acute exposure to radiation of APA
- in the inciting agent, the production of new RBCs falls, but the RBCs decline slowly because of their long survival
- the first few hours, there is neutrophilic leukocytosis
- after first day, decrease in lymphocytes and is responsible for leukopenia
- after 5 days, granulocytes begin to decrease
- later, platelets decrease
Describe treatment for APA
- APA responds to immunosuppressive therapy, but success in treating this disease appears to be the degree of organ destruction, the capacity for tissue regeneration, and perhaps most importantly, a drug regimen that can control a misdirected and extraordinarily potent immune response
- can be cured by stem cell transplantation or immunosuppressive drug therapy
Describe the pathophysiology of Fanconi’s anemia
- best described congenital for of APA
- produced due to one or more mutations in the FAC gene
Describe laboratory finds of Fanconi’s Anemia
- it is characterized by a progressive pancytopenia over years
- diagnosis is usually made in children 5-10 years old.
- chromosome studies with the addition of diepoxybutane is the test of choice to ID FA. Increased chromosome breakage confirms the condition
What are clinical signs and symptoms of Fanconi’s anemia ?
- about 50% of patients show clinical abnormalities such as:
- short stature
- microcephaly
- malformed thumbs
- strabismus
- mental retardation
Describe etiology of Fanconi’s anemia
- inherited through an autosomal recessive mode with the exception of the FA-B subtype
What are test methods for Fanconis anemia?
- gold standard is demonstration of increased chromosomal breakage following exposure to clastogenes
Describe Dyskeratosis Congenita
- inherited BM failure syndrome
- characterized by the mucocutaneous triad of:
—> abnormal skin pigmentation
—> Nail dystrophy
—> Mucosal leukoplakia - BM failure accounts for a predisposition to malignancy and fatal pulmonary complications
Describe the etiology of Pure Red Cell Aplasia (PRCA)
- Acute (transient): parvovirus, other infections, drugs, riboflavin deficiency
- Acquired chronic: idiopathic, associated with thymoma and lymphoma
- congenital: Diamond-Blackfan syndrome
Describe Acute (transient) PRCA
- the more common diagnosis for a child
- affects young children under the age of 8, with most cases diagnosed between 1-3 years old.
- pretend by a history of viral infection within the past 3 months is frequent
- Self-limiting illness
- pathogenesis: humoral inhibition of erythropoiesis or decreased stem cells.
Describe acquired PRCA
- selective failure of RBC production
- rarely occurs in middle-aged adults
- approximately 50% are associated with thymomas
- reticulocytopenia and a cellular marrow devoid of all but primitive erythroid precursors
Describe chronic acquired PRCA
- associated with drugs, collagen vascular disorders and lymphoproliferative disorders
- also on the spectrum of autoimmune cytopenias with antibodies that target erythroid stem cells of normoblasts
What are signs and symptoms of Diamond-Blackfan anemia (DPA)
- proapoptotic hematopoiesis
- BM failure
- short stature
- birth defects
- cancer predisposition
What are other names for Diamond-Blackfan anemia?
- congenital pure red cell aplasia
- congenital hypoplastic anemia
Describe etiology of DBA
- congenital mutations in RPS19 and other genes encoding ribosomal proteins cause DBA
Describe pathophysiology of DBA
- total of 77 mutations have been described to date
- mutation target the protein production of either the 40s or 60s subunits
—> hypoproliferation of erythroid cells and the enhanced sensitivity of hematopoietic progenitors to apoptosis
—> defective maturation or ribosomal subunits delay translation of globin genes, which leads to erythroid-specific apoptosis and anemia
What are the classic diagnostic criteria for DBA/
- anemia appearing prior to the first birthday
- normal or slightly decreased neutrophil count
- variable platelet counts, often increased
- macrocytosis
- normal bone marrow cellularity with few red cells precursors
Describe treatment for DBA
- approximately 75% of patents respond at least partially to steroids
- the overall long-term survival rate is approximately 65%, although many patients require long-time steroid treatment
Describe the types of Congenital Dyserythropoietic anemia (CDA)
- characterized by indirect hyperbilirubinemia, ineffective erythropoiesis, and peculliarly shaped multi nuclear erthroblasts
- type 1– type 4
Describe type 1 CDA
- demonstrates a mildly macrocytic anemia with prominent anisocytosis and poik
Describe type 2 CDA
- most common type
- patients have erythrocytes that are similar to those patients with PNH
Describe testing for type 2 CDA
- Ham’s and sucrose lysis tests can be used to differentiate between type 2 CDA and PNH
- PNH is positive for both Ha’s and sucrose lysis tests, where as CDA type 3 is only positive for the Ham’s test (HEMPAS)
Describe type 3 CDA
- similar to type 1
Describe type 4 CDA
- similar to type 2 but differs, in part, because of the lack of serological abnormalities
Describe physiology of CDA
- not entirely certain in BM failure
- one hypothesis states a foreign agent such as a drug or virus enters the body and attaches itself to a pluirpotent HSC. This attachment promotes an immunre response and destroy the altered stem cell.
- another hypothesis states cellular and humoral abnormalities in hematopoietic regulation and altered marrow microenvironment have also been implicated
Describe laboratory findings of CDA
- if all cell lines are involved, the patent will have a decreased H&H and RBC count with leukopenia and thrombocytopenia
- if only the RBC cell line is affected, only the H&H and RBC count will be affected
- BM findings will parallel CBC findings in pertinence to the aforementioned conditions and display a lack of maturational activity
What is the hematologic manifestation in addition to severe Neutropenia: subtype Mutated Neutrophil elastase?
Leukemia predisposition
What is the hematologic manifestation in addition to severe neutropenia; subtype Growth Factor independent transcription repressor 1 deficiency?
Lymphopenia
What is the hematologic manifestation in addition to severe neutropenia; subtype HAX-1 deficiency?
leukemia predisposition
What is the hematologic manifestation in addition to severe neutropenia; subtype G6PD deficiency?
Thrombocytopenia
What is the hematologic manifestation of addition to severe neutropenia; subtype X-linked neutropenia?
- lymphopenia
- leukemia predisposition
What is the hematologic manifestation in addition to severe neutropenia; subtype Vacuolar protein sorting-associated 45 deficiency?
- myelofibrosis
What is the hematologic manifestation in addition to severe neutropenia; subtype Jagunal homolog 1 deficiency?
- Neutrophil dysfunction
- CSF3-hyporesponsiveness
What hematologic manifestation in addition to severe neutropenia; subtype Bi-allelic CSF3R deficiency?
CSF3 unresponsiveness
Describe severe congenital neutropenia (SCN)
- term for a group of genetically heterogenous disorders of bone marrow failure
- usually diagnosed shortly after birth
- characterized by a chronic shortage of neutrophils
Describe etiology of severe congenital neutropenia
- mutations are genetic cause
- low absolute neutrophil count
Describe treatment of SCN
- most receive lifelong treatment with G-CSF
- G-CSF has improved life expectancy of SCN patients
Describe Schwachman-Diamond syndrome
- inherited condition that affects many parts of the body, particularly the bone marrow, pancreas, and skeleton system
- third most common BM failure after Fanconi’s
- inherited in an autosomal recessive pattern.
- mutations in SBDS have been identified in about 90% of people with the characteristic features of Shwachman-Diamond syndrome
Describe etiology of Shwachman-Diamond syndrome
- bone marrow malfunctions and does not make some or all types of WBC
- shortage of neutrophils causes neutropenia, bone marrow abnormalities leading to anemia or thrombocytosis
Decribe pathophysiology of Shwachman-Diamond syndrome
- have a higher-than-average chance of developing myelodysplastic syndrome (MDS) and aplastic anemia and acute myeloid leukemia (AML)
- pancreatic dysfunction
- skeletal abnormalties
Describe Congenital Amegakaryocytic thrombocytopenia (CAMT)
- rare autosomal recessive bone marrow failure syndrome expressed in infancy with or without physical anomalies that presents with thrombocytopenia
- there is an absence of megakaryocytes in the bone marrow with no associated physical abnormalities
Describe classification of CAMT
- based on the course and outcome of the disease as follows:
- type I
- type II
- type III
Describe type I CAMT
- early onset of severe pancytopenia
- decreased bone marrow activity,
- very low platelet counts
- median platelet count is 21 x 10^9/L or below
Describe type II CAMT
- milder form with transient increase of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 and 6 years or later
- median platelet count is usually 35-132 x 10^9/L
Describe type III CAMT
- there is ineffective megakaryopoiesis
Describe peripheral blood smear diagnostic features of CAMT
- include abnormal size platelets,
- absence of platelet alpha granules, Dohle-like bodies, or microcytosis
What is CAMT frequently associated with?
APA
The sudden appearance of APA or PRCA is often caused by:
- an immune process
APA can occur years before a diagnosis of:
- paroxysmal nocturnal hemoglobinuria
- myelodysplasia
- acute myelogenous leukemia
If a patient with APA is referred to an exhibiting pancytopenia, which cell lines are affected?
- erythrocytes
- Leukocytes
- thrombocytes
What is a characteristic of familial APA?
A subset of Fanconis anemia
A characteristic of PRCA is:
Characterized by selective failure of RBC production
A characteristic of DBA is:
A rare congenital form of red cell aplasia
Fanconis anemia is associated with abnormal genes located on chromosome ______,_______?
9, 20
Acute (transient) red cell aplasia can be associated with:
A recent viral infection
What can Iron deficiency anemia (IDA) can be caused by?
- absolute iron deficiency
- functional iron deficiency
What does Absolute iron deficiency represent?
- a decrease in total body iron caused by blood loss
- decreased intake of iron, or
- increased utilization of iron
What does functional iron deficiency represent?
Inadequate utilization of iron stores, such as iron sequestration syndromes like ACD/AOL
Describe iron overload
Can result from various causes, including:
- inherited alterations in factors that control iron uptake and retention
- chronic disorders like sideroblastic anemia
- iron therapy or transfusion
- hemolytic anemias
- hereditary hemochromatosis (HH)
What is a false assumption about IDA?
Confined to resource limited-countries
Describe pathophysiology of iron deficiency and anemia
- worldwide, more than 40% of children have frequent infections causes by poor iron intake and/or parasitic infections
- older anemia patients are more likely to experience physical decline and disability and have higher hospitalization rates than those without
Describe etiology of Iron deficiency and anemia
- 1/3 of all cases of anemia are due to chronic blood loss, nutritional deficiencies or poor iron absorption
- another 1/3 of all cases of anemia are due to chronic inflammation, or a combination of both
- the last 1/3 is unexplained
- decreased iron intake
- faulty or incomplete iron absorption
- increased iron utilization
- pathological iron loss, ie, GI bleeding, malignancy
Physiological iron loss, ie, pregnancy, menstruation
Describe early diagnosis of Iron deficiency and anemia
- early diagnosis of iron deficiency is essential in non anemic infants and toddlers (under age 2)
- equally important in pregnant women to reduce maternal-fetal morbidity
What groups does iron deficiency continue to be common in the U.S.?
- toddlers
- adolescent girls
- women of childbearing age
Describe physiology of Iron deficiency and anemia
- humans have 35-50 mg or iron per kg of body weight
- the average adult has 3.5-5.0 g of total iron
- iron loss is very small, amounting to less than mg/d, mostly due to exfoliation of epithelial cells from the GI and urinary tracts, skin epidermal cells, and RBCs in menstruating women
- as iron depletion occurs, erythropoiesis also becomes restrictive
Where is operational iron mostly found?
Hb or myoglobin with 2/3 of it in Hb
Examples of causes of iron deficiency anemia
- decreased iron intake: iron-deficient diets
- increased iron utilization: potential growth spurt and adolescent growth spurt
- iron loss (physiological): menstruation and pregnancy
- Faulty/incomplete iron absorption
—> autoimmune gastritis
—> celiac disease
—> H. Pylori infection - iron loss (pathological)
—> GI bleeding
—> urogenital bleeding
—> pulmonary hemosiderosis
—> intravascular hemolysis
—> malignancy (colon cancer)
Compare and contrast primary and secondary overload disorders
- primary: iron absorption is increased from normal diet because of inherited alteration in factors that control iron uptake and retention.
- secondary: may arise in patients with chronic disorders or hemolytic anemia
What is the most common genetic disorder for iron overload in the U.S.
Hereditary Hemochromatosis (HH)
Describe iron needs for Normal infant to term
- iron stores are adequate to maintain iron sufficiency for approximately 4 months of postnatal growth
Describe Iron needs premature infants
- total body iron is lower than full term newborn.
- they have faster rate of postnatal growth than infants down at term, so unless the diet is supplemented with iron, they become iron depleted more rapidly than full-term infants.
- iron deficiency can develop by 2-3 months of age in premature infants
How much iron does breast milk and cows milk have?
0.5-1.0 mg/L
Describe absorption of iron from Breast Milk
- uniquely high, about 50% on average, and tends to compensate for its low concentration
Describe absorption of iron from cows milk
- only 10% of iron wholes cows milk is absorbed.
- about 4 % of iron is absorbed from iron-fortified cow milk that contains 12 mg/L
Describe dietary iron
There are two broad types of dietary iron:
- approximately 90% of iron from food is in the form of iron salts and is referred to as nonheme iron (leafy vegetables, broccoli, spinach, legumes, and lentils)
- approximately 10% is from heme iron (red meat and organ meat)
What are the sequential phases of iron deficiency?
- Stage 1 (prenatal)
—> decrease in storage of iron (ferritin) - Stage 2 (latent)
—> decrease in functional circulating iron for erythropoiesis (decreased serum iron and increased TIBC/UIBC) - Stage 3 (anemia)
—> decrease in circulating RBC parameters (RBC, H&H)
—> decrease in oxygen delivery to peripheral tissues
Describe signs and symptoms of IDA
- paleness
- weakness
- fatigue
- Papilledema: optic disk swelling
- psychomotor and mental impairment in first 2 years
- Pica: compulsive ingestion of nonnutritive substance: ice, wood, chalk, or dirt
Describe chronic blood loss of IDA
- frequently associated with GI tract
—> if blood is lost in small amounts over extended periods of time, both the clinical and hematologic features seen in acute bleeding are not present
—> a noticeable anemia does not usually develop until after storage iron is depleted
—> at first, anemia appears NC/NC but eventually, erythropoiesis and Hb production are impaired producing a microcytic/hypochromic morphology
Describe hematology of IDA
- a progressive disease so result may shift as disease progresses
- MCV: NC —> microcytic
- MCHC: NC—> hypochromic
- Retic. Count: low or normal
- RBC and H&H: normal —> decreased
- platelet count and WBC count might be elevated due to EPO/TPO homology
What is IDA an example of?
Ineffective erythropoiesis: iron “double hits” both RBC and production and Hb production so often times when patients are iron deficient, retic production will decrease
What is an effective early indicator of iron deficiency?
Reticulocyte Hb content (CHr)
What could infants and toddlers suffer from with iron deficiency?
Cognitive and psychomotor development problems as a result of inadequate iron in the synthesis of Hb
Describe serum iron test of IDA
Measures circulating iron bound to transferrin
Describe transferrin saturation of IDA
Measures percentage of transferrin occupied by iron
Describe the serum ferritin test of IDA
Measures storage iron
Describe Soluble transferrin receptors (sTfR)
Measures soluble transferrin receptor concentration
Anemia results in illnesses as diverse as:
-inflammation
- infection
- malignancy or various systemic diseases
What are half of AOI/ACD cases caused by?
Subacute or chronic infections
What are microbial agents associated with anemia of inflammation?
- Bacterial (M. Tuberculosis)
- Fungal (C. neoformans)
- Viral (HIV, cytomegalovirus)
What are NON microbial agent causes of AOI or ACD?
- neoplasms
- RA
- Rheumatic fever
- SLE
- Uremia
- Chronic liver disease
AOI/ACD is a hypoproliferative defect that is NOT related to:
Any nutritional deficiency
What is the principle pathogenesis of ACD?q
- hepcidin, a small plasma proteins that is a key molecule in controlling iron absorption and recycling
What are mechanisms associated with AOI/malignancy?
- Increased hepcidin production
- Alternations in production of proinflammatory cytokines: interleukins (IL-1), (IL-6); tumor necrosis factor alpha (TNFalpha); interferons
- Hemolysis (drug induced, microangiopathic, autoimmune)
- Effects of chemotherapy
- Nutritional deficiencies
- Blood loss
What are characteristics of AOI associated with malignancy can be as follows:
- decreased erythrocyte production because of direct non marrow infiltration by malignant tumor cells or by primary marrow cell malignancies
- production and release of TNF-alpha and IL_1 by macrophages
- increased erythrocyte destruction present in immune or microangiopathic hemolytic anemia
- acute chronic blood loss
- toxic effects of invasive therapy (chemotherapy or radiation therapy)
- indirect multiple causes such as anemias associated with malignant disease, anemias associated with major organ failure and various hemolytic anemias
The systemic diseases that produce AOI are accompanied by the release of acute-phase reactants in the blood. They are:
- elevated CRP
- fibrinogen
- haptoglobin
- ceruloplasmin
AOI/ACD response becomes unified in a common pathway of metabolic events initiated by:
- IL-1-B from activated macrophages
- then IL-1-B initiates cascade of evens mediated by the cytokines released from macrophages, lymphocytes and other numerous cells within the body
What is IL-1-B specifically responsible for?
- production of fever
- neutrophilia
- leukocytosis
- acute-phase protein synthesis
- stimulation of production of lymphokine’s and the release of lactoferrin from granulocytes
What laboratory results would suggest inflammation or infection (AOI/ACD)?
- elevated platelet counts
- elevated total leukocyte counts
- evidence of acute-phase reactants. CRP, an acute phase protein, is frequently a surrogate marker that may or may not correlate with hepcidin levels
Describe AOI/ACD hematology
- usually a mild hypoprolific anemia
- Hct usually fixed in the 28-32% range
- in some cases, the Hb may be as low as 5 g/dL
Describe serum iron of IDA vs ACD
IDA—> significant decrease
ACD—> decreased
Describe transferrin (total-binding capacity) in IDA vs ACD
IDA—> increased
ACD—> decreased or normal
Describe TIBC in IDA vs ACD
IDA—> increased
ACD—> normal or decreased
Describe transferrin saturation levels in IDA vs ACD
IDA—> decreased
ACD—> decreased
Describe serum ferritin in IDA vs ACD
IDA—> increased
ACD—> decreased or normal
Describ soluble transferrin receptors (sTfR) in IDA vs ACD
IDA—> decreased
ACD —> Normal
Describe treatment of AOI/ACD
- treatment of underlying cause of anemia is the most direct approach
- supporative therapy through blood transfusion may be warranted when Hb levels reach critical levels
- recombinant human EPO: newer treatment alternative that has been showed to counteract the suppressive effects of cytokines
Describe Sideroblastic Anemia (SA)
- can be inherited or acquired characterized by ringed sideroblasts in the BM
What are the classifications of inherited and acquired SA?
- Nonsyndromic congenital SA
- inherited syndromic conditions
- Myeloid neoplasms with ringed rideroblasts
- miscellaneous acquired sideroblastic anemias
Describe etiology of SA
- genetic causes
- drugs secondary to isonaiazid (INH), chloramphenicol or after chemotherapy and toxins, like alcohol and chronic lead poisoning
- Disease (hematologic, neoplasticism, and inflammatory)
- miscellaneous disorder (uremia, thyrotoxicosis and porphyria)
- idiopathic
Describe physiology of SA
- body has a sufficient amount of iron but unable to incorporate into Hb
- Accumulates in the mitochondria
- heme enzyme abnormality is a decrease in delta-ALA synthase deficiency
- Prussian blue iron stain reveals the excess iron as blue deposits circling the nucleus like a pearl necklace
What are laboratory characteristics of SA
- hypercellular marrow with normal reticulocyte count
- Mature, nonnucleated RBCs are generally hypochromic with normocytic and/or microcytic
- basophilic stippling and/or pappenheimer bodies with dimorphic cell population may be present
Describe the etiology of Hereditary Hemochromatosis (HH)
- genetic error of metabolism that produces inappropiately increased GI absorption of iron due to hepcidin deficiency
- Pregnancy, menstruation and regular blood donations are thought to offer protective effects and delay onset of symptoms
Describe the HH classifications
- Hemochromatosis type 1: High iron HFE gene related
- Hemochromatosis type 2: Juvenile hemochromatosis
- Hemochromatosis type 3: mutation of transferrin receptor 2 (TfR2) gene
- Hemochromatosis type 4: mutations of ferroportin-1 gene
How is porphyria classified?
- clinical presentation (acute vs chronic)
- source of enzyme deficiency
- site of enzyme deficiency in the heme biosynthetic pathway
What are clinical presentations of Porphyria’s?
- Neurological symptoms
- Skins problems
What is the treatment for iron overload?
- therapeutic phlebotomy or iron chelation therapy
What is the inherited defects of Porphyria?
- a rare autosomal recessive condition, congenital erythropoietic porphyria
What is an acquired defect of Porphyria?
Lead poisoning
What occurs if the globin synthesis is impaired?
Protoporphyrin synthesis is correspondingly reduced
Vis versa
What condition are the defects of globulin synthesis manifested in?
Thalassemias
Most operational iron in human beings is found in:
Heme portion of Hb and myeloglobin
Faulty iron absorption can result from:
Celiac disease
Pathological iron loss can be caused by:
Colon cancer
What is physiological iron loss can be caused by:
Heavy menstruation
Tranferrin represents a:
- beta globulin that moves iron
- glycoprotein that moves iron
In stage 3 IDA, the erythrocytic indices are typically:
MCV decreased
MCH decreased
MCHC decreased
If the patient peripheral blood smear reveals a microcytic, hypochromic anemia, classic iron study results in uncomplicated cases would be the follwoing:
Serum iron: decreased
TIBC: increased
Serum ferritin: decreased
% saturation: decreased
If a patient is suffering from an uncomplicated condition of severe iron deficiency, the expected laboratory assay results would be characteristics of:
Serum iron: decreased
TIBC: increased
Serum ferritin: decreased
% saturation: decreased
BM iron storage: decreased
% sideroblast in BM: decreased
The bone marrow of patient, previously diagnosed with anemia, was examined because of the lack of a response to vitamin therapy for her fatigue. Prussian blue staining was performed on a bone marrow smear, but the results were negative. It is likely that this patient is suffering from:
IDA
The typical peripheral blood film of AOI typically reveals:
NC/NC
What is the most appropriate treatment for AOI?
Treatment of the inflammatory condition
Storage iron in the human body is:
- found in hepatocytes
- found in macrophages
- sequestered as ferritin
What is the most sensitive assay for the diagnosis of HH?
Transferrin saturation
Prussian blue cytochemical staining identifies:
Siderotic granules
If the globin synthesis is insufficient in a patient, iron accumlates in the cell as _________ aggregates
Ferritin
Describe macrocytic anemias
- macrocytosis (increase in MCV) can be observed in megaloblastic anemia but can be caused by nonmegaloblastic etiologies
- nonmegaloblastic macrocytic anemias lack a common pathophysiology
What are some examples of nonmegaloblastic macrocytic anemias?
- alcoholism
- liver disease
- myelodysplastic syndrome
Hemolytic anemia - APA
- DBA
What are megaloblastic anemias characterized by:
- hypercellular marrow with nuclear to cytoplasmic asynchrony
- intramedullary cell death due to ineffective erythropoiesis
- leukopenia and thrombocytopenia are present
What are the two major categories of megaloblastic anemias based on etiology?
- vitamin b12 deficiency
- folic acid deficiency i
Describe the etiology of megaloblastic anemias
- increased utilization of B12 due to parasitic infections such as Diphyllobothrium Latium tape-worm
- pathogenic bacteria is disorders such as diverticulitis and small-bowl stricture
- malabsorption syndrome caused by gastric resection, carcinoma, and some forms of celiac disease or sprue
- inflammatory disorders of the terminal ileum
Describe etiology of pernicious anemia (PA)
- may be associated with autoimmune endocrinopathies and anti receptor autoimmune disease
- a genetic predisposition to PA is suggested by the clustering of the disease and of gastric autoantibodies in families
- the underlying gastritis that causes pernicious anemia is immunologically related to an autoantibody to intrinsic factor, a serum inhibitor of intrinsic factor and autoantibodies to parietal cells.
What may PA be associated with?
- Hashimoto’s thyroiditis
- Insulin-dependent diabetes
- Addisons disease
- Primary ovarian failure
Describe PA epidemiology
- 1.9% of persons older than 60 years have pernicious anemia
- The median age at diagnosis is 60
- slightly more women are affected than men
Describe folate physiology of PA
- necessary for production of thymidne nucleotides used in DNA production
- Tetrahydrofolate donates a methyl group to dUMP to form thymidine
Describe vitamin B12 physiology of PA
- the source of folate 5-methyltetrahydrofolate
- methyl group is removed to make tetrahydrofolate and donated to detoxify homocysteine into methionine
- the substance the removes the methyl group is vitamin B12
Describe the pathophysiology of PA
- both folate and vitamin B12 have the same effect on DNA production, but folate has a direct implication whereas vitamin B12 has an indirect application
- the lack of thymidine leaves empty spaces in the DNA replicate that one temporarily filled by uracil, but eventually, the replicated DNA is nonfunctional, which causes cell division to stop
- the result is a macrocytic cell; one that is large and incapable of dividing anymore
Describe Nuclear cytoplasmic asynchrony
- precursor being to divide. The lack of vitamin B12 or folate cause mitosis. To lad behind in the nucleus
- the result is a cell with a normal cytoplasmic appearance but a younger looking nuclear appearance
- this is most prominent in the polychromaophilic normoblast stage of development
What are the 3 binding proteins capable of binding vitamin B12?
- intrinsic factor (IF)
- Transcobalamin II
- R proteins
What are the signs and symptoms of PA?
- skin color changes to lemon-yellow
- nail beds, skin creases, and periodical areas may become hyper pigmented owning to melanin deposition
- angular cheilitis (cracking at corners of the mouth)
- dyspepsicia
- diarrhea
- glossitis
- painful tongue
- early graying of hair
- tiredness
- dyspnea on exertion
- vertigo
- tinnitus secondary too anemia
- congestive heart failure
- angina
- palpitations may be noted
- neurological and cognitive abnormalities
What are the laboratory findings of PA?
- Hb, microHct, and RBC count are low
- MCV may be high as 130 fL
- MCH varies but is usually increased in 90% of cases
- moderate to significant anisocytosis and poikilcytosis
- many microcytic, ovalocytic red cells precursors, notably metarubricytes
- platelets are also typically decreased in number
- orthochromic Megaloblast
What are red cell inclusions found in PA?
- basophilic stippling
- HJ bodies
- Cabot rings
Describe abnormalties of leukocytes in PA
- hypersegmented (more than four lobes) neutrophils
- an increase in the percentage of eosinophils
What are the follow-up tests performed for vitamin B12 deficiency?
- > 400 pg/mL = none (not PA)
- > 400 pg/mL with neurological symptoms = MMA and homocysteine (may confirm B12 deficiency)
- 100-400 pg/mL, <0.4 umol/L = MMA (not PA)
- 100-400 pg/mL, >0.4 umol/L = None (PA)
- <100 pg/mL = none (PA)
What is the follow up test for folate is if the value is low-normal?
RBC folate
What are the ranges of serum cobalamin (pg/mL) assay?
Normal: 200-900
Negative balance: 150-500
Depleted stores: 100-300
Deficiency in tissues: 50-250
Anemia: 50-250
What are the ranges for MMA (umol/L) assay?
Normal: <0.4
Negative balance: <0.4
Depleted stores: <0.4
Deficiency in tissues: 0.4-20
Anemia: 1-20
Describe MCV levels of deficiency in tissues and anemia of B12
Deficiency in tissues: 90-110 pg
Anemia: 100-130 pg
What is the Hb value in anemia?
<12 g/dL
Describe the clinical chemistry of Vitamin B12 deficiency
- serum haptoglobin-binding capacity: decreased
- Serum vitamin B12: decreased
- folate: normal
- serum iron: increased
- TIBC: normal or decreased
- % transferrin: increased
- serum lactic dehydrogenase isoenzymes 1 and 2– significantly increased
- unconjugated bilirubin: increased
- urinary methlymalonic acid and homocysteine levels : elevated
- extremely elevated LDH, isoenzymes 1 and 2, is an important diagnostic finding
- uric acid levels are low secondary to decreased DNA synthesis
Describe treatment for vitamin B12 deficiency
- regularity monthly intramuscular injections of at least 100 mg of vitamin B12 to correct the vitamin deficiency
- Retic count increase 2-3 days of treatment
- peaks at 5-8 days
- Hct improves 1 week and will normalize with 4-8 weeks after treatment
- MCV typically increases the first 3-4 days and will normalize in 25-78 days
Describe etiology of folic acid etiology
- drugs can interfere with absorption or proper distribution of folic acid
- increased utilization caused by pregnancy or acute leukemia
- lack of folate in diet
- malabsorption disorders such as sprue or gluten sensitivity
- biologic competition for dietary folate due to bacterial overgrowth in the intestine
- medications
- alcoholism
Describe treatment of folic acid deficiency
- with antimetabolites that are folate antagonists
What are sources of folates
- yeast
- green leafy vegetables
- organ meats
What can folic acid deficiency lead to
Megaloblastic anemia
What is the most common pharmacological cause of folic acid deficiency?
Alcohol
What are the ranges for serum folic acid (ng/mL) assay?
Normal: 5-20
Negative balance: <3
Depleted stores: <3
Deficiency in tissues: <3
Anemia: >3
What are the ranges of RBC folic acid (ng/mL) assay
Normal: >200
Negative balance: >200
Depleted stores: <200
Deficiency in tissues: <200
anemia: <200
What are the ranges of serum homocysteine (umol/L) assay?
Normal: 5-15
Negative balance: 5-15
Depleted stores: 5-15
Deficiency in tissues: 15-250
Anemia : 15-250
What is more typical of nonmegaloblastic than megaloblastic?
Oval macrocytes
In megaloblastic anemias, what is the typical erythrocytic indices?
- MCV and MCH increased
- MCHC is normal
What can be found in a patient with classic megaloblastic anemia?
- ovalocyte
- hypersegmented neutrophils
What laboratory assay is most sensitive to decreased levels of cobalamin?
- transcobalamin assays
The underlying type A gastritis that causes pernicious anemia is immunologically related to
- autoantibody to IF
- autoantibody to parietal cells
A lack of Intrinsic factor could be due to:
Gastrectomy
In a case of classic pernious anemia, the patient has
- leukopenia
- hypersegmented neutrophils
- anemia
The reticulocyte count in a patient with untreated pernicious anemia is characterized by:
- <1.0%
The liver stores enough folate to meet daily requirements for how long?
3-6 months
The peripheral erythrocyte morphology in folate deficiency is similar to pernicious anemia and the RBCs are:
Large
What is the common denominator in hemolytic anemia (HA)?
- premature erythrocyte destruction initiated primarily by trapping of cells in the sinuses of the spleen or liver (extravascular) and the blood vessels (intravascular)
Describe intrinsic causes of HA
- Hb composition (hemoglobinopathy)
- RBC membrane defects
- RBC enzyme defects
Describe extrinsic causes of hemolytic anemia
- vascular defects
- antibodies and/or complement
- infectious agents, such as bacteria or parasites
- toxins or mechanical devices
What are other ways of organizing HA themes?
- inherited vs acquired
- intravascular vs extravascular
- immune vs non immune
What can compensate for RBC reduction?
- Increased BM activity
- if BM fails to increase production, anemia develops
What are the various mechanisms of complement?
- classic pathway
- mannose-binding lectin pathway
- alternative pathway
- thrombin that directly cleaves C3 and acts as C5 convertase
- Plasmin and kallikrein directly cleaves C3 and its activation fragments
What triggers the classical pathway?
- by IgG or IgM antibodies coevolved with active immunity
What triggers the mannose-binding lectin pathway?
- by carbohydrates found on bacteria associated with pathogen recognition receptors
What activates the alternative pathway?
By the slow spontaneous hydrolysis of the complement component, C3
Describe activation of complement
- Normally, complement proteins circulate in an inactive form
- activation is tightly regulated by several membrane-bound and soluble complement regulatory proteins
- activation of complement via any pathway amplifies as it progresses and terminates with the formation of MAC
- cond
What are conditions such as PNH and aHUS caused by?
- mutations and/or autoantibodies that inactivates these regulatory proteins and activate complement via the alternative pathway
Describe classical pathway
- one the major effector mechanisms of antibody-mediated immunity
- includes C1-C9 (not in order)
- C3 has the largest quantity of
- Three major stages: recognition, amplification, and MAC
- accelerates osmotic cytologic reaction
Describe Alternative pathway
- shows similarity with classical pathway
- predominantly a non-antibody initiated pathway
Describe the mannose-binding lectin pathway
- member of the calcium depending lectins, the collectins
- Hb in structure to C1q
- pattern recognition molecule of the innate immune system
- binds to arrays of terminal mannose groups in a variety of bacteria
What can HA be divided into?
- inherited disorders (intrinsic)
- acquired disorders (extrinsic)
- further subdivisions are based on site of destruction
—> intravacular
—> extravascular
Describe site of destruction of RBC of intravascular vs extravascular HA
Intra: within blood vessels
Extra: spleen and liver
Describe mechanim of intravascular vs extravascular HA
Intra: activation of IgM or IgG
Extra: cell-mediated phagocytosis of IgM or IgG- coated cells
Describe laboratory findings of intravascular vs. extravascular HA
- intra: hemoglobinuria direct antiglobulin test and Hemosiderinuria
Extra: positive direct antiglobulin test erythrocytes
Describe etiology of inherited HA
- may affect basic membrane structure, the erythrocyte enzymes, or the Hb molecules within the Red cells
Describe structural membrane defect of inherited HA
- the ability of RBCs to deform and return to their biconcave disc shape in determined by:
—> flexibility of the membrane
—> cytoplasmic viscosity
—> cell surface-to-volume ratio
Inherited Ha pathology arises by:
- altering the amount or function of the expressed protien
- compromising the integrity of the membrane
- contribute to abnormal erythrocyte morphology
Describe Hereditary Spherocytosis
- most common hereditary HA among Northern Europeans
- loss of erythrocytic membrane surface due to membrane protein defect
- hemolysis in extravascular in spleen
- decreased surfaces area-to-volume ratio changing the shape from discoid to spherocyte
Describe hereditary elliptocytosis
- defect in membrane skeleton
- Nine clinical forms
- increase in oval and elongated red cells to greater then 25%
- most patients have little to no hemolysis
- in symptomatic patients, splenectomy may be indicated
Describe hereditary pyropoikilocytosis (HPP)
- rare autosomal disorder, representing a subset of common hereditary elliptocytosis HE, seen primarily in blacks
- manifested in infancy or early childhood as a severe HA with significant poik
- bizarre shapes are evident
- MCV range = 55-74 fL because of prevalence of microspherocytes
Describe hereditary Xerocytosis
- hereditary xerocytosis is a permeability disorder
- in vitro, the thermal instability of spectrum suggests a defect in qualitative spectrin abnormality
- The net loss of intracellular K+ exceeds passive Na+ influx, yielding a net Na+ gain. This causes the red cells to dehydrate
- PB smear shows a variety of cells: target, stomatocytes, spherocytes and hypochromic
Describe hereditary stomatocytosis
- seen in genetic Hb defect, thalassemia and lead poisoning, HS and alcoholic disorders
- cation abnormality where RBCs contain increased Na+ and decreased K+
- cells are uniconcave
- MCHC is usually decreased and MCV may be increased
- anemia is usually mild to moderate
- Rhnull disease is also associated with the presence of stomatocytes
Describe Rh Null disease
- also called Rh deficiency syndrome
- rare hereditary disorder causing mild, compensated chronic hemolytic anemia
- this disorder is associated with stomatocytosis and spherocytosis
Describe Acanthocytosis
- dense contracted or spheriodal RBCS with multiple thorny projections or spicules
- prevalent in 2 disorders: abetalipoproteinemia and spur cell anemia
- are a manifestation of the profound disturbance in plasma lipoprotein levels found in these disorders
- moderate anemia may develop in your children but adults suffer only mild Anemia
- all indices and osmotic fragility are Normal
Describe spur cell HA
- this form is seen in patients with established alcoholic cirrhosis
Describe neuroacanthocytosis
- neuroacanthocytosis (NA) is a heterogenous group of neurodegenerative disorders associated with acanthrocytosis in peripheral blood
Describe erythrocytic enzyme defect
- disorder of erythrocyte metabolism can be grouped with congenital nonspherocytic HA (CNSHA)
- types:
—> G6PD
—> pyruvate kinase (PK)
—> methemoglobin reductive - varying degrees of clinical presentation and severity
Describe G6PD deficiency
- x-linked enzymopathy affects 400 million people worldwide
- catalyzes reaction: G6P + NADP —> 6PG + NADPH
- Lab findings:
—> quantitative decrease in G6PD
—> positive autohemolysis
—> Heinz bodies on PB smear
What is the G6PD enzyme responsible for?
Protecting the cell from oxidative stress
Describe pyruvate kinase
- accounts for 90% for the inherited defects of glycolysis
- inherited as autosomal recessive
- Pennsylvania Amish have highest frequency
- is involved in anaerobic glycolysis that generates ATP
- the loss of ATP produces loss of water and results in cell shrinkage and rigidity, this rigidity distorts the RBC causing hemolysis
Describe laboratory findings of pyruvate Kinase
- NC/NC
- polychromasia
- elevated 2,3 DPG
- quantitative decrease in PK level
Describe Methemoglobin reductase deficiency
- Hb with oxidized iron (ferric) is called methemoglobin
- Hereditary deficiency of the enzyme NADH-methemoglobin reductase (NADH diaphorase) results in increased methemoglobin
What is clinical presentation of methemoglobin reductase deficiency?
- involves cyanosis because the methemoglobin cannot carry oxygen to the tissues
What are types of acquired HA?
- Chemicals, drugs, venoms: copper and lead
- Infections microorganisms: bacteria and protozoa
- immune mechanims (antibodies): cold hemagglutinin disease, idiopathic
- physical agents: severe burns
- traumatic and microantagiopathic HA: Hemolytic uremia syndrome, prosthetic cardiac valves
What are 3 bacteria associated with Acquired HA?
- bartonella baciliformis
- borrelia recurrentis
- clostridium perfringens
What are 3 parasites associated with acquired HA?
- Babesia microti
- Babesia divergents
- Leishmania species
How are acquired HA classified?
- autoimmune hemolytic anemia
- isoimmune hemolytic anemia
- drug induced hemolytic anemia
What viruses are associated with HA
Cytomegalovirus
EBV
