Week 23-4: Anemia, Bleeding Disorders and Hematologic Neoplasms Flashcards
1
Q
Most common causes of iron deficiency anemia (3)
A
BLOOD LOSS is #1
Iron-poor diet
Malabsorption
2
Q
Significance of iron deficiency anemia
A
most common nutritional deficiency in N America. Affects 20% of pre-menopausal women and 50% of pregnant women
3
Q
Biochemical findings in iron deficiency
Serum Iron
Serum transferrin (TIBC)
%Saturation of transferrin
Ferritin
Free erythrocyte protoporphyrin
A
Serum Iron - low
Serum transferrin (TIBC) - high
%Saturation of transferrin - low
Ferritin - low
Free erythrocyte protoporphyrin - high
4
Q
Hematologic findings in iron deficiency
Hemoglobin
MCV
MCH (mean corpuscular hemoglobin)
Peripheral blood smear
Platelet count
A
- Hemoglobin - low
- MCV - low
- MCH (mean corpuscular hemoglobin) - low
- Peripheral blood smear - small cells of varying sizes, hypochromatic; pencil cells
- Platelet count - high
5
Q
Cause of hemochromatosis and how does it work?
A
- genetic disorder with autosomal recessive inheritance.
- Caused by a mutation that reduces hepcidin expression.
- This means that iron may more freely exit cells via ferroportin.
- Iron builds up in parenchymal cells of liver, heart, pancreas and other tissues. Build up over time and symptoms arise later in life.
6
Q
Lab findings for hemochromatosis Serum Iron Serum transferrin (TIBC) %Saturation of transferrin Ferritin
A
Serum Iron - High Serum transferrin (TIBC) - Low %Saturation of transferrin - High Ferritin - High
7
Q
Causes of B12 deficiency (4)
A
poor nutrition (vegans)
Pernicious anemia
Total or partial gastrectomy
Intestinal disease
8
Q
Causes of folate deficiency
A
poor nutrition (elderly, poverty, alcoholic)
Increased utilization of folate (pregnancy, lactation, malignancy, inflammation, hemolytic anemia)
Intestinal disease;
Drug Induced (i.e., anticonvulsants);
9
Q
What are the 3 major components of the RBC?
A
- membrane (needs ot be tough and have a large SA) 2. Hb (responsible for on/offloading of oxygen) 3. Enzymes (need to have enough enzymes to look after the cell for its 120 day life because RBCs don’t have DNA to make more)
10
Q
Hemolytic Anemia - characteristics (3)
A
- ANEMIA - decreased Hb concentration;
- JAUNDICE - increased red cell breakdown (causing hyperbilirubinemia and cholelithiasis)
- SPLENOMEGALY - increase bone marrow compensation (leading to reticulocytosis and splenomegaly)
should also see reticulocytosis if the BM is properly compensating
11
Q
Cause of hemolytic anemia
A
MALARIA is the major genetic driving force.
12
Q
Causes and distribution of hereditary spherocytosis
A
- mutations in RBC membrane support proteins: ankyrin, spectrin, Band 3, and protein 4.2.
- Mostly autosomal dominant with some more serious autosomal recessive variants. More prevalent in N Europeans.
13
Q
Pathology in hereditary spherocytosis
A
- Mutations to membrane support proteins (ankyrin, spectrin, Band 3, or protein 4.2) make RBCs fragile.
- Cells are fragile and lose SA - become spherocytes.
- RBCs experience ‘splenic conditioning’ which refers to progressive loss of membrane each time the spherocytes try to squeeze through splenic vasculature (EXTRAVASCULAR hemolysis). The spherocytes are rigid and lyse easily
14
Q
Symptom triad in hereditary spherocytosis and critical symptoms that may occur
A
anemia, jaundice, splenomegaly
critical symptoms: aplastic crisis, choliesthasis, massive splenomegaly
15
Q
Diagnosis of hereditary spherocytosis
A
- blood smear (for spherocytes and polychromasia)
- osmotic fragility test (in vitro hemolysis with decreasing NaCl concentration)
- Flow cytometry (best; most diagnostic)
16
Q
Management of Hereditary spherocytosis (2)
A
- supportive treatment (folic acid, spleen protection)
- splenectomy is a symptomatic cure but it comes with complications and must be met with immune prophylaxis because losing the spleen severely compromises the immune system.
17
Q
what are the hemoglobinopathies?
A
Beta-Thalassemia Major and Sickle Cell Anemia
18
Q
Distribution of hemoglobinopathies
A
High incidence in southern europe (italy, greece), middle east, south asia, south east asia
19
Q
What is B Thalassemia Major?
A
- Mutation in the beta-globin gene. Decreased beta-globin production results in imbalanced alpha : beta globin pairing. Excess alpha chains precipitates damage to RBC membranes.
- Ineffective erythropoiesis
- Severe anemia, bone marrow expansion, and hepatosplenomegaly
20
Q
major characteristics of beta thalassemia major
A
- Severe anemia
- bone marrow expansion (characteristic changes to physical appearance of patients)
- hepatosplenomegaly
21
Q
distribution of beta thalassemia
A
High numbers of carriers in S mediterranean, middle east, N Africa, S Asia, SE Asia, and S China.
22
Q
Treatment of B-Thalassemia
A
- Regular transfusions required for B Thal Major. Starting around 6-12 months old (after fetal Hb has dissipated).
- Regular transfusions (ever 3-4 wks) lead to high iron deposition so iron chelation therapy begins after 10-20 transfusions.
23
Q
Complications associated with B Thalassemia (5)
A
- Bone marrow expansion (leads to osteoporosis)
- Endocrine failure
- Transfusion hemosiderosis (leads to CHF, liver cirrhosis and liver CA)
- Transfusion-related complications (i.e., infections, transfusion reactions)
- Psycho-social impact
24
Q
Diagnosis of B thalassemia
A
Hemoglobin electrophoresis;
HIgh performance liquid chromatography;
25
Distribution of sickle cell anemia
Sub-saharan afric and also seen in middle east, south Europe and Indian subcontinent.
26
Cause and pathology of sickle cell anemia (6)
* SIngle gene mutation.
* The mutated HbS polymerizes when deoxygenated, causing RBC to be stiff and deformed (sickled).
* Sickle cells sludge in capillaries, leading to recurrent infarctions (especially in spleen, BM, kidneys).
* Sickle cells lyse (intravascular hemolysis).
* Damaged RBCs are adherent to vessels and can cause proliferative vasculopathy, which may lead to a stroke.
* Drop in NO associated with hemolysis leads to increased vascular tone and HTN.
*
27
Complications of sickle cell disease (8)
* Infections (hyposplenism, encapsulated bacteria)
* Vaso-occlusive crises (very painful, common in long bones, back, abdomen)
* Acute chest syndrome (due to sickling in lungs)
* Stroke
* Kidneys - hyposthenuria (refers to damage to countercurrent multiplier system that results in increased urination and dehydration)
* pulmonary hypertension
* aplastic crises (with parvovirus B19 infection)
* spenic sequestration crisis (need urgen transfusion)
28
Diagnosing sickle cell disease (2)
Sickedex screen;
Hb electrophoresis
29
Management for sickle cell disease (5)
* Supportive care (hydration and pain control);
* Prevent and treat infections;
* Drug (hydroxyurea) to elevate numbers of fetal hemoglobin.
* Blood transfusions with care not to over transfuse because hyperviscosity can worsen pathology.
* Gene therapy.
30
The two major enzymopathies
GDPD (glucose-6-phosphate dehydrogenase) and PK (pyruvate kinase) deficiencies
31
Pathology of G6PD deficiency
Shortened half-life of G6PD enzyme results in reduced glutathione availability. GLutathione is a major antioxidant. Without glutathione, Hb is oxidated and RBC membrane is subjected to oxidative damage, ultimately leading to hemolysis.
32
Cause of G6PD deficiency
Sex-linked inheritance of the mutation - more common in boys.
33
oxidative challenge in G6PD deficiency
Things that cause oxidative stress on cells exacerbate pathology of G6PD deficiency. Oxidative challenges include some infections, drugs, fava beans, moth balls.
34
What do RBCs look like in G6PD deficiency?
* Bite cells and blister cells.
* Intravascular hemolysis due to instability of the cells.
35
How may G6PD present?
Neonatal jaundice;
Episodic or chronic hemolysis.
* especially with oxidative challenges (infections, drugs, fava beans)
36
Diagnosis of G6PD deficiency
Enzyme assay
37
management of G6PD deficiency
* avoid fava beans and oxidizing drugs
* vigilance during severe infections
* Treat acute hemolysis with hydration alkalinization and possibly packed RBC transfusion.
38
Pathology of pyruvate kinase deficiency
* Pyruvate kinase is key in the rate-controlling step of glycolysis. Deficient PK undermines ATP production in RBCs.
* ATP depletion in cells results in morphological changes to cells (they get spiky) and eventual hemolysis
39
Tolerance of anemia in PK deficiency
PK deficiency is associated with improved oxygen offloading from Hb, so pts with PK deficiency tolerate their anemia relatively well.
40
Symptoms of PK deficiency (3)
* Neonatal jaundice;
* life long anemia (but well tolerated);
* Mild jaundice, cholelthiasis;
41
Management of PK deficiency
* Supportive;
* Splenectomy not usually helpful;
* Transfusion may be needed at times of BM suppression.
42
Senile Purpura
- A bruising/bleeding problem of the vasculature - Age-dependent deterioration of the vascular supporting structure, leading to bruising on the Dorset of the hands and forearms - no serious bleeding - can also be induced by longterm endogenous or exogenous steroid exposure.
43
Von Willebrand Disease
* A bleeding disorder caused by inherited defects in the concentration, structure or function of von Willebrand factor.
* Type 1 (reduced VWF; common)
* Type 2 (dysfunctional VWF protein; rare)
* Type 3 (absolute deficiency of VWF; extremely rare).
* mostly autosomal dominant with variable penetrance (can be recessive)
* Prevalence 1:1000 to 1:10,000
44
What are the three types of VWF disease?
1. Type 1 - reduced VWF protein (most common)
2. Type 2 - dysfunctional VWF protein (uncommon)
3. Type 3 - no VWF protein (Coagulation factor VIII suffers because it lacks protection from VWF carrier protein; extremely rare)
45
How do each of the VW disease types present?
Type 1 & 2 - mucocutaneous bleeding
Type 3 - severe mucocutaneous bleeding. May see joint/muscle bleeding
46
Hemophilia
## Footnote
- what is it, what are the two types, and how is it acquired?
* An inherited bleeding disorder with mild, moderate or severe deficiency of a coagulation factor.
* **Hemophilia A** = Factor VIII deficiency (1:10,000 births)
* **Hemophilia B** = Factor IX deficiency (more rare) X-linked recessive inheritance
47
Pathophysiology of hemophilia and how that will present in a pt
* This is a coagulation factor problem.
* Deficiency of Factor VIII (A) or IX (B) undermines the clotting cascade. So the Extrinsic pathway is still functional, but clotting cascade through the Intrinsic pathway is non-functional. This means that thrombin is only generated slowly
* pt will experience prolonged bleeding after injury with weak, fragile clots that are prone to re-bleeding.
48
Explain the graded presentation of hemophilia
Hemophilia can present as mild to severe bleeding. The amount of coagulation factor protein made is directly linked to the severity of bleeding. At severe levels the pt experiences spontaneous bleeding starting at a young age. In mild presentation the bleeding my only arise with trauma or surgery and impairment may not be evident until adulthood.
49
3 coagulation factor problems that are acquired
Liver disease; Anticoagulants (i.e., heparin or warfarin); Vitamin K deficiency;
50
How does liver disease cause bleeding issues
It’s a coagulation factor problem because coagulation factors are produced in the liver. Patients will present with mildly exaggerated bleeding because the liver can compensate to an extent.
51
How can anticoagulants lead to bleeding issues?
It’s a coagulation factor problem. Severe bleeding results from overdose, trauma, or procedures. The bleeding can be severe or life-threatening.
52
How does Vitamin K deficiency lead to a bleeding disorder?
Vitamin K is an important cofactors in the synthesis of several coagulation proteins. Vit K deficiency will lead to mild bleeding disorder.
53
Treating senile/steroid purpura?
No specific treatment. Limit exposure to steroids; Caution with respect to the delicate skin; Recognize that aspirin, anti-inflammatories and anti-coagulants may worsen bleeding;
54
Treatment for Von Willebrand Disease
1. Administer **DDAVP** to promote release of endogenous VWF stores. This can usually yield a 3-5 fold rise in VWF and Factor VIII levels in Type 1 VWF, but is not effective in a qualitative and absolute VWF deficit (I.e., not helpful in Type 2 or 3).
2. Administer exogenous VWF and Factor VIII. Plasma derived VWF-VIII concentrate of a VWF recombinant (lacking VIII). Given for Type 2 and 3 VWF disorder. Administered by IV with half life of 8-12 hours.
55
Two major ways that cancer kills
Systematically... by consuming nutrients and energy that the body needs to survive (“Cachexia”). Locally... by injuring or impairing critical organ functions.
56
Derivatives of myeloid stem cells
Granulocytes, erythrocytes, monocytes, and megakaryocytes
57
Derivatives of lymphoid stem cells
B cells (plasma cells) and T cells
58
What are Lymphoid neoplasms?
Neoplasms arising in Lymphoid tissue Usually a lymph node, but can be in extranodal tissue or in the BM. Most often presents with an enlarged lymph node (lymphoma = lumps). Cannot be cured surgically. Requires chemotherapy +/- radiation. Hodgkin and Non-Hodgkin types. Non-hodgkin can be B or T cell.
59
Pathology of acute leukemia
The mutation leads to maturation arrest, relentless cell division and immortality of cells. Malignant blasts fill the marrow space and spill out into the peripheral blood. Leads to suppression of normal hematopoiesis, which causes cytopenias or pancytopenia.
60
How might acute leukemia present in patients?
Acute leukemia lead to various cytopenias. Patients will have complaints related to low cells counts. Ex: anemia --\> fatigue thrombocytopenia --\> weird bruises, petichiae
61
"acute" leukemia refers specifically to what feature of the cancer?
The fact that all of the cells are blasts (whether they are myeloid or lymphoid blasts)
62
If a 1:1 mixing study comes back with a normal INR, what does that suggest?
It suggests that the pt has a coagulation factor deficiency rather than an issue with inhibition of a coagulation factor. Usually it's Factor 8 that is deficient, because that is more common (Hemophilia A).
63
If a 1:1 mixing study comes back with a prolonged INR, what does that suggest?
It suggests that the prolonged INR is due to some form of inhibition of coagulation factors.
64
What is a 1:1 mixing study used for?
To determine if a prolonged INR is due to a deficiency of coagulation factors or inhibition of coagulation factors.
65
Presentation of AML
Symptoms related to pancytopenia (fatigue, bruising/bleeding, infections, etc) Constitutional ("B" symptoms), which include: fevers, drenching night sweats, weight loss \>10% in 6 mo
66
How does Warfarin increase clotting time?
Warfarin is a vitamin K antagonist. Vitamin K is a critical cofactor in production of many coagulation factors. Warfarin therefore interferes with both the intrinsic and extrinsic coagulation pathways, leading to increased clotting time.
67
Tumor Lysis Syndrome When does it occur? What is it?
An emergent presentation of AML. Can also occur when you start chemo. As cells start breaking down, they release DNA into the blood. Purines from DNA release uric acid, which is toxic to the kidneys at high levels and can lead to renal failure. Protein breakdown can also contribute to the renal failure. Further, K release from the cells can lead to cardiac arrhythmias and neuromuscular irritability.
68
Definition of Leukemia
A malignancy of hematopoietic stem cells arising in the bone marrow, in which the (normal) bone marrow is almost entirely replaced. Leukemia can be acute or chronic. In acute all cells are blasts and in chronic the leukemia cells are more mature.
69
What is acute myeloid leukemia?
A myeloid malignancy of WBCs, in which all malignant cells are blasts. It is the result of mutations in a hematopoietic stem cell. Classified based on what mutation is present.
70
In whom is AML more common?
More common in adults than children
71
What is the prognosis for AML
prognosis depends on the mutations that are present.
72
Cause of acute leukemia
Mutation in a hematopoietic stem cell, usually idiopathic, but can be due to radiation or chemical exposure. Rarely there is a genetic predisposition.
73
Prognosis for acute myeloid leukemia (AML)
generally worse than ALL (acute lymphoid leukemia). It is worse for older patients and more complex mutations. Cure is about 40% with intensive chemotherapy +/- stem cell transplant.
74
pancytopenia
Low RBCs, neutrophils, and platelets
75
Lab findings in Acute Myeloid Leukemia
Pancytopenia (low RBCs, low neutrophils, low platelets) ; HIGH WBC count due to many circulating blasts;
76
What are Auer rods (on blood film)
Red needle-like includion within the cytoplasm of some acute myeloid leukemia blasts. These are pathognomic of AML!! But now every AML case has them. So if we see Auer rods it's definitely AML, but if we don't seem them it still could be AML.
77
Clinical Presentation of ALL
Very similar to AML. - Symptoms of pancytopenia (fatigue, bruising/bleeding, infections, etc) - Constitutional ("B" Symptoms): fevers, drenching night sweats, weight los \> 10% in 6 mo ALSO (unique to ALL) - palpable lymph nodes - CNS involvement (headaches, numbness)
78
Prognosis of ALL
Very good in children! 85% cure rate with intensive chemo over 2 years. Must consider long term treatment effects (CNS radiation). Adults are harder to treat. Cure rate is less than 40% even with stem cell transplant.
79
Presentation of AML
Symptoms related to pancytopenia (fatigue, bruising/bleeding, infections, etc) Constitutional ("B" symptoms), which include: fevers, drenching night sweats, weight loss \>10% in 6 mo
80
Emergency Presentation of AML
- Tumor lysis syndrome (TLS) - Hperviscosity Febrile neutropenia DIC (disseminated intravascular coagulation)
81
Workup for MDS
CBC (normal to low cell counts due to cells being held in BM);
Peripheral blood smear (bilobed neutrophils, large and dysplastic RBCs);
Rule out other causes of macrocytosis (B12, folate, TSH);
Bone marrow aspirate and biopsy: Bone marrow is hypercellular with dysplastic cells
82
Hyperviscosity
An emergent complication of AML. This happens when the blast count is very high. Blasts are BIG so they are good at clogging blood vessels. The pt may experience mucosal bleeding, visual changes, neurologic symptoms (headache, decreased LOC), dyspnea
83
How would you respond to hyperviscosity presentation of AML?
Urgent chemotherapy, avoid RBC transfusion, may need leukapheresis (remove WBCs). ALl with the goal of decreasing blood viscosity asap.
84
Prognosis of MDS
Possible transformation to AML - worst possible complication because the AML that arises from MDS is worse and harder to treat than de novo AML.
85
Acute Promyelocytic Leukemia
An acute myeloid leukemia with a translocation at t(15 ; 17). This one has a good prognosis but also is prone to complication with DIC, which has a high mortality rate in first 48 hours.
86
Treatment for AML
Depends on their age and how sick they are. For younger/fit pts: multiple rounds of intensive chemo +/- stem cell transplant aiming for cure Older/unfit pts: palliative treatment such as gentler chemo, novel drugs, clinical trials Supportive care (RBC and platelet transfusions, treat infections, lower blast count
87
HLA tissue typing
We look for a 10/10 match when donating bone marrow. Full siblings have a 25% chance of being a match. Parents can only ever be a 50% match. There are also stem cell drives that have tons of people tested to see if there is an unrelated donor match out there. The chance of finding a match is much better for caucasian people.
88
Define Acute Lymphoid Leukemia (ALL)
A lymphoid malignancy arising in WBCs, in which all malignant cells are blasts.
89
In whom is ALL more common?
More common in children than adults, and is THE MOST COMMON MALIGNANCY IN CHILDREN
90
Pathology of ALL
A lymphoid stem cell undergoes a mutation in the bone marrow that makes it immortal.
91
Clinical Presentation of ALL
Very similar to AML. - Symptoms of pancytopenia (fatigue, bruising/bleeding, infections, etc) - Constitutional ("B" Symptoms): fevers, drenching night sweats, weight los \> 10% in 6 mo ALSO (unique to ALL) - palpable lymph nodes - CNS involvement (headaches, numbness)
92
Prognosis of ALL
Very good in children! 85% cure rate with intensive chemo over 2 years. Most consider long term treatment effects.
93
Define Myelodysplastic Syndromes
These are clonal disorders that lead to: - Ineffective myeloid hematopoiesis - Dysplasia Must have \<20% balsts in blood ( \>20% is automatically AML) Has the potential to transform into AML. Often considered a pre-leukemia state, but not all AMLs start with MDS.
94
Lab findings for MDS
Pancytopenia: cells are being produced but they can't exit BM into peripheral blood. Dysplasia: found on peripheral blood smear; super odd neutrophils (bilobed; John Lennon); RBC macrocytosis and dysplasia.
95
Workup for MDS
CBC (normal to low cell counts due to cells being held in BM); Peripheral blood smear (bilobed neutrophils, large and dysplastic RBCs); Rule out other causes of macrocytosis (B12, folate, TSH); Bone marrow aspirate and biopsy: Bone marrow is hypercellular with dysplastic cells
96
Risk factors for MDS
Older age (rare under age 50); Exposure to organic compounds (e.g., benzene); Exposure to prior chemo or radiation therapy; Cigarette smoking;
97
Presentation of MDS
Fatigue, bleeding, infections due to pancytopenia.
98
Prognosis of MDS
Possible transformation to AML - worst possible complication because the AML that arises from MDS is worse and harder to treat than de novo AML.
99
Where can stem cells be sourced?
Bone marrow (harvested in the OR); Peripheral blood (more common now); Umbilical cord (public and private cord banks);
100
The two kinds of stem cell transplants
Autologous (from own blood); Allogenic (another person's blood, umbilical cord)
101
HLA tissue typing
We look for a 10/10 match when donating bone marrow. Full siblings have a 25% chance of being a match. Parents can only ever be a 50% match. There are also stem cell drives that have tons of people tested to see if there is an unrelated donor match out there. The chance of finding a match is much better for caucasian people.
102
What would a PT and PTT show in a hemophilia?
The PTT would be abnormal but a PT/INR would be normal. This is because the PTT tests the intrinsic pathway, which includes Factor 8 and 9. PT only tests the extrinsic pathway.
103
4 stages of RBC development (after hematopoietic stem cell)
Proerythroblast: committed to being an RBC; wearing EPO receptors
Normoblast: last nucleated stage
Reticulocytes: Expel nucleus and then move into the peripheral blood 2 days later, where they extrude other organelles
Mature RBC: 24 hours after going into the peripheral blood
104
Erythropoietin
* Regulates formation and release of RBCs
* Secreted by the kidney \>\> liver
* Increases at high altitude
* Interacts with receptors on proerythroblasts
105
3 major components of RBCs
- membrane
- hemoglobin
- enzymes
106
Membrane proteins on RBCs (5)
Integral membrane proteins:
* **Glycophorin C** - maintains cell shape
* **Band 3** - prevents membrane surface loss/damage during travels
Peripheral membrane proteins:
* **Spectrin** - maintains cell shape
* **Protein 4.2 -** anchor cytoskeleton to integral membrane proteins
* **Ankyrin** - anchor cytoskeleton to integral membrane proteins (band 3)
107
How is hemoglobin synthesized?
Synthesized by reticulocytes before they go into peripheral blood. They make almost all of the Hb they're ever going tohave at this time, with some residual rRNA making a little more birefly after entering vasculature.
108
Structure of hemoglobin
4 globins and 4 hemes
globins surround and protect the heme. Globins are usually 2alpha and 2beta (HbA).
heme is a porphyrin ring that contains Fe, which reversibly binds O2.
109
Describe erypoptosis and parts recycling
* RBCs die after about 4 months because their membranes get too old
* SPlenic macrophages phagocytose old RBCs in the spleen and liver.
* Globins broken into AAs that are reused
* Heme extremed with bilirubin
* Iron brought back to BM by transferring to be reuused in synthesis of more Hb
110
What is the pentose phosphate pathway and its significance in anemia
* The process of RBC taking up glucose and converting it to 6-phosphogluconate. The process produces **reduced glutathione**, which is a key antioxidant in the RBC.
* The process requires the enzyme **G6PD**
* People who are **G6PD deficient** will have hemolytic anemia due to inability of RBCs to withstand oxidative stress
111
G6PD deficiency
* Most common cause of enzyme-deficienct hemolytic anemia
* x-linked, variable expression
* Pt unable to produce as much reduced glutathione (antioxidant), which causes RBCs to be prone to lysis in states of oxidative stress (aspirin, fava beans)
112
Describe the importance of pyruvate kinase in RBCs and what happens when it is deficient
* Pyruvate kinase is a key enzyme in glycolysis. RBCs don't have mitochondria so they rely on glycolysis for ATP production.
* In pyruvate kinase deficiency, RBCs can't make enough ATP so they lyse --\> hemolytic anemia
*
113
A high reticulocyte count suggests what kind of anemia?
A blood loss or hemolytic anemia (not an anemia due to decreased RBC production)
114
explain what is meant by an inappropriately normal reticulocyte count in the context of anemia?
the BM can compensate for reduction in RBCs due to blood loss or hemolysis. The BM should compensate by making more RBCs, which should increase peripheral reticulocyte counts. A normal retic count suggests that the body isn't compensating - worrying.
In an inappropriately normal retic count (i.e., normocytic but no increased reticulocytes), we suspect decreased RBC production in BM.
* _intrinsic issue_:
* *nutrient deficiency:* B12, ferritin, iron, folate
* *Trophic factor deficiency*: EPO androgen (check creatinine)
* *suppression:* Inflammation (check CRP)
* _Extrinsic BM limitation_: Do a BM biopsy
* Abnormal cell development (MDS, leukemia, aplastic anemia, RBC aplasia)
* Marrow replacement (malignancy, myelofibrosis, infection)
115
Absorption of Iron and 4 important proteins involved in its absorption and transport
* Fe absorbed in intestine
* **Ferric reductase** converts Fe3+ to Fe2+ so that it can be taken in at the apical surface
* **Ferroportin** transports Fe2+ on the basolateral surface so that iron can get into the blood
* **Hephaestin** is a basolateral membrane protein that converts Fe 2+ back to Fe3+ before it heads off to the BM via **transferrin**
116
Iron storage in the body: Where is it and 2 important proteins
* 2/3 body iron stored in Hb
* The rest of the body's iron is in the liver, BM, and spleen and other tissues
* **Ferritin** is a holow protein ball that can hold up to 4500 Fe atoms. Low ferritin is therefore diagnositc for iron deficiency
* **Hemosiderin** is an insoluble complex or iron. This means it lasts longer, but it is more difficult to liberate iron from hemosiderin.
117
Major causes of anemia in developing countries and at-risk populations in canada
Iron, folate, and B12 deficiences
118
How does B12 or folate deficiency cause anemia?
* B12 is a cofactor for turning folate into its usable form (THF) in cells. We need that usable form of folate for RBCs to synthesize DNA
* In B12/folate deficiency, erythroblasts in BM have delayed nucleus maturation because DNA synthesis is defective
* The ultimate result is **megaloblastic anemia**
119
megaloblastic anemia
* caused by B12 or folate deficiency
* Cells can't make enough DNA to divide so RBCs get really big and variable in size/shape
* ANemia because there just aren't enough RBCs out there.
120
What is the role of malaria in RBC disorders?
It is the driving force for inherited RBC disorders
121
What might you see on a blood smear of B Thalassemia Major
* Microcytic, hypochromatic RBCs
* Target cells
* Basophilic stippling of RBCs
122
What are the cardinal symptoms of anemia
* Fatigue
* Dyspnea/chest pain on exertion
* Jaundice (hemolytic)
* Splenomegaly (hemolytic)
123
What are the characteristics of all microcytic anemias?
* RBC underfilling due to abnormalities in iron, heme, or globin
* Cells are hypochromic and microcytic (MCV \< 80)
124
What is the differential for microcytic anemia and how can we tell them apart?
***we always need to rule out occult bleeding***
* _Thalassemia Trait_ - results from reduced globin production
* Ferritin is normal
* Diagnose with serum protein electrophoresis
* _Iron deficiency_ - results from low iron availability
* Ferritin \< 15
* _anemia of chronic disease_ - results from reduced iron availability
* Cardinal feature: MCV is only slightly reduced and anemia tends to be mild
* Ferritin is normal to high
* CRP for diagnosis
125
What may schistocytes mean?
microangiopathic hemolytic anemia (related to DIC);
126
What tests would you do for a normocytic anemia with a high reticulocyte count?
We suspect bleeding or hemolysis.
For bleeding check
* ferritin
* GI
* urinalysis
For hemolysis check
* bilirubin (total, direct)
* LDH
* DAT
* Haptoglobin
127
If you see macrocytosis with high retic count, what are you thinking?
It's probably a hemolytic anemia. The reiculocytes are making the MCV look high because retics are so large.
128
2 categories of macrocytic anemia and how to differentiate them on blood smear
* **Megaloblastic anemia** (will have **polynuclear neutrophils** - lots of lobes in the nuclei because not enough DNA to divide!)
* **Non-megaloblastic anemia** (will have **pgeroid neutrophils** aka John Lennon neutrophils with 2 lobes).
129
3 causes of megaloblastic anemia
* B12 deficiency
* folate deficiency
* Drugs that interfere with DNA synthesis
130
5 causes of non-megaloblastic macrocytic anemia
* Liver disease/chronic EtOH
* HIV infection/therapy
* Myelodysplastic syndrome
* Myeloma
* Hypothyroidism
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Direct vs indirect bilirubin testing
Direct bilirubin is conjugated
Indirect bilirubin is unconjugated - this is released by RBCs during hemolysis so it makes a good test for hemolysis.
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LDH test
Enzyme in RBCs that is released in hemolysis
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Purpose of DAT testing
Direct antiglobulin. A positive result shows that the anemia is immune-mediated. It also tells you if the anemia is dependent on cold temperature. Warm anemia is IgG mediate and cold anemia is IgM mediated.
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Warm vs cold anemia
Distinction important in immune-mediated hemolytic anemia.
Warm - IgG; Phagocytosis by reticuloendothelial cells in the spleen
Cold - IgM (flare ups in cold temp); Intravascular hemolysis and RE-mediated phagocytosis in the spleen.
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What does a low haptoglobin result mean in anemia?
Haptoglobin is busy transporting globins from broken down RBCs - this is a hemolytic anemia.
136
Explain the process of normal hemostasis
1. **Primary Hemostasis** (Platelets and VWF)
* Von Willebrand Factor is activated by exposure to tissue factors in damaged vessel wall --\> VWF uncoils and divides
* VWF grabes platelets --\> _primary platelet plug_
2. **Secondary Hemostasis** (clotting factors)
* Propagation of clotting process
* Platelets are activated - membranes coated in -ve charge that is necessary to active coagulation protein zymogens
* Results in a _stable fibrin clot_
3. **Termination of Clotting** via anti-thrombotic control mechanisms
4. **Fibrinolysis** (removal of the clot and wound healing)
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describe the coagulation cascade
* _Extrinsic Pathway_ involves tissue factor and factor 7.
* _Intrsinsic pathway_ involves factors 12, 11, 9, 8
* _Common pathway_ starts at factor 10, 5, 2, 1 and leads to thrombin, which mediated generation of fibrin from fibrinogen, which is key in the stable fibrin clot.
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How might a vitamin K deficiency affect bleeding?
* Vitamin K is central in the production of coagulation factors 10, 9, 7, 2 (1972 was a good year to have a kid) and protein C and protein S
* A Vitmain K deficiency will therefore lead to a deficiency in these factors and related bleedings disorders.
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How does warfarin work?
It's a Vitamin K antagonist - it interferes with Vitamin K's role in the production gof clotting factors (10, 9, 7, 2). If you exceed therapeutic dose of Warfarin, you may present with a bleeding disorder associated with a deficiency in those clotting factors.
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How may a therapeutic dose of warfin become a toxic dose in the context of bleeidng disorders
* Changes in diet - must take in a stable amount of vitamin K because warfarin is a Vit K antagonist and we need a certain amount of Vit K available to produce clotting factors
* Antibiotic usage may affect productiong of Vitamin K by gut bacteria
* Medications that affect the metabolism of warfarin by cytochrome P450
141
How does liver disease cause coagulopathy
* A production issue
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what is the role of an immediate 50:50 mix in diagnosing bleeding disorders
Rules out an inhibitor of coagulation factor and points toward a deficiency in coagulation factors.
The pt blood is mixed with control blood.
* If mixing results in coagulation then there is likely a factor deficiency (often hemophilia B; but it could be VW disease because VWF protects factor 8 from degradation).
* If mixing does not result in coagulation, then it is likely that a coagulation inhibitor is at play (lupus, anticoagulant)
143
PT/INR vs PTT tests
PTT tests the intrinsic coagulation pathway
PT/INR tests the extrinsic pathway
neither of them test platelet function!
144
Vessel-related causes of bleeding
Senile pupura;
Disseminated intravascular coagulopathy;
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platelet/VWF-related causes of bleeding
Von Willebrand disease;
Congenital thrombocytopenia;
Immune/non-immune thrombocytopenia
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Coagulation factor problems that cause bleeding disorders (4)
1. Hemophilia (A or B)
2. Liver disease
3. ANticoagulants
4. Vitamin K deficiency
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How is Von Willebrand Disease Diagnosed?
VWF levels and functionality testing
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Management of von Willebrand disease
_Type 1:_ treat with **DDAVP**, which releases VWF stores from cells. This won't work for the other types because there is an absolute deficiency or the VWF is no good to begin with.
_Type 2 & 3_: Provide exogenous VWF by IV (may be recombinant or plasma derived)
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Diagnosis of Hemophilia A or B
Factor VIII and IX assay
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Key things to ask on history from a pt with abnormal bleeding
* Their bleeding history (when, how much, what kind, rashes)
* Family history
* Use of medications
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Lab assessment of platelet-type bleeding (4)
* CBC - low platelet count much more common
* Peripheral blood smear
* VWF testing (INR/PTT)
* Platelet function testing (**PFA-100)**
* if platelets are dispersed then light won't pass through
* add reagent and platelets should clump up and allow light to pass through.
* *this test is affected by ASA / NSAIDs*
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Qualitative platelet disorders
* Less common than quantitative platelet disorders. Acquired.
* Could be due to
* Drugs: NSAIDs, aspirin, heparin
* Systemic conditions: renal failure, cardiopulmonary bypass
* Hematologic disease: MDS, myeloproliferative disease, apraproteinemia
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Treatment for hemophilia
* Give recombinant coagulation factor proteins (factor VIII and IX deficiency)
* **Desmopressin** for a mild factor VIII deficiency
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Treament for vessel disorders that are causing bleeding
No specific treatment
* limit steroid exposure and recognize that aspirin, anti-inflammatory and anti-coagulants may worsen bleeding and bruising
* Caution about the fragility of the tissues
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What is the bleeding like for different categories of bleeding disorders?
* Non-hematologic (vessel-related) and platelet/VWF defects will present with petechiae, bruising, mucosal bleeding, and menorrhagia
* Coagulation factor deficiencies undermine secondary hemostasis so the bleeding is more severe
* joint/muscle bleeding, GIT bleeding, excess surgical bleeding.
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Causes of reduced platelet production
* Congenital (rare)
* Look for FHx and giant platelets on smear
* Acquired
* Nutritional (B12 or folate deficiency)
* Infiltrative (cancer)
* BM failure (aplastic anemia, myelodysplastic syndrome)
* Medication (chemo)
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When to give a platelet transfusion
When platelets are \< 10
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When would splenic platelet sequestration occur?
The spleen holds 1/3 of circulating platelet pool. Any cause of splenomegaly will sequester more platelets.
Possible causes
* congestive (cirrhosis, portal HTN)
* Infiltrative (blood cancers)
* Work hypertrophy (infections, some autoimmune diseases)
159
160
What is Immune Thrombocytopenia? What is its course?
* Platelet equivalent of autoimmune hemolytic anemia
* Reticulo-endothelial/spleen-mediated clearance of antibody coated platelets (spleen not enlarged)
* Platelet count variable
* Usually post-viral and self-limiting in children
* Usually more chronic in adults (more common in women)
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Symptoms of Immune Thrombocytopenia
* platelet count variable - rarely has clinical manifestations unless plt \< 30
* Easy bruising, mucosal bleeding, petechiae
162
Causes of immune thrombocytopennia
* Usually post-viral in children
* More common in adult women
* Associated with connective tissue disease (i.e., SLE) or lymphoproliferative disease (i.e., CLL)
* ***Can be triggered by meds***
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Treatment for immune thrombocytopenia
Usually self-limiting in children.
In adults - immune suppression. Platelet transfusions are not helpful.
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What is thrombotic microangiopathy?
It's a clinicopathological syndrome that results from a number of etiologies (I'm pretty sure this is the same as DIC)
* Key features:
* Endothelial injury
* MAHA (microangiopathic hemolytic anemia)
* low platelets
* Organ injury from small vessel ischemia
* Causes microvascular occlusion, causing organ injury
* Results in consumptive thrombocytopenia
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Causes of thombotic microangiopathy
It's a clinicopathological syndrome that results from a number of etiologies (I'm pretty sure this is the same as DIC)
* hypertensive meregency
* midications and illicit drugs
* toxin-mediated endotheliul damage (HUS)
* autoimmunity against ASAMTS13
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What is the classic pentad of symptoms for thombotic thrombosytopenic purpura?
1. Thrombocytopenia \*\*
2. Microangiopathic hemolytic anemia\*\*
3. Fever
4. Seurologic symptoms and signs
5. Renal impairment
\*\*consider this as a diagnosis if you see low platelets and evidence of hemolysis
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Treatment for thrombotic thrombocytopenic purpura (TTP)
* MEDICAL EMERGENCY - mortality 90% without treatment
* _Plasma exchange_ (remove autoantibody if it is autoimmune)
* Daily treatments until platelet count normalizes
* Aspirin (reduce microthrombosis)
* Corticosteroids for most cases
* *Platelet transfusions are contraindicated*
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when you see bite cells and blister cells, what are you thinking is the cause of hemolysis?
Oxidative stress in a patient with G6PD deficiency. Various drugs can lead to xoidative injury
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Immune Hemolytic Anemia
Presentation
Diagnosis
Causes
* Presentation: typical anemia
* Diagnosis
* Positive DAT (direct antiglobulin test)
* Spherocytes on blood film
* Causes
* Many drugs (cephalosporins, penicillins)
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\*\*\*\*\*Heparin Induced Thrombocytopenia: Mechanism
* Heparin binds **p****latelet factor 4 (**released from platelets)
* The heparin-PF4 complex is bound by **IgG** and marks it for clearance
* Platelet clearance AND activation occur - therefore VERY STRONG CLOTTING TENDENCY (=v dangerous)
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Diagnosing heparin-induced thrombocytopenia
First do an **immunoassay** for the HIT antibody. If it is present, then send to hamilton for the more accurate **platelet activation assay**
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When should you proceed with heparin-induced thrombocytopenia testing?
4 Ts
* **T**hrombocytopenia is present
* **T**iming of fall in platelets aligns with starting heparin.
* **T**hrombotic signs and symptoms
* Ano**T**her cause of platelet drop is not evident
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174
What drug is famous for causing neutropenia?
CLOZAPINE
175
Drug induced myelosuppression
Commonly occurs with chemotherapy.
The myelosuppression is predictable and blood counts have an expected nadir, then recovery.
Usually a pancytopenia.
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More common drug-induced anemias (3)
Oxidant hemolysis (for a pt w G6PD deficiency)
Immune hemolytic anemia
Worsened bleeding with an anticoagulant
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4 drug-induced thrombocytopenias
Heparin-induced thrombocytopenia
Drug-induced immune thromboctopenia
Thrombotic microangiopathy (and also anemia)
Bone marrow suppression
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Drug induced pancytopenia may be the result of what mechanism?
Myelosuppression
179
Vitamins we need to make RBCs (3)
Iron, B12, folic acid
180
b12 supplementation in pernicious anemia
Because oral absorption is impaired, intramuscular preparation is standard or a high oral dose overcome the impairment
181
Circumstances where folic acid supplementation may be a good idea?
Hemolytic anemia
pregnancy
(also check and treat a comborbid B12 deficiency)
182
What is th ebig concern with B12 deficiency?
neurologic damage
183
What are some situations when using erythropoiesis stimulating agents would be appropriate? (5)
* Chronic Kidney Disease \*\*\* most common and most important
* Used in almost all dialysis and predialysis patients with low hemoglobin
* Must ensure that iron stores are replete
* Low risk MDS (anemia bc low RBC production)
* Chemo-induced anemia (rarely)
* Prior to surgery to reduce transfusions
* Jehova's witness with anemia
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when to use thrombopoietin receptor agonists
* Effective for immune thrombocytopenia
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4 paths of lymphomagenesis
1. Random genetic transformation
2. Oncogenic viruses (i.e., EBV)
3. Antigen OVer-stimulation (T cells proliferate to manage an antigen and then forget to die down)
4. Immunosuppression (iatrogenic, HIV, age)
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3 ways to classify lymphoid neoplasms
1. Historical (hodgkin vs nonhodgkin)
2. by cell type (B or T or NK)
3. clinical behaviour (high grade low grade)
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hodgkin vs nonhodgkin lymphoma
**Hodgkin** has reed sternberg cells (owl cells) and swollen lymph nodes that are busy repsonding to these weird malignant cells.
**Non Hodgkin** - all of the cells in the tumor are malignant lymphocyte
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Low grade vs high grade lymphomas
_Low grade_ = *Indolent lymphoma*
* Tumor grows slowly over the course of lears
* Lymphocyte accumulation due to defective apoptosis
* Malignant lymphocytes are usually small
* Treatment often not required at the time of diagnosis
* Incurable
_HIgh grade_ = aggressive lymphoma
* tumor grows rapidly over the cours of hours-weeks
* Lymphocyte accumulation due to uncontrolled cellular proliferation
* Malignant lymphocytes are usually large and agly
* Treatment required at the time of diagnosis
* Potentially curable
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Most common lymphomas in the western world
#1 Diffuse large B cell lymphoma
#2 Follicular lymphoma
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Treatment for non-hodgkin lymphomas
All involve some sort of _systemic therapy_
* **Non-targeted therapies**
* *Chemo* (inhibit cell proliferation)
* *Radiation* (damage dividing cells)
* *Immunotherapy* (kill malignant cells)
* **Targeted molecular therapies** - antibodies directed against particular proteins that are critical in the growth and survival of the lymphoma cells // Other proteins that interfere with cell growth and survival of the lymphoma cells.
191
Lytic lesions and hypercalcemia in Multiple Myeloma
* Malignant cells produce substances that promote bone trabeculae destruction and _"lytic" lesions_
* Loss of bone leads to
* pathological _fractures_
* release of Ca from bone and intro blood --\> _hypercalcemia_
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Acronym for clinical findings in multiple myeloma
* Calcium elevated: from bone lysis
* Renal insufficiency: monoclonal immunoglobulins (esp light chains) and hypercalcemia damage the kidney
* Anemia: from marrow suppression by malignant plasma cells, and from renal failure (low erythropoietin)
* Bone pain and pathological fractures: from bone lytic lesions seen on X-ray (not bone scan)
* \*\*most common presentation is back pain not responding to rest/physio or a vertebral compression fracture
* infections: suppressed normal antibody (immunoglobulin) production
193
classic presenting symptom for plasma cell myeloma
back pain that doesn't get better with rest/physio or a compression fracture
194
Hypercalcemia is a sx of what cancer and how can it present
Symptom of plasma cell myeloma.
Presents as nausea, constipation and difficulty urinating.
195
Common sx of myeloproliferative neoplasms
* fatigue
* wt loss
* night sweats
* abdominal fullness (due ot massive splenomegaly)
* anorexia
196
evaluation for an incidental finding of increased WBC counts
We worry that it is a myeloproliferative neoplasm
* Complete history and exam
* CBC and differential
* Bone marrow aspirate and biopsy
* chromosome analysis "cytogenetics"
* serum EPO and JAK 2 mutation
* abdominal ultrasound - splenomegaly
197
What is meant by a 'left shift'
Presence of immature myeloid lineage cells... Characteristic of myeloproliferative neoplasms but could be due to other disease or infection.
198
Significance of the Philadelphia chromosome
the first cytogenic abnormality identified that leads to chromic myeloid leukemia.
Result of t(9;22), which affects the BCR and ABL.
199
Treatment for chromic myeloidleukemia; how effective is it?
Tyrosine kinase inhibitors specifically targeted at the problem mutation (BCR-ABL);
**Imatinib** and other mAbs.
These improve life expectancy a lot compared to previous therapies.
Always new drugs emerging though!
200
What is polycythemia?
It just means elevated hemotocrit (too many RBCs).
201
What are the different causes of polycythemia?
* _Spurious Polycythemia_: occurs in dehydration; RBC levels/hematocrit look high because of reduced plasma volume
* _True polycythemia_:
* _Secondary Polycythemia_: BM response to hypoxia or high EPO is to make more RBCs. May occur in chronic hypoxia due to lung disease or in renal cell CA (high EPO)
* _Polycythemia Vera_: Excessive RBC production from abnormal BM, without EPO stimulation
202
what is the key mutation behing polycythemia vera?
JAK 2 mutation.
The mutated JAK2 protein binds to the EPO-receptor. The binding promotes signaling independent of APO stimultion and hypersensitivity to cytokin.
203
Common challenges in phlebotomy
Venous access;
Lightheadedness and fatigue afterwards;
Vasovagal response;
204
What must be ruled out before making an essential thrombocytopenia diagnosis
Iron deficiency;
Reactive changes - infection, inflammation, malignancy;
205
Complications of essential thrombocythemia
* The platelets may be functional or dysfunctional, which means that pt may clot or bleed
* _Thrombotic complications_:
* venous thrombosis (DVT, PE)
* Arterial thrombosis (MI)
* _Bleeding complications_: bruising, GI bleeding
206
Imatinib
A TK inhibitor targetting the mutant gene in chronic myeloid leukemia.
207
What is the mutation in chronic myeloid leukemia?
t(9;22)
208
blood smear shows many large red blood cells with a bluish cytoplasm. Why??
Reticulocytes - retained RNA in their cytoplasm
209
longstanding anemia in a chinese canadian with a family history is most likely to be due to...
B thalassemia major
210
blood smear for b thalassemia major shows
microcytic, hypochromatic RBCs with target cells and basophilic stippling
211
pencil cells are characteristic of
iron deficiency anemia
212
in hereditary hemochromatosis, where is most of the excess iron located?
Present in tissues bound to ferritin and hemosiderin
213
What are we likely to see on blood film of a non-cancer macrocytic anemia?
Oval macrocytes and hypersegmented neutrophils
214
why do pts with sick cell anemia get infections a lot?
Most of them have infarcted their spleens by adulthood
215
what supplement would you recommend to a patient with warm immune hemolytic anemia
Folic acid, because folic acid stores can be depleted quickly with increased erythropoiesis.
216
how common is g6pd deficiency and how is it acquired?
* Most common cause of enzyme-deficienct hemolytic anemia
* x-linked, variable expression
217
What would a blood smear for PK deficiency show?
spiky RBCs
218
Chronic Lymphocytic Leukemia
Also called B cell small cell lymphocytic leukemia
Small, mature B cells that proliferate into BM, blood, lymph nodes;
219
Diagnositics for chronic lymphocytic leukemia
Blood film --\> Soccer ball cells;
lymph node biopsy --\> extensive infiltration;
+/- immunophenotyping.
220
Prognosis and treatment for chronic lymphocytic leukemia
Indolent - incurable;
Patients liv emany years with the disease;
Non-hodgkins treatments (systemic therapies and immunotherapy)
221
Follicular Lymphoma: What is it and prognosis/treatment
Low grade B cell lymphoma with a follicular growth pattern
T(14;18)
Non-hodgkins treatment;
Indolent/incurable, but most patients live for many years with it
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Diffuse large B cell lymphoma
High grade B cell lymphoma in lymph nodes and extranodal lymphoid tissues;
Diffuse growth pattern;
Aggressive, but some are curable;
If cure isn't achieved relatively quickly, patients die within months to years;
Non-hodgkin treatment
223
Plasma cell myeloma
Aka multiple myeloma;
Malignancy of plasma cells that secrete a clonal immunoglobulin;
224
Diagnosis of plasma cell myeloma
* Blood smear - perinuclear halo;
* Serum protein electrophoresis - thick single band representing presence of "M protein"
* BM biopsy/aspirate - increased plasma cells
225
treatment and prognosis for plasma cell myeloma
* survival ~5-7 years with modern treatments;
* The goal is to reduce mAbs
* Stem cell transplant and chemo for pt under 70 years;
* Novel treatments are significantly improving outcomes
226
Chronic myeloid leukemia
Malignancy of pluripotent stem cells resulting in overproduction gof granulocytes, often accompanies with high RBCs and platelets.
227
Diagnostics for chronic myeloid leukemia
hypercellular BM;
Cytogenetics - **philadelphia chromosome** (one abnormality that is implicated in some cases)
228
Treating chronic myeloid leukemia
TK inhibitor - **imatinib**
229
Progression of chronic myeloid leukemia
chronic phase of stability for 5-6 years;
Accelerated phase 6-9 mo;
Blast crisis phase 3-6 mo before death;
230
Polycythemia vera
Excessive RBC production from abnormal BM without EPO stimulation.
Results from a mutation in JAK2, which causes inappropriate stimulation of EPO receptor resulting in RBC proliferation.
231
Complications of polycythemia vera
* Facial plethora, erythromelalgia
* incresed blood viscosity --\> thrombus
* Platelet dysfunction --\> bleeding
* Increased histamine --\> pruritis and peptic ulcers
* Increased uric acid --\> gout
232
Treatment and prognosis of polycythemia vera
May progress to myelofibrosis or AML;
Phlemotamy to maintain hematocrit \< 45%;
ASA 81 mg/day;
Hydroxyurea to control excessive platelet counts and decrease needs for phlebotamy;
233
Essential thrombocythemia
Very high platelet count;
Platelets may be functinal or dysfunctional (so patient may clot or bleed)
No philadelphia chromosome, but pt may be JAK2 positive;
See megakaryocytes and hyperplasia on testing;
234
Idiopathic myelofibrosis
Fibrosis fills the bone marrow resulting in pancytopenia
