Heme/Lymph Flashcards
1
Q
What triggers coagulation in extrinsic pathway?
A
Tissue injury releases tissue factor (thromboplastin)
2
Q
What is deficiency of Hemophilia B?
A
Coagulation factor IX (9) deficiency
3
Q
What is deficiency of Hemophilia A?
A
Factor 8
4
Q
What is rate limited of coagulation cascade?
A
Convergence of extrinsic and intrinsic at Factor 10
5
Q
Function of Protein C and S?
A
Inhibit Factors Va and VIIIa
6
Q
Why does Warfarin transiently increase clot formation?
A
Warfarin inhibits Factors 2, 7, 9 and 10; but it also inhibits protein C and S MORE rapidly than clotting factors –> this transiently increases clot formation before the other factors are inhibited
-This is why we start Heparin first
7
Q
What is the final common pathway?
A
Factor 10 –>10a
10a + 5a activate prothrombin to thrombin
Thrombin + 13a activate fibrin monomers into fibrin mesh
8
Q
What is function of Antithrombin?
A
Inhibits thrombin from activating fibrin
9
Q
What drug increases effectiveness of thrombin?
A
Heparin
10
Q
How does coagulase affect coagulation pathway? What produces coagulase?
A
Coagulase activates thrombin
Made by Staph aureus
11
Q
What other ions/proteins are necessary for coagulation cascade?
A
Calcium
Phospholipid
12
Q
What are the functions of factor 12a?
A
1) 12a activates 11 –> 11a
2) 12a converts prekallikrein to kallikrein –> then kallikrein cleaves plasminogen to form plasmin –> plasmin breaks down fibrin mesh
- Kallikrein also converts HMWK to bradykinin –> Bradykinin vasodilates, increases vascular permeability and mediates pain (coagulation and inflammation are interconnected)
13
Q
What does the prothrombin time measure?
A
Take plasma and add tissue factor –> measure how long it takes clot to form
Tests how effectively tissue factor can activate the tissue factor pathway and the final common pathway
Testing factors 7, 10, 5 and 2 (prothrombin)
Always reported as INR (1 is normal)
14
Q
What does partial thromboplastin time measure?
A
Plasma + silica or something that activates tissue activating pathway
- Also have to add phospholipids that normally combine with tissue factor to form thromboplastin
- Tests function of contact activation pathway and final common pathway
- Tests 12, 11, 9 and 8, 10, 5 and 2
15
Q
What does bleeding time measure?
A
Should take 2-9 minutes
A function of platelet function
Disorders of coagulation cascade will not affect bleeding time
16
Q
Hemophilia A and Hemophilia B
a. effect which pathway?
b. Effects on PT and PTT
A
a. Intrinsic pathway
b. Increased PTT, not effect on PT or INR
17
Q
Symptoms of Hemophilia A/B
A
Macrohemorrhage –> hemarthroses, easy bruising, bleeding after trauma or surgery
18
Q
Treatment for Hemophilia A, B and C
A
A - Desmopressin + factor 8 concentrate
B - factor 9 concentrate
C - factor 11 concentrate
19
Q
Vitamin K Deficiency
a. Effects on PT, PTT
b. Mechanism
A
a. Increased PT, PTT
b. Decreased 10, 7, 9, 2
c. Vitamin K dietary deficiency, newborns (no gut bacteria), someone taking antibiotics, patients on Warfarin, end stage liver disease
20
Q
Factor V Leidin
a. What does Factor V do?
b. Mechanism of disease
A
a. Factor V is a cofactor for factor 10 –> helps it activate thrombin
b. Factor V Leiden mutations makes Va resistant to inactivation by protein C –> increased coagulation
21
Q
Prothrombin gene mutation (G20210A)
a. Mechanism
b. Effect
A
a. Mutation in 3’ intranslated region
b. Increased production of prothrombin –> increased plasma levels and venous clots
22
Q
Antithrombin deficiency
a. Effect
b. PT/PTT
A
a. Unable to activate thrombin
b. No direct effect on PT, PTT or thrombin time but the increase in PTT is diminished after adding Heparin (reduced effect)
23
Q
Protein C deficiency (or protein S)
A
Unable to activate factors 5 and 8 –> can’t shut off coagulation cascade –> increased risk of thrombotic skin necrosis with hemorrhage following administration of Warfarin
24
Q
Skin and subcutaneous tissue necrosis after warfarin administration
A
Protein C deficiency
25
Mechanism of Heparin
Cofactor for activation of antithrombin --> decreased thrombin and factor 10a (only prevents clot from getting bigger or new clots from forming)
VERY SHORT HALF LIFE
26
Uses of Heparin
PE, acute stroke, MI, DVT
| Can be used during PREGNANCY
27
What lab do we measure to monitor Heparin?
PTT
28
S/E of Heparin
Bleeding
Bone loss, osteoporosis
Heparin-Induced Thrombocytopenia (HIT) --> heparin binds to platelet factor 4 --> autoantibody complexes can then activate platelets to aggregate --> then they get removed from circulation and destroyed --> thrombosis and thrombocytopenia
29
What do you do for Heparin Induced Thrombocytopenia?
Stop Heparin
| Start different anticoagulant like direct thrombin inhibitor (dabigatran, bivalirudin)
30
Direct Thrombin Inhibitors (specifically ones derived from Hirudin from leech spit)
Lepirudin
Bivalirudin
Desirudin
31
Direct Thrombin Inhibitors (NOT from hirudin)
Argatroban
| Dabigatran
32
Low-molecular weight Heparins
Enoxaparin
| Dalteparin
33
Advantages of low-molecular weight Heparins
| Disadvantages?
```
Better bioavailability
2-4 times longer half life
Administered SubQ
Don't need lab monitoring
Disadvantage - not easily reversible
```
34
Fondaparinux
Activates antithrombin to inhibit Factor Xa
| Not a Heparin derivative
35
Mechanism of LMW Heparins?
Stimulate antithrombin to inactivate Factor Xa
36
Direct Factor 10a inhibitors
Rivaroxaban
| Apixaban
37
Warfarin mechanism
Inhibits epoxide reductase --> interferes with gamma-carboxylation of vitamin K dependent clotting factors 2,7,9,10 Protein C and S
(Epoxide reducase recycles vitamin K)
38
Uses of Warfarin
Chronic antricoagulation --> Atrial fibrillation, DVT prophylaxis, DVT treatment, PE treatment
39
When is Warfarin C/I?
Pregnant patients - crosses placenta and is teratogenic
40
Toxicity of Warfarin
Bleeding, teratogen, skin/tissue necrosis, transient hyper coagulability
41
Reversal of Heparin
Protamine Sulfate
42
Reversal of Warfarin
```
Vitamin K (oral) - takes days to do anything to reverse effects because have to wait for liver to make more clotting factors
Fresh frozen plasma
```
43
Half life in Heparin vs. Warfarin
Short half life - Heparin
| LONG half life - Warfarin
44
Onset of action in Heparin vs. Warfarin
Rapid (seconds) - Heparin
| Slow - Warfarin
45
Thrombolytics
a. mechanism
b. Use
a. activated Plasmin --> lyses fibrin clot
| b. EARLY ST elevation MI (< 3-6 hours), acute stroke, severe PE
46
S/E of thrombolytics
Bleeding (C/I in active bleeding, recent surgery, HTN, history of intracranial bleeding, coagulation defect)
47
Used to monitor coagulation in patient taking Warfarn
PT and INR
48
Characteristics of RBC
a. life span
b. shape
c. source of energy
a. 120 days
b. biconcave (spectrin), anucleate
c. Glucose 90% anaerobical metabolized to lactate, 10% used in HMP shunt
49
What is anisocytosis?
RBC of varying sizes
50
What is poikilocytosis?
RBC of varying shapes
51
What is a reticulocyte? What dose it reflect?
Immature RBC; reflects erythroid proliferation
52
What is polycythemia or erythrocytosis?
Too many RBCs
53
Basophilic stippling
| Associated pathology?
```
Little purple red dots (clumps of denatured RNA in basophil)
Lead poisoning (also thalassemias, anemia of chronic disease, alcohol abuse)
```
54
Echinocyte (burr cell)
Regular, uniform spikes all over surface
| Seen in uremia, renal failure
55
Spurr cell (Acanthocyte)
IRREGULAR spiked cells
Liver disease
Abetalipoproteinemia
56
Spherocyte
RBCs that lose biconcave shape
| -seen in Hereditary Spherocytosis
57
Schistocytes
Fragments of RBC that look like helmets
-Seen in DIC, TTP/HUS, HELLP, (pathologic intravascular clotting that RBCs are being forced through) from mechanical hemolysis
58
Target cells
```
Look like bulls eye
THAL
Thalassemia
Hemoglobin C disease
Asplenia
Liver disease (also see acanthocytes)
```
59
Sickle cells
Crescent shaped
| In sickle cell anemia
60
Howell Jolly body
Basophilic nuclear remnants found in RBCs
-Normally removed from RBCs by splenic macrophages; seen in patients with functional hyposplenia or asplenia (trauma, immune thrombocytopenia purpora splenic removal)
61
Heinz bodies
When hemoglobin gets oxidized and precipitates out of solution in RBC --> little clumps of Hgb
- Spleen bites the Hgb clumps out of RBCs
- Seen in G6PD deficiency (oxidative damage causes Heinz bodies)
62
How do you tell Heinz body from Howell Jolly Body?
Can only have ONE Howel jolly body but can have MANY Heinz bodies
63
Teardrop cells
Shaped like teardrops
| -Seen with myelofibrosis
64
Elliptical shape cells (pencil cells)
Hereditary Elliptocytosis
65
Ring Sideroblasts
ABNORMAL
- Seen in Bone marrow
- Lead poisoning*** (big one), drugs, myelodysplastic syndromes
- Sign of underlying diagnosis
66
Sideroblasts
Nucleated RBC precursor with granules of iron in mitochondria
- Found in BM of healthy people
- If you have disorder that affects heme synthesis and body can't use all iron granules --> the granules surround and encircle the nucleus --> form ring
67
What happens if you transfuse incompatible blood type?
Antibody-mediated type II hypersensitivity
68
What is Erythroblastosis Fetalis?
Due to Rh incompatibility
Maternal Abs to fetal RBC antigens (Rh-D)
Rh- moms don't have antibodies to Rh-D but after they are exposed to babies RBCs they form them (after first pregnancy)
-If babies blood comes into contact with babies blood in first pregnancy, mom's immune system is sensitized to Rh- antigen and mom develops Abs --> then IgG can cross placenta and attack RBCs --> hemolysis --> Hgb breaks down into bilirubin and causes jaundice
69
Clinical features of Erythroblastosis Fetalis in infant
Anemia due to hemolysis of RBC by maternal Abs
Jaundice --> kernicterus possible
Hydrops fetalis (fetal edema)
Intrauterine death
70
Treatment of Erythroblastosis Fetalis
Administer RhoGAM (anti-Rh immunoglobulin) to Rh- pregnant women during 3rd trimester to prevent maternal anti-Rh IgG production (and any time there is trauma)
71
What kind of RBCs do you see in G6PD deficiency?
Bite cells
| Heinz bodies
72
When do primitive blood cell progenitors appear in yolk sac?
at 3 weeks; come from mesonephros
73
Young Liver Synthesizes Blood
```
Yolk Sac (week 3-8)
Liver (and spleen)
Bone marrow (at 28 weeks)
```
74
Which part of skeleton is hematopoietically active?
Infancy and childhood - entire skeleton (sternum, pelvis, ribs, long bones, vertebrae, cranial)
Late adolescence, adulthood - vertebrae, sternum, ribs, pelvis
75
Fetal hemoglobin?
| Adult hemoglobin?
Fetal - 2 alpha chains, 2 gamma chains (gamma has lower affinity for 2,3 DPG --> higher affinity for oxygen)
Adult - 2 alpha chains, 2 beta chains
76
```
Hemoglobin variants
HbA
HbA2
HbA1c
HbF
HbGower
```
```
HbA - 97% of normal (a2B2)
HbA2 - 2% of normal (a2delta2)
HbA1c - poorly controlled diabetes
HbF - fetal hemoglobin (a2gamma2)
HbGower - embryonic Hgb (2 zeta and 2 episilon chains)
```
77
HbS
Sickle cell Hgb
alpha 2, betaS2
Glu --> val in B chain
78
HbC
Hemoglobin C disease
alpha 2, betaC2
Glu --> lys in Beta chain
79
HbBart's
```
Severe alpha thalassemia
gamma 4 (no alpha chain)
```
80
HbH
Severe alpha thalassemia
| B4 (no alpha chains)
81
What is rate limiting enzyme of heme synthesis?
| What does it require?
aminolevulinic acid synthase (ALA synthase)
It makes glycine and succinyl-CoA into aminolevulinic acid
Requires Vitamin B6
82
What enzyme is defective in acute intermittent porphyria?
Porphobilinogen deaminase
| Can't make porphobilinogen into hydroxymethylbilane
83
Presentation of acute intermittent porphyria
```
Abdominal pain (neuropathic)
Port wine- colored urine
Polyneuropathy
Psychological disturbanes
Precipitated by drugs (cytochrome p450 inducers, alcohol, starvation)
```
84
How do you treat acute intermittent porphyria?
Glucose and heme --> inhibit ALA synthase (no build up of neuro toxic products)
85
5 P's of acute intermittent porphyria
```
Pain in abdomen
Polyneuropathy
Port wine-colored urine
Psychological disturbances
Precipitated by drugs
```
86
What enzyme is defective in Porphyria Cutanea Tarda?
Uroporphyrinogen decarboxylase
| Uroporphyrin accumulates and causes tea colored urine
87
Presentation of Porphyria Cutanea Tarda
```
Most common form!
Blistering of skin and photosensitivity
Hypertrichosis
Facial hyperpigmentation
Tea-colored urine
Hepatitis C and alcoholism
Elevation of LFTs (AST, ALT)
(Think of homeless man)
```
88
How does lead poisoning affect heme synthesis pathway?
Inhibits Ferrochelatase --> Protoporphyin accumulates
| Inhibits ALA dehydratase
89
Presentation of lead poisoning
Microcytic anemia (basophilic stippling) GI (abdominal colic) and Kidney disease
Mental deterioration in kids (also lead lines in bones, gingiva)
Headache, memory loss, demyelination in adults
90
Treatment of lead poisoning
EDTA or succimer to chelate lead
| Dimercaprol + succimer in kids for very severe lead poisoning
91
What is Polycythemia vera?
Monoclonal proliferation of RBCs
92
Causes of polycythemia vera
Chronic hypoxia --> to increase O2 carrying capacity (pulmonary disease, cyanotic heart disease, high altitudes)
Tumors
Trisomy 21 at birth
93
Tumors that cause polycythemia vera
| Potentially Really High Hematocrit
Pheochromocytoma
Renal cell carcinoma
Hepatocellular carcinoma
Hemangioblastoma
94
Relative Polycythemia
Plasma volume is reduced so that red cell count is increased relative to plasma volume
95
Absolute polycythemia
Plasma volume is normal and you have too many RBCs
96
Appropriate absolute polycythemia
a. plasma volume
b. RBC mass
c. O2 saturation
d. EPO levels
e. associations
a. no change
b. Increased
c. decreased
d. increased
e. seen in lung disease, congenital heart disease, high altitude
97
Inappropriate absolute polycythemia
a. plasma volume
b. RBC mass
c. O2 saturation
d. EPO levels
e. associations
a. no change
b. Increased
c. no change
d. increased
e. renal cell carcinoma, hepatocellular carinoma, hydronephrosis
98
Polycythemia vera
a. plasma volume
b. RBC mass
c. O2 saturation
d. EPO levels
e. associations
a. increased
b. really increased
c. no change
d. decreased
- EPO decreased due to negative feedback suppressing renal EPO production
99
Relative polycythemia
a. plasma volume
b. RBC mass
c. O2 saturation
d. EPO levels
e. Associations
a. decreased
b. no change
c. no change
d. no change
e. Decreased plasma volume like dehydration and burns
100
Microcytic Anemia
```
Iron Deficiency Anemia
Alpha thalassemia
Beta thalassemia
Lead poisoning
Sideroblastic anemia
Anemia of Chronic Disease
```
101
Iron Deficiency Anemia - causes
```
Poor intake
Blood loss (menstruation or GI chronic occult blood loss)
```
102
IDA - characteristics
Hypochromic
| Microcytic
103
What is Plummer Vinson syndrome?
Iron deficiency anemia
Esophageal web
Atrophic glossitis
104
Alpha Thalassemia - cause
| Affects who?
Defect in alpha globin gene deletions --> defect in alpha globin synthesis
African/Asian populations
105
alpha thalassemia
a. mutation of one allele
b. mutation in 2 alleles
c. mutate 3 alleles
d. mutate 4 alleles
a. no anemia
b. alpha thal trait, no anemia
c. Hemoglobin H disease (beta globins pair up with each other )
d. incompatible with life - Hemoglobin Barts - four gamma globes --> causes hydrous fetalis and death
106
Beta thalassemia cause
| Affects who?
Defect in beta globin gene (point mutation) --> decreased beta globin synthesis
Mediterranean populations
107
B-thalassemia minor (heterozygote)
B chain is underproduced
Usually asymptomatic
Diagnosis confirmed by increased HbA2 (>3.5%) on electrophoresis
108
B-thalassemia major (homozygote)
B chain is absent --> severe anemia requiring blood transfusion
Marrow expansion (crew cut on skull X-ray) --> skeletal deformities, chipmunk facies
Extramedullary hematopoiesis leads to hepatosplenomegaly
-Increased risk of parvovirus B19 induced aplastic crisis
109
Why do you have to confirm diagnosis of iron deficiency in patients with microcytic anemia before you start iron supplements?
They might have beta thalassemia in which case they would have increased iron from thalassemia
110
Peripheral smear of thalassemia shows...
Target cells
111
What are two enzymes in heme synthesis that are affected by lead poisoning?
Ferrochelatase
| ALA dehydratase
112
Causes of sideroblastic anemia
Lead poisoning
Alcohol
Drugs (seizure drugs, Rifampin)
Hereditary X linked defect in ALA synthase
113
Anemia of chronic disease
| Iron, Ferritin levels
From defective iron utilization
Iron is trapped in macrophages so serum iron is LOW
Ferritin is normal or HIGH
114
Macrocytic anemia
a. Megaloblastic anemia
b. Non-megaloblastic anemia
a. B12 deficiency, Folate deficiency , orotic aciduria
| b. Liver disease, Alcoholism, Reticulocytes
115
RBC appearance in B12/folate deficiency
Hypersegmented neutrophils (>6 lobes)
116
Causes of B12 deficiency
```
Insufficient intake
Malabsorption (Crohn, removal of terminal ileum)
Pernicious anemia
Diphyllobothrium latum (fish tapeworm)
Gastrectomy
```
117
Causes of folate deficiency
Malnutrition (alcoholics)
Malabsorption
Drugs (methotrexate, phenytoin, trimethoprim)
Increased requirement (pregnancy, hemolytic anemia)
118
Findings in
a. Folate deficiency
b. B12 deficiency
a. NO NEUROLOGIC SYMPTOMS; increased homocysteine, normal methylmalonic acid; megaloblastic anemia
b. Neurologic symptoms (subacute combined degeneration, spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction, dementia, neuropathy); Methylmalonic acid INCREASED, increased homocysteine
119
Why does B12 deficiency cause subacute combined degeneration?
B12 is involved in fatty acid pathways and myelin synthesis
120
Why should you not treat with empiric folic acid for megaloblastic anemia?
It might fix anemia but if B12 is deficient it will NOT correct neurologic deficits
121
What is orotic aciduria?
Defect in UMP synthase (pyrmidine synthase)
Causes orotic acid in urine, megaloblastic anemia Developmental delay
Failure to thrive
NO hyperammonemia (vs. ornithine transcarbamylase deficiency)
122
NON-megaloblastic macrocytic anemia cause
```
DNA synthesis is NOT impaired
Alcoholism
Liver disease
Hypothyroidism
Reticulocytosis
Drugs (5-FU, Zidovudine, Hydroxyurea)
```
123
Normocytic NON-hemolytic anemia causes
Anemia of chronic disease
| Aplastic anemia
124
Anemia of chronic disease
a. cause
b. Iron, TIBC, Ferritin levels
a. Lots of inflammation causes lots of inflammatory mediators like Hepcidin to be increased --> inhibits iron transport because iron is trapped in macrophages
b. Decreased iron, decreased TIBC, Increased Ferritin
125
Conditions associated with anemia of chronic disease
SLE, RA, Neoplastic disorders, CKD
126
Aplastic anemia
a. causes
b. Findings
c. symptoms
a. Radiation***** and drugs, Viral agents (parvovirus B19, EBV, HIV, HCV), Fanconi anemia (DNA repair defect), Idiopathic (immune mediated)
b. Pancytopenia (anemia, leukopenia, thrombocytopenia)
Normal cell morphology but HYPOCELLULAR BONE MARROW With fatty infiltration
c. Fatigue, malaise, pallor, purpura, petechiae, infection
127
Treatment of aplastic anemia
Withdrawal of offending agent
Bone marrow allograft
RBC/platelet transfusion
Bone marrow stimulation
128
What test can be used to diagnose Beta thalassemia minor?
Hemoglobin electrophoresis to look for higher than normal levels of HbA2
129
Megaloblastic anemia not correctable by B12 or Folate
Orotic Aciduria
130
Microcytic anemia reversible with B6
Sideroblastic anemia
131
Drugs that can cause sideroblastic anemia
Isoniazid (inhibits B6)
Lead
Copper deficiency
B6 deficiency
132
HIV patient with macrocytic anemia
Zidovudine
133
Normocytic anemia with elevated creatinine
Chronic kidney disease resulting in low EPO
134
Skull x-ray shows "hair on end" appearance
Result of marrow hyperplasia (crew cut)
135
Basophilic stippling of RBCs
Lead poisoning
136
Co-factor required for pyruvate dehydrogenase
Tender Loving Care For No-one
What other enzyme requires these?
```
Thiamine
Lipoid acid
Coenzyme A
FAD
NAD
-Also required by Alpha-ketoglutarate dehydrogenase
```
137
Intravascular or Extravascular hemolysis?
a. Decreased serum haptoglobin
b. Increased LDH
c. Increased unconjugated bilirubin
a. Massive intravascular hemolysis causes haptoglobin to bind all free hemoglobin
b. released from RBCs (intravascular OR extravascular hemolysis)
c. Seen in extravascular hemolysis (with intravascular all the heme would be bound by haptoglobin)
138
Intravascular hemolysis Causes
Autoimmune hemolytic anemia
Paroxysmal nocturnal hemoglobinuria
Mechanical destruction of RBCs
139
Extravascular hemolysis
| Causes
Hereditary spherocytosis (spleen recognizes abnormal cells)
G6PD Deficiency (extravascular AND intravascular)
Pyruvate kinase deficiency
Sickle cell
Hemoglobin C disease
140
Hereditary spherocytosis defect
Defect in Ankyrin and spectrin (proteins interacting with RBC membrane skeleton and plasma membrane) --> red cells are small round spheres with NO central pallor and less surface area
141
Hereditary spherocytosis
a. Increased MCHC - why?
b. increased RDW - why?
c. Why does it cause hemolysis
a. Increased Mean corpuscular hemoglobin content; same amount of Hgb but they are smaller so it is more concentrated
b. Not as much variability with red cell size
c. Spleen recognizes cells as normal and removes them --> splenomegaly
142
Diagnostic test for Hereditary spherocytosis
Osmotic fragility test (high percentage of lysis in NaCl)
143
Treatment for hereditary spherocytosis
Splenectomy (so that it doesn't remove red cells) --> then you see Howell Jolly bodies
144
G6PD deficiency defect
X linked recessive
| Defect in G6PD --> causes decreased glutathione and increased RBC susceptibility to oxidative stress
145
Stressors that cause anemia in G6PD deficiency
Fava beans
Sulfa drugs
Anti-malarials
Infections
146
Symptoms of G6PD deficiency
Back pain, hemoglobinuria a few days after oxidant stress
147
Pyruvate kinase deficiency causes...
Intrinsic hemolytic anemia
Defect in pyruvate kinase --> decreased ATP --> rigid RBCs
Hemolytic anemia in newborn
148
Paroxysmal Nocturnal Hemoglobinuria defect
Red cells missing surface markers CD55 and CD59 so complement attacks them and lyses them
149
What is test for PNH?
Ham's test - add acid to lower pH and that activates complement and lyses RBCs
150
Triad of PNH
Coombs - hemolytic anemia
Pancytopenia
Venous thrombosis
151
Sickle cell disease defect
Hemoglobin S mutation is single aa replacement where valine is used instead of glutamic acid at position 6 --> allow Hgb to polymerize in RBC
152
What triggers sickling in SCD?
Hypoxemia
Dehydration
Acidosis
153
Complications of Sickle Cell Disease
Aplastic crisis
Autosplenectomy
Splenic infarct
Salmonella osteomyelitis
Painful crises (vaso-occlusive)--> acute chest syndrome, avascular necrosis, stroke, dactylitis
Renal papillary necrosis and microhematuria
154
What organism causes osteomyelitis in SCD?
Salmonella
155
Treatment for SCD
Hydroxyurea
| BM transplantation
156
Hemoglobin C disease defect
Glutamic acid--> Lysine mutation in B globin
157
Microangiopathic anemia cause
RBCs are mechanically damaged as they pass through lumen of obstructed vessel --> in DIC, TIP/HUS, lupus, malignant HTN --> RBC gets chopped up by shear force or fibrin strands
158
Macroangiopathic anemia cause
Damage to cells by forces in LARGER vessels (prosthetic heart valves, aortic stenosis)
159
Autoimmune Hemolytic Anemia a. Warm agglutinins
| b. Cold agglutinins
a. IgG Abs attach to red cells and cause them to agglutinate AT BODY TEMP
b. IgM Abs that only cause problems when temp is lower
160
Cold agglutinins occur in...
Infections with EBV, mycoplasma
| Malignancies (CLL)
161
Warm agglutinins occur in...
```
SLE
Malignancies (CLL)
Drugs (methyldopa)
Viruses (EBV, HIV)
Congenital immune abnormality
```
162
Direct Coombs Test
Anti-Ig antibody (Coombs reagent) is added to patient's blood --> the RBCs agglutinate if RBCs are coated with Ig
163
Indirect Coombs Test
Normal RBCs added to patient's serum --> if serum has anti-RBC surface Ig, RBCs agglutinate when Coombs reagent is added
164
Direct Coombs test is positive in:
Hemolytic disease of newborn
Drug-induced autoimmune hemolysis anemia
Hemolytic transfusion reactions
165
Indirect Coombs test positive when:
Abs present to foreign blood (test blood prior to transfusion, screen maternal antibodies to a fetus' blood)
166
Painful cyanosis of fingers and toes with hemolytic anemia
Cold autoimmune hemolytic anemia
167
Red urine in the morning, and fragile RBCs
PNH
168
Basophilic nuclear remnants in RBCs
Howell-Jolly bodies
169
Autosplenectomy
Sickle cell (from auto-infarcting)
170
Drug used to treat sickle cell disease
Hydroxyurea
171
Where do platelets come from?
Megakaryocytes
172
How long do platelets live?
8-10 days; have no nucleus
173
What is vWF? Where does it come from?
| What is it's function?
It comes from Weibel-Palade bodies of endothelial cells and alpha granules of platelets
It complexes with and stabilizes factor 8 (elevated PTT with deficiency)
It binds to exposed collagen and then platelets binds vWF via Gp2b receptor at site of injury
174
How do platelets become activated after adhesion?
They change shape and ADP binding to receptor induces Gp2b/3a expression at platelet surface
175
How do platelets aggregate after activation?
Fibrinogen binds Gp2b/3a and link platelets
176
Pro-aggregation of platelet factors
TXA2 (released by platelets)
Decreased blood flow
Increased platelet aggregation
177
Anti-aggregation of platelet factors
PGI2 and NO (endothelial cells)
Increased blood flow
Decreased platelet aggregation
178
Aspirin mechanism
Inhibits cyclooxygenase --> permanently blocks the conversion of arachidonic acid to thromboxane A2
179
Effects of Aspirin on bleeding, PT, PTT
Increased bleeding time
| No effect on PT, PTT
180
Uses of Aspirin
Reduce fever
Treat pain
Anti-inflammatory
Anti-platelet
181
S/E of Aspirin
Bleeding
Peptic ulcers (no protective prostaglandins)
Hyperventilation (stimulates respiratory centers of brain) --> respiratory alkalosis (but transitions to metabolic acidosis)
Reye's syndrome (Hepatoencephalopathy)
182
Mechanism of Clopidogrel
ADP receptor inhibitor (inhibits platelet aggregation by preventing expression of GP2b/3a)
183
Uses of Clopidogrel
ACS, Coronary stenting
184
2b/3a INhibitors
Abciximab
Eptifibatide
Tirofiban
185
ADP receptor blockers
Clopidogrel
Prasugrel
Ticagrelor (reversible)
Ticlopidine (causes neutropenia)
186
Uses for Gp2b/3a inhbitors
NSTEMI
Acute coronary syndrome
unstable angina
Percutaneous transluminal coronary angioplasty
187
Platelet abnormalities symptoms
```
Mucous membrane bleeding
Epistaxis
Petechiae
Purpura
Increased bleeding time
```
188
Immune Thrombocytopenia
a. mechanism
b. Signs
c. BM biopsy shows...
a. Autoimmune disease with Abs to Gp2b/3a --> immune system removes and destroys them
b. Platelet count is low
c. Increased megakaryocytic on BM biopsy
189
Treatment for ITP
Steroids
IV immunoglobulin
Splenectomy
190
Thrombotic thrombocytopenia purpura
a. mechanism
b. signs/symptoms
c.
a. platelets are excessively activated because of increased large vWF multimers --> widespread thrombosis --> uses up all the platelets and causes thrombocytopenia and bleeding
b. pentad of neurologic and renal symptoms: fever, thrombocytopenia, microangiopathic hemolytic anemia
191
Defect in TTP
Inhibition or deficiency of ADAMTS13 (metalloproteases) that cleaves and degrades vWF multimers
192
Treatment for TTP
Plasmapheresis
| Steroids
193
What condition is TTP closely linked to?
Hemolytic Uremic Syndrome
194
What is triad of findings in HUS?
Microangiopathic hemolytic anemia
Renal symptoms
Thrombocytopenia
195
Five features of TTP/HUS
| Nasty Fever Torched His Kidneys
```
Neurologic
Fever
Thrombocytopenia
Hemolysis
Kidney failure
```
196
What is HUS associated with in kids?
E. coli 0157H7
197
Bernard Soulier syndrome defect
Defect in glycoprotein 1b --> platelet can't bind collagen --> defect of platelet plug formation from defect in adhesion
198
Glanzmann thrombasthenia defect
Defect in Gp2b/3a --> defect in platelet aggregation --> platelet count normal, bleeding time prolonged
199
von Willebrand disease
a. defect
b. causes
a. defect in vonWillebrand factor
b. defect in platelet plug formation from defect in adhesion AND intrinsic pathway coagulation defect
c. Increased PTT and increased bleeding time
200
Treatment of vWF disease
Desmopressin (increased release of vWF in storage sites of endothelial cells)
201
Disseminated Intravascular Coagulation
| a. mechanism
a. widespread activation of clotting --> deficiency in clotting factors and platelets --> bleeding state
202
Causes of DIC
| STOP Making New Thrombi
```
Sepsis
Trauma
Obstetric complications!!!!!
acute Pancreatitis
Malignancy
Nephrotic syndrome
Transfusion
```
203
DIC
a. PT and PTT
b. Bleeding time
c. Fibrinogen
d. D-dimer
a. Prolonged
b. increased bleeding time
c. low fibrinogen
d. high fibrin split products (d-dimer)
204
peripheral smear of DIC
Schistocytes
205
Presentation of DIC
Multi organ failure
| Bleeding
206
Most common inherited bleeding disorder
vWF disease
207
What does leukemia affect?
| What does lymphoma affect?
Bone marrow, maybe peripheral blood
| Lymphoma is tumor in lymph nodes
208
What makes lymphoma a Hodgkin lymphoma?
- Presence of Reed Sternberg cells (bilobed nuclear, clearing around nuclei, owl eye appearance, clearing around cell from cell shrinking)
- Found in single group of lymph nodes (extra nodal involvement is rare)
- Painless, nontender lymphadenopathy (nodes feel firm and rubbery)
- Lymphadenopathy in mediastinum
- Constitutional B symptoms: Low grade fever, night sweats, weight loss
209
Who gets Hodgkin lymphoma?
- Bimodal age (age 20 and 65)
| - More common in men (except nodular sclerosing)
210
What are most non-Hodgkin lymphomas? Age distribution?
B cell lymphomas
| Age distribution is widely variable
211
How do symptoms of non-Hodgkin compare to Hodgkin?
Fewer constitutional symptoms
212
What are certain types of non-Hodgkin lymphoma associated with?
HIV and immunocompromised
213
How do Reed Sternberg cells relate to prognosis?
The fewer cells the better prognosis
214
What is the most common type of Hodgkin lymphoma?
Nodular sclerosing type
215
Which type of Nodular sclerosing Hodgkin lymphoma has the best prognosis?
Lymphocyte rich form
| Lymphocyte mixed or depleted form has worst prognosis
216
What are cell markers of Reed Sternberg cells?
CD15+
| CD30+
217
Most common type of NH lymphoma in adults
Diffuse large B cell lymphoma
218
Translocation in diffuse large B cell lymphomas
t(14:18)
219
Follicular lymphoma translocation
t(14;18) of heavy chain Ig (14) and BCL-2 (18) --> BCL2 inhibits apoptosis
220
Burkitt lymphoma translocation
t(8;14) --> translocation of c-myc and heavy chain Ig
221
Mantle cell lymphoma translocation
t(11;14) --> translocation of cyclin D1 and heavy chain Ig
222
Starry sky appearance (sheets of lymphocytes with interspersed macrophages)
Burkitt lymphoma
223
Associated with EBV
Burkitt lymphoma
224
Endemic form of Burkitt lymphoma
Jaw lesion
225
Indolent course of lymphoma; painless waxing and waning lymphadenopathy
Follicular lymphoma
226
Associated with Sjogrens, Hashimotos, and H. pylori
Marginal cell MALToma
227
Adults present with cutaneous lesions (Japan, West African, Caribbean)
Adult T cell Lymphoma
228
Lytic bone lesions, Hypercalcemia
Adult T cell Lymphoma
229
Caused by HTLV (associated with IV drug abuse)
Adult T cell Lymphoma
230
Presents with skin patches/plaques characterized by atypical CD4 cells with cerebriform nuclei
Mycosis fungoides
231
If mycosis fungoides progresses to blood
Sezary syndrome
232
Associated with long term celiac disease
Intestinal T cell lymphoma
233
Lymphoma equivalent of CLL
Small lymphocytic lymphoma
234
Cancer most commonly associated with a non-infectious fever
Hodgkin lymphoma
235
Large B cells with bilobed nuclei and prominent owl's eye inclusions
Reed Sternberg Cells seen in Hodgkin Lymphoma
236
Large B cells with bilobed nuclei and prominent owl's eye inclusions
Reed Sternberg Cells seen in Hodgkin Lymphoma
237
What's the difference between acute and chronic leukemia?
Acute - rapid onset and rapidly progressive, >50% blasts on BM biopsy, (myeloblasts in AML, Lymphoblasts in ALL), numerous blast cells (>20% blasts), often associated with pancytopenia
Chronic -
238
ALL is most common in...
Children Female
| Whites > Blacks
239
Common presentation of T-ALL
Mediastinal mass presenting as SVC like syndrome
240
Prognosis of ALL
Good prognosis in children (up to 90% remission)
241
TdT+, CD10+
TdT+ is a marker of preT and preB cells
| CD10+ is markers of preB cells
242
ALL translocation that equals better prognosis
t(12;21)
243
ALL association
Down syndrome
244
Common ALL symptom
Bone pain
245
```
ALL association
(We all fall down)
```
Down syndrome
246
Common ALL symptom
Bone pain
247
Age of onset for AML
median onset 65 years
248
AML blood smear shows:
```
Auer rods (peroxidase cytoplasmic inclusions seen in M3 AML)
Increased circulating myeloblasts
```
249
Risk factors for AML
Prior exposure to alkylating chemotherapy, radiation, myeloproliferaetive disorders, Down syndrome
250
t(15;17)
M3 AML subtype responds to all-trans retinoid acid (vitamin A), inducing differentiation of myeloblasts (Acute promyelocytic AML)
251
DIC common presentation of:
M3 AML
252
CD13/33+
AML
253
PAS (-)
AML
254
What's the difference between acute and chronic leukemia?
Acute - rapid onset and rapidly progressive, >50% blasts on BM biopsy, (myeloblasts in AML, Lymphoblasts in ALL), numerous blast cells (>20% blasts), often associated with pancytopenia
Chronic - Insidious onset and gradual progression (months to years), mature cells (
255
PAS (-)
AML
256
Most common adult leukemia seen in western countries
CLL
257
Who does CLL affect?
Adults over age 50
258
95% have B cell markers
CLL
259
Smudge cells
CLL
260
Autoimmune hemolytic anemia
CLL
261
Autoimmune hemolytic anemia
CLL
262
CD20+, CD5+ B cell Neoplasm
SLL/CLL
263
Defined by the Philadelphia chromosome t(9;22), BCR-ABL
CML
264
Presents with increased neutrophils, metamyelocytes, basophils; splenomegaly
CML
265
Responds to Imatinib
CML
266
Very low LAP as a result of low activity in mature granulocytes
(vs. Leukemoid reaction which has Increased LAP)
| CML
267
Autoimmune hemolytic anemia
| warm or cold agglutinins
CLL
268
Presents with increased neutrophils, metamyelocytes, basophils; splenomegaly, fatigue, abdominal pain
CML
269
Very low LAP as a result of low activity in mature granulocytes
(vs. Leukemoid reaction which has Increased LAP)
| CML
270
Age of presentation of CML
25-60
271
a. CLL progress to ALL?
| b. CML progress to AML?
a. 10% progress to ALL
| b. 80% progress to AML; this is Blast crisis
272
What is Philadelphia chromosome?
t(9;22) BCR ABL mutation
| Encodes constitutively activated tyrosine kinase --> malignant transformation
273
What is Philadelphia chromosome?
t(9;22) BCR ABL mutation
| Encodes constitutively activated tyrosine kinase --> malignant transformation
274
t(8;14)
Burkitt lymphoma
275
t(15;17)
M3 AML (auer rods); treated with ATRA
276
t(8;21)
AML
| This is why patients with Trisomy 21 have increased incidence of AML.
277
What is Leukemoid reaction?
```
Increased WBC as a reaction to a stressor
Predominantly neutrophils
Left shift (5-10% immature bands)
Increased LAP (CML has decreased LAP)
```
278
What is Myelodysplastic syndrome?
Dysplasia of the hematopoietic cells in the myeloid tissue
279
What is Pseudo-Pelger Huet anomaly?
Neutrophils with bilobed nuclei; seen after chemotherapy
280
What are myeloproliferative disorders?
Neoplastic transformation of a single myeloid precursor -->
Monoclonal proliferation of mature myeloid cells
Polycythemia vera
Essential thrombocytosis
Myelofibrosis
281
Mutation common in myeloproliferative disorders
JAk2 --> encodes Janus kinase 2 --> switched on all the time --> constantly getting growth factor signal to make more cells
282
What is Polycythemia vera? What is the mutation?
Jak2 mutation in red cell precursor; causes increased hematocrit without elevated EPO
283
Presentation of polycythemia vera
Intense itching after hot shower (from increased basophils)
Erythromelalgia (severe, burning pain and red-blue coloration) from episode blood clots in vessels of extremities
Plethora (redness of face)
Hyper viscosity of blood
Splenomegaly
Headache
284
What is essential thrombocytosis
Overproduction of abnormal platelets --> bleeding, thrombosis
285
What does BM look like in Essential thrombocytosis?
Has enlarged megakaryocytes
286
What is myelofibrosis?
Fibrosis and obliteration of the marrow space
| Causes teardrop red cells
287
What is myelofibrosis?
Fibrosis and obliteration of the marrow space
| Causes teardrop red cells
288
What is multiple myeloma?
Monoclonal plasma cell cancer that arises in marrow and produces lots of IgG (55%) or IgA (25%)
289
Most common primary tumor arising within bone in people >40-50
Multiple myeloma
290
Most common primary tumor arising within bone in people >40-50
Multiple myeloma
291
How do you identify plasma cells?
Clock face chromatin and intracytoplasmic inclusions containing immunoglobulin
292
Presentation of multiple myeloma
Anemia (plasma cells interfere with production of other cells in BM)
Renal insufficiency (form casts and plug up kidneys)
Back Pain (bc they secrete ostend cytokines) Punched out lytic bone lesions!
Hypercalcemia
Susceptibilty to infection (decreased production of healthy immune cells)
Amyloidosis
293
Serum protein electrophoresis for Multiple myeloma shows:
Monoclonal antibody (M) spike
294
Bence Jones proteins
Immunoglobulin light chains in urine detected on urine protein electrophoresis
BUT Do NOT see elevated protein on regular urinalysis
295
Peripheral smear of multiple myeloma
Rouleaux formation (RBCs stacked like poker chips in bloos smear)
296
Peripheral smear of multiple myeloma
Rouleaux formation (RBCs stacked like poker chips in bloos smear)
297
What is Waldenstrom macroglobulinemia?
Shows M spike that is IgM
Hyperviscosity syndrome and Amyloidosis (blurred vision, Raynaud phenomenon)
No CRAB findings
298
Plasmacytoma
2 types: solitary plasmacytoma of bone and extra medullary plasmacytoma (predilection for head and neck -specifically nose)
299
What is Monoclonal Gammopathy of Undetermined significance?
Monoclonal expansion of plasma cells, asymptomatic, may lead to multiple myeloma
Need to be monitored
300
What is Monoclonal Gammopathy of Undetermined significance?
Monoclonal expansion of plasma cells, asymptomatic, may lead to multiple myeloma
Need to be monitored
301
Most common leukemia in children
ALL
302
Acute leukemia positive for peroxidase
AML
