Chapter 14-RBCs And Bleeding Disorders Flashcards
What is the major difference regarding the spleen between intravascular and extravascular hemolysis
Splenomegaly is not seen in intravascular hemolysis
What is the antibody present in cold hemolysin antibodies
IgG
In addition to a mutation in the Beta chain, which event in the alpha chain further worsens the prognosis
Gaining an Alpha chain chromosome, leading to further imbalance and alpha chain deposition
How does acute blood loss affect white cells
- massive decreased in blood pressure results in increased levels of adrenergic hormones
- mobilizes granulocytes and Increased leukocytosis
Which type of Von Willebrand disease is quantitative
Type 1 and 3
What is the significance of HgH
Such a high affinity for Oxygen that it can be let go and used normally
What are the histological appearances during megablastic anemia
- macrocyclic and oval that lack the central pallor of normal RBCs and appear hyperchromic, but no rise in MCHC
- Low reticulocyte count
- Neutrophils show nuclear hypersegmentation 6 lobules
What is the pathogenesis of hemolytic uremic syndrome (HUS)
- Infection with E Coli O157:H7 which contains the Shiga like toxin
- Creates endothelial defects that cause the accumulation of platelets
What is the mechanism that HIV induced thrombocytopenia
Megakaryocytes possess the receptors CD4 and CXCR4, which allows for infection
-Furthermore, can cause B cell hyperplasia and lead to production of alloantibodies to the platelets
What are the numbers and locations of the hemoglobin components
- 2 alphas from an identical pair on chromosome 16
- 2 betas on a single gene on chromosome 11
What is Kasabach-Merritt syndrome
associated with DIC:
-giant hematomas as a result of thrombi forming within the neoplasm because of stasis and recurrent trauma to the blood vessels
Which form of hemolysis is seen in G6PD deficiency
Extravascular and intravascular hemolysis
What is the method of pathogenesis is cold antibody anemia
Temperature falls, IgM binds to RBCs and fixes complement, C3b deposits, temperature warms up and allowed to flood, the C3b binds to phagocytes and is removed
What are the lab test values seen in thrombotic microangiopathies
Aka TTP and HUS
-PT and PTT are normal
What is the amino acid substitution in the cause of HbC
Lysine for glutamate
What is the mechanisms of disease in the case of atypical hemolytic uremic syndome (HUS)
Defects in complement protein H, CD46, or factor I
*All inhibit the activation of the alternative pathways
What is the role of OCs in avitaminatosis
-Decreased absorption
Following blood loss, how long does it take for the CFU-Es to mature and appear as newly released RBCs (reticulocytes) in the Peripheral blood
5 days
What is the treatment for hereditary spherocytosis
Splenectomy, which solves the problem of anemia as they are not removed by macrophages
In those patients with hereditary spherocytosis (HS) what is the underlying cause of an aplastic crisis
Infection of the parvovirus, which infects and kills the progenitors in the bone marrow
What is the cause of chronic immune thrombocytopenia purpura (ITP)
Autoantibody destruction of platlets
What are the characteristics clinical findings in hemophilia A
- Easy bruising
- Massive Bleeding felling procedures
- spontaneous hemorrhages in trauma locations
*Patechiae are absent
What is occuring during myelophthisic anemia
There is morrow failure as a result of displacement by a space occupying lesion
What are the secondary clinical features seen in Beta thalassemia major
- Splenomegaly (extramedulary site)
- cardiac disease usually cause of death (hemochromatosis)
What is the most common cause of B0 thalassemias
Chain terminator mutations
What is the target of cold hemolysin antibodies and what is the mechanism of action
1) IgG binds to the P group on RBCs in cold regions of the body.
2) Lysis occurs when those cells reach warmer areas
3) Causes intravascular hemolysis and hemogloburia
What is the cause of absolute primary polycythemia
-Intrinsic abnormality of hematopoietic precursors
What are the levels of inorganic iron uptake Decreased by
Tannates (in tea)
Carbonates
Oxalates
Phosphates
Why does hydrops fetalis only start to emerge during the third trimester of pregnancy
In early development, there is gamma and delta chains that are functional, however later in development there is need to the alpha chains
What is the most common inherited bleeding disorder of humans
Von Willebrand disease
What is the difference in presentation between acquired and congenital TTP thrombotic thrombocytopenia purpura
Acquired- tends to be alloantibodies to ADAMS13 that inhibit its activity
Congenital- tends to show in adolescence and episodic
What is the mechanism of action in the case of TMPRSS6 and its role anemia
Mutation in the protein that normally suppresses the level of hepcidin at low iron levels. Therefore, even at low levels of iron, there is high levels of hepcidin
What are the clinical presentations of aplastic anemia
Progressive:
- weakness, pallor, dyspnea,
- thrombocytopenia (petechiae and ecchymosis)
- neutropenia (minor infections or onset of chills and fever
What is the process flowing acute blood loss to replace the loss products
1) Blood volume is restored by the intravascular shift of water from the interstitial fluid compartment
2) Results in hemodilation and lowering of the hematocrit
3) Signals for the increased production of erythropoietin
4) proliferation of committed erythropoietin progenitors (CFU-E)
What is the inheritability of paraoxysmal nocturnal hemoglobinuria (PNH)
X linked, but only inheriting one is sufficient to cause disease
What are morphological changes seen in pernicious anemia
- Fundic gland atrophy
- tongue becomes shiny, glazed, and “beefy” aka atrophic glossitis
- demyelination of the dorsal and lateral spinal
How is PNH diagnosed
Flow cytometry
What will folate treat and not treat in respect to vitamin B12 deficiency
Will treat the B12 anemia, but will not the neurological issues that arise
Where is the prevalence of hereditary soherocytosis more prevalent
Northern Europe
How is iron 2+ transported across the apical membrane of duodenum
DMT1
What is the defect in Glanzmann thrombasthenia
Platelets fail to aggregate in response to ADP, collagen, epi, thrombin due to:
-Defect in IIb-IIIa, which is the bridge formation via binding to fibrinogen
What is the pathogenesis of thrombotic thrombocytopenia purpura
Deficiency of ADAMTS13 aka vWF metalloprotease
What is the tendency for sickle cells to form when deoxygenated
Polymerizes to form stacks of cells
What complication can be seen in the Gi tract with cases of Extreme hemolysis
Pigment gallstones
Which infections have seen to cause aplastic anemia
-viral hepatitis of the Non-A, Non-B, non-C and non-G
What is the most common cause of primary polycythemia
Polycythemia Vera
What are the three categories that bleeding disorders due to defective platelet functions are divided into
1) Defects in adhesion
2) Defects in aggregation
3) Defects in secretion
What is aplastic anemia a disorder that is characterized by
-syndrome of chronic hematopoietic failure and CYYTOPENIA
Which factor is affected in hemophilia A
Factor VIII
What are the features that hemolytic anemias share
- shortened red cell life span
- elevated erythropoietin levels
- accumulation of hemoglobin degradation products that accumulate as a result of the hemolysis
The most severe forms of hemophilia A are seen in which mutation
Inversion involving the X chromosome where there is entire elimination of Factor VIII production
What are the morphological features seen in pernicious anemia
Chronic strophic gastritis:
- loss of parietal cells
- prominent infiltrate of lymphocytesand plasma cells
- megaloblastic changes in mucosal cells
What are the principal clinical features of extravascular hemolysis
- Anemia
- splenomegaly
- jaundice
What are the histological findings in the cause of trauma induced hemolytic anemia
- Shisctocytes (red cell fragments)
- Burr cells (pointy cells)
- Triangle cells
What are the clinical features that can be seen in severe iron deficiency
-Koilonychia (spoon nails)
-alopecia
-atrophic changes to tongue and gastric mucosa leading to intestinal malabsorption
-pica
Plummer Vinson syndrome
What is a good plasma value that correlates with the total body storage levels of iron
-plasma ferritin
What are the variants that cause the most severe disease of G6PD issues
G6PD-
G6PD Mediterranean
What is the lifespan of the RBCs in the cause of hereditary spherocytosis (HS)
10 to 20 days as opposed to 120 days
Which patients population is at a higher risk for alpha thalassemia
Asian
What is the product leading to anemia in chronic diseases and what are the other common values
IL-6 causes the increased levels of hepcidin:
- Low serum iron
- Low binding capacity
- high stores of iron in macrophages and ferritin levels
What are the classic signs of avitamintosis
- cheilosis
- Glossitis
- Dermatisis
What are the histological features in G6PD deficient cells
- Heinz bodies
- Bite cells (where a portion containing the Heinz body was removed by a macrophage)
What are the mutations in hereditary spherocytosis (HS)
Ankyrin, band 3, spectrin, band 4.2
What is the cause of hydrops fetalis
-Most severe alpha thalassemia, with deletions of all four chains
What are the antibodies in immune thrombocytopenia purpura (ITP) against
IgG against gp IIb-IIIa or Ib-IX
What is the cause of secondary absolute polycythemia
-Red progenitors are responding to an increased level of erythropoietin
What are the complications that arise in Beta-thalassemia as a result of the increased levels of erythropoietin
Extra-medullary sites, as well as hyperplasia in the marrow leading to:
- erosion of the bony cortex
- Impairment of bone growth
- skeletal abnormalities
- Cachexia
Which two conditions are classified under thrombi microangiopathy
TTP- thrombotic thrombocytopenia purpura
HUS- Hemolytic-uremic syndrome
What is hereditary hemorrhagic telangiectasia (aka Weber-Oiler-Rendu syndrome)
Autosomal dominant condition that causes modulation to TGF-Beta, leading to dilated, tortuous blood vessels with thin walls. This is very prone to bleeding
How does bleeding into tissues differ from bleeding into the gut or out of the body
Iron is not recaptured, so if its not into the tissue, there is the risk of iron deficiency
How is iron transported in the blood
transferrin
Where does the majority hemolytic anemias have premature destruction of RBCs
Within macrophages located in the spleen, also known as extravascular hemolysis
How does the treatment of pure red cell aplasia differ with regards to the presence and abscence of a thymoma
With thymoma: resection leads to improvement
Without: immunosuppressive therapy
What are the main two causes of megablastic anemia
Vitamin B12 and Folate deficiency
In newborns with alpha thalassemia, what is found in their blood with regards to parts of hemoglobin
-Excess gamma globulin forming gamma tetramers known as hemoglobin Barts
What is the location of action for type 3 antibodies in pernicious anemia
Present in 85-90% or patients and are recognizing the alpha and beta subunits of the proton pump of the gastric parietal cells
What is iron stored and bound to
IN the parenchymal cells of the liver, especially ferritin
-Macrophages in other tissues
What is the level of hepcidin in Beta-thalassemia and what is its effect
Decreased, leading to excess iron absorption due to mechanism:
- erythropoietin suppresses hepcidin, which decreases iron absorption
- Iron becomes excess and can lead to secondary hemochromatosis
In general, wha is the cause of marcocytic anemias
-abnormalities that impair the maturation of erythropoietin precursors in the bone marrow
As free haptoglobin decreases during intravascular hemolysis, what happens to the remaining free hemoglobin
Oxidizes to methemoglobin, which is brown
How do the majority of the clotting factor related defects present
- Large postraumatic ecchymoses or hematomas
- prolonged bleeding after a laceration of surgical procedure
“Patients presented with excessive bleeding following a dentist procedure”
What is the mechanism of hemolysis in paroxysmal nocturnal hemoglobinuria
Intravascular as the RBCs are prone to hemolysis via the MAC complex due to the lack of GPI proteins
Which population is shown to have cold hemolysis type anemia
Children following a viral infection
What is the most common nutritional disorder in the world
Iron leading to decreased hemoglobin synthesis
IN those patients that survive beta thalassemia major, what is the effect seen in the bones of the patients
- Have the “crew cut” in the skull
- cheekbones and other prominences are enlarged and distorted
What is the relation and mechanism of telomerase defects in the causation of aplastic anemia
Telomerase is responsible for keeping the DNA long in order to allow for long term replication. Without it, the stem cells will undergo hematopoietic cell exhaustion
What is the mechanism that thrombotic thrombocytopenia purpura (TPP) causes disease
1) Missing ADAMTS13 does not degrade vWF
2) vWF is allowed to accumulate and activate platelets
What is occurring during pure red cell aplasia
Primary marrow disorder in which only erythropoietin progenitors are suppressed or absent
What is the result of a splicing event causing beta thalassemia
-Production of abnormal and normal RNA, so there is still some normal Beta-globin present
In the case of immune thrombocytopenia purpura (ITP), what is the effect of a splenomegaly
Hrombocytopenia is markedly improved
What are some of the clinical signs of DIC
- Thombi in microvasculatrue
- microangiopathic hemolytic anemia
- bilateral renal cortical necrosis
- Waterhouse-Friderichsen Syndrome
- Giant hematomas (Kasabach-Merritt syndrome)
When are microangiopathic diseases seen
DIC TTP HUS Malignant hypertension SLE Cancers
What is the most significant trauma caused hemolysis
- Cardiac valve prosthesis
- Microangiopatic diseases
Once within the ileum pal cells, how does the B12 reach the blood
Binds to transccobalamin 2
What is the survival of a fetus and child with hydrops fetalis dependant on
Blood transfusions for life, with a stem cell transplant having some effect
What are the other lab and blood findings in the case of myelophthisic anemia
Displacement causes:
- abnormal release of nucleated erythroid precursors and immaterial granulocytic from into the blood (leukoerythroblastosis)
- tear drop shaped RBCs
What is the result of a chain terminator mutations in the production of beta thalassemias
B0
- Insertion of a stop codon
- Insertion or deletions that shift the reading frame
*Both result in the cessation of normal Beta globin
What is Henoch-Schonlein purpura
Systemic immune disorder that is characterized by:
- purpuric rash
- colicky abdominal pain
- ployarthralgia
- acute glomerulonephritis (immune complex deposition)
What are the changes in blood levels in folic acid from B12
- The respective level will be decreased
- Increased Serum homocysteine
- methylmalonate levels are normal in folate
- No Neurological changes
What is the heritability of Von Willebrand disease
Autosomal dominant
What does the RBC look like in the cause of Beta-thalassemia
Underhemoglobinized
-hypochromic, microcytic red cells with diminished survival of the RBC and oxygen carrying capacity
What are the lab values in the case of chronic immune thrombocytopenia purpura (ITP)
- low platelet count
- normal or increased megakaryocytes in bone marrow
- large platelets
- Normal PT and PTT
What are the bleeding times seen in bleeding disorders, and what are the common locations
- Bleeding times (PT and PTT) are normal
- Commonly seen in skin or mucus membranes, especially the gingivae
What is the response if there is splenomegaly and suspected aplastic anemia
Aplastic anemia does not have splenomegaly, so the diagnosis can be ruled out. Aplastic anemia also does not have hypercellularity, but rather hypocellularity
Which type of antibody is present in cold antibody type and which condition are they particularly active
-IgM, present when it is cold
What are the clinical presentations of intravascular hemolysis
- Anemia
- hemoglobinemia
- hemoglobulinuria
- hemosiderinuria
- jaundice
What is the relation to sickling and transit time through the microvascular beds
Most tissue has flow that is too quick to cause symptoms, however in normal spleen and marrow, the time is long enough to allow adhesion to vasculature and cause sickling
*Can also be seen in inflamed vessels
What is the state of cellularity in aplastic anemia and what method is used to confirm the diagnosis
Hypocellular, and will produce a “dry” bone aspiration, so much have a bone marrow biopsy
What is the diagnosis of pernicious anemia base upon
1) Moderate to severe megaloblastic anemia
2) Leukopenia with hypersegmented granulocytes
3) low serum B12
4) elevated homcysteine and methymalonic acid
*Confirmed by outpouring of reticulocytes and rise in hematocrit levels 5 days after parenteral administering of B12
What is the acute chest syndrome that can arise as a result of sickle cell anemia
Vaso-occlusive crisis involving the lungs, which presents as fever, cough, chest pain, and pulmonary infiltrates
What are the most common locations involved in sickle cell disease with regards to locations for vaso-occlusive crisis
-bones, lungs, liver, brain, spleen, penis
What are the two general underlying causes for aplastic anemia
- Extrinsic immune mediate suppression of the bone marrow
- Intrinsic abnormal stem cells
What are the morphological and histological findings in the case of immune thrombocytopenia purpura (ITP)
- Spleen of normal size
- Increased megakaryocytes in the marrow
- peripheral blood shows large platelets
What are the levels of serum iron, ferritin, and total plasma iron binding levels in iron deficiency, and hepcidin
- Low levels of serum iron
- Low levels of serum ferritin (binds to iron in storage)
- High binding levels (refers to high levels of transferrin)
- Low levels of hepcidin
What does B12 bind to in the saliva after it is released from food
Haptocorrin
What is the relation between kidney failure and anemia
Kidney failure causes the decreased amount of erythropietin release in addition to:
- defect that reduces the life span of RBCs
- iron deficiency due to platlet dysfunction and bleeding
What are the clinical presentations of chronic immune thrombocytopenia purpura (ITP)
- bleeding into the skin and mucosal surfaces
- easy bruising, nose bleeding, gingiva bleeding, hemorrhages into soft tissues
- Melana, hematuria, excessive mentraul flow
What is the mechanism that B12 leads to neuronal damage
- Increased plasma levels and urine levels of methylmalonic acid
- leads to the formation incorparation of abnormal fatty acids into neuronal tissue and myelin breakdown
Paraxosysmal nocturnal hemoglobulinuria is seen to be lacking which GPI proteins
1) CD55- aka decay accelerating protein
2) CD59- membrane inhibitor of reactive lysis
3) C8
*results in loss of the inhibition on C3 convertase and prevention of the complement pathways
What are the alleles that cause beta thalassemia major
Having two alleles such as:
B+/B+
B+/B0
B0/B0
What is the affect of sickle cell anemia on the kidney, and how can this lead to further complications
Causes hypertonicity in the renal medulla that leads to hyposthenuria, which is the inability to concentrate the urine. This leads to dehydration and further complications of sickle cell
What are tthe state of the RBCs in aplastic anemia
- Macrocytic and normochromic
* Reticuocytopenia as there is no bone marrow activity
If the hemoglobin or methemoglobin are not uptaken, what is the final place that it may be recovered
The proximal tubules of the kidney
What endocrine disorder is associated with anemia
Hypothyroidism, which is associated with mild normocytic,normochromic anemia
What is the most common type of immunohemolytic anemia and what is the mechanism
Warm antibody type, aka IgG, mostly extravascular hemolysis as the phagocytes engulf the RBCs
What is the source of B12
Parietal cells in the fundus of the stomach
What is the cause of hemoglobin disease, aka HgH
Deletion of 3 alpha globin genes
What is the effect on the blood cells in the cause of hydrops fetalis
-Such as high affinity for oxygen that it is unable to let go in the tissues
Which pathogens is cold antibody anemia commonly seen
- Mycoplasma pneumonia
- Epstein Barr virus
- CMV
- Influenza
- HIV
Which factor is affected in hemophilia B
IX
What is the leading cause of death in those patients with paraoxysmal nocturnal hemoglobinuria
Thrombosis, with 40% having venous thrombosis involving the hepatic, portal, or cerebral veins
Which patients are commonly seen to have DIC and how is it treated
Pregnant patients and resides with delivery of the fetus
In children and adults with alpha thalassemia, what is found in their blood with regards to parts of hemoglobin
-excess Beta globin leading to Beta globin tetramers known as HbH
What are the disorders of platelet secretion due to
Defective release of mediators such as thromboxanes and granule-bound ADP that signals the release
What is the basic lab finding in the cause of polycythemia
-Increased RBC count and increased hematocrit
What is the defect in Bernard-soulier syndrome
Defective adhesion due to:
-lack of Ib-IX which is the receptor for vWF and is required for platelet adherence to the endothelial surface
What is the most common and important anemias associated with red blood cell underproduction due to
Nutritional deficiencies
What are the products of G6PD deficiency in RBCs
-Crosslinking of sulfhydroxyl groups on globin chains, leading to Hienz body formations
What is the treatment for immune thrombocytopenia purpura (ITP)
Glucocorticoids
Splenectomy is stabilizing in 2/3 of patients
In the majority of patients withe aplastic anemia, which conditions are suspected
Autoimmune
What is the cause of relative polycythemia
Fluid loss due to:
- Dehydration
- Vomiting
- diarrhea
- diuretics
What are the histological features of hereditary spherocytosis
Loss of the central zone of pallor normally seen in RBCs
Where does bleeding tend to take place in those with clotting factor defects
IN the GI tract, urinary tract, and weight bearing joints
Where in the tree of cells does paroxysmal nocturnal hemoglobinuria occur and why is the significant
-Occurs in the hematopoietic stem cell, which means all the progeny contains the GPI defect, including WBC and platlets
What are the factors being tested in PTT test
Intrinsic and common clotting pathways:
- Factor 5, 8, 9, 10, 11, 12, prothrombin, or fibrinogen
- Or antibody interfering
What is the general triad seen in sickle cell anemia
- hemolytic anemia
- microvascualr obstruction
- ischemic tissue damage
Which neoplasms have been shown to have cold antibody anemia
B cell neoplasms
How does having a PIGA deletion lead to an increased proliferation in certain disease and which disease is it commonly seen with
Seen with aplastic anemia, which is due to autoimmune. In conditions were there is autoimmunity to GPI proteins (as in aplastic anemia), the cells containing the PIGA (seen in PNH) are safe and allowed to proliferate
What is the treatment for acute immune thrombocytopenia purpura (ITP)
Self limited
Hereditary clotting defects tend to have how many factors affected
1
Acquired clotting factor defects tend to have how many defects affected
Multiple
Which type of Von Willebrand disease is qualitative
Type 2
What is the mechanism that scurvy, helps Danilo’s, and cushing’s can cause bleeding disorders due to vessel wall injury
-collagen defects in the wall causing weakness and bleeding
What is the heritability of Hemophilia A
X linked recessive, therefore more common in males
What are the symptoms in Hemolytic-uremic syndome (HUS)
- Thrombocytopenia
- Microangiopathic hemolytic anemia
What is occuring during Hereditary spherocytosis
Intrinsic defects in the RBCs membrane skeleton that cause it to take the shake of a spheroid, less deformable and more vulnerable to splenic sequestration and destruction
In the cause of cobalamin deficiency, what is the product building up
N5-methyl FH4, which would normally be converted FH4 (lack of FH4 means lack of DNA synthesis)
What are the components in the normal structure of RBC membranes
- Ankyrin and band 4.2 binds spectrin to ion transporter, band 3
- Protein 4.1 binds the tail of spectin to protein glycophorin A
What are the reactions where vitamin B12 are needed
- homocysteine to methionine via methionine synthase
- taking N5-methyl FH4 to FH4 (crucial for allowing DNA synthesis)
What is the process the pathogenesis process that causes sickle cells to be dehydrated
1) Deranged membrane causes the influx of calcium into the cell.
2) Calcium causes the cross linking of the membrane proteins
3) Membrane proteins activate an ion channel that causes the loss of potassium and water
Which is the most common type of Von Willebrand disease
Type 1 (70%)
What are some of the locations of thrombi seen in DIC
Brain, heart, lungs, kidneys, adrenal, spleen, liver
What is the clinical result of HgH disease
They oxidize, leading to inclusions that promote the red blood cell sequestrion and phagocytosis in the spleen, which can even go on to resemble beta thalassemias
Where does B12 bind to IF
In the stomach it is released from haptocorrin via pancreatic proteases and binds to IF
When does thalassemia major tend to become symptomatic
6-9 months after birth due to the switch from HbF to HbA
What is a diagnostic histiologic finding in the case of iron deficiency
- Disappearance of stainable (Prussian blue) iron from macrophages in the bone marrow
- Microcytic (small) hypochromic (pale) anemia
What other conditions are commonly seen to coexist with pernicious anemia
- autoimmune thyroiditis
- autoimmune adrenalitis
How are Heinz bodies seen
Seen in RBCs with G6PD deficiency, stained with crystal violet
What is the heritability of Hemophila B
X linked recessive
What is a silent carrier state with regards to alpha thalassemia
-Only a single mutation in one of the four chains, giving a barely noticeable change in the hemoglobin levels of the patients
What is the function of vWF
Promotes platelet adhesion
Promotes cross bridge formation
Which conditions can stabilize HIF-1alpha and what is the significance
Conditions that stabilize hypoxia induced factor-1a that stimulates erythropoietin levels:
- Chuvash polycythemia
- Prolyl hydroxylase mutations
WHat is the function of hephaestin
Oxidize iron from 2+ —> 3+ so it can be bound to transferrin
What are the most common causes/triggers for hemolysis due to G6PD deficiency
Oxidation stress due to infection, typically viral hepatitis, pneumonia, typhoid fever
What is the most common method of mutation seen in beta+ thalassemia
Splicing mutations
What is the result of promotor region mutations in the production of Beta-thalassemia
B+
-This reduced the production by 70-80%, so there is some normal and some abnormal production
Which form of Von Willebrand disease is most concerning
Type 3, which has very low levels of vWF
What are the clinical features seen in hereditary spherocytosis (HS)
- osmotic lysis of RBCs in hypotonic solutions
- Increased mean cell hemoglobin concentration (due to loss of water and potassium)
- Anemia
- splenomegaly
- Jaundice
What is occurring in Type 1 thrombocytopenia following heparin
-rapid onset in which it is self limiting despite continuation of treatment
What is the function of methotrexate and its effects
inhibits dihydrofolate reductase, inhibits DNA synthesis and effects all fast growing cells of the bone marrow and GI tract
What is the age group that pernicious anemia is seen
Rarely younger than 30, generally 60 years old
What is the mechanism of pathogenesis in pernicious anemia
Megaloblastic anemia caused by an autoimmune condition where there is impaired production of IF
What type of anemia is produced by iron deficiency
Hypochromic microcytic anemia
What is the age group seen to have aplastic anemia
Any age or sex
What is the relation of mean cell hemoglobin concentrations (MCHC) and what are conditions that impact it
Increased MCHC leads to increased tendency to polymerize:
- Dehydration makes it worse
- alpha thalassemia makes it better
What are the levels of inorganic iron absorption increased by
- ascorbic acid
- citric acid
- amino acids
- sugars in the diet
What is the level of hepcidin during hemochromatosis
Low levels of hepcidin even at high levels of iron
What is the genetic abnormality seen in paroxysmal nocturnal hemoglobinuria (PNH)
Phosphotidyl glycine complementation group A gene (PIGA) that codes for GPI proteins
How is vWF function assay tested
-ristocetin agglutination, which activates the vWF
What is the prognosis of HUS
Good, as supportive is allowing a complete recovery, but there may be some renal damage
What is the age group and population seen to develop immune thrombocytopenia purpura (ITP)
-women younger than 40 years old
What is occurring in fanconi syndrome and what is the connection to aplastic anemia
Lack of DNA repair mechanism, leading to marrow hypofunction, as well as hypoplasia of the kidney, spleen and bone anomalies (most common the thumb and radii)
What is the mechanism of action in anemia of chronic disease
Chronic inflammation causes increased levels of hepcidin, leading to the inhibition of iron uptake
What other values are abnormal in RBCs seen in hereditary spherocytosis (HS)
- Loss of potassium
- loss of water
- loss of glucose
- Decreased pH
IN general, what is the cause of microcytic hypochromic anemias
Disorders of hemoglobin synthesis, most often hemoglobin synthesis
What are the three major causes of folic acid deficiency
- Decreased intake
- Increased requirement
- impaired utilization
Which world locations are more prone to thalassemia syndromes
- Mediterranean basin
- Middle east
- tropical Africa
- India
- Asia
What is the underlying effect of thalassemias
- Decreased RBC life span
- Decreased RBC production
What are the three categories of anemia of chronic disease and what are some examples
- Chronic microbial infections: osteomyelitis, bacterial endocarditis, lung abcess
- Chronic Immune dysfunctions: RA and regional enteritis
- Neoplasms: carcinomas of lungs and breast, Hodgkin lymphoma
In the cause of immune thrombocytopenia purpura (ITP), what should be considered if there is splenomegaly
immune thrombocytopenia purpura (ITP) secondary to a B cell neoplasm
How does ineffective erythropoiesis cause secondary hemochromatosis
- High levels of erythropoietin causes a decreased level of hepcidin
- Low levels of hepcidin allow the increased iron uptake although the levels are high and it is the inabilty to make functional RBCs that are the issue, not the lack of iron
What are the two forms of beta thalassemias
- B0 mutations- which have no beta-globin synthesis
- B+ mutations- which have reduced but detectable synthesis
What is the mechanism that drug reactions cause bleeding disorders of vessel walls
-drug induced immune complexes in the vessel walls
What are patients with elevated homocysteine at a higher risk for
- Atherosclerosis
- Thrombosis
What are the two clinically significant acquired defects of platelet functions
1) NSAIDs and Aspirin inhibit COX
2) Uremia
Which cells are most at risk for hemolysis in G6PD deficiency
Older cells, as the half life of the G6PD proteins is lowered
What is an effective treatment for PNH
Treatment of an antibody that prevents activation of C5 into C5a
What is extravascular hemolysis
Destruction of the RBCs in the spleen by the macrophages
What is Gaisbock syndrome
“Stress” polycythemia, commonly seen in obese, hypertensive, stressed individuals
What is the location of action for Type 2 antibodies in pernicious anemia
- Prevents binding of IF to its ileal receptor cubulin
* Founds in a large portion of patients
What is the appearance of reticulocytes
Aka newly released RBCs
-Larger in size, blue-red polychromatophilic cytoplasms
What is haptoglobin, and what is its function
an alpha2 globulin, binds to free hemoglobin that escapes the macrophages and prevents it from entering the urine
What are the two types of drug induced warm antibody type immunohemolytic anemias
1) Antigenic drugs (penicillin and cephalosporins) which bind to RBCs and the antibodies to drug cause hemolysis of the RBCs
2) Breaking of central tolerance (alpha-methyldopa) which break the tolerance and produce antibodies to the RBC components
What is the function of Type 1 antibodies in pernicious anemia
75% have type 1, which prevents binding of B12 to IF
*Found in plasma and gastric juices
Which conditions are common to cause myelophthisic anemia
-Metastatic cancer, such as breast, lung, and prostate
What are the clinal features in the fetus during hydrops fetalis
-pallor, generalized edema, massive hepatosplenomegaly
What is the overall danger of Von Willebrand disease
Not very much, as it may present following a surgery or dental procedure, but it relatively mild
What other conditions can cause vitamin B12 deficiency
- achlorhydria and loss of pepsin secretion cause cause the inabilty to release B12 from foods
- Gastrectomy Decreases IF release
- Loss of pancreatic function decreases B12 release from haptocorrin
Megablastic anemias have which underlying cause
Defects in the DNA synthesis leading to ineffective hematopoiesis leading to abnormal large RBCs and precursors
What is the cause of acute immune thrombocytopenia purpura (ITP)
Disease of childhood 1 to 2 weeks after a viral infection
Which conditions are at a higher risk for developing chronic immune thrombocytopenia purpura (ITP)
- SLE
- HIV
- C bell neoplasmas
What type of mutation is seen in hereditary spherocytosis
Frameshifts leading to production of no proteins at all
What is the heritability of G6P dehydrogenase deficiency
X linked recessive
How is Iron 2+ transported across the basilar membrane of duodenal cells
Ferroportin 1
What are the clinical features of anemia
- Pale, weak, malaise, easily fatugable
- dyspnea on exertion
- Hypoxia caused fatty changes to liver, myocardium, and kidney
Hemophilia A is a defect in which clotting factor
VIII
What are the clotting factors that are affected with Vitamin K deficiency
2, 7,9,10 and protein C
The clinical features of acute blood loss are dependent on what
On the rate of hemorrhage and whether the bleeding is external or internal
What is the result of the increased production of alpha globin in comparison the Beta in Beta thalassemia
Unpaired alpha chains result in precipitation in red cell precursors, forming insoluble inclusions, causing membrane damage as the main pathological effect
What does the diagnosis of immunohemolytic anemia depend on
-detection of antibodies and/or complement on RBCs via direct Coombs test
Which drugs are most often implicated in the formation of thrombocytopenia
Quinine
Quinidine
Vancomycin
Which infections can cause bleeding disorders of the vessel walls
- Infective endocarditis
- Meningococcemia*** most deadly if missed
What is the mechanism of pathogenesis in the cause of Type 2 thrombocytopenia as a result of heparin treatment
-Antibodies bind platelet factor 4 and activate the platelets
What are the morphological and histological findings in sick cell disease
- Howell-Jolly bodies (aka target cells as a result of RBC dehydration)
- Crewcut appearance on X ray
Which conditions are associated withe the formation of pure red cell aplasia
- Thymoma
- Large granular lymphocytic leukemia
- drug exposure
- autoimmune
- Parvovirus
Where is dietary iron absorbed
Proximal duodenum
Why is there a tendency for hemolysis at night in PNH
There is a drop in pH during sleep, increasing the activity of the complement system
What is the only hemolytic anemia that is an acquired genetic defect
Paroxysmal nocturnal hemoglobinuria
What is another name for B12
Cobalamin
What are the mechanisms that sickle cell trait helps defend against malaria infection
- parasite decreases pH, causing sickling and removal of RBC
- sickling impairs the protein PfEMP-1, which would normally cause the infected cells to stick to the endothelium
What is the pentrad of thrombotic thrombocytopenia purpura (TTP)
- Fever
- Thrombocytopenia
- microangiopathic hemolytic anemia
- Transient Neurological deficits
- renal failure
What are the common causes of intravascular hemolysis
- Mechanical injury
- Complement fixation
- intracellular parasites
- exogenous toxic factors
Where is IF-B12 absorbed and how
In the ileum, the complex binds to cubulin on the surface of the ileum
What locations are patients with hereditary hemorrhagic telangiectasia (aka Weber-Oiler-Rendu syndrome) prone to bleeding
-mucous membranes under the nose, tongue, mouth, and eyes, and GI
What are the enzymes that help to reduce iron to 2+ and allow for absorption in the duodenum
Ferritinreductases such as STEAP3 and b cytochromes
What is the most common cause of iron deficiency in the western world
Chronic blood loss
What is the inheritance pattern of hereditary spherocytosis
Autosomal dominant
What is a potential complication from hemoglobin reabsorbed in the kidneys
-Renal hemosiderosis, which is increased iron in the kidney, particularly the tubular cells
What is the impact of Von Willebrand disease on other clotting factors
Because it stabilizes VIII, it can appear as deficiency of that factor and prolong PTT
What factors are being tested in a PT test
Extrinsic and common coagulation pathways:
-Factor 5, 7, 10, prothrombin, and fibrinogen
What is the function of hepcidin
Regulates the level of iron by blocking ferroportion and absorption of iron from the gut
What is the diagnosis in the cause of acute immune thrombocytopenia purpura (ITP) in a child without a viral prodrome
Childhood case of chronic immune thrombocytopenia purpura (ITP) that follows the same path
What is the triad of Plummer Vinson syndrome
1) esophageal webs
2) microcytic hypochromic anemia
3) atrophic glossitis
What is occurring in Type 2 thrombocytopenia induced by heparin treatment
- Occurs 5 to 14 days after treatment
- life threatening thrombosis
What condition are those with pernicious anemia and gastric atrophy at a higher risk for
Gastric carcinoma
