Factoids for DHM block Flashcards
(136 cards)
1
Q
FLT3 and c-kit
A
stem cell receptor trosine kinases frequently mutated in AML
2
Q
Notch
A
stem cell non-kinase recetor frequently mutated in T cell ALL
3
Q
Pathways to treat and inhibit acute leukemia
A
- FLT3 and c-kit
- Notch
4
Q
EPO
A
- Produced by renal intersitital cells in response to hypoxia
- EPO promoter activated by hypoxia inducible factor (HIF) - HIF degradation requires Von Hippel-Lindau protein, delete in RCC
5
Q
Found in almost all cases of polycythemia vera?
A
Mutation in cytoplasmic tyrosine kinase, JAK-2 which transduces the EPO signal
6
Q
What prevetns overexpression of EPO in the kidney?
A
Von Hippel Lindau protein
7
Q
Marker for blasts and stem cells?
A
- CD34+
- Only small fraction <1% of these are pluripotent stem cells
8
Q
Most specific marker for myeloid?
A
Myeloperoxidase - most abundant in promyelocyts, primary granules
9
Q
Secondary granules for:
Neutrophils
Eosinophils
Basophils
A
NADPH oxidase
aryl sulfatase
Histamine, heparin
10
Q
Express nonspecific esterase
A
Monocytes
11
Q
Express glycophorin
A
Erythrocytes
12
Q
What is measured by teh spectrophotometer?
A
Hemoblobin concentration
13
Q
What is measured by the flow cytometer?
A
Cell volume and number
14
Q
Spherocytosis are also seen in which diseases?
A
- Immune hemolytic anemia
- Clostridia infection
- Spherocytes seen in combination with other poikilocytes in the following:
- Microangiopathic hemolytic anemia
- Oxidant hemolysis
- Post-transfusion
15
Q
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
A
Extravascular and intravascular hemolysis
X-linked inheritance
Common in African and Mediterranean populations
G6PD A- = principal deficient variant found in African ancestry
G6PD “Mediterranean” = most common deficient variant in Caucasians
16
Q
What two metabolites are decreased in RBCs with G6PD deficiency?
A
- NADPH
- Reduced glutathione (GSH)
Lack of reduced glutathione (GSH) causes globin sulfhydryl group oxidation and hemoglobin precipitation
17
Q
What is the hallmark peripheral blood finding in G6PD deficiency?
A
Bite cells and spherocytes
18
Q
Heinz body test for G6PD
A
Incubate blood w/ and w/o (control) an oxidant.
Denatured Hb precipitates
Stain with methyl violet or crystal violet
19
Q
Sickle Cell Disease
A
Genetics
Glu to Val mutation at amino acid 6 of β chain (β6Val)
Sickle cell disease – Homozygous (HbSS)
S-Trait –Heterozygous (HbAS)
Clinically benign (No anemia)
Normal peripheral blood smear
8% of African-Americans
Protective from malaria infection
20
Q
RBC survival in SCA
A
Chronic hemolysis (RBC survival ~20 days)
Patients are susceptible to aplastic crises
Chronic hyperbilirubinemia, gallstones
21
Q
What additional findings would you expect on the blood smear of an adult with HbSS due to loss of splenic function?
A
Inclusions
Howell-Jolly bodies
Pappenheimer bodies
Target cells
22
Q
What kind of agent will you use to cause sickling of RBCs in vitro as a test for sickling (“solubility test”)?
A
Sickling Test and Solubility Test
Add metabisulfite to diluted blood
Blood becomes turbid in the test tube, you can’t read written text on paper behind it.
Positive in all sickling hemoglobins : SS, sickle cell trait (SA), etc.
23
Q
Thalassemia syndromes
A
Decreased production of structurally normal globin chains (in contrast to hemoglobinopathies)
Severity of manifestations is related to degree of α and β globin chain imbalance (excess of unaffected chain)
Microcytic, hypochromic anemia
Hemolytic anemia leads to marrow erythroid hyperplasia and expansion
24
Q
If -thalassemia is caused by point mutations, why is the hemoglobin protein molecule structurally normal?
A
Because the point mutations are not missense mutations.
25
β Thalassemia Minor (trait)
Heterozygous (β0/β or β+/β)
RBCs are small with mild or no anemia.
RBC count is increased to compensate for small RBC size
Blood smear shows microcytosis, mild (usually not much) hypochromia
Microcytosis is also seen in iron deficiency anemia, but in that case there is significant anemia
26
How do you know it’s not iron deficiency anemia causing the microcytosis?
There is not much anemia, but there is marked microcytosis
Patient has had microcytosis from infancy (beta) or birth (alpha)
RDW is not very increased
Normal iron parameters if you need to check
27
No HbA (HbF 98%, HbA2 2%).
Homozygous βo (Cooley’s anemia)
28
About 97% HbA(22), 2%HbA2(22),1%HbF(22)
Normal
29
HbA present (HbF: 60-95%, HbA2 may be increased)
Homozygous β+ or βo/β+ (thalassemia intermedia)
30
HbA2: 3.5-7% (normal: 1.6-3.5%)
β-Thal minor (trait)
31
α Thalassemia
Caused almost always by -globin gene deletions
The genome has 2 α genes each chromosome 16 for a total of 4 α genes in a diploid cell
32
HbH disease
* -/- -/α
* α Thalassemia one α gene present
* Moderate severity; resembles β-thalassemia intermedia
* Golf ball cells form precipitated HbH (Beta4)
33
Thalassemia trait
* -/- α/α (Asian)
* -/α -/α (African)
Asymptomatic, like β-thalassemia minor
Low MCV
α Thalassemia 2 α genes
34
Silent carrier for alpha thalassemia
α Thalassemia 3 alpha genes
-/α α/α
Asymptomatic; no red cell abnormality
Normal MCV
35
$$$ What causes alpha thalassemia? What causes beta thalassemias?
alpha-thalassemia **gene deletions**
Beta-thalassemia **point mutations**
36
Paroxysmal nocturnal hemoglobinuria
Only example of an acquired hemolytic anemia that is intrinsic to red cells
Due to somatic mutation of gene (PIG-A) essential for glycosyl-phosphatidylinositol (GPI) anchor
37
Important GPI anchored proteins:
Membrane inhibitor of reactive lysis (CD59) MAC
Decay-accelerating factor (CD55) Alternative and classical
38
Clinical findings in PNH
Anemia
Periodic acute intravascular hemolysis (classic situation)
Hemoglobinuria
classically in the morning
Secondary iron deficiency anemia from hemoglobinuria is common
Associated with stress, infections, etc.
Classic presentations are the exception
May also have neutropenia, thrombocytopenia
Thrombotic complications (including Budd-Chiari syndrome)
39
Diagnosis for PNH?
Diagnosis
Flow cytometry to analyze for presence or lack of **GPI linked proteins on cells (CD59 and CD55)**
40
Treatment for PNH
Eculizumab. Humanized monoclonal antibody to complement factor 5
41
Drug reaction with eosinophilia and systemic symptoms (DRESS) is:
A reaction that typically occurs 2 to 6 weeks after the drug is first used
42
A fixed drug eruption
Is commonly found in the genitalia
43
Steven Johnson syndrome
Can cause neutropenia, which can be masked by treatment with steroids
44
The differential diagnosis of SJ syndrome and TEN include all of the following except
Include: Acute generalized exanthematous pustulosis, Ritter disease, Pemphigus
NOT: pityriasis rosea
45
The following are associated with SJS and TEN except:
Associated with: Treatment with IV immunoglobulin, Release of perforin and granzyme B from cytotoxic T lymphocytes, Fas ligan activation on keratinocyte membranes
NOT ASSOCIATED with HLA-B27
46
Whole Blood Donation
* Contains the red blood cells, white blood cells and plasma constituents of circulating blood
* Collection bag contains an anticoagulant preservation solution
* Usual blood donation
* Collected primarily for separation into components: RBCs, platelets, plasma
* 450 to 500 mL, minimum Hct 38%
47
“Packed” RBCs
**_•Usual component for RBC therapy_**
•Prepared by centrifugation of the WB donation which removes most of the plasma
•Stored at 4ºC, storage life is 35 days (may be frozen)
•Dosage: Each unit Hb level by 1 g/dL (or Hct by 3%)
**_•Compatibility testing is needed!_**
48
Types of RBC Compatibility testing needed
* ABO/Rh type, antibody screen and crossmatch is needed before transfusion
* The patient‟s ABO group must be compatible with ABO antibodies in the recipient‟s plasma.
49
How can platelets be produced for donation?
Can be produced from a whole blood donation (“random donor” platelets) or collected by **_apheresis_** (“single donor” platelets).
50
What is apheresis?
A process by which whole blood is removed from the donor by a closed-system instrument which houses a centrifuge that separates the blood components, selectively removes the desired component, and then recombines the remaining components for return to the donor.
51
Do Platelet recepientsneed compatibility testing?
* Platelets stored at 22°C to 24°C, storage life: 5 days
* Dosage: Single donor platelets should contain at least 3 x 1011 platelets and are expected to increase the platelet count 30,000 to 60,000/μL
* No compatibility testing needed, prefer ABO-compatible with the recipient‟s RBCs
52
FFP
* Preparation: After removal of the RBC fraction of the whole blood donation, the platelet-rich plasma then subjected to a “hard” centrifugation to remove the platelets and most WBCs to form “platelet-poor” plasma.
* Product is frozen and stored at -18°C.
* Storage: 5 years
* When thawed, stored at 1° to 6°C and storage life of 24 hours
53
What is the required compatibility needed when giving FFP?
Compatibility testing not needed BUT _plasma must be ABO-compatible_ with the recipient‟s RBCs
54
What is CRYO?
* The **cold-precipitated concentration of Factor VIII** (the „antihemophilic factor‟--AHF)
* Just prior to transfusion, CRYO is quick-thawed at 37°C and is pooled with other units
* Storage life: 12 months (in frozen state), 6 hours after thawing/4 hours after pooling
Contains most of the factor VIII and some of the fibrinogen from the original plasma
–Also, factor XIII, von Willebrand factor and fibronectin
•Contains at least 80 U of factor VIII
•Compatibility testing not needed but prefer ABO-compatible with the recipient‟s RBCs
55
What happens if there is an ABO mismatch?
**•IgM** (Activate complement)
•React at room temperature or colder
•Produce strong direct agglutination in vitro
**_•Cause rapid intravascular hemolysis if the wrong ABO group is transfused._**
•Serum grouping as part of blood group typing testing is unique to the ABO group.
56
What is the most potent antigen outside the ABO system?
Second most important blood group system.
•“Rh” refers not only to a specific RBC antigen (the **D antigen) but also to a complex blood group system** that (currently) includes nearly 50 different antigenic specificities.
•Rh antigens are highly immunogenic.
**–D antigen is the most potent antigen outside the ABO system.**
•Determination of D status is required for donor testing and compatibility.
–Rh Positive if test for D antigen is positive
•IgG
•react at 37ºC
•Produced following exposure to foreign RBCs from transfusion or during pregnancy
57
What are the steps in Pretransfusion Compatibility Testing
* Appropriate Identification and Collection of Recipient Specimen
* ABO and Rh Testing
* Historical Record Check
* Screening for Unexpected Antibodies
* Crossmatch
58
Most common error?
The major cause of transfusion-associated fatalities is **_clerical error_** resulting in incorrect ABO determination.
–The most common cause of error is **_misidentification of the intended recipient._**
59
What is the crossmatch?
* Donor RBCs mixed with recipient serum and observed for agglutination
* Final check for compatibility
* Final check to detect unexpected antibodies
60
What are transfusion reactions?
•Definition: Any unfavorable transfusion-related event that occurs in a patient during or after transfusion of blood components.
•Classification:
–Immune vs. Non-immune
–Acute (Immediate) vs. Delayed
61
Most common cause of transfusion-associated fatalities?
•Transfusion-associated death rare: 1 in 100,000 RBC units transfused
–Major national patient safety concern
**_•Acute hemolytic transfusion reactions most common cause of transfusion-associated fatalities_**
•Clerical error prime factor in majority of these
62
Rates of non-fatal transfusion reactions?
* *•Acute/Immediate or Delayed Hemolytic Reactions**: 1:6,000 units transfused
* *•Nonhemolytic Febrile Reactions**: 1 to 2 per 100
* *•Allergic Reactions**: 1 to 2 per 100
63
4 most commonly identified RBC antibodies causing IHTRs?
Immediate Hemolytic Transfusion Reaction
•Occurs very soon after transfusion of incompatible RBCs
•Four most commonly identified RBC antibodies causing IHTRs :
**–Anti-A
–Anti-Kell
–Anti-Kidd a
–Anti-Duffy a**
64
How do RBCs die in transusion reactions?
RBC destruction occur primarily by intravascular hemolysis
65
Delayed Hemolytic Transfusion Reaction
* Occurs about 3 to 7 days after transfusion
* An anamnestic response from previous sensitization from previous pregnancy, transfusion or transplant
* Antibody not detected in routine pretransfusion testing
66
How do RBCs die in Delayed Hemolytic Transfusion Reaction
•RBC destruction occurs primarily by **_extravascular hemolysis_**
•Signs and symptoms are milder compared to IHTR and is commonly subclinical
–Usually mild fever or fever with chills and/or mild to moderate jaundice
•Only treat symptomatic anemia; monitor patient to reduce risk of renal failure
67
68
What is Febrile Nonhemolytic Transfusion Reaction
* One of most common transfusion reactions
* Definition: 1°C/2°F rise in temperature associated during or shortly after transfusion and having no other explanation
69
Allergic (Urticarial) Transfusion Reaction
* Appear within minutes of transfusion and represent mild immediate hypersensitivity type immune reactions to plasma proteins
* Over 500 known plasma proteins, thousands not known and many different (and possibly immunogenic!) allotypes or post-translational modifications
* One of the most common transfusion reactions
70
transfusion related acute lung injury (TRALI)
•Cause is not understood
**–Leukocyte antibodies consistently found in donor or patient plasma**
•Proposed mechanisms for lung injury
–Anti-WBC antibodies in donor or patient plasma initiates complement-mediated direct pulmonary capillary injury
–Anti-WBC antibodies react with patient WBCs to trigger production of C3a and C5a
Either mechanism has a final common pathway of stimulating tissue mast cells and platelets to release histamine and serotonin resulting in leukocyte emboli in pulmonary capillary beds, inducing the **ARDS clinical picture**
71
Signs and symptoms of TRALI?
transfusion related acute lung injury
•Signs and symptoms
–Chills, cough, fever, cyanosis, hypotension and increasing respiratory distress shortly after transfusion
•Must test both donor and patient serum for anti-WBC antibodies
•Diagnosis by exclusion
•Supportive treatment as for ARDS
72
Transfusion-Transmitted Sepsis
•RBCs: Psychrophilic (cold-growing) organisms
–Yersinia enterocolitica (transient donor bacteremia) or Pseudomonas fluorescens (donor skin contamination)
–Reaction due to endotoxin
73
Most common blood component associated with bacterial contamination
Platelets - Donor skin contaminants: Staph. epidermidis
74
Frequency of post-transfusion HBV
–The single most important transfusion-transmitted infection?
HIV transmitted?
1:137,000 units (2000)
**Most important - Hepatitis C Virus**
–Screening: anti-HCV antibody and nucleic acid testing (NAT) for HCV RNA
–Appearance of anti-HCV has a large mean detection window of 82 days; NAT for HCV RNA in pooled samples has reduced window period to mean of 25 days
Transfusion-transmitted HIV now very rare: about 1 in 1.9 million units
75
What enzymatic reaction uses cobalamin and is not tied to folate metabolism?
Methylmalonyl CoA mutase requires B12 but not folate, converts methylmalonyl CoA to Succinyl CoA
76
What builds up in B12 deficiency?
Methylmalonyl CoA
77
How do the effects of folate and B12 deficiency differ?
Neuropathy in B12 deficiency
Subacute combined degeneration of the spinal cord
Folic acid fails to improve neurologic deficits due to B12 deficiency
However, folate supplements will correct the anemia due to B12 deficiency
78
How do you evaluate B12 and folate measurements?
* Serum folate
* Red cell folate
* Serum B12
79
Chronic Atrophic Gastritis
Almost always immune mediated. (H. pylori gastritis is rarely severe enough)
T cell mediated damage to gastric fundic glands
Atrophy, intestinal metaplasia
Antibodies
* Type I (75% of CAG patients): Block intrinsic factor binding to B12
* Type II: Prevent binding of intrinsic factor/ B12 complex to receptor in ileum
* Type III: Not specific to pernicious anemia
Bind gastric proton pump
Therapy of B12 deficiency
Lifelong B12 injections
80
What is the most common cause of iron deficiency anemia in the U.S?
Impaired absorption
Increased requirement (pregnancy or lactation)
Chronic blood loss
Menorrhagia
GI bleeding (upper or lower)
Ulcer, Crohn’s disease, UC, polyps, diverticulosis, carcinoma
81
In iron deficiency anemia, will the reticulocyte count be low, normal or high? Why?
Low, suggests underproduction due to inability to produce hemoglobin (low iron = low heme = low Hb = microcytic anemia) Can't make RBCs without Hb!!
82
Laboratory tests for iron deficiency
Bone marrow aspirate smear iron (Prussian blue) stain: gold standard
Serum iron
Total iron binding capacity
Serum ferritin
83
Pathogenesis of Anemia of chronic disease?
* Inflammatory cytokines cause decreased erythropoietin production
* Impediment in the transfer of iron from the storage pool to the erythroid precursors -\> increased hepcidin production by liver
- \> Hepcidin decreases stromal/macrophage cell surface membrane ferroportin expression, preventing iron release
84
IDA versus Anemia of Chronic Disease
Both will have a low total serum iron, but in iron deficiency anemia the transferrin saturation is decreased.
RBCs are usually normal (no hypochromia or anisocytosis) in anemia of chronic disease
Usually increased marrow storage iron in anemia of chronic disease
Transferrin receptors increased in IDA
Reticulocyte Hb decreased in IDA
85
How would you distinguish between iron deficiency anemia and thalassemia intermedia in a microcytic hypochromic anemia?
History
Reticulocyte count
Hemoglobin electrophoresis
Basophilic stippling
86
Aplastic Anemia
**Pancytopenia (not just anemia) Bad name!**
Failure of multipotent stem cell
Peripheral blood
* Pancytopenia
* Normocytic or slightly macrocytic red blood cells
* Decreased polychromasia
87
Most common cause of aplastic anemia
There is a long list, but idiopathic is by far the most common, and this is an autoimmune disease.
88
Pure red cell aplasia
Acquired, chronic (Autoimmune disorder)
**Association with thymoma, large granular lymphocyte leukemia**
Need to be careful not to mistake this for a myelodysplastic syndrome
Constitutional, chronic (Diamond-Blackfan anemia)
Extremely rare
Many cases have heterozygous mutations in ribosomal proteins
Pure red cell aplasia is not the term for transient aplasia due to viral infection (Parvovirus B19)
89
Classification of AIHA
Based on the **_thermal range_** at which an in vitro agglutination reaction is observed
–Warm—reaction strongest at 37°C
–Cold—reaction strongest below 20° to 24° (“benign” or normal) or greater than 30°C (“pathologic”)
90
Diseases Associated with WAIHA
Hematological/Lymphoid Neoplasms: CLL
•Autoimmune Diseases: SLE
•Infectious Diseases: Viral
•Immunodeficiency Diseases: hypogammaglobulinemia
•GI Diseases: UC
•Benign Tumors: Ovarian dermoid cysts
91
Cold Agglutinin Disease
•Clinical features vary from mild and subclinical (usually) to severe and life-threatening (rarely)
•Usually seasonal
•Signs and symptoms
–Acrocyanosis, Raynaud’s phenomenon
–Hemoglobinuria
–Weakness, pallor
92
Secondary Cold AIHA
•Occurs as a transient disorder secondary to infection or chronic lymphoproliferative disorders
**_–Mycoplasma pneumonia_**
–Infectious mononucleosis
–CLL, myeloma
•Autoantibody is IgM with anti-I specificity
93
Paroxysmal Cold Hemoglobinuria (PCH)
* Least common type of AIHA
* More common in children than other types in association with viral illnesses
* Dramatic clinical presentation: Acute paroxysmal or intermittent episodes of hemoglobinuria upon exposure to cold
94
Serological Characteristics of PCH
**_•Biphasic autohemolysin_**
–The autoantibody binds to the patient’s RBCs at low temperature in the peripheral circulation and fixes C’ to the surface
–When the cells return to the core body temperature, hemolysis occurs as the sensitized cells undergo C’-mediated intravascular lysis
**_•Autoantibody is IgG with anti-P specificity_** (Donath-Landsteiner antibody)
95
NRTI’s
* abacavir
* lamivudine
* tenofovir
* emtricitabine
96
NNRTI’s
efavirenz
97
PI’s
atazanavir, darunavir
98
Toxicity of Abacavir?
hypersensitivity reactions
99
Toxicities of Efavirenz
* central nervous system toxicity
* pregnancy
100
Maraviroc
* interferes with the entry of HIV-1 into cells
* CCR5 inhibitors prevent HIV entry by binding to the CCR5 receptor and blocking the interaction between HIV-1 gp120 and the CCR5 receptor.
101
Enfuvirtide
* interferes with the entry of HIV-1 into cells
* gp41 subunit of the viral glycoprotein and prevents the conformation changes required for the fusion of viral and cellular membranes.
102
Lamivudine (3TC)
* Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
* **nucleoside** analog of cytidine
* Triphosphorylated intracellularly to active form
* Competitive inhibitors of HIV reverse transcriptase. Competes with the natural substrate (i.e. corresponding nucleic acid)
* Renal Excretion - Adjust for RI!
103
Abacavir (ABC)
* Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
* **Nucleoside analog of guanosine**
* Triphosphorylated intracellularly to active form
* Competitive inhibitors of HIV reverse transcriptase. Competes with the natural substrate (i.e. corresponding nucleic acid)
* Renal excretion - No adjust for renal insufficiency
104
Tenofovir (TDF)
* Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
* **_nucleotide_** analog (all the rest are nucleosides) analog of **adenine**
* co-administered in fed state with Didanosine results in 40% increase in Didanosine plasma levels.
* **Di**phosphorylated intracellularly to active form
* Competitive inhibitors of HIV reverse transcriptase.
* Renal excretin - YES adjust
105
Elimination of the NRTIs?
Renal, adjust all except for Abacavir (metabolized first then renally excreted)
106
Emtricitabine (FTC)
* Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
* nucleoside analog of cytidine (Smae as lamivudine)
* Triphosphorylated intracellularly to active form
* Competitive inhibitors of HIV reverse transcriptase.
* Renally excreted - adjust for RI
107
RIbavirin should not be combined with?
* Ribavirin inhibits phosphorylation of zidovudine; additive bone marrow suppression (avoid co-administration)
* Ribavirin increases intracellular levels of didanosine (co-administration not recommended)
108
Tenofovir has what major side effect?
Renal toxicity
109
NRTI with hypersensitivty reaction
* *Abacavir**: possible increase in cardiovascular events; hypersensitivity reaction (flu-like illness) 5% incidence
i. Median onset 9 days (1-6 weeks)
ii. Association with MHC Class 1 allele HLA-B\*5701
110
NRTI with peripheral neuropathy (52%), Lipodystrophy (Fat atrophy), rare rapidly progressive ascending neuromuscular weakness (ascending demyelinating polyneuropathy may mimic Guillain-Barre Syndrome),
Stavudine
111
Efavirenz (EFV)
* Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
* No intracellular metabolism needed for activation
* Reversible non-competitive inhibitor of HIV reverse transcriptase
* by binding to reverse transcriptase, blocking of the RNA-dependent and DNA-dependent DNA polymerase action of the enzyme is disrupted
* High fat increases concentrations 80%
112
Major Side effect or EFV
* **Central nervous system symptoms in 50%** (dizziness, altered dreams, confusion, impaired concentration generally subsides in 2-4 weeks),
* **increased triglycerides, LDL and HDL,** false positive cannabinoid test, teratogenic in monkeys.
* **Avoid in pregnancy.**
* **Increase in trunk fat** has been reported but causal relationship has not been established.
113
Multidrug resistance seen in NNRTIs?
**K103N** (only etravirine and rilpivirine remain active)
114
Antiretroviral- Integrase Inhibitors
Major side effects of one of these drugs
* Raltegravir (RAL)
* inhibits the catalytic activity of HIV-1 integrase,
b. inhibition of integrase prevents insertion of linear HIV-1 DNA into host cell DNA
c. prevents the formation of HIV-1 provirus
* Raltegravir: **CPK elevations and myositis and rhabdomyolysis** have been reported. Rare hypersensitivity reactions which can manifest with severe skin rashes. Increase in trunk fat has been observed but causal relationship not established.
115
Major PI's?
* Atazanavir (ATV)
* Darunavir (DRV)
116
Atazanavir (ATV)
* PI
* Blocks protease cleavage of viral gag and gag-pol polyproteins, which results in formation of immature noninfectious viral particles
* No intracellular metabolism required.
117
Take with food
requires acid environment for absorption
separate antacids by ≥ 2 hrs, H2 blockers by 12 hrs unless on ritonavir and no proton pump inhibitors
The PI Atazanavir (ATV)
118
Darunavir (DRV)
* PI
* Take with food
* MOA: Blocks protease cleavage of viral gag and gag-pol polyproteins, which results in formation of immature noninfectious viral particles
* PI's end in -navir
119
Drugs to avoid in NNRTIs
* rifampin
* rifapentine
* rifabutin
* midazolam
* triazolam
* PPIs
120
Dipyridamole
* MOA: coronary vasodilator (by inhibiting the cellular uptake of adenosine) and also has weak antiplatelet activity
* Increases intracellular cAMP by inhibiting phosphodiesterase enzyme → results in decreased Thromboxane A2 synthesis
* also potentiates the effect of PGI2 and decrease platelet adhesion
121
GP IIb/IIIa receptor antagonists
Abciximab (long acting 18-24)
Eptifibatide (short acting 6-12)
Tirofiban (short acting)
Indication: These drugs are used in patients undergoing percutaneous coronary intervention, for unstable angina, and for post MI
Adverse events: Bleeding, thrombocytopenia,
122
Abciximab
Abciximab is a monoclonal antibody against glycoprotein IIb/IIIa receptors on the platelets
Prevents the binding of fibrinogen and other adhesive molecules (von Willebrand factor) to GP IIb/IIIa → prevention of platelet aggregation
IV administration (along with heparin or aspirin)
123
NRTIs
* Zidovudine (ZDV)
* Didanosine (ddI)
* Stavudine (d4T)
* Lamivudine (3TC)
* Abacavir (ABC)
* Tenofovir (TDF)
* Emtricitabine (FTC)
124
NNRTI’s
* **Efavirenz (EFV)**
* Nevirapine
* Delavirdine
* Etravirine
* Rilpivirine
125
Protease Inhibitor
* **atazanavir (ATV)**
* **darunavir (DRV)**
* all ending in -navir
126
Preferred HIV treatment option
Preferred 2 nucleoside reverse transcriptase inhibitors + 3rd drug Choose 1 from Column A and 1 from Column B
**Tenofovir/emtricitabine** +
* Efavirenz
* Atazanavir/ritonavir
* Darunavir/ritonavir
* Raltegravir
127
SE of maraviroc?
CCR5 Inhibitors
**Allergic reactions
Rash, hepatotoxicity**
128
SE of enfuvirtide?
90 mg SC bid (1.2 ml)
gp41 fusion w/CD4 membrane (fusion inhibitor)
Injection site reactions
Bacterial pneumonia
Hypersensitivity ≤ 1%
129
SE: Lactic acidosis?
All Nucleoside RTI's
130
Major SE of Non-Nucleoside RTIs?
Rash in all
Hepatitis/necrosis in Nevirapine
Efavirenz has CNS symptoms, false + cannabinoid test
131
AVOID these therapies
* Avoid all monotherapies or dual nucleoside regimens Zidovudine + Stavudine
* Nevirapine women CD4 ≥ 250, men CD4 \> 400 Efavirenz in 1st trimester pregnancy
132
A patient with TB and Parkinson’s disease who likes to drink gin and tonic develops a platelet count of 2,000/mcL. What do you do?
Consider secondary causes
–Drug induced (rifampicin, L-DOPA, quinidine)
133
DRUG-INDUCED THROMBOCYTOPENIA
Results from antibody-mediated destruction of platelets following ingestion of drugs
–Commonly involved drugs quinine, quinidine, penicillin, thiazide diuretics, methyldopa and heparin
134
Thrombocytopenia of HIV
–Direct infection of megakaryocytes by HIV
•CD4 and CXCR4 receptors for HIV are present on megakaryocytes
–Antibodies against HIV gp120 antibodies cross reacti wht GPIIbIIIa cause secondary ITP
135
How can you tell whether a boy with bleeding and low factor VIII levels has hemophilia A or von Willebrand’s disease?
Ristocetin cofactor test
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What is “compensated” DIC?
Ongoing thrombosis and clot lysis at a slow rate without depletion of coagulation factors Liver can keep up production Normal PT, PTT Positive D-dimer test
