Hematology Flashcards
1
Q
Define anisocytosis and poikilocytosis.
A
varying size and varying shape
2
Q
What is the primary source of energy for RBCs?
A
glucose
3
Q
What is the life span of erythrocytes and platelets?
A
- erythrocytes: 120 days
- platelets: 8-10 days
4
Q
What do we call the two most significant granules in platelets? What does each contain?
A
- alpha granules contain vWF, fibrinogen, and fibronectin
- delta (dense) granules contain ADP and Ca2+
5
Q
What is GPIb?
A
the vWF receptor found on platelets
6
Q
What is GP IIb-IIIa?
A
the fibrinogen receptor found on platelets
7
Q
What are the contents of the specific and azurophilic granules of neutrophils?
A
- specific contain alkaline phosphatase, collagenase, lysozyme, and lactoferrin
- azurophilic contain proteinases, acid phosphatase, myeloperoxidase, and B-glucuronidase
8
Q
Hyper-segmented neutrophils (>5 lobes) are a feature of which hematologic disorder?
A
B12 or folate deficiency (megaloblastic anemia)
9
Q
List the four most important neutrophil chemoattractants.
A
- bacterial products
- LTB4
- IL-8
- C5a
10
Q
How can we identify monocytes in circulation?
A
they have large, kidney-shaped nuclei
11
Q
What is the purpose of monocytes?
A
they differentiate into macrophages in tissues
12
Q
Which cell population is responsible for responding to bacterial LPS and initiating septic shock? What CD is responsible for binding LPS?
A
macrophages express CD14, which binds LPS
13
Q
Macrophages are activated by what cytokine?
A
IFNy
14
Q
What is major basic protein?
A
an eosinophilic protein that defends against helminths
15
Q
What are the five most significant causes of eosinophilia?
A
“NAACP”
- neoplasia (specifically, Hodgkin Lymphoma)
- asthma
- allergic process
- chronic adrenal insufficiency
- parasites
16
Q
Basophil granules contain what two important products?
A
- heparin and histamine
- it synthesizes leukotrienes on demand
17
Q
What substance can prevent mast cell degranulation and is therefore used in asthma prophylaxis?
A
cromolyn sodium
18
Q
What are Langerhans cells?
A
dendritic cells found in the dermis
19
Q
Describe the appearance of lymphocytes.
A
- they have a round, dense nucleus
- scant, pale cytoplasm
20
Q
What is the characteristic appearance of plasma cells?
A
a “clock-face” nucleus located at the periphery of the cell
21
Q
Where does erythropoiesis occur in the developing fetus and after birth?
A
- begins in the yolk sac 3-8 weeks into gestation
- moves to the liver and then spleen
- produced in the marrow starting at roughly 18 weeks gestation in all bones
- as an individual ages, erythropoiesis is concentrated in the flat bones of the axial skeleton
22
Q
Why does HbF have a higher O2 affinity than HbA?
A
because it has a lower affinity for 2,3-BPG
23
Q
What are embryonic globins?
A
epsilon and zeta globins expressed in the early developing fetus until HbF levels build up
24
Q
Antibodies in our plasma against ABO blood antigens are of which isotype?
A
mostly IgM
25
Which mothers must be treated with RhoGAM during and after pregnancy?
those that are Rh- (aka Rhd)
26
What is Hemolytic Disease of the Newborn? How is it prevented?
- Rhd mothers exposed to fetal RhD blood (often during delivery) make anti-D IgG
- in subsequent pregnancies this IgG crosses the placenta, causing erythroblastosis fetalis
- this is prevented by administering RhoGAM to Rhd pregnant women during the third trimester
27
What is ABO hemolytic disease of the newborn? How is it treated?
- anti-A or anti-B IgG from type O mothers crosses the placenta, attacking the fetal erythrocytes
- these antibodies are preformed so it can occur in the first pregnancy and does not worsen in future pregnancies
- presents with mild jaundice in the neonate within 24 hours of birth
- treat with phototherapy
28
In what order do the various hemoglobins run on electrophoresis?
A Fat Santa Claus
- HbA runs the furthest from the cathode
- HbF runs next
- HbS after that
- HbC runs the shortest distance
29
What is kallikrein?
a molecule that activates bradykinin
30
What are the major effects of bradykinin?
- vasodilation of the arteriole
- increased vascular permeability in the post-cap venule
- pain
31
Which coagulation cascade proteins are Vitamin K dependent?
- 2, 7, 9, 10
| - plus protein C and S
32
What activates the intrinsic pathway of the coagulation cascade?
- collagen
- basement membrane
- activated platelets
- HMWK
33
What is aminocaproic acid?
- a lysine analog that inhibits proteolytic enzymes like tPA
| - it is therefore used to treat bleeding disorders or bleeding during and after surgery
34
Draw the coagulation cascade (intrinsic, extrinsic, propagation, and common pathways) and list the enzymes important in fibrinolysis.
See page 383 of FA
35
Describe the role of Vitamin K in the coagulation cascade including how it is activated and what function it performs.
- it is activated by epoxide reductase in the liver
- reduced vitamin K then serves as a cofactor for gammaglutamyl transferase
- the gammacarboxylation of glutamate residues on coagulation cascade proteins adds a second positive charge, allowing Ca2+ to bind, inducing a conformation change that inserts the protein into the phospholipid membrane where it can interact with the necessary cofactor phosphatidylserine
36
How does warfarin act as an anti-coagulant?
it inhibits vitamin K epoxide reductase
37
What is antithrombin III? How does it work? What is it's net effect? What are it's primary targets?
- it is an anti-coagulant
| - heparin enhances it's activity which is to cleave the serine proteases FIIa and FXa
38
Describe the steps of platelet plug formation (aka primary hemostasis).
- endothelial damage triggers transient vasoconstriction via neural reflex and release of endothelin
- vWF from alpha-granules and Weibel-Palade bodies binds exposed collagen
- platelets bind vWF via GPIb and undergo a conformational change, releasing ADP, Ca2+ and TXA2
- ADP binding to platelet receptors induces GPIIb-IIIa expression on platelet surfaces while thromboxane A2 promotes platelet aggregation
- fibrinogen binds GPIIb-IIIa and links platelets
39
What is thromboxane A2?
a prothrombic protein synthesized by platelets once activated using COX which then serves to activate additional platelets and promote platelet aggregation
40
Failure of platelet agglutination with ristocetin occurs in what two diseases?
vWF disease and Bernard-Soulier syndrome
41
What are Heinz bodies? What disease are they associated with? How are they formed? What do they lead to?
- a feature of G6PD deficiency
- form when oxidative stress precipitates hemoglobin (by forming sulfide bonds)
- likely removed by the spleen to form bite cells
42
What are Howell-Jolly bodies? When are they seen?
they are basophilic nuclear remnants found in RBCs that are normally removed by splenic macrophages but are seen in patients with asplenia or splenic dysfunction
43
Basophilic stippling of RBCs is indicative of what three pathologies?
- lead poisoning
- sideroblastic anemia (defect in porphyrin metabolism)
- myelodysplastic syndromes
44
Dacrocytes (tear drop-shaped RBCs) are indicative of what pathology?
a bone marrow infiltrate
45
What are bite cells? How are they formed?
bite cells are feature of G6PD deficiency which from when oxidative stress precipitates hemoglobin, forming Heinz bodies which are then removed by splenic macrophages leaving bite cells
46
How do acanthocytes (spur cells) differ from echinocytes (burr cells)? When are both seen?
- they are pathologic RBCs
- echinocytes have smaller, more uniform projections than acanthocytes
- acanthocytes: liver disease and a state of cholesterol dysregulation called abetalipoproteinemia
- echinocytes: end-stage renal disease, liver disease, pyruvate kinase deficiency
47
What pathology are elliptocytes associated with?
they are seen in hereditary elliptocytosis, an asymptomatic condition caused by mutations in genes encoding RBC membrane proteins like spectrin
48
What are ringed sideroblasts?
pathologic RBCs found in those with sideroblastic anemia and formed via the excess accumulation of iron in mitochondria
49
Target cells are a feature of which pathologies?
"HALT" said the hunter to his target
- HbC disease
- Asplenia
- Liver disease
- Thalassemia
50
Orotic Aciduria
- an autosomal recessive defect in UMP synthase, a pyrimidine synthesis pathway enzyme responsible for converting orotic acid to UMP
- presents in children with failure to thrive, developmental delay, and megaloblastic anemia refractory to folate or B12
- normal levels of ammonia (versus ornithine transcarbamylase deficiency)
- treat with UMP to bypass the mutated enzyme
51
All megaloblastic anemias have what in common?
- impaired DNA synthesis
| - presenting with a macrocytic anemia, hyper-segmented neutrophils, and glossitis
52
Name four megaloblastic anemias.
- folate deficiency
- B12 deficiency
- orotic aciduria
- Diamond-Blackfan anemia
53
Diamond-Blackfan anemia
- a megaloblastic anemia with rapid-onset in the first year of life
- due to an intrinsic defect in erythroid progenitor cells
- presents with elevated HbF, short stature, craniofacial abnormalities, and upper extremity malformations (e.g. triphalangeal thumbs)
54
Nonmegaloblastic macrocytic anemia
- a macrocytic anemia in which DNA synthesis is not impaired
- caused by alcoholism or liver disease
- presents with a macrocytic anemia without hypersegmented neutrophils
55
Fanconi Anemia
- an aplastic anemia caused by a DNA repair defect
- results in bone marrow failure
- presents with a non-hemolytic normocytic anemia, short stature, cafe-au-lait spots, and thumb/radial defects
- increased risk for neoplasias
56
What is the role of transferrin? Ferritin?
transferrin is the transport form of iron while ferritin is the storage form
57
How do corticosteroids affect differential WBC counts?
- sequester eosinophils in lymph nodes, causing an EOSINOPENIA
- trigger apoptosis of lymphocytes, causing a LYMPHPENIA
- decrease activation of neutrophil adhesion molecules, impairing migration, causing a NEUTROPHILIA
58
Lead poisoning resembles what other group of disorders?
resembles porphyria because lead inhibits specific enzymes needed in heme synthesis
59
Lead Poisoning
- lead inhibits ferrochelatase and ALA dehydratase, enzymes needed for heme synthesis
- ALA and protoporphyrin accumulate in the blood
- presents with a microcytic, sideroblastic anemia with basophilic stippling, GI and kidney disease
- causes mental deterioration in children (most likely from exposure to lead paint)
- causes headache, memory loss, and demyelination in adults (most likely from exposure to batteries or ammunition)
60
Porphyria cutanea tarda
- the most common porphyria
- a blistering cutaneous photosensitivity caused by uroporphyrinogen decarboxylase deficiency
- AD with incomplete penetrance, symptoms begin after a stressor like HCV, alcoholism, estrogen replacement
- uroporphyrin builds up in the urine (tea-colored urine)
- treat with phlebotomy to reduce hepatic iron stores
61
Acute Intermittent Porphyria
- the most common acute neurologic porphyria
- caused by an AD porphobilinogen (PBG) deaminase deficiency
- PBG and ALA build up and are neurotoxic, cause neurodegeneration, impair glutamate release, and elevate 5-HT levels
- cause abdominal pain, then psych distress, then polyneuropathy along with port wine-colored urine
- precipitated by drugs, alcohol, and starvation
- treat with heme, which inhibits ALA synthase
62
How are acute neurologic porphyrias treated?
with heme, because it feeds back and inhibits ALA synthase
63
Iron poisoning
- cell death arises due to peroxidation of membrane lipids
- presents with nausea, vomiting, gastric bleeding, lethargy, and GI obstruction due to scarring
- treat with chelation (IV deferoxamine or oral deferasirox) and dialysis
64
INR is a normalized form of what other lab value?
PT
65
Which coagulation test, PT or PTT, is used to follow those on warfarin? Heparin?
- PT is used to follow warfarin
| - PTT to follow heparin
66
When is fresh frozen plasma given? Provide three specific instances/examples.
- to increase coagulation factor levels as is the case in DIC
- patients with cirrhosis
- immediate warfarin reversal
67
What is in cryoprecipitate?
contains:
- fibrinogen
- FVIII
- FXIII
- vWF
- fibronectin
68
List five risks of blood transfusions.
- infection transmission (most likely HBV)
- hypocalcemia (citrate is a calcium chelator)
- hyperkalemia (lysed RBCs)
- iron overload and secondary hemochromatosis
- transfusion reaction
69
What clinical features distinguish Hodgkin lymphoma from NHL?
- most often localized to a single group of nodes
- spreads contiguously and rarely affects the mesenteric nodes
- characterized by the presence of Reed-Sternberg cells
- has a bimodal age distribution
- associated with EBV
70
Describe Reed-Sternberg cells.
- markers of Hodgkin lymphoma
- binucleate
- CD15 and CD30 positive
- of B cell origin
71
What is Primary central nervous system lymphoma?
- a CNS lymphoma considered to be an AIDS-defining illness
- presents with confusion, memory loss, and seizures as well as a mass lesion on MRI
- need to distinguish this mass from toxoplasmosis via CSF analysis
72
What is Pseudo-Pelger-Huet anomaly?
the presence of neutrophils with bi-lobed nuclei following chemotherapy
73
With which hematologic neoplasia is each of the following associated with and which gene is affected by each:
- t(8;14)
- t(9;22)
- t(11;14)
- t(14;18)
- t (15;17)
- 8;14: c-myc activation of Burkitt lymphoma
- 9;22: BCR-ABL fusion protein of CML or Ph+ ALL
- 11;14: cyclinD1 activation of mantle cell lymphoma
- 14;18: bcl-2 activation of follicular lymphoma
- 15;17: interruption RAR-a receptor gene of associated with acute promyelocytic leukemia
74
What is thrombomodulin? Describe the downstream effects.
- a protein that changes the enzymatic activity of FIIa such that it activates Protein C
- Protein S further activates Protein C, which then inactivates FVa and FVIIIa
75
Describe the mechanism, clinical uses, test for monitoring, and adverse effects of heparin. How is it reversed?
- it functions by enhancing the activity of antithrombin III, which cleaves FIIa and FXa
- works well for immediate anticoagulation and can be used during pregnancy because it does not cross the placenta
- monitored via PTT
- adverse effects include heparin-induced thrombocytopenia, osteoporosis, bleeding
- protamine sulfate is the antidote, it is positively charged and binds negatively charged heparin
76
What is the antidote for heparin therapy? How does it function?
protamine sulfate is a positive molecule that binds the negatively charged heparin molecules
77
List the three important LMWH-like drugs. How do they compare to heparin?
- includes:
- -> enoxaparin
- -> dalteparin
- -> fondaparinux
- they have greater selectivity for Xa, better bioavailability, longer half lives, and don't require monitoring
- however they are not easily reversible
78
Enoxaparin
- a low-molecular weight heparin
- greater selectivity for Xa, better bioavailability, longer half lives, and don't require monitoring
- however not easily reversible
79
Dalteparin
- a low-molecular weight heparin
- greater selectivity for Xa, better bioavailability, longer half lives, and don't require monitoring
- however not easily reversible
80
Fondaparinux
- a drug that functions as a low-molecular weight heparin
- greater selectivity for Xa, better bioavailability, longer half lives, and don't require monitoring
- however not easily reversible
81
Bivalirudin
- a direct thrombin inhibitor
- can be used in cases of heparin-induce thrombocytopenia and does not require monitoring
- may cause bleeding but there are no specific reversal agents
82
Describe the mechanism, clinical uses, test for monitoring, adverse effects, and reversal mechanism of warfarin. How is it reversed?
- it blocks the vitamin K epoxide reductase, indirectly inhibiting the vitamin K dependent coagulation proteins, thereby affecting the extrinsic pathway
- monitored using PT
- used for chronic anticoagulation and not in pregnant women
- may cause bleeding, skin/tissue necrosis, or have teratogenic effects
- reverse using vitamin K and fresh frozen plasma
83
Which can be used during pregnancy, heparin or warfarin?
heparin
84
What is heparin bridging? Why is it used?
heparin is frequently used when starting warfarin because it serves as an immediate anticoagulant during the initial period when warfarin induces a hyper coagulable state
85
What is warfarin skin necrosis?
- a side effect of warfarin seen when heparin bridging is not used
- Proteins C and S have shorter half lives than the other vitamin-K dependent coagulation proteins so warfarin actually induces an initial hyper-coagulable state
- due to this state, small vessel microthrombi cause skin necrosis
86
Compare heparin to warfarin.
- heparin is larger and therefore only given parenterally while warfarin is smaller and given orally
- heparin acts in the blood on antithrombin III while warfarin acts in the liver on vitamin K epoxide reductase
- heparin acts immediately while warfarin is limited by the half-lives of normal clotting factors
- heparin is easier to reverse with protamine sulfate than warfarin with fresh frozen plasma and vitamin K
- heparin is monitored using PTT while warfarin is monitored using PT
- heparin, unlike warfarin, is safe during pregnancy
87
Mucocutaneous bleeding is a sign of what kind of hemostasis disorder? Hemarthrosis and hematomas are signs of what kind of hemostasis disorder?
- mucocutaneous bleeding is indicative of a primary hemostasis disorder (platelet abnormalities)
- hemarthrosis and hematomas are indicative of secondary hemostasis disorders (coagulation abnormalities)
88
How does mucocutaneous bleeding associated with a primary hemostasis disorder manifest?
```
mucosal involvement leads to
- epistaxis
- hemoptysis
- GI bleeding
- hematuria
- menorrhagia
- intracranial bleeding
skin involvement leads to
- petechiae, purpura, and ecchymosis
```
89
Thrombocytopenia most often becomes symptomatic when it reaches what degree?
fewer than 50K platelets
90
Immune Thrombocytopenic Purpura (ITP)
- the most common cause of thrombocytopenia
- plasma cells in the spleen produce autoantibodies to platelet antigens, particularly GPIIb-IIIa, and these antibody-bound platelets are cleared by splenic macrophages
- can be divided into an acute form, seen more commonly in children weeks after a viral infection or immunization, and a chronic form, seen more commonly in adults
- the chronic form is particularly common amongst women of childbearing age and ITP in the mother may induce a short-lived thrombocytopenia in offspring as the IgG crosses the placenta
- presents with normal PT/PTT, thrombocytopenia, increased megakaryocytic on bone marrow biopsy
- treat with corticosteroids, IVIG, or splenectomy
91
Thrombotic Thrombocytopenic purpura
- an ADAMTS-13 deficiency, often due to autoantibodies, leaves ultra large vWF, leading to abnormal platelet adhesion and a pathologic formation of platelet microthrombi which consumes platelets and shears RBCs
- presents with a classic pentad of CNS abnormalities, renal abnormalities, mucocutaneous bleeding, hemolytic anemia, and schistocytes
- bleeding time is increased, PT/PTT is normal, thrombocytopenia, anemia, schistocytes, elevated LDH, and increased megakaryocytic in bone marrow
- treat with plasmapharesis and corticosteroids
92
Hemolytic Uremic Syndrome
- endothelial damage due to drugs or infection (primarily shiga toxin-producing bacteria like E. Coli, O157:H7), results in a pathologic formation of platelet micro thrombi which consumes platelets and shears RBCs
- presents with renal abnormalities, mucocutaneous bleeding, hemolytic anemia, and schistocytes
- other findings include thrombocytopenia, increased bleeding time, normal PT/PTT, and increased megakaryocytic
- treat with plasmapheresis and corticosteroids
93
Bernard-Soulier syndrome
- a genetic GPIb-IX deficiency that impairs platelet adhesion
- presents with a mild thrombocytopenia (because poorly functioning platelets are removed) as well as slightly enlarged platelets (because immature ones are being released - B-S = "Big Suckers")
- risocetin test will be abnormal because the platelets can't bind vWF well
94
Glanzmann Thromboasthenia
- a genetic GPIIb-IIIA deficiency that impairs platelet aggregation
- fibrinogen binding is impaired but vWF binding is intact, so a risocetin test will be normal
95
How does aspirin function as an anti-thrombotic?
it inhibits COX, impairing thromboxane A2 production by activated platelets, which in turn impairs aggregation
96
List four qualitative platelet disorders.
- Bernard-Soulier syndrome (GPIb-IX deficiency)
- Glanzmann Thromboasthenia (GPIIb-IIIa deficiency)
- Aspirin (impairs TXA2 formation)
- Uremia (impairs adhesion and aggregation)
97
Where does the calcium needed for the coagulation cascade come from?
dense granules of activated platelets
98
What clinical features would you expect if someone had a secondary hemostasis disorder? What about a primary hemostasis disorder?
- primary: mucocutaneous bleeding in the form of epistaxis, GI bleeding, menorrhagia, hematuria, hemoptysis, and petechiae
- secondary: hemarthrosis, hematomas,and rebreeding after surgical procedures (commonly noticed after a circumcision or wisdom tooth extraction)
99
What is the difference between PT and PTT?
- PT is used to monitor the extrinsic pathway (fewer letters = fewer enzymes) and those on warfarin therapy
- PTT is used to monitor the intrinsic pathway (more letters = more enzymes) and those on heparin therapy ("hep" has three letters like PTT)
100
Hemophilia A
- an X-linked recessive FVIII deficiency
- presents with deep bleeding and post-surgical bleeding, the degree of which remains relatively constant from generation to generation
- PTT is elevated but corrected by 1:1 mixing
- platelet count and bleeding time are normal
101
Hemophilia B
- an X-linked recessive FIX deficiency
- presents with deep bleeding and post-surgical bleeding, the degree of which remains relatively constant from generation to generation
- PTT is elevated but corrected by 1:1 mixing
- platelet count and bleeding time are normal
102
How can one distinguish hemophilia A from a FVIII inhibitor?
hemophilia A will correct with 1:1 mixing while an inhibitor disorder will not
103
Von Willebrand Disease
- the most common inherited coagulation disorder
- a genetic qualitative or quantitative vWF deficiency (type I is partial quant, type II is qual, type III is complete quant)
- it presents with mucocutaneous bleeding that varies from generation to generation as well as an increase in bleeding time, an increased PTT, and an abnormal risocetin test
- treat with desmopressin, which increases the release of vWF from endothelial cells
104
Which bleeding and coagulation tests are abnormal in those with a Von Willbrand Disease? Why?
- bleeding time is prolonged (because of impair platelet adhesion)
- PTT is prolonged (because it is a FVIII carrier protein)
- risocetin test is abnormal
105
List three causes of vitamin K deficiency, which may lead to a coagulation disorder. Explain each.
- newborns lack GI bacteria that normally synthesize VitK
- long-term antibiotic therapy disrupts those same bacteria
- malabsorption
106
Why is large-volume transfusion often followed by transfusion of cryo?
because the large volume dilutes coagulation factors, inducing a relative deficiency
107
Heparin-Induced Thrombocytopenia
- IgG is formed against a heparin-platelet factor 4 complex, and these platelets are cleared by the spleen
- often presents with thrombosis despite thrombocytopenia, this is because destroyed platelets may activate the remaining platelets
108
DIC
- a pathologic activation of the coagulation cascade which consumes platelets (resulting in mucocutaneous bleeding) and induces widespread microthrombi formation (resulting in ischemia and infarction)
- causes range from obstetric complications (tissue thromboplastin in amniotic fluid activates the cascade), sepsis (endotoxins induce endothelial cells to make tissue factor), adenocarcinoma (mucin activates cascade), acute promyelocytic leukemia (Auer rods induce coagulation), or rattlesnake bite
- in contrast to HUS/TTP, these microthrombi are platelet and fibrin-rich
- the best screening test is elevated D-dimers, but there is also a thrombocytopenia, elevated PT and PTT, diminish d fibrinogen, and a hemolytic anemia with schistocytes
- treat with cryo
109
List the causes of DIC and the reasoning behind each.
- obstetric complication: tissue thromboplastin in the amniotic fluid activates the cascade
- sepsis: endotoxins trigger cytokine release, which activate the cascade
- adenocarcinoma: mucin activates the cascade
- acute promyelocytic anemia: Auer rods trigger coagulation
- rattlesnake bite
110
What are the functions of plasmin?
it serves as a fibrinolytic enzyme by cleaving fibrin and serum fibrinogen, destroying clotting factors, and blocking platelet aggregation
111
Describe Disorders of Fibrinolysis
- a bleeding disorder due to plasmin overactivity, which results in excessive cleavage of serum fibrinogen and inhibition of platelet aggregation
- typically due to radial prostatectomy (urokinase is released and activates plasmin) cirrhosis of the liver (reduces a2-antiplasmin production)
- presents like DIC except that D-dimers aren't elevated: low levels of fibrinogen, elevated PT/PTT, and increased bleeding time
- treat with aminocaproic acid, which blocks activation of plasminogen
112
If a patient presents with the classic findings of DIC but D-dimers aren't elevated, what diagnosis does this suggest?
- a fibrinolytic disorder of over active plasmin because plasmin inhibits coagulation proteins and reduces serum fibrinogen, but does so without forming clots first
- most often after a radical prostatectomy (release of urokinase activates plasmin) or cirrhosis (less a2-antiplasmin)
113
What are lines of Zahn?
a histologic finding of alternating layers of platelets/fibrin and RBCs, which is indicative of a thrombosis and can help differentiate it from a postmortem clot
114
How can a thrombosis be differentiated from a postmortem clot?
lines of Zahn and attachment to the vessel wall are both suggestive of a thrombosis
115
What is Virchow's triad?
the three major risk factors for thrombosis
- endothelial cell damage
- disrupted blood flow
- hyper-coagulable state
116
List three things that might contribute to a DVT by disrupting blood flow.
things that induce stasis or turbulence:
- immobilization
- cardiac wall dysfunction
- aneurysm
117
Through what mechanisms do endothelial cells normally prevent thrombosis?
- block exposure of sub endothelial collagen and underlying tissue factor
- produce prostacyclin and NO to promote vasodilation and inhibit platelet aggregation
- secrete heparin-like molecules
- secrete tPA
- secrete thrombomodulin
118
List three causes of endothelial damage that can contribute to Virchow's triad and thrombosis.
- atherosclerosis
- vasculitis
- high levels of homocysteine
119
List two causes of elevated homocysteine in the blood? How do these work? Why is elevated homocysteine a danger?
- B12 or folate deficiency: mildly elevates homocysteine levels because folic acid circulates as methyl-THF and the methyl group is transferred to cobalamin (B12), which transfers it to homocysteine to produce methionine
- cystathionine beta synthase deficiency: CBS converts homocysteine to cystathionine
- elevated homocysteine is a problem because it causes endothelial damage and can contribute to thrombosis
120
Cystathione Beta Synthase Deficiency
- a CBS deficiency prevents conversion of homocysteine to cystathionine
- results in elevated homocysteine levels in the blood with homocystinuria
- characterized by vessel thrombosis (homocysteine damages endothelial cells), mental retardation, lens dislocation, and long slender fingers
121
What is Protein C or S deficiency? What two things does it increase the risk for?
- an autosomal dominant condition which results in less inactivation of FV and FVIII, leading to a hyper coagulable state
- increases the risk of recurrent DVT or DVT at a young age
- increases the risk for warfarin skin necrosis because warfarin already results in a temporary deficiency of C and S relative to factors II, VII, IX, and X
122
What deficiency increases the risk for warfarin skin necrosis?
- Protein C or S deficiency because warfarin already results in a temporary deficiency of C and S relative to factors II, VII, IX, and X
- a deficiency which decreasing their relative concentrations even more increases the likelihood of thrombi which induce skin necrosis
123
Factor V Leiden
- a mutated form of FV which lacks the cleavage site for deactivation by proteins C and S
- the most common inherited cause of hyper coagulable state
124
Prothrombin 20210A
- a point mutation in the 3'-UTR of prothrombin improves the mRNA stability, resulting in increased gene expression
- excess prothrombin promotes a hyper coagulable state
125
How can you recognize an antithrombin III deficiency?
- it increases the risk of recurrent DVT or DVT at young age
| - PTT won't rise with standard heparin dosing and requires high dose heparin instead
126
List five causes of a hyper coagulable state.
- Protein C or S deficiency
- Factor V Leiden
- Prothrombin 20210A
- ATIII deficiency
- Oral contraceptives
127
In what way do estrogens impact hemostasis?
they induce a hyper coagulable state because they induce increased production of coagulation factors
128
What is an emboli?
an intravascular mass that travels and occludes downstream vessels, most commonly a thromboembolus
129
What is an atherosclerotic embolus? How can it be identified?
it is an embolus formed by an atherosclerotic plaque that dislodges and it can be identified by the presence of cholesterol clefts
130
Fat emboli are most commonly associated with what?
a bone fracture
131
How does a fat emboli generally present?
- seen after a bone fracture
| - presents with dyspnea and petechiae on the skin overlying the chest
132
What are the most common causes of gas emboli?
- nitrogen gas can precipitate out of the blood during rapid ascent of a diver, causing MSK pain (bends) and respiratory symptoms (chokes)
- the chronic form (Caisson disease) is characterized by multifocal ischemic necrosis of the bone
- gas emboli may also occur during laparoscopic surgery (during which air is pumped into the abdomen
133
Emboli
- thromboembolism is most common
- atherosclerotic emboli can be identified by the presence of cholesterol clefts
- fat emboli are associated with bone fractures and often present with dyspnea and petechiae on the skin overlying the chest
- gas emboli are most commonly nitrogen precipitating in the blood during rapid ascension of a diver, which cause bends (MSK pain) and chokes (respiratory symptoms), but can also be chronic (Caisson disease with multifocal ischemic necrosis of bone) or follow laparoscopic surgery
- amniotic fluid emboli can occur during labor or delivery and present with SOA, neurologic symptoms, and DIC (tissue thromboplastin in the fluid); the emboli are characterized by squamous cells and keratinous debris
134
Describe amniotic fluid emboli and the way in which they present.
- seen during labor and delivery
- characterized by squamous cells and keratinous debris
- present with SOA, neuro symptoms, and DIC due to the coagulant nature of tissue thromboplastin in the fluid
135
Why is amniotic fluid a procoagulant? How does this often manifest?
- it contains tissue thromboplastin (FX)
| - induces DIC during labor and delivery
136
Pulmonary Embolism
- an emboli in the pulmonary arterial system
- usually asymptomatic due to the dual blood supply of the lung and the fact the emboli are usually small
- may cause pulmonary infarction if they obstruct larger arteries, particularly in the setting of a pre-existing cardiopulmonary compromise
- if symptomatic, they present with SOA, hemoptysis, pleuritic chest pain, and V/Q mismatch
- sudden death may occur with a large, saddle embolus and pulmonary hypertension may arise with chronic emboli
- diagnose with D-dimer and spiral CT
137
What are the common symptoms of anemia?
- weakness, fatigue
- dyspnea
- pale conjunctiva and skin
- headache, lightheadedness
- angina
138
What are the lab value definitions of anemia?
a reduction in circulating RBC mass, Hb<13.5 in men and Hb<12.5 in women
139
Iron Deficiency Anemia
- the most common type of anemia
- an iron deficiency reduces hemoglobin production contributing to a microcytic anemia
- most common in breast-feeding infants (human milk is low in iron), children with a dietary deficiency, adults (males with peptic ulcers or females experiencing pregnancy or menorrhagia), elderly (with colon polyps or hookworm), or patients with gastrectomy
- initially, storage iron is depleted, then serum iron is depleted, then there is a normocytic anemia, followed by a microcytic, hypo chromic anemia
- presents with koilonychia, pica, and anemia
- labs: low ferritin, high TIBC, low % saturation, low serum iron, elevated erythrocyte protoporphyrin, increased RDW
- treat with ferrous sulfate
- can be a feature of Plummer-Vinson syndrome
140
What is the most common nutritional deficiency in the world?
iron deficiency
141
Describe the process of iron absorption and mobilization.
- it is absorbed in the duodenum as meat-derived heme forms or vegetable-derived non-heme forms
- enterocytes transport this iron across the cell membrane into blood via ferroportin, which is regulated by hepcidin
- transferrin transports ironic the blood and delivers it to hepatocytes and nurse macrophages in the marrow where it is stored as ferritin
142
Why is iron always bound in the body?
because in the bound form, its ability to form free radicals via the Fenton reaction is impaired
143
What are serum iron, TIBC, % saturation, and serum ferritin?
- serum iron is a measure of total iron in the blood
- TIBC is a measure of transferrin molecules
- %sat is a measure of transferrin molecules bound by iron
- serum ferritin reflects stored iron levels
144
What are the common causes of iron deficiency anemia?
- breast-feeding infants: human milk is low in iron
- children: nutritional deficiency
- adults: men with peptic ulcers and women with menorrhagia or pregnancy
- elderly: those with colon polyps or hookworm
- patients with a gastrectomy: the acid aids in absorption because it maintains Fe2+ state
145
Plummer Vinson syndrome
- iron deficiency anemia with esophageal webbing and atrophic glossitis
- presents with anemia, dysphagia, and beefy-red tongue
146
Anemia of Chronic Disease
- an anemia associated with chronic inflammation with increases IL-6 production, up regulating hepcidin
- this makes sense because the body wants to limit bacterial access to iron
- ultimately, hepcidin sequesters iron in storage sites by inhibiting iron absorption, limiting release from macrophages, and suppressing EPO production
- it begins with a normocytic anemia that progresses to microcytic
- labs: increased ferritin, reduced TIBC, lower serum iron, and lower % saturation
147
How can IDA be differentiated from anemia of chronic disease?
iron labs
- IDA has lowered ferritin and elevated TIBC
- ACD has elevated ferritin and lowered TIBC (which makes sense because it's trying to sequester iron in storage sites where bacteria can't get to it)
148
Sideroblastic Anemia
- a microcytic anemia due to defective protoporphyrin synthesis
- most commonly caused by an X-linked deficiency of ALA synthase, which converts succinyl-CoA and glycine to ALA
- other causes include lead poisoning, which inhibits ALAD and ferrochelatase; and VitB6 deficiency, secondary to isoniazid treatment, which is a required ALAS cofactor
- iron-laden mitochondria form a ring around the nucleus, which are then called ringed-sideroblasts
- ferritin is high, TIBC is low, serum iron is high, and % saturation is high (all opposite IDA, consistent with iron overload)
149
a-Thalassemia
- deletion of one or more alpha genes on chromosome 16
- 1: asymptomatic, 2: mild anemia with increased RBC count
- importantly, 2 deletions can be cis or trans with the cis form more common in Asians and the trans form being more common in Africans
- 3: HbH (B4) disease with severe anemia
- 4: HbBarts (y4) and hydrops fetalis
150
B-Thalassemia Minor
- a mutation of one of the beta genes on chromosome 11
- most common in Mediterraneans and Africans
- B-thalassemia minor is largely asymptomatic but may present as a microcytic anemia with target cells and slightly elevated HbA2 and HbF
151
B-Thalassemia Major
- a mutation of two of the beta genes on chromosome 11 results in unpaired alpha chains precipitating and damaging RBC membranes contributing to ineffective hematopoiesis and extravascular hemolysis
- massive erythropoiesis ensues leading hepatosplenomegaly as well as the crewcut sign and chipmunk facies (bone expansion)
- HbF is protective at birth
- most common in Mediterraneans and Africans
- high risk of aplastic crisis with B19 infection
- chronic transfusions are necessary and contribute to secondary hemochromatosis
- target cells and nucleated red cells appear on a smear
- elevated HbA2 and HbF
152
Folate Deficiency Anemia
- a megaloblastic, macrocytic anemia characterized by impaired synthesis of DNA precursors
- caused by poor diet, increased demand, or use of folate antagonists such as methotrexate
- body stores are minimal so deficiency can occur quickly
- presents with a macrocytic anemia, hyper-segmented neutrophils, glossitis, increased homocysteine, and normal methylmalonic acid
153
Describe sources of folate, how it is absorbed, and the extent to which it is stored.
- found in green vegetables and some fruits
- absorbed in the jejunum
- body stores are minimal
154
How can folate deficiency anemia be differentiated from B12 deficiency anemia?
- B12 is accompanied by neurologic symptoms
| - B12 is characterized by elevated methylmalonic acid while levels are normal in those with a folate deficiency
155
B12 Deficiency Anemia
- a megaloblastic, macrocytic anemia
- takes a long time to develop because hepatic stores are large
- most often due to pernicious anemia, pancreatic insufficiency, damage to the terminal ileum (Crohn disease or Diphyllobothrium datum), or veganism
- presents with hyper-segmented neutrophils, glossitis, and demyelination of the spinal cord contributing to poor proprioception, impaired vibratory sensation, and spastic paresis
- labs reveal elevated homocysteine and methylmalonic acid
156
Describe how B12 is absorbed.
- salivary gland enzymes liberate it
- it is then bound by R-binder and carried through the stomach
- pancreatic proteases in the duodenum detach it from R-binder
- it is then bound by intrinsic factor from gastric parietal cells and the complex is absorbed in the ileum
157
Pernicious Anemia
a specific from of B12 deficiency anemia in which autoantibodies form against gastric parietal cells, impairing intrinsic factor production and therefore B12 absorption
158
Through what mechanism does B12 deficiency anemia present with neurologic symptoms?
- B12 is a necessary cofactor for the conversion of methylmalonic acid to succinyl-CoA in fatty acid metabolism
- increased methylmalonic acid impairs spinal cord myelinization
- this is particularly evident in the dorsal column and lateral corticospinal tracts
159
A properly functioning marrow responds to anemia by increasing the reticulocyte to what level?
more than 3% corrected RC
160
What is the corrected reticulocyte count? Why is it needed?
- needed because any anemia falsely elevates the RC given that there is a decrease in total RBCs and the RC is a percentage of RBCs
- corrected by taking RC x Hct/45
161
What features are common to all extravascular hemolytic anemias?
- anemia with splenomegaly given the rapid clearance of RBCs
| - elevated unconjugated bilirubin contributes to jaundice and gall stones
162
What features are common to all intravascular hemolytic anemias?
- elevated serum LDH and decreased serum haptoglobin
- hemoglobinuria and hemaglobinemia
- hemosiderinuria due to absorption of hemoglobin by tubular cells which accumulates as hemosiderin until those tubular cells are shed
- iron deficiency anemia secondary to hemoglobinuria
163
What is haptoglobin?
a serum protein that is responsible for scavenging free hemoglobin
164
Hereditary Spherocytosis
- a defect in one of the cytoskeleton-membrane tethering proteins (ankyrin, spectrin, band 3, or protein 4.2), which leads to blebs of membrane being lost over time, rending cells round
- those spherocytes are unable to navigate splenic sinusoids and are cleared, resulting in anemia
- RDW and MCHC are elevated since cells get smaller with each bleb that is lost but don't lose hemoglobin
- presents like other extravascular hemolytic anemias (splenomegaly, gallstones, jaundice) and an increased risk for aplastic crisis
- diagnosed via an osmotic fragility test in which cells are placed in a hypotonic solution
- treat with splenectomy
165
Describe the pathogenesis and basics of sickle cell disease.
- an autosomal recessive Glu to Val mutation in the beta chain, which creates a hydrophobic pocket for polymerization
- HbS polymerizes when deoxygenated, particularly with hypoxemia, dehydration, acidosis, or increased transit time
- HbF and HbA are protective while HbC allows polymerization
- sickling causes membrane damage leading to predominately extravascular hemolysis but some intravascular
- followed by massive erythroid hyperplasia (hepatosplenomegaly, crew cut sign, and chipmunk facies)
- dactylics is a common presenting sing in infants
- high risk of aplastic crisis
- extensive sickling will lead to complications of vast-occlusion: autosplenectomy and infection is the leading cause of death in children while acute chest syndrome precipitated by pneumonia is the most common cause of death in adults
- screen with metabisulfite test and diagnose via electrophoresis
166
Describe the symptoms of sickle cell disease.
- extravascular hemolysis: jaundice, gall stones, anemia, splenomegaly
- intravascular hemolysis: target cells, decreased haptoglobin
- increased erythropoiesis: hepatosplenomegaly and crew cut sign
- vast-occlusion: dacylitis, autosplenectomy (infection with encapsulated organisms, risk of Salmonella paratyphi osteomyelitis, Howell-Jolly bodies), acute chest syndrome (precipitated by pneumonia which slows transit time via vasodilation and presents with SOA, chest pain, lung infiltrates), MSK pain crisis, renal papillary necrosis resulting in hematuria and proteinuria
167
Sickle Cell Trait
- the presence of one mutated and one normal B chain
- results in more than 50% HbA, so sickling doesn't occur except in the renal medulla which is extremely hypoxic and hypertonic
- renal medulla sickling caused micro infarcts leading to hematuria and, classically, the inability to concentrate urine
168
What is metabisulfite screening?
a test that causes cells with any amount of HbS to sickle (positive in SC disease and trait)
169
Hemoglobin C
- an autosomal recessive mutation of the B chain in which Glu is replaced by Lys
- presents with a mild extravascular hemolysis
- characteristic HbC crystals are seen in RBCs on a blood smear
170
Paroxysmal Nocturnal Hemoglobinuria
- an intravascular hemolysis that results from an acquired GPI deficiency or mutation in the PIGA gene
- GPI serves as an anchor CD55 and CD59, which are decay accelerating factor and MAC inhibitor, respectively
- in the absence of these proteins, cells are vulnerable to complement-mediated lysis, especially at night when breathing becomes shallow and their is a mild acidosis
- presents with hematuria, pancytopenia, and thrombosis as destroyed platelets activate functional ones
- complications include iron deficiency anemia and AML
- screen for using a sucrose test, which activates complement, and diagnose using an acidified serum test or flow cytometry
- treat with eculizumab
171
Why might a thrombocytopenia present with thrombosis?
- because as cells are lysed, their platelet activating factors are released into circulation, activating the remaining platelets
- this is a feature of heparin-induced thrombocytopenia and paroxysmal nocturnal hemoglobinuria
172
G6PDH Deficiency
- an X-linked recessive defect that limits production of NADPH and thus glutathione, which is needed for neutralization of reactive oxygen species
- this leaves cells susceptible to oxidative stress and intravascular hemolysis; usually induced by infection, primaquine, sulfa drugs, dapsone, or fava beans
- presents with hemoglobinuria and back pain hours after exposure; Heinz bodies and bite cells can be seen on a blood smear
- the African variant has a more mildly reduced half-life of G6PDH than the Mediterranean variant
- enzyme studies are performed weeks after a hemolytic episode because during the episode, G6PDH-deficient cells are all lysed
173
Warm Immune Hemolytic Anemia
- an IgG mediated extravascular hemolysis
- IgG binds RBCs in the central body at warm temperatures and membrane-Ig complexes are consumed by splenic macrophages, leaving spherocytes
- the most common cause is SLE but CLL, penicillin, and cephalosporins are classic associations
- treated with steroids, IVIG, or splenectomy
174
What is Cold Immune Hemolytic Anemia?
- IgM binds RBCs and fixes complement in the relatively cold temperature of the extremities
- RBCs usually inactivate this complement but residual C3b serves as an opsonin for splenic macrophages, rendering spherocytes
- if complement activation is extreme it can lead to intravascular hemolysis
- strongly associated with Mycoplasma pneumoniae and infectious mono
175
Microangiopathic Hemolytic Anemia
- a collection intravascular hemolytic anemias
- includes TTP, HUS, HELLP, and DIC, which all form microthrombi, as well as prosthetic heart valves and aortic stenosis
- schistocytes are a characteristic feature as is iron deficiency anemia secondary to hemoglobinuria
176
Aplastic crisis is often triggered by what infection in those with sickle cell anemia, B-thalassemia, or hereditary spherocytosis?
Parvovirus B19
177
Aplastic Anemia
- a pancytopenia in which biopsy reveals an empty, fatty marrow and in which EPO is appropriately elevated
- treat with transfusions and marrow stimulating factors
178
What is a myelophthisic process?
- any pathologic process that replaces bone marrow and therefore results in a pancytopenia
- presents with tear drop-shaped RBCs, leukoerythroblastosis, and a left shift
179
What constitutes a normal white cell count?
5-10 K/ul
180
List two non-neoplastic causes of neutropenia.
- drug toxicity, particularly alkylating agents
| - severe infection, increased extravasation reduces neutrophil count
181
List four non-neoplastic causes of lymphopenia.
- immunodeficiency (DiGeorge syndrome or HIV)
- high cortisol state (induces apoptosis)
- autoimmune destruction
- whole body radiation
182
The first sign of whole body radiation is what?
lymphopenia
183
In a left shift, how can you identify immature neutrophils in circulation?
reduced expression of Fc receptors (CD16)
184
What are the three most significant causes of eosinophilia?
- allergic reactions
- parasitic infections
- Hodgkin lymphoma
185
Basophilia is a classic sign of what disease?
CML
186
What may cause a lymphocytic leukocytosis?
- viral infection induces T cell hyperplasia
- Bordetella pertussis induces a B cell proliferation because the bacteria produce lymphocytosis-promoting factor, which blocks circulating lymphocytes from extravasating
187
Infectious Mono
- a lymphocytic leukocytosis comprised of CD8 T cells
- most commonly due to EBV with CMV infection less common
- primarily infects the oropharynx, liver, and B cells causing pharyngitis and hepatitis
- CD8 response leads to generalized lymphadenopathy due to hyperplasia in the paracortex and splenomegaly due to hyperplasia in the periarterial lymphatic sheath
- increased risk of splenic rupture, ampicillin rash, and B-cell lymphoma
- screen using the mono spot test, which detects IgM antibodies that cross-react with horse or sheep RBCs (called heterophiles antibodies) one week after infection
- a negative monospot test suggests CMV rather than EBV
- definitively diagnosed based on serologic testing for the EBV viral capsid
188
If a patient presents with a classic case of mono but the mono spot test is negative, it suggests what?
- either the test was run too early in the infection
| - or the infectious agent is CMV rather than EBV
189
Why do we recommend patients with infectious mono not play contact sports?
because the CD8 response leads to splenomegaly, which increases the risk of splenic rupture
190
What are acute leukemias?
- those characterized by the accumulation of >20% blasts in the bone marrow, which crowds out normal hematopoiesis
- causes thrombocytopenia, anemia and neutropenia but a high white count as blasts enter circulation
191
Acute Lymphoblastic Leukemia
- an acute leukemia of lymphoid blasts, positive for TdT
- more common in children and often associated with Down syndrome, presenting after the age of 5
- more commonly a B-cell than T-cell type
- responds well to chemotherapy but requires prophylaxis to the scrotum and CSF since chemo doesn't cross into these tissues well
- t(12;21) has a good prognosis while Ph+ has a bad prognosis
192
Acute Myeloid Leukemia
- an acute leukemia of myeloid blasts
- often see Auer rods, crystal aggregates of MPO
- more common in older adults
- may arise from pre-existing dysplasia or secondary to alkylating agents or radiotherapy
- Acute promyelocytic leukemia is the most important subtype but there is also acute monocytes leukemia (a proliferation of monoblasts, typically lacking MPO and characteristically infiltrating the gums) and acute megakaryoblastic leukemia (also lacking MPO and associated with Down syndrome, presenting before age 5).
193
What two associations are there between Down syndrome and acute leukemia.
- ALL is associated with Down's syndrome but presents after the age of 5
- AML (megakaryoblastic subtype) is associated as well but presents before the age of 5
194
Acute Promyelocytic Leukemia
- a subtype of AML characterized by a t(15;17) translocation which disrupts the retinoic acid receptor (RAR)
- a risk for DIC given the presence of Auer rods
- treat with ATRA which causes the blasts to mature and die off
195
Chronic Lymphocytic Leukemia (CLL/SLL)
- a neoplastic proliferation of naive B cells that are CD5, CD20 positive
- the most common leukemia overall
- smudge cells are seen on blood smear
- involvement of lymph nodes leads to LAD and is called SLL
- complications stem from proliferating, dysfunctional B cells which produce little or self-reactive immunoglobulin: hypogammaglobulinemia (infections) and autoimmune hemolytic anemia
- a Richter Transformation is a transformation to diffuse large B cell lymphoma
196
Hairy Cell Leukemia
- a proliferation of mature B cells
- those cells are positive for tartrate-resistant acid phosphatase (TRAP)
- accumulation of hairy cells, specifically in red pulp, causes splenomegaly, there is a "dry tap" of bone marrow, and LAD is usually absent
- responds very well to 2-CDA, an adenosine deaminase inhibitor that causes accumulation of adenosine to levels toxic for neoplastic B cells
197
Adult T-Cell Leukemia/Lymphoma
- a neoplastic proliferation of mature CD4 T cells
- associated with HTLV-1 and most commonly seen in Japan and the Caribbean
- often presents with LAD, hepatosplenomegaly, and lytic bone lesions with hypercalcemia
- can be differentiated from multiple myeloma based on the presence of a skin rash
198
If you see someone with lytic "punched out" bone lesions and hypercalcemia, what are two things that should be on your differential?
- multiple myeloma
| - HTLV-1 and adult T-cell leukemia/lymphoma
199
Mycosis Fungoides
- a neoplastic proliferation of mature CD4 T cells with a tropism for the skin
- produces a rash and Pautrier micro abscesses
- spread to involve the blood, producing Sezary syndrome, which is often identified by circulating lymphocytes that have cerebriform nuclei
200
Myelsodysplastic syndrome
- a cytopenia with hypercellular marrow, abnormal maturation of cells, and increased blasts <20%
- often die from infection or bleeding or progress to an acute leukemia
201
All myeloproliferative disorders share an increased risk for what complications? What is the exception?
- hyperuricemia and grout (due to high turnover of cells)
- progression to myelofibrosis
- progression to acute leukemia
- essential thrombocythemia is the exception and isn't at increased risk for any of the above
202
Chronic Myeloid Leukemia
- a proliferation of mature myeloid cells, particularly granulocytes, due to a defect in the pluripotent stem cell
- a disease of late adulthood
- due to a t(9;22) mutation creating a BCR-ABL fusion protein with excess tyrosine kinase activity
- classically presents with basophilia
- splenomegaly suggests a progression to the accelerate phase or blast crisis (AML or ALL)
- treat with imatinib (aka Gleevec), which binds and blocks the ATP-binding domain of the fusion protein
- must distinguish it from a leukemoid reaction based on negative leukocyte alkaline phosphatase (LAP), the absence of Dohle bodies and toxic granulation, increased basophils, and the mutation
203
How can CML be differentiated from a leukemioid reaction?
- granulocytes in a leukemoid reaction tend to have Dohle bodies and toxic granulation
- granulocytes in a leukemoid reaction have higher leukocyte alkaline phosphatase levels
- a leukemoid reaction tends not to have basophilia
- only CML is marked by t(9;22)
204
Polycythemia Vera
- a proliferation of mature myeloid cells, particularly erythrocytes but also granulocytes and platelets
- associated with a JAK2 mutation in the pseudokinase domain, which reduces auto-inhibition
- clinical symptoms related to hyperviscosity of the blood and include dizziness, blurry vision, headache, venous thrombosis, flushed face due to congestion, and itching, especially after bathing (due to histamine release from excess mast cells)
- classically, thrombosis of the hepatic vein leads to Budd-Chiari syndrome and liver necrosis
- must distinguish it from a reactive polycythemia based on EPO levels and SaO2 levels which are decreased and normal, respecitvely
205
How can you distinguish polycythemia vera from a reactive polycythemia vera due to RCC?
a RCC will serve as a site for ectopic EPO production, which stimulates the erythrocytic proliferation; as such, EPO is high and SaO2 is normal
206
Essential Thrombocythemia
- a proliferation of mature myeloid cells, particularly platelets
- associated with JAK2, MPL, and calreticulin mutations
- symptoms are derived from the increased risk of bleeding and/or thrombosis (too many platelets or too immature to function properly)
- in contrast to the other myeloproliferative disorders, ET rarely progresses to myelofibrosis or acute leukemia and there is no significant hyperuricemia or gout because there is no nuclear turnover associated with platelet turnover
207
Why do myeloproliferative disorders increase an individuals risk for gout?
the accelerated turnover of cells leads to turnover of nuclear material and hyperuricemia
208
Primary Myelofibrosis
- a proliferation of mature myeloid cells, particularly megakaryocytic
- associated with a JAK2, MPL, or calreticulin mutation
- as megakaryocytes proliferate they release excess platelet-derived growth factor, causing marrow fibrosis
- presents with splenomegaly, leukerythroblastosis with a left shift, and increased risk of infection, thrombosis, and bleeding
209
Mastocytosis
- a proliferation of mature myeloid cells, particularly mast cells
- associated with a c-KIT mutation
- presents with urticaria pigmentosa
- stains positive for CD117 and tryptase
210
How does the etiology of painless LAD compare to that of painful LAD?
- painless is usually a sign of chronic inflammation or neoplasia
- painful is usually a sign of acute infection
211
What is most likely to cause follicular hyperplasia, paracortex hyperplasia, and hyperplasia of sinus histiocytes in a lymph node?
- follicular is most often seen with RA and in the early stages of HIV infection because follicular dendritic cells are HIV-susceptible
- paracortex follows viral infection
- sinus hyperplasia is seen in lymph nodes that are draining a tissue with cancer
212
Follicular Lymphoma
- a neoplastic proliferation of small B cells that forms follicle-like nodules
- drive by t(14;18), which results in over expression of Bcl-2, which prevents apoptosis
- treat with rituximab
- may progress to diffuse large B-cell lymphoma
- can be distinguished from follicular hyperplasia by the lack of tingible body macrophages, Bcl2 over expression, monoclonality, and disruption of the normal lymph node architecture
213
How can follicular lymphoma be distinguished from follicular hyperplasia?
- lack of tingible body macrophages
- Bcl2 over-expression
- monoclonality
- disruption of the normal lymph node architecture with follicles found in the paracortex and medulla
214
Mantle Cell Lymphoma
- a proliferation of small B cells that expands the mantle zone directly outside the follicle
- presents in late adulthood with painless LAD
- drive by t(11;14) with over expression of cyclinD1, which drives the cells through the G1/S transition
215
Marginal Zone Lymphoma
- a proliferation of small B cells that expands the marginal zone
- associated with chronic inflammatory states (Hashimoto thyroiditis, Sjogren syndrome, H. pylori)
- MALTomas are marginal zone lymphomas of mucosal sites and may regress with treatment of H. pylori
216
Burkitt Lymphoma
- a neoplastic proliferation of intermediate-sized B cells
- the fastest growing human tumor and therefore it may cause tumor lysis syndrome
- the sporadic form is strongly associated with EBV and classically presents with a mandibular mass
- the African form classically presents with an abdominal mass
- the HIV-related form presents with a nodal mass
- all are drive by t(8;14), which over expresses c-Myc, an oncogene
- characterized on histology by high mitotic index and a "starry-sky" appearance made by tingible macrophages
217
Diffuse Large B-Cell Lympoma
- a proliferation of large B cells which grow diffusely in sheets
- the most common form of NHL and clinically aggressive
- arises sporadically and from transformations of low-grade lymphomas
218
Describe the significant features of the subtypes of Hodgkin Lymphoma.
- the most common subtype is nodular sclerosis which classically presents with an enlarging cervical or mediastinal lymph node in a young adult and histology of that node reveals bands of sclerosis
- the lymphocyte-rich subtype has the best prognosis
- the mixed cellularity subtype is often associated with abundant eosinophils (recruited by IL-5)
- lymphocyte-depleted is the most aggressive of all types
219
Multiple Myeloma
- a plasma cell proliferation
- the most common primary malignancy of bone
- may be driven by high serum IL-6, which stimulates plasma cell growth and immunoglobulin production
- malignant cells produce osteoclast-activating factor causing hypercalcemia and the characteristic bone lesions
- presents with CRAB criteria: hyperCalcemia, Renal failure, Anemia, and Bone lesions
- can detect an M spike of IgG or IgA on serum protein electrophoresis as well as rouleaux formation
- increased risk of infection and free light chains may deposit in tissues, causing primary AL amyloidosis
- renal failure is due to filtration of free light chain, known as Bence Jones protein, which causes tubular necrosis
220
The most common primary malignancy of bone is what? What is the most common malignancy of bone?
- multiple myeloma is the most common primary malignancy
| - metastatic cancer is the most common overall
221
How do Reed-Sternberg cells recruit eosinophils in the mixed cellularity subtype?
via IL-5
222
Monoclonal Gammopathy of Undetermined Significance
- increased serum protein with an M spike on serum protein electrophoresis, without the other clinical features of multiple myeloma
- carries a 1% annual risk of transformation to multiple myeloma
223
Waldenstrom Macroglobulinemia
- a B-cell lymphoma with monoclonal IgM production
- presents with LAD and an M spike
- other symptoms arise from the hyperviscosity that arises: retinal hemorrhage and stroke as well as the possibility of bleeding since viscous serum impairs platelet aggregation
224
Langerhans Cell Histiocytosis
- a proliferation of langerhans cells, specialized dendritic cells found predominately in the skin
- Birbeck granules and CD1a+ S-100+ cells are classic findings
- Letterer-Siwe disease is a malignant proliferation that presents with skin rash and cystic skeletal defects (more diffuse disease, common in those < 2 y.o.)
- Hand-Schuller-Christian disease is a malignant proliferation that affects bone and endocrine systems of those 2-5
- Eosinophilic Granuloma is a benign variant with bone and lung nodules, most common in those over the age of five
