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IHO > Exam 5 > Flashcards

Exam 5 Flashcards

1
Q

Streptococcus pneumoniae

A

• pneumococcal pneumonia: 400,000 hospitalizations per year, 36% of adult community acquired pneumonia, fatality rate: 5-7%, higher in elderly
• pneumococcal bacteremia: 12,000 cases per year, fatality ~20%, up to 60% in elderly

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2
Q

Streptococcus pneumonia meningitis

A

• 3-6,000 cases per year
• fatality: 8% in children, 22% in adults
• risk factors: decreased immune function, asplenia, chronic heart/pulmonary/liver/renal disease
• leading cause of bacterial meningitis of my children younger than five
• common causes of acute otitis media

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3
Q

How is the effectiveness of the influenza vaccine monitored?

A

Presentation to medical attention

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4
Q

Who is the influenza vaccine recommended for?

A

Everyone older than six months of age

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5
Q

What is the current vaccine target for influenza?

A

The hemagglutinin head

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6
Q

What is the proposed future influenza vaccine target?

A

The stalk region— Less immunogenic, but more conserved, and it is a target for a universal vaccine

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7
Q

What are the basic reproduction numbers for common viruses/diseases?

A

• MERS: 0.8
• influenza: 1.5
• Ebola: 2.0
• COVID-19: 2.5
• SARS: 3.5
• mumps: 4.5
• rubella: 6.0
• smallpox: 6.0
• measles: 16.0

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8
Q

What are some common causes a vaccine hesitancy?

A

• vaccines do not work
• I am not at risk
• natural infection is better
• autism
• ethical/moral/religious objections
• lack of trust

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9
Q

What theory predicts hesitancy and vaccination?

A

Moral foundation theory: care/harm, fairness/cheating, authority/subversion, liberty/oppression

Most significantly associated: purity and liberty

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10
Q

Strategies to achieve full vaccination status:

A

• healthcare maintenance visits
• automatic processes
• community-based resources
• state databases
• measure immunization as a quality metric

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11
Q

What are the contraindications to immunizations?

A

• severe allergy
• encephalopathy (pertussis)
• history of intussusception or SCID (rotavirus vaccine)
• live vaccine in immunosuppressed or pregnant persons (illness)

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12
Q

What is passive immunity?

A

• maternal antibody
• specific immunoglobulin
• blood products, such as convalescent plasma, IVIG

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13
Q

What is active immunity?

A

• infection
• vaccination

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14
Q

Vaccine types

A

1.) whole virus: killed, live attenuated
2.) subunit: protein, virus-like particle, toxoid
3.) vector: replicating, or non-replicating
4.) nucleic acid: DNA, mRNA

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15
Q

Live attenuated vaccine

A

• weakened live virus
• produce cell mediated and neutralizing antibody immunity
• decreased effectiveness until 6 to 12 months of age

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16
Q

Which vaccines are live attenuated?

A

Viral: measles, mumps, rubella, varicella zoster, yellow fever, rotavirus, intranasal, influenza, oral polio

Bacterial: oral typhoid, BCG

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17
Q

Viral vector vaccination

A

Adenoviral vector: Ebola, SARS-CoV2

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18
Q

Inactivated vaccination

A

• usually requires multiple doses, and this is humoral immunity
• whole, or fractional

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19
Q

Whole inactivated vaccinations

A

Polio, hep A, rabies, influenza, pertussis, typhoid, cholera, plague

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20
Q

Fractional inactivated vaccinations

A

Protein based: toxoid— tetanus, diphtheria, subunit— hepB, influenza, acellular pertussis, HPV, anthrax

Polysaccharide based: pure— pneumococcal 23, conjugate— pneumococcal 13, Hib

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21
Q

Which pneumococcal vaccination is given to children ?

A

• PCV 13 at 2, 4, and 6 months (4th dose at 12-15mo)
• immunosuppressed conditions also get PPSV23 after age 2

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22
Q

What pneumococcal vaccination is given to adults?

A

• >65: one dose of PVC20, or PCV15 if PPSV23 > 1 year later
• 19-64: underlying medical conditions, PCV 20 followed by PPSV. Repeated at 65.

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23
Q

What is CLL?

A
  • a clonal B cell malignancy
  • progressive accumulation of long lived mature lymphocytes
  • INCREASE BCL2 !
  • CD5+, CD23+
  • most common leukemia in the western world
  • M>F, 65-70year onset
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24
Q

What causes CLL?

A
  • occupational: farming, rubber manufact., asbestos
  • cytogenetics: Trisomy 12, structural abnormalities in chromosomes 13, 14, and 11
  • proto-oncogene for c-fgr 9a (src family tyrosine kinase increase)
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25
Q

What unique symptoms does CLL have?

A
  • asymptomatic at diagnosis
  • most common complaint: fatigue
  • Well’s syndrome (insect bite sensitivity)
  • B symptoms
  • enlarged nodes and infections
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26
Q

CLL laboratory findings

A
  • Lymphocyte > 5000 is required
  • basket/smudge cells
  • concomitant pancytopenia
  • marrow aspirate shows >30% of the nucleated cells being lymphoid cells
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27
Q

Immunophenotype of CLL

A
  • CD 5+
  • CD 23+
  • CD19/20+
  • CD22 (low)
  • light chains present (kappa/lambda)
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28
Q

What test will be positive in 25% of CLL patients and why?

A

Direct Coomb’s test– this is because CLL can cause autoimmune hemolytic anemia

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29
Q

What happens to the lymph nodes in CLL?

A
  • loss of nodal architecture
  • diffuse infiltration of small lymphocytes
  • lymphadenopathy
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30
Q

What factors of CLL lead to poor prognosis?

A
  • advanced Rai/Binet stage
  • peripheral lymphocyte doubling time <12 mo
  • diffuse marrow histology
  • increased number of prolymphocytes or cleaved cells
  • poor chemo response
  • high microglobulin level
  • abnormal karyotyping
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31
Q

Abnormal cytogenetics in CLL from best to worst prognosis:

A
  • 13q deletion
  • normal
  • 12q trisomy
  • 11q deletion
  • 17p deletion (worst- usually see p53 loss here as well)

Others: CD38 (poorer outcome), ZAP70 status, and increased thymidine kinase activity

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32
Q

Loss of somatic hypermutation in CLL leads to:

A

much worse outcomes (10 year survival vs 24 year survival for mutated)

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33
Q

What are the major complications of CLL?

A
  • Autoimmune hemolytic anemia
  • pure red cell aplasia
  • immune-mediated thrombocytopenia
  • depressed Ig levels
  • Hypogammaglobulinemia
  • Richter’s transformation
  • severe infections
  • bleeding
  • secondary malignancies / AML
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34
Q

Treatment options for CLL:

A

1.) Monotherapy ( glucocorticoids, alkylating agents, or purine analogs/antimetabolites)
2.) Combo therapy (CVP, CHOP, Chlorambucil/cyclophos/predisone or fludara/cyclophos/mitoxantrone)
3.) Monoclonal antibodies (Alemtuzumab/antiCD52, and Rituximab/anti-CD20
4.) Splenectomy
5.) Radiotherapy

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35
Q

What are the new and novel treatments for CLL?

A
  • Oblimersen (BCL2 directed antisense oligonucleotide)
  • Lenalidomide
  • Flavopiridol
  • Anti-CD23
  • Anti-CD40
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36
Q

What mosquito carries malaria?

A

Anopheles mosquito is the vectors- transmits the plasmodium species

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37
Q

What populations are vulnerable to malaria?

A
  • young children under 5 (esp if malnourished)
  • pregnant women
  • patients with other conditions (AIDS)
  • travelers without prior exposure to plasmodium
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38
Q

What is Plasmodium?

A
  • An apicomlexan parasite; it possesses an apicoplast (organelle with a residual but functional chloroplast-like genome)
  • Toxoplasma gondii and cryptosporidium parvum are other species that have this
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39
Q

Where does Plasmodium reproduce?

A

in the hepatocytes/hepatic parenchymal cells (Exoerythrocytic phase) and in the erythrocytes (erythrocytic phase)

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40
Q

What is it called when plasmodium is going through mitosis in hepatocytes/erythrocytes?

A

Schizont

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41
Q

What is it called when plasmodium is traveling throughout the body freely?

A

Merozoites

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42
Q

What is it called when plasmodium enters the body/blood through mosquito saliva?

A

Sporozoites

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43
Q

How do the main symptoms of Malaria occur?

A

Release of merozoites into bloodstream –> release of TNF-alpha and other inflammatory cytokines –> paroxysms and fever –> erythrocyte infection (cyclical)

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44
Q

Where do malaria symptoms stem from?

A
  • erythrocyte infection
  1. hemolytic anemia (fatigue, HA, jaundice, splenomegaly, dark urine)
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45
Q

what are the expected labs for Malaria?

A
  • Thrombocytopenia (low platelet count)
  • increased lactate dehydrogenase due to hemolysis
  • normochromic, normocytic anemia (predominantly in intravascular hemolysis)
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46
Q

What malaria species remain dormant in the liver?

A

Plasmodium Vivax and Plasmodium ovale (they are called hypnozoites in this phase)

  • this causes relapsing malaria months or years later
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47
Q

The 3 Rs of Malaria

A
  1. Relapse: hypnozoites of P. vivax and P. ovale
  2. Recrudescence: infection was ineffectively treated and some parasites survived the treatment
  3. Reinfection: individual acquired a new infection due to another mosquito bite
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48
Q

Which malaria variant is the greatest in severity and why?

A
  • Plasmodium Falciparum, because it has an additional virulence factor (PfEMP1) that makes RBCs sticky and causes cytoadherence (decreased blood flow)
  • causes hemolytic anemia and ischemic damage
    2% of parasite switch PfEMP1 each generation to evade antibody response
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49
Q

Plasmodium Falciparum

A
  • high level of parasitemia
  • severe hemolytic anemia
  • cerebral symptoms
  • renal failure
  • pulmonary edema
  • death
  • ** Splenic rupture is RARE
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50
Q

Plasmodium Vivax

A
  • low level of parasitemia
  • Mild hemolytic anemia
  • rare nephrotic syndrome
  • ** splenic rupture more common and can be life threatening
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51
Q

Why is plasmodium falciparum so much worse of a malaria strain?

A
  • can infect RBCs of any age, including reticulocytes
  • causes clumping (rosette) of infected RBCs and adhesion (sequestration) to endothelium, reducing blood flow
  • TNF, IFN-gamma, and IL-1 suppress RBC production, increase fever, induce tissue damage, and increase endothelial receptors to increase sequestration
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52
Q

Malaria intrinsic resistance

A

Mutations affecting RBCs maintained where Malaria is endemic but not elsewhere- benefit is decreased malarial severity

Examples: HbS (sickle cell), alpha and beta-thalessemia (spherocytosis), G6PD deficiency, absence of DARC, band3, spectrin

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53
Q

Why is absence of DARC a malaria intrinsic resistance?

A

P. vivax enters the RBC by binding to DARC and most of the West African population does not have DARC (Duffy surface blood group)

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54
Q

Acquired malaria resistance

A

reduced illness despite infection in endemic areas indicates partial immune-mediated resistance

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55
Q

How is Malaria diagnosed?

A
  • stained peripheral (thick and thin) smears
  • asexual stage in RBC is seen and identified
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56
Q

What will you see on Malaria morphology?

A
  • numerous rings, thin elongated gametocytes (usually p. falciparum)
  • Shuffner’s dots, round full gametocytes (usually p. vivax)
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57
Q

What does Ovale morphology look like?

A
  • Shuffner’s dots
  • rings
  • abnl shape gamteocyte
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58
Q

What does malariae morphology look like?

A
  • Finer Ziemann dots
  • rings
  • round gametocytes
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59
Q

An inorganic crystal from the detoxification of heme that is produced frequently in malaria

A

Hemozoin– very dark in color, makes macrophages dark

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60
Q

What is cerebral malaria?

A
  • 1-10% of p. falciparum infection in non-immune individuals (6mo-4yrs or travelers)
  • brain vessels become plugged by parasitic sticky RBCs
  • local hypoxia
  • local inflammation (Dureck granulomata)
  • pulmonary edema, DIC, and death
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61
Q

Why is cerebral malaria so detrimental?

A
  • diffuse encephalopathy
  • 10% permanent neuro damage
  • 30-50% mortality
  • petechial hemorrhage most common in the white matter
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62
Q

Blackwater fever

A
  • associated with malaria infection
  • Massive intravascular hemolysis
  • Hemoglobinemia
  • Hemoglobinuria
  • jaundice
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63
Q

Chloroquine anti-malarial drug

A
  • use: prophylactic or acute attack
  • mech: interferes with heme handling, binds to FPIX to inhibit conversion of it to hemozoin (FPIX is toxic to the parasite)
  • concentrates into parasitized RBCs
  • SE: dizziness, HA, severe eye damage/blindness
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64
Q

Quinine and Quinidine anti-malarial drug

A
  • resistance is not as readily developed
  • used in chloroquine resistance
  • mech: most likely the same as chloroquine
  • SE: **CARDIAC TOXICITY, monitoring required, hypotension and hypoglycemia, Cinchonism (blurred vision, nauseam tinnitus, permanent damage to vision, hearing and balance)
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65
Q

Mefloquine anti-malarial drug

A
  • mech: most likely the same as chloroquine
  • once a week for prophylaxis
  • SE: nausea, vomiting, neuropsychiatric reactions including visual and auditory hallucinations (dose-related)
  • not preferred as there is resistance noted for this drug as well
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66
Q

Atovaquone and Proguanil anti-malarial drug

A
  • atovaquone mech: depolarizes parasitic mitochondria and inhibits their electron transport
  • proguanil mech: inhibits dihydrofolate reductase, selective for the plasmodial enzyme (not active against hepatic stages)
    -SE: GI disturbances, slow onset
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67
Q

Artemisinins and ACT

A
  • artemisinin based combination therapy
  • Artesunate followed by atovaquone/proguanil or doxycycline or mefloquine
  • arthemether + lumefantrine (oral combo)
  • TAKE AWAY: do not use artemisinins alone, it may cause resistance
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68
Q

Artemisinins anti-malarial drug

A

-Mech: heme iron in the malarial pigment acts on the drug to produce free radicals that damage parasite proteins. Inhibits a calcium ion ATPase in p. falciparum. Covalently binds to over 100 proteins in the parasite
- RAPID and POTENT (not against hepatic forms)
- do not use alone in order to avoid selection of resistance organisms

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69
Q

Lumefantrine anti-malarial drug

A
  • unknown mechanism
  • effective against erythrocytic stage
  • in combo with artemether
  • rapid initial reduction in parasite biomass afforded by artemether and then clearance of remaining viable parasites by the more slowly eliminated lumefantrine
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70
Q

Primaquine or Tafenoquine as the Radical Cure/prevention of relapse

A
  • drug of choice to eliminate hepatic forms of P. vivax and P. ovale by eradicating hypnozoite forms in the liver
  • Mech: unknown, maybe generation of ROS or interference with electron transport chain in parasite
  • Primaquine SE: GI distress, N/V, HA, pruritis, leukopenia, methemoglobinemia
  • Tafenoquine SE: decreased hemoglobin, psychiatric effects, N/V, HA, dizziness
  • Biggest SE concern: Hemolytic anemia in people with ** G6PD deficiency
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71
Q

Difference in ADME of Tafenoquine vs Primaquine:

A

Tafenoquine: 15 day half life, one dose and done

Primaquine: daily dose for 2 weeks

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72
Q

Most protozoan and helminth parasites appear in US individuals if:

A

they are immigrants or have traveled to endemic areas

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73
Q

Trypanosomatid-caused diseases

A

Insect vectors: sand fly, triatomine bug, tsetse fly
Diseases:
1.) Visceral Leishmaniasis
2.) cutaneous leishmaniasis
3.) mucocutaneous leishmaniasis
4.) Chagas disease (american trypanosomatid)
5.) african sleeping sickness (HAT)

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74
Q

Clinical findings of Leishmaniasis

A
  • Ulcerative skin with a raised outer border (cutaneous)
  • Mucocutaneous infects the mucosa and mouth
  • Marked splenomegaly seen in visceral leishmaniasis
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75
Q

Where is Leishmaniasis found?

A
  • East Africa
  • Asia
  • Latin America
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76
Q

Cutaneous Leishmaniasis

A
  • most common
  • Symptoms: 1+ skin sores that change in size and appearance. Volcano-like with raised edge and center crater, can be painful or painless, sometimes with lymph node swelling near the sore
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77
Q

Which Leishmaniasis cause cutaneous leishmaniasis?

A

In Asia, Middle East, and Africa: L. tropica, major, aethiopica, infantum, donovani

In Latin America: L. mexicana, amazonensis, venezuelensis, and subgenus Viannia

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78
Q

Mucocutaneous leishmaniasis

A
  • very rare
  • results from metastasis of an untreated cutaneous case
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79
Q

Visceral leishmaniasis

A
  • Bangladesh, Brazil, Ethiopia, India, South Sudan, and Sudan
  • Also called Kala-azar
  • LIFE THREATENING
  • Symptoms: weightloss, enlarged spleen and liver, swollen glands, pancytopenia
  • from: L. donovani, L. infantum
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80
Q

Leishmaniasis treatment:

A
  • organic antimonials: Sodium stibogluconate, meglumine antimoniate
  • Miltefosine: oral, good for antimonial resistance, high toxicity
  • Liposomal amphotericin B: only for visceral, injection, binds to ergosterol to form pores in membranes, nephrotoxicity and infusion toxicity
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81
Q

Chagas Disease

A
  • American trypanosomiasis
  • caused by infection with flagellated protozoan parasite trypanosoma cruzi transmitted by a triatomine (kissing) bug
  • Romana sign
  • chagastic cardiomyopathy: dilated with apical atrophy
  • megacolon
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82
Q

Romana sign

A

Unilateral periorbital swelling, marker of acute Chagas disease (seen rarely)

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83
Q

Where is Chagas disease?

A

Latin America and Mexico

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84
Q

Stages of Chagas disease

A

ACUTE:
- asymptomatic, or mild innate immune response to infection
- sometimes CHAGOMA is present,
CHRONIC:
- 60-80% chronic indeterminant, 20-40% chronic disease
- T. cruzi replicates intracellularly
- immune response: myocarditis, megaesophagus, megacolon

  • can be oral, or transfusion related (oral is severe)
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85
Q

Treatment for Chagas disease:

A
  • Nifurtimox and Benznidazole orally
  • Mech: induces oxidative stress by inhibiting NADPH dependent dehydrogenases, impairment of mitochondrial membrane potential
  • Requires: bacteria-like type 1 nitroreductase to turn it to active phase
  • SE: toxic, N/V, myalgia, weakness, peripheral neuropathy
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86
Q

African sleeping sickness (African trypanosomiasis, HAT)

A
  • T. brucei
  • always extracellular
  • transmitted by Tsetse fly: T.B. gambiense in West Africa and T.B. rhodesiense in East Africa
  • First stage: chancre at bite site, fever, HA, swollen lymph nodes, muscle and joint pain, rash and itchiness
  • Second stage: CNS involvement, neuro symptoms of somnolence, altered gait, tremors, cranial neuropathy, urinary incontinence, personality changes, coma
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87
Q

When does CNS involvement occur in african sleeping sickness?

A
  • gambiense: after 1-2 years of infection, death in 3 if not treated
  • Rhodesiense: after a few weeks, death in a few months if not treated
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88
Q

Immune evasion by Leishmania, T. cruzi, and T. Brucei

A

Leishmaniasis: intracellular replication
T. Cruzi: intracellular replication
T. Brucei: antigenic variation (VSG switch, variable surface glycoprotein), always extracellular, divides in bloodstream

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89
Q

Suramin

A
  • treatment of African sleeping sickness
  • mech: inhibitory effect on enzymes of the PPP and glycolytic pathways. Selectively accumulated in trypanosomes
  • SE: N/V, shock, LOC, peripheral neuropathy, photophobia, urticaria, pruritis, nephrotoxicty
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90
Q

Pentamidine

A
  • treatment of African sleeping sickness
  • mech: interferes with DNA replication of its unique mitochondrial genome, selectively accumulated in trypanosomes
  • SE: hypotension, tachycardia, vomiting, hypoglycemia
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91
Q

Eflornithine

A
  • treatment of African sleeping sickness
  • mech: inhibits ornithine decarboxylase, which turns over faster in human cells than trypanosomes
  • SE: fever, HA, hypertension, rash, peripheral neuropathy and tremor, GI problems
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92
Q

Melarsoprol

A
  • treatment of African sleeping sickness
  • mech: an arsenical, unknown mech, potentially related to metabolism. administered in PEG, “arsenic in antifreeze”
  • SE: resistance is increasing, fever, hypertension, vomiting, albuminuria, painful, encephalopathy
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93
Q

Fexinidazole

A
  • treatment of African sleeping sickness
  • mech: acts through bioactivation by parasite nitroreductase enzymes to generate reactive amines and/or other metabolites
  • Completely oral (first of its kind)
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94
Q

Tissue nematodes

A

1.) Onchocerciasis (river blindness)
2.) Elephantitis (lymphatic filariasis)
3.) Loa Loa filariasis (loiasis)

  • Toxocara canis and toxocara cati
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95
Q

Blackflies of the genus Simulium

A
  • insect vector that carries helminth
  • onchocerciasis by onchocerca volvulus (river blindness)
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96
Q

Female mosquito

A
  • insect vector that carries helminth
  • Wuchereria bancrofti
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97
Q

Deerflies (yellow flies) of the genus Chrysops

A
  • insect vector that carries helminth
  • Loa loa
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98
Q

Onchocerciasis (river blindness, Robles disease)

A
  • sub-saharan africa, tropical americas, Yemen, and middle east
  • caused by onchocerca volvulus, travelers most likely to become infected
  • Symptoms: EYES AND SKIN, nodules under the skin, hyperpigmented, severe itching, keratitis leading to blindness, opacity in affected eye areas, chronic infection –> thin skin
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99
Q

How to diagnose Onchocerciasis (river blindness, Robles disease)

A

Skin snip method

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100
Q

Treatment of Onchocerciasis (river blindness, Robles disease)

A

1.) Ivermectin: oral, effective against microfilariae that cause disease symptoms (no effect on adult worms)
Mech: binds and blocks glutamate gated chloride channels that are present on invertebrate muscle and nerve cells

2.) doxycycline: effective against wolbachia pipientis

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101
Q

Lymphatic filariasis (elephantitis)

A
  • endemic in tropical areas in Asia, Africa, the Western Pacific, and parts of the Caribbean and South America
  • leading cause of permanent disability worldwide
  • The adult worms live only in the human lymph system
  • Symptoms: lymphedema and elephantitis, hydrocele
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102
Q

Elephantitis

A

A syndrome brought one from long-term obstruction of the lymphatic vessels that leads to engorgement and thickened skin. It causes disfigurement, often in the legs

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103
Q

Definitive diagnosis of Lymphatic filariasis (elephantitis)

A
  • Blood smear. Microfilariae that cause the Lymphatic filariasis circulate in the blood at night (blood collection done at night)
  • elevated levels of antifilarial IgG4 in the blood
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104
Q

Treatment of Lymphatic filariasis (elephantitis)

A
  • Diethylcarbamazine: oral, kills microfilaria and adult worms
  • Mech: arachidonic acid metabolic pathway in microfilaria (generally well tolerated)
  • Contraindications: onchocerciasis, DEC can worsen the eye disease
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105
Q

Loa Loa filariasis (Loiasis)

A
  • West and central Africa, esp in rainforests and when deerflies are prevalent
  • previous eye worms are common
  • adult worms reside in subcutaneous tissue
  • Symptoms: eye worm, localized, non-tender swellings in the arms and legs and near joints (calabar swellings), itching, high eosinophil count
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106
Q

Treament of Loa Loa filariasis (Loiasis)

A
  • Diethylcarbamazine: oral, kills microfilaria and adult worms
  • Mech: arachidonic acid metabolic pathway in microfilaria (generally well tolerated)
  • contraindication: heavy infections are at risk of encephalopathy when treated with DEC
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107
Q

Toxoplasmosis:

A
  • toxoplasma gondii parasite ingested as a tissue cyst in uncooked meat or an oocyst from unwashed produce/ cat feces
  • neutropic parasite, intracelluar encystment is in host muscle and brain cells
  • vulnerable: immunocompromised individuals, and pregnant women
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108
Q

Toxoplasmosis is the most common _____ in HIV patients

A

Focal brain disorder. Associated with cerebral abscesses, fever, confusion, HA, seizures, nausea, poor coordination, ring-enhancing lesions on MRI

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109
Q

Ocular toxoplasmosis

A

Associated with red, painful, photophobic eye, decrease in visual acuity, and “headlight in the fog” lesion with surrounding chorioretinal scars in one eye

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110
Q

Congenital toxoplasmosis

A
  • danger to pregnant women because of the danger to the fetus
  • causes: stillbirth, miscarriage, abnl head size, vision loss, mental disability, seizures
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111
Q

Infant “classic triad” from congenital toxoplasmosis

A
  • Chorioretinitis
  • Hydrocephalus
  • intracranial calcifications
  • the earlier in pregnancy the infection occurs, the more severe the symptoms
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112
Q

Treatment for toxoplasmosis

A
  1. Atovaquone (quinone antimicrobial)
  2. Sulfadiazine and pyrimethamine (folinic acid often co-administered)

Pregnant women: Spiramycin (a macrolide that does not cross the placenta)

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113
Q

Cell-mediated immunity

A

1.) antigen specific effector cells such as CD8+ and CD4+ leading to adaptive response and antigen specific

2.) Antigen non-specific: NK cell, innate response (and adaptive), non-specific

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114
Q

Steps of cell mediated immunity

A

1.) T cells come in contact with an APC
2.) Becoming activated by a licensed APC
3.) T cells come in contact with infected cell

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115
Q

Where do naive T cells come in contact with antigen?

A

lymph nodes and secondary lymphoid tissues

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116
Q

Trafficking within lymph nodes

A
  • T cells enter via HEVs and interact with APCs leading to either activation or exit from lymph node
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117
Q

What chemokines attract cells to lymph nodes?

A
  • CCL19 via dendritic cells to attract T cell to the lymph nodes
  • CCL21 (ligand for CCR7) via stromal cells and HEVs
  • CXCL13 is secreted by B cells to attract more B cells
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118
Q

T cell activity in lymph node:

A
  1. minutes-24hrs: APC activation, Ag enters
  2. 1-24hrs: T cell/APC interaction
  3. 24-96hrs: T cell proliferation and differentiation
  4. 72-96hrs: egress of effector cells
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119
Q

B cell activity in the lymph node:

A
  1. Minutes: soluble Ag entry
  2. Minutes-6hrs: B cell/Ag interaction
  3. 6hrs: B cell migration to T cell zone
  4. 24-48hrs: B cell proliferation and migration to outer follicular zone
  5. 48-96hrs: development of the germinal center
  6. 72-96hrs: egress of effector cells
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120
Q

Three signals required to activate T cells by a licensed APC

A
  1. activation of MHC molecule
  2. Co-stimulation: B7/CD28:CD80/86
  3. Cytokines: differentiation (IL2 for CD8)
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121
Q

Rule of 8:

A
  • exogenous antigen: MHC2, CD4+
  • endogenous antigen: MHC1, CD8
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122
Q

What promotes robust antibody response?

A

Linked recognition of antigen by T cells and B cells

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123
Q

Naive CTL precursor

A
  • low IL2 production
  • low CD25 (IL2R) expression
  • no granzyme/perforin
  • express L-selectin and CCR7
  • low levels of CD44 and LFA1
  • no cytotoxic function
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124
Q

Activated CTL

A
  • high IL2 production
  • upregulated Cd25 expression
  • granules with granzyme and perforin
  • express low levels of L-selectin and CCR7
  • express high levels of CD44 and LFA1
  • cytotoxic function
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125
Q

Cellular polarization of T cells during specific antigen recognition allows:

A

Effector molecules to be focused on the antigen-bearing target cell

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126
Q

Pathway to apoptosis

A

1.) Fas:FasL –> caspase 8 –> BID –> Release of cytochrome C/caspase 9 and caspase 3 –> apoptosis

2.) Perforin/granzyme –> BID –> Release of cytochrome C/caspase 9 and caspase 3 –> apoptosis

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127
Q

Binding of Fas:FasL initiates:

A

the extrinsic pathway of apoptosis (Fas:FasL –> death domain active –> FADD –> caspase 8 –> apoptosis)

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128
Q

Cytoplasmic granules and CTL target killing

A
  • Granzyme B: a serine protease –> caspase cleavage –> apoptosis
  • Perforin: oligomeric pore-forming protein
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129
Q

Fas:FasL mediated apoptosis for CTL target killing

A
  • FasL (CD95) expressed on cell surface of CTL binds Fas on target cell
  • signaling pathway leads to apoptosis
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130
Q

Natural Killer Cells

A
  • lymphoid characteristics without specific antigen receptors
  • CD56+, CD16+, (Fc-gamma-RIII binds to IgG1 and IgG3)
  • killing initiated by “absence of self”
  • MAJOR ROLE: protection against infected, stressed, and cancerous cells. Contain infections until adaptive immunity kicks in
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131
Q

What innate cytokines stimulate NK cells?

A
  • IFN-alpha
  • IFN-beta
  • IL-12
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132
Q

NK cells secrete:

A

IFN-gamma that leads to Th1 response and helps recruit macrophages

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133
Q

Difference between cytotoxic T cells and NK cells:

A
  1. NK cells do not have any receptor arrangements
  2. NK cells kill without restriction to MHC Class 1 or 2
  3. NK cells do not have positive or negative selection in Thymus
134
Q

Killing by NK cells depends on the balance between:

A
  • activating and inhibiting signals
  • inhibiting signals always dominate (MHC1 signals)
  • opposing signals of the receptors keep NK cells in check
135
Q

How do NK cells kill target cells?

A
  • TRAIL: tumor necrosis factor apoptosis inducing ligand
  • also granzyme/perforin and FasL
136
Q

How does TRAIL work?

A
  • TRAIL on NK cells binds to death receptors DR4 and DR5
  • Leads to induction of caspase 8- induced apoptosis
137
Q

Antibody dependent cellular toxicity (ADCC)

A
  • CD16+, CD32+
  • effectors cells of ADCC: NK, macrophages, monocytes, neutrophils, eosinophils
  • effector cell bind antigen:antibody conjugates via the Fc receptor on the cell surface
138
Q

What are the antibody effector functions?

A
  1. virus and toxin neutralization by surrounding and preventing pathogen-host binding
  2. opsonization by FcR on macrophage–> phagocytosis
  3. Complement fixation and formation of the MAC –> phagolysis/cytosis
  4. ADCC –> NK induced apoptosis
139
Q

antibody coated target cells can be killed by NK cells via:

A

antibody dependent cell-mediates cytotoxicity (ADCC)

140
Q

What do NK cell TCRs recognize ?

A
  • glycolipids presented on MHC class-like molecule called “CD1d”
  • NOT MHC
  • no T cell markers, no memory, kills almost exclusively by Fas:FasL
141
Q

How do NK cells contribute to driving immune responses forward?

A
  • secrete regulatory cytokines (IL4, IL10)
  • secrete pro-inflammatory cytokines (IL2, IL17, IFN-gamma)
  • no priming needed, early immune response– bridges the gap
  • High basal level of IL12R that increases with TCR binding or exposure to IL12
  • positive feedback
142
Q

Thimerosal

A
  • added preservative to multi-dose units of vaccines that can create ethyl mercury when broken down by serum thioesterase
143
Q

Andrew Wakefield

A
  • autism claim doctor who was crazy and lost his license :)
144
Q

The Cutter incident

A
  • 1955: 200 people paralyzed and 10 dead after contracting polio from salk polio vaccine containing virus that had not been inactivated
  • Drove the creation of the National Childhood Vaccine Injury Act (VICP) where the government assumes all liability from vaccine manufacturer for litigation claims on vaccines approved by the FDA
145
Q

Institute of Medicine Summary of Causality

A

Table that list all vaccines with corresponding adverse event and temporal associations that are recognizable as immediately compensable by the VICP

146
Q

VICP workflow

A

Patient claim –> Legal petition –> Secretory HHS –> department of justice –> Medical expert panel OR compensate –> adjudicate claim OR compensate –> US dept of justice –> Federal special master “Vaccine Court”

147
Q

What are the big public health concerns about vaccine contents?

A
  • Active/inactivated virus
  • Thimerosal (mercury)
  • Adjuvants (aluminum)
  • Inert items
148
Q

Hyperleukocytosis

A
  • > 100,000 blast count
  • APML, monocytic AML, inv(16) 11q23-
  • treat with hydroxyurea, leukopheresis, chemotherapy
149
Q

What diagnostic do you avoid if there is greater than 100K platelets?

A

Traumatic Lumbar Puncture

150
Q

What is commonly seen in AML, and APML, myeloid lineages only?

151
Q

How do kids present with leukemia?

A
  • Usually ALL, 30-40% of cancer is leukemia
  • Anemia, thrombocytopenia, neutropenia
  • widespread of leukemia cells (1 trillion in body)
152
Q

Required for diagnosis of AML

A
  • 20% myeloblasts in bone marrow
  • always check CYTOGENETICS
153
Q

AML translocations

A

Favorable: t(8;21), inv(16)(p13.1q22), t(16;16), NPM1 without FLT3-ITD

Intermediate 1: NPM1 with FLT3-ITD

Intermediate 2: t(9;11)(p22;q23), MLLT3-MLL

Adverse: inv(3)(q21;q26.2), t(3;3)(q21;q26.2), t(6;9), t(v;11), del(5q), abl(17p)

154
Q

Risk groups based on cytogenetics for AML

A

Low risk: inv(16), t(8;21)
High risk: monosomy 7, 5q-
Standard risk: everything else

155
Q

Favorable features for AML:

A
  • age < 55
  • absence of infection/sepsis
  • absence of antecedent MDS
  • low WBC
  • good cytogenetics ( t(8;21), t(16;q6),
  • normal karyotype with NPM1+, Flt3-
  • Presence of Auer rods
156
Q

Unfavorable features for AML:

A
  • poor risk cytogenetics
  • age >60
  • presence of infection/sepsis
  • presence of prior MDS or if it is secondary AML
  • Extreme leukocytosis
  • extramedullary disease
  • 11q23- from secondary AML-BAD
157
Q

Treatment for AML

A
  • typically 7+3 regimen of anthracycline (idarubicin) and then cytosine arabinoside
  • Newer: Venetoclax (BCL2 inhibitor) and hypomethylating agents (decitabine and azacytidine) for elderly and failed 7+3
158
Q

Acute promyelocytic leukemia, APML (M3)

A
  • most with t(15;17) fusion gene of PML/RAR-alpha
  • poor prognosis disease with t(11;17)
  • induction therapy with ATRA (all trans retinoic acid)
  • relapse = arsenic trioxide
  • DIC and Auer rods are common with APML, AML M3
159
Q

What kills leukemia patients acutely?

A
  • tumor lysis syndrome (give allopurinol and IV fluids, watch electrolytes)
  • infection/sepsis
  • bleeding and concomitant DIC
  • respiratory failure (seen with anterior mediastinal masses in ALL, etc)
160
Q

General HIV treatment strategy

A
  • 2 NRTIs + INSTI
  • 1 NRTI + INSTI
  • 2 NRTIs + boosted PI
  • 2 NRTIs + NNRTI
161
Q

NucleoSIDE Reverse transcriptase inhibitors (NRTIs)

A
  • zidovudine, Lamivudine, emtricitabine, abacavir

MECH: competitively inhibit reverse transcriptase and can be incorporated into viral DNA chain and cause termination.
** required phosphorylation by cellular enzymes to the triphosphate to be active

162
Q

Side effects of NRTIs

A
  • fatal syndrome of lactic acidosis with hepatic steatosis due to mitochondrial toxicity
  • fat redistribution and hyperlipidemia
  • certain NRTI combos avoids due to DDIs and resistance patterns
163
Q

Zidovudine side effects

A
  • granulocytopenia and anemia in up to 45% (hematological monitoring at 2 week intervals)
  • CNS disturbances: severe HA, nausea, insomnia, malaise
164
Q

Lamivudine and Emtricitabine side effects

A
  • best tolerated, also active against Hep B
165
Q

Abacavir side effects:

A
  • hypersensitivity reactions
  • TEST FOR HLA-B*5701 ! - allele risk for developing a severe hypersensitivity
166
Q

NucleoTIDE reverse transcriptase inhibitor (NRTI)

A
  • nucleotides are phosphorylated nucleosides
  • Tenofovir is the only one in this category

MECH: competitively inhibit reverse transcriptase and can be incorporated into viral DNA chain and cause termination,

167
Q

Side effects of Tenofovir

A
  • N/V/D
  • fatal syndrome of lactic acidosis with hepatic steatosis due to mitochondrial toxicity
  • Potential for RENAL FAILURE, so avoid in patients with low GFR
168
Q

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

A
  • Efavirenz
  • Rilpivirine
  • Doravirine

MECH: NNRTIs bind directly to the reverse transcriptase at a site different from the NRTIs. The enzyme cannot produce viral DNA after that
- Do NOT require phosphorylation
- no cross resistance with NRTIs

169
Q

Side effects of NNRTIs

A
  • GI intolerance
  • skin rash
  • induces/inhibits CYP450 (DDIs)
170
Q

Side effects of Efavirenz

A
  • CNS, nightmares, dizziness, depression, and psychosis
    (Doravirine has less)
171
Q

Side effects of Rilpivirine

A
  • isn’t as effective, do not use with patients who have pretreatment viral loads of > 100,000 copies per mL
172
Q

Protease inhibitors

A
  • Atazanavir
  • Darunavir
  • Ritonavir

MECH: prevent protease action required for maturation of the fully assembled virus. As the virus is budding, proteolytic cleavage occurs (of the Gag-pol polyprotein). Without this cleavage, the virus is not infectious
* active against viral strains resistant to reverse transcriptase inhibitors

173
Q

Side effects of Protease inhibitors

A
  • peripheral lipoatrophy and central fat accumulation
  • metabolized by and inhibit CYP3A4
    GI disturbances
  • Hepatotoxicity
  • hyperglycemia and insulin resistance
  • dyslipidemia
  • cardiac conduction abnormalities
174
Q

Ritonavir boosting

A
  • Ritonavir is a potent inhibitor of CYP3A4 so it is used in smaller doses to increase the serum concentrations of other PIs and decrease their dosage/frequency
175
Q

Cobicistat

A
  • pharmacokinetic enhancer
  • inhibits CYP3A4 and certain intestinal transport proteins
  • not a PI but can act as a booster
  • more selective CYP3A4 inhibition and slight fewer DDIs
176
Q

Integrase strand transfer inhibitors (INSTI)

A
  • Bictegravir, Raltegravir, Dolutegravir, Elvitegravir, cabotegravir

MECH: bind integrase to inhibit strand transfer, the final step of provirus integration. Fewer DDI than PI or NNRTI

  • not many SE, effective firstline drug
177
Q

Cabotegravir with Rilpivirine

A
  • INSTI with NNRTI
  • once monthly IM injection can be used as an optimization strategy for people with HIV currently on oral antiretroviral therapy (ART) with documented viral suppression for at least 3 months
  • 28 day oral trial to determine tolerability before injecting
178
Q

Entry inhibitors

A
  • Fusion inhibitor: Enfuvirtide (T20)
  • CCR5 antagonist: Maraviroc
179
Q

Enfuvirtide

A
  • Fusion inhibitor
  • subcutaneous 2x daily, only HIV drug that is not oral

MECH: binds to gp41 to prevent the conformational change that facilitated the fusion of the viral and host membranes

SE: local rxns, hypersensitivity (rare)

180
Q

Maraviroc

A
  • CCR5 antagonist

MECH: Binds specifically and selectively to host CCR5, therefore preventing entry of R5 strains

SE: pyrexia, rash, postural dizziness

181
Q

Issues with HIV therapy

A

1.) compliance
2.) Drug resistance
3.) Pre-exposure prophylaxis (emtricitabine/tenofovir) reduced risk by 99% for sex and 74% for IV drug use

182
Q

Treg versus Teff cells in homeostasis:

A
  • too many Treg: cancer
  • too many Teff: autoimmunity
183
Q

Central tolerance

A
  • results from the deletions of most T and B cells with high binding affinity for self antigens before they mature
  • T cells are removed by neg selection in the thymus
  • B cells are removed by neg selection in the bone marrow
184
Q

Peripheral tolerance

A
  • occurs when autoreactive lymphocytes make it to maturity in secondary lymphoid tissue
  • regulatory cells, limited life of activated lymphocytes (programmed death after activation)
185
Q

If you miss any of the key signals for activation of T cells, what is the result?

A

T cell anergy: when a T cell cannot respond to normal stimulation after failure to activate properly

186
Q

Regulatory T cells (Tregs) are:

A
  • specialized CD4+ T cells that suppress immune responses and inhibit autoimmune responses
  • they make up around 10% of all CD4+ T cells
  • They are: CD4+, CD25+ (IL2 receptor), CTLA-4+ and FoxP3+
187
Q

Two subsets of Tregs:

A

1.) Natural: thymically derived developing from self reactive T cells that express conventional a:beta T cell receptors. Selected by thymus for high affinity binding to MHC molecules containing self
2.) inducible: Made in the periphery when CD4+ T cells are exposed to TGF-beta

188
Q

What do Tregs do?

A
  • suppress effector T cell’s proliferation, suppression requires binding to the TCR (CTLA-4 is inhibitory signal)
  • secrete anti-inflam cytokines: IL10, TGF-beta, and IL35
  • cause cytokine deprivation by binding up all the cytokines
  • apoptosis induction by release of granzyme/perforin
189
Q

What is CTLA-4?

A
  • Cytotoxic T lymphocyte antigen 4
  • surface inhibitory receptor with high affinity for CD80/86
  • expressed on Tregs and Teffs
  • binding CTLA4 by APCs decreases APC response to antigen and co-stimulatory capacity
190
Q

IPEX syndrome

A
  • mutations in the FoxP3 gene that results in the absence of Treg cells leading to autoimmune condition
191
Q

The nature of the immune response is determined by:

A
  • form, dose, and route of antigen
  • the APCs
  • the genetics of the individual
  • hx of previous exposure
  • concurrent infections with the individual
192
Q

How does regulation by antigen occur?

A
  • Continual exposure to antigen is needed to maintain T and B cell response/proliferation
  • when Ag levels decrease, IL2 and IL2R (CD25) levels drop, and antigen specific T cells go through apoptosis
  • 10% of cells live on to give rise to the T and B memory cell population
193
Q

what are some molecules needed to induce tolerance in T cells?

A
  • E-cadherin
  • PD1L
  • CD1-3
  • CD152 (CTLA4)
  • ICOS-L (CD275)
  • and cytokines (IL10, TGF-beta)
194
Q

Antibody blocking

A
  • administered antibodies for the purpose of binding antigen in competition with B cells
  • Examples: anti-Rh given to Rh neg mom with Rh positive baby, RhoGAM shot binds up all the Rh so that mom’s immune system won’t react
195
Q

What types of Tregs have which chemokine receptors?

A
  • Th1: CXCR3, CCR5
  • Th2: CCR3, CCR4, CCR8
  • Th17: CCR6
196
Q

Where are the immune privileged sites of the body?

A
  • anterior chamber of the eye
  • testes
  • they have Migration inhibition factor (MIF) to prevent detrimental immune response in these areas
  • also inhibits NK cells
  • have high levels of TGF-beta and IL10
197
Q

Severe combined immunodeficiency (SCID)

A
  • a group of rare disorders caused by mutations in different genes involved in the development and function of lymphocytes
  • Loss of common gamma chain IL2/IL7 is most detrimental
198
Q

What are the most common types of immunodeficiencies?

A
  • Humoral, B cell (50%)
  • Combined, T + B cell (20%)
  • phagocytic (18%)
  • Cellular, T cell (10%)
  • Complement (2%)
199
Q

What are the 4 different ways immunodeficiencies occur?

A
  1. Decreased production of the cells
  2. decreased lifespan of the cells
  3. Broken inputs (cannot respond)
  4. Broken outputs (cannot act)
200
Q

X-linked agammaglobulinemia

A
  • Absence of B cells
  • Family Hx of an X-linked recessive abnormality
  • recurrent infections (pneumonia, otitis media, ) common at 6-12months old
  • Low serum Ig and peripheral B cell count
  • lack of tonsils
  • Mutation in the BTK gene leading to defective B cell receptor signaling and impairing B cell survival/ differentiation
201
Q

Treatment of X-linked agmmagloulinemia (XLA)

A

injections of gamma globulin

202
Q

DiGeorge syndrome

A
  • absence of T cells and other abnormalities
  • Microdeletion of Chr 22 (22q11.2) resulting in the loss of multiple genes, including TBX1 –> no development of the thymus
  • low birth weight, dysmorphic facial features, congenital heart defects, hypocalcemia
  • low absolute lymphocytes and undetectable amount of T cells (B and NK are normal)
203
Q

Treatment for DiGeorge syndrome

A
  • cannot correct the disease, only symptomatic
  • consists of injections of correcting the heart defects and managing the hypocalcemia
  • IV injections of immunoglobulin to improve immune capacity
204
Q

Omenn syndrome

A
  • Defect in V(D)J recombination resulting in severe immunodeficiency
  • Loose bowel movements (Coliform) and severe rash (candida) shortly after birth
  • WBC count can reveal normal overall cell numbers with high levels of eosinophils and monocytes, low neutrophils and very low lymphocytes
  • low/undetectable IgG, IgA, and IgM
  • high levels of IgE
  • no thymic shadow (atrophy from low T cells)
205
Q

Treatment for Omenn syndrome

A
  • bone marrow transplant for full correction
206
Q

What is mutated in Omenn syndrome?

A
  • RAG 1/2 mutations and other VDJ recombination proteins
  • phenotype shows no T cells, no B cells, normal NK cells
207
Q

X-linked severe combined immunodeficiency (SCID)

A
  • Defective IL2R gamma chain (CD132 gene found at Xq11)
  • Cannot respond to class 1 cytokines, IL-7
  • loss of T cell development
  • Symptoms: thrush of the mouth and diaper area, persistent cough (pneuomocystis jiroveci) infection, pneumonia, diarrhea,
208
Q

Treatment to prevent infections in X-linked severe combined immunodeficiency (SCID)

A
  • TMP-SMX given prophylactically at 8 weeks of life
  • IVIG also given
  • live viral vaccines must be avoided
  • Cure via: bone marrow transplant (80-90% success rate if completed in the first 3.5 months)
209
Q

Adenosine deaminase deficiency (ADA) SCID

A
  • defective enzyme leading to toxic buildup of metabolites
  • ADA found on Chromosome 20, autosomal recessive
  • No thymic shadow, ADA found in T lymphocytes at levels 13x higher than other cells in the body
  • Phenotype: no B cells, no T cells, no NK cells
210
Q

Treatment for adenosine deaminase deficiency SCID

A
  • Bone marrow transplantation
211
Q

Ataxia- Telangiectasia

A
  • Defect in dsDNA repair via the ATM gene, NHEJ and HRR cannot repair/paste back together the broken strands because ATM cannot recognize they are broken
212
Q

Symptoms of Ataxia-telangiectasia

A
  • Recurrent infections
  • Difficulty walking
  • dilated superficial blood vessels (telangiectasia) in the conjunctivae and outer ear
  • HIGH IgM
  • poor response to immunizations
  • Low levels of CD4+, CD8+, and B cells
  • Lab diagnostic: radiosensitivity of EBV-transformed B cell line
213
Q

Hyper-IgM syndrome

A
  • CD40L deficiency (T cell problem)
  • failure of immunoglobulin class switching
  • X-linked, CD40L gene at Xq26
  • results in no lymph node germinal centers, failure to make protective antibody responses to infections and no immunological memory
214
Q

Treatment for Hyper-IgM syndrome

A
  • IV Ig globulin
  • bone marrow transplant
215
Q

Wiskott-Aldrich Syndrome

A
  • Defect in actin cytoskeleton reorganization resulting in multiple T cell functional defects
  • X-linked, WAS gene that makes the WASP protein (only expressed in WBCs and megakaryocytes)
  • T cell movement and NK function impaired
  • Thrombocytopenia with few and small platelets
  • increased infections with pyogenic bacteria
  • ECZEMA common (T cells cannot get to periphery)
216
Q

Chronic mucocutaneous candidiasis

A
  • T cell dysfunction, typically resulting from defects in IL17 or IL17 receptor genes –> Lose IL17 signaling
  • Noninvasive candida albicans infections are common in the mucous membranes and on the skin (T cells completely unreactive to the presence of candida- Th17 needed)
217
Q

Hyper-IgE syndrome (Job syndrome)

A
  • Defect in Th17 lineage differentiation from autosomal dominant defect in STAT3
  • causes recurrect staph skin abscesses, pneumonia, and very high serum IgE levels
  • patients retain their primary teeth
218
Q

Common variable deficiency

A
  • MOST COMMON adaptive immune system deficiency
  • Defect in B cell differentiation, failure to go through class switch recombination
  • Low levels of IgG, IgA, IgE, memory cells, and plasma cells
  • issues with peripheral B cell survival
  • usually presents after the AGE OF 2, and can be acquired LATER in life
  • increased risk of: pulmonary infections, lymphoma, and autoimmune diseases
  • NO CD27: no switching to memory B cells
219
Q

Petechiae

A
  • pinpoint round spots on the skin or mucosal surfaces due to bleeding from capillaries
  • red, brown, or purple clusters that look like a rash
  • flat, non-blanchable
  • 1-2mm
  • ** suggests platelet or small vessel/primary hemostasis problem
220
Q

Purpura

A
  • Red or purple discolored spots or blotches of skin or mucosal surfaces that do not blanch with pressure
  • from extravasation of blood from the tissue
  • > 3mm
  • usually problem of primary hemostasis
  • if palpable, consider vasculitis
221
Q

Ecchymosis

A
  • area of hemorrhagic discoloration larger than 1 cm (bruising)
  • color changes with time during resorption
  • when abnormal, suggests ** problem of secondary hemostasis (clotting)
222
Q

hematoma

A
  • extravasation of sufficient blood to create a palpable mass of blood
  • a solid swelling of clotted blood in tissues
  • when abnormal, suggests ** problem of secondary hemostasis (clotting)
223
Q

What are the platelet labs?

A
  • platelet count
  • bleeding time
  • ristocetin aggregation test for vWF
224
Q

Coagulation system tests:

A
  • prothrombin time (PT)
  • Activated partial thromboplastin time (aPTT)
  • thrombin time (TT)
  • mixing studies
225
Q

Fibrinolytic system tests:

A
  • FDP assay
  • D-dimer assay
226
Q

Why do we do a prothrombin time test?

A
  • Normal: 11-15 seconds
  • Tests for Factors 3, 7, 10, 2, 1
  • Used to detect final common pathway def (factor 10), a factor 7 deficiency, or to evaluate the severity of liver disease
227
Q

Why do we do an aPTT?

A
  • intrinsic and final common pathways
  • tests for factors 12, 11, 9, 8, 10, 5, 2, 1
  • used to monitor patients on heparin/hemophilia patients, and it standardizes reporting of PT results for patients taking warfarin (INR)
228
Q

Abnormal PT/PTT evaluation

A
  • rule out liver failure/insufficiency
  • major cause of elevated: DIC
  • diagnosis of true factor deficiency or a specific factor inhibitor on the differential
229
Q

Ristocetin aggregation test:

A
  • evaluates interaction of vWF with the antibiotic ristocetin (facilitiates binding of factor to platelets)
  • represented by graph curve: if the curve is flat then vWF is markedly decreased or absent
230
Q

Thrombin time (TT)

A
  • evaluates the last stage of the clot
  • evaluates for factor I
  • thrombin is added to the patients plasma in a test tube where it converts fibrinogen to fibrin to form a clot (seconds)
231
Q

Mixing studies:

A
  • tests the ability of mixing 0.5mL of normal plasma with 0.5mL of patient’s plasma to correct the prolonged PT or APTT
  • if corrected: true factor deficiency
  • if not corrected: circulating antibody against a factor
  • Checking with 50% factor activity
232
Q

Coagulation factor assay

A
  • uses plasma with known factor deficiency and assesses the ability of the patient plasma to correct that deficiency (mixing study)
  • if corrected: patient plasma contains adequate factor activity for the deficient factor in the test
  • if not corrected: patient plasma shares a defect in the factor deficient in the test sample
233
Q

Specific coagulation protein defects (antigen assay)

A
  • uses antibodies to determine the presence, absence, or concentration of a given factor
  • used in combo with activity assay to assess defects
    1. activity loss with preserved protein = dysfunctional protein
    2. activity loss due to protein loss = absent/decreased protein
234
Q

What does EDTA do?

A
  • disassociates GP2b3a complexes and aggregation studies are not possible
  • use sodium citrate as the anticoagulant instead
235
Q

What can flow cytometry assess for hemostasis?

A
  • platelet activation and expression of markers of secretion (P-selectin moves from granule to surface)
  • useful for Glanzmann thrombasthenia and Bernard-Soulier syndrome
236
Q

Global hemostasis assay (ROTEM)

A
  • real time analysis of clot formation, clot stability, and clot resolution from fibrinolysis
  • assesses clotting time and kinetics of clot formation, clot firmness, and clot lysis index
237
Q

Clinical manifestations of bleeding disorders: defects in primary hemostasis

A
  • easy bruising
  • Petechiae
  • purpura
  • ecchymosis
  • spontaneous bleeding from mucosal surfaces
238
Q

Clinical manifestations of bleeding disorders: defects in secondary hemostasis

A
  • prolonged deep bleeding into joints/muscles or hematomas
  • spontaneous bleeding (severe factor deficiency) or post-injury (mild factor deficiency)
  • hemoperitoneum
  • hemarthrosis
  • central nervous system hemorrhage
239
Q

What is hemostasis?

A
  • regulated process involving platelets, clotting factors, and endothelium occurring at a site of vascular injury culminating in the formation of blood clot, serving to prevent or limit bleeding
240
Q

What happens during hemostasis?

A
  • arteriolar vasoconstriction
  • primary hemostasis (formation of platelet plug)
  • secondary hemostasis (deposition of fibrin)
  • clot stabilization
  • clot resorption
241
Q

What regulates the balance between formation and dissolution of hemostatic plug ?

A

1.) Cellular component- platelet and endothelial cells (PMN and monocytes too)

2.) Plasma proteins- clot formation (coagulation), clot dissolution (fibrinolysis), and naturally occurring serine protease inhibitors (anticoagulation)

242
Q

Thrombosis

A
  • intravascular mass formed from blood components adherent to the vessel wall
  • Pathogenesis: Virchow triad of
    1. endothelial injury
    2. stasis or turbulence of blood flow
    3. blood hypercoagulability
243
Q

Potent vasoconstrictor that augments the fast reaction of the neuronal reflex:

A

Endothelin (endothelial cell derived vasoconstrictor)

  • it reduces blood flow to injury
244
Q

What causes primary hemostasis, the platelet plug?

A
  • exposed subendothelial Von Willebrand factor and collagen that promotes adherence of platelets to the site of injury and activation
  • platelet changes from round disc to spiky flat plates and release secretory granules that attract more platelets for aggregation
245
Q

What causes the secondary hemostasis, the deposition of fibrin?

A
  • Tissue factor exposed at the injury site (a procoagulant from smooth muscle cells and fibroblasts) binds and activates factor 7 — cascade –> generate of thrombin –> cleavage by thrombin of fibrinogen to fibrin for the meshwork
  • consolidation of the initial platelet plug
246
Q

What causes clot stabilization and resorption?

A
  • polymerized fibrin and platelet aggregates undergo contraction forming a solid permanent plug
  • prevents further hemorrhage
  • clot limited to injury site
247
Q

What do platelets require to function?

A
  • glycoprotein receptors
  • contractile cytoskeleton
  • 2 types of cytoplasmic granules (alpha and dense)
248
Q

What are the platelet alpha granules?

A
  • P-selectin adhesion molecule on membrane
  • contain fibrinogen, coagulation factor 5, and Von Willebrand factor
  • contain wound healing factors (fibronectin, platelet factor 4, PDGF, TFG-beta)
249
Q

What are the platelet dense granules?

A
  • ADP and ATP
  • ionized calcium
  • serotonin and epinephrine
250
Q

How are platelets binding to the surface of damaged endothelial cells?

A
  • Von willebrand factor bridge between GP1b and exposed collagen
  • shape change from GP2b3a increases affinity for fibrinogen
  • negative phosphatidylserine binds calcium
  • calcium serves as nucleation site for assembly of factor protens
251
Q

What is happening during primary hemostasis?

A
  • thrombin activates platelets through GPCR PAR (proteases activated receptor)
  • this releases ADP and initiates additional rounds of platelet activation
  • TXA2 is released (potent inducer of platelets)
252
Q

Which factors are vitamin K dependent?

A

Factors 2, 7, 9, 10

253
Q

What is the main initiator or coagulation?

A

in vivo tissue factor – cleaves 7 to 7a

254
Q

“Most important factor”

A
  • Thrombin 2a
  • various enzymatic roles
  • converts fibrinogen to fibrin
255
Q

What is plasmin?

A
  • a fibrinolytic that cleaves insoluble fibrin monomers and fibrinogen into fibrin and FDPs (which can be measured in lab for DIC)
  • it helps to break down a stable clot in order to restore blood flow
256
Q

FDP assay:

A

detects all breakdown products of fibrinogen or insoluble fibrin clots by plasmin

257
Q

D-dimer assay:

A
  • detects only cross linked insoluble fibrin monomers in a fibrin clot
  • screening for DIC and embolism
  • used to evaluate response to fibrinolytic therapy
258
Q

What factor is responsible for fibrin stabilizing factor crosslinking the fibrin?

A

Factor 8
- activated by thrombin and Calcium as a cofactor

259
Q

What limits coagulation in the blood?

A
  • restriction of clot to injury site
  • dilution (blood flow washes away activated factors)
  • negatively charged phospholipids are restricted to activated platelets at injury site
  • intact endothelium possesses inherent counter regulatory mechanisms
260
Q

What are the endothelial inherent counter regulatory mechanisms for platelet aggregation

A
  • antithrombin3
  • Prostacyclin
  • Nitrous oxide (NO)
  • ADP
  • low plasma Ca2+
261
Q

What are some natural anticoag effects in the body?

A
  • Thrombomodulin
  • endothelial cell Protein C receptor
  • Protein S
  • tissue factor pathway inhibitor
  • heparin-like molecules
262
Q

HIV classification

A
  • Retroviridae
  • dsRNA
  • Baltimore class 6
  • icosahedral nucleocapsid
  • enveloped (including gp120 and gp41)
  • Tropism: CD4+, chemokine receptor positive cells (CD4+ T cells, monocytes, and macrophages)
263
Q

What does the HIV particle consist of?

A
  • Protein capsid
  • protein matrix
  • phospholipid membrane
  • membrane glycolipids
264
Q

What are the 3 functional enzymes that facilitate infection in HIV?

A
  • reverse transcriptase
  • integrase
  • protease
  • (gag, pol, env)
265
Q

Gag

A

HIV capsid proteins (p24, etc)

266
Q

pol

A

HIV reverse transcriptase, protease and integrase

267
Q

env

A

HIV envelope glycoproteins gp120, gp41

268
Q

LTRs

A

HIV integrase sites, bind host transcription factors NFkB, Sp1, TBP

269
Q

What are the transcriptional regulators of HIV?

A
  • tat
  • rev
  • nef
270
Q

What is the initiation binding between HIV infection and host cell?

A
  • gp120 and CD4
  • host chemokine R (CXCR4, CCR5) and gp41
271
Q

What can occupy HIV1 binding site and block infection?

A
  • Stromal derived factor (SDF-1)
  • normally functions to bind CXCR4 on lymphocytes and direct their homing to tissues
272
Q

What does HIV integrase do?

A
  • forms a complex at each end of the DNA HIV-1
  • two bases removed at the 3’ ends, creating an overhang
  • integrase inserts the HIV genome into the host genome
273
Q

Steps of the HIV infection cycle:

A
  1. Binding of HIV envelope gp’s to host cell receptors
  2. envelope fusion with plasma membrane
  3. reverse transcriptase to dsDNA
  4. integration
  5. expression of regulatory genes (rev, nef, tat) from spliced
  6. expression of structural genes (gag, env, pol) from unspliced
  7. proteolytic processing of viral proteins
  8. assembly of viral particles and budding from host cell
274
Q

What is the main pathology of HIV-1 infection and how?

A
  • loss of CD4+ T cells
  • killing of both infected and non-infected helper T cells by binding of env to CXCR4 to induce autophagy and apoptosis
275
Q

What precedes the formation of antibodies against HIV?

A

a spike in p24 antigen (a capsid protein encoded by gag)

276
Q

How to diagnose HIV

A
  1. Screening ELISA
  2. confirmed by HIV1/2 discrimination ELISA or western blot
277
Q

What to monitor in patients with HIV

A
  1. CD4+ T cell enumeration by flow cytometry
  2. Polymerase chain reaction to measure viral RNA (nucleic acid testing, NAT)
278
Q

What is the most strongly antigenic protein in HIV?

A

the p24 capsid protein

279
Q

HIV screening and generations

A
  • 1st gen: Ab EIA at 50 days
  • 2nd gen: Ab EIA at 35 days
  • 3rd gen: ab EIA at 21 days
  • 4th gen: HIV p24 ag + Ab EIA at 18 days
  • NAT: detectable HIV RNA at 10 days
280
Q

CD4 counts in AIDS/HIV

A
  • normal: 600-1200
  • immunocompromised: <500
  • AIDS: <200
  • severe AIDS: <50
281
Q

Opportunistic infections seen in HIV

A

VIRAL: kaposi sarcoma, CMV

FUNGAL: candida, pneumocystis jirovecii

PROTOZOA: cryptococcus, toxoplasma gondii

282
Q

Major treatment turning point for HIV: ACTG 320 study

A
  • Zidovudine and lamivudine (NRTIs) with or without indinavir
283
Q

Amino acids with amino group side chains

A

-lysine
- glutamine
- arginine

284
Q

Megakaryocytes are:

A
  • polyploid
  • they undergo genome replication without cytokinesis (no division)
  • they start making platelets at about 16N, and can be up to 64N
285
Q

What is a podosome?

A

megakaryocyte projections around endothelial cells and into circulating vasculature. Platelets bud off

286
Q

What is unique about platelets?

A
  • they are granulocytes (they contain clot promoting substances)
  • they have glycoprotein receptors (GP2b/3a) for fibrinogen
  • canalicular network that greatly increases their surface area
  • have mitochondria and glycogen stores
287
Q

What do GP1a and GP1b bind to?

A
  • GP1a and collagen
  • GP1b and von willebrand factor
  • this tethering causes platelet activation
288
Q

What binds fibrinogen and aggregates proteins?

A
  • Tethering of a platelet to the site of damage exposes the GP2b/GP3b complex
289
Q

What links platelets together?

A

-release of ADP, thrombin, and TXA2 released from the platelet signal in autocrine and paracrine fashion to activate GP2b/GP3a and that binds to fibrinogen which links platelets together

290
Q

What two things happen when platelets become activated?

A
  1. they extend pseupodia and increase their surface area
  2. concentration of phosphatidylserine at the solvent exposed membrane to increase the negative charge of the membrane
291
Q

Zymogen enzymes that are serine proteases

A
  • factor 7
  • factor 9
  • factor 10
  • factor 11
  • factor 2 (prothrombin/thrombin)
292
Q

Zymogen enzymes that are transaminases

293
Q

Cofactors of coagulation

A
  • Tissue factor
  • Factor 5
  • factor 8
294
Q

Regulatory proteins of coagulation

A
  • Protein S
  • Protein C (activated by cleavage via serine protease)
  • Thrombomodulin
295
Q

Vitamin K

A
  • Main dietary: Phylloquinone, green leafy veg
  • Oxidized form from fermentation: Menaquinone
  • Synthetic: Menadione
  • Pharmaceutical for newborns: Phytonodione
296
Q

Why is vitamin K important in coagulation?

A

-the hydroquinone form made by vitamin K reductase is the active cofactor for vit. K dependent carboxylase.
- it forms an epoxide during the carboxylation of glutamates near the amino terminus in factor zymogens
- epoxide reductase regenerates vitamin K

297
Q

Why is glutamate carboxylation in coagulation factors important?

A
  • increases the negative charge to allow interaction through a calcium bridge
298
Q

Factor 13 cross-links fibrin peptide chains through:

A

transamination of lysine and glutamine side chains, covalently linking them

299
Q

Antiplatelet, anticoagulant, profibrinolytic

A

Antiplatelet: NO, CD39 (ADPase), prostacyclin/PGI2

Anticoagulation: Heparin sulfate, Thrombomodulin, EPCR, TFPI

Profibrinolytic: t-PA, u-PA

300
Q

What is the major circulating thrombin inhibitor?

A

Antithrombin3

  • heparin facilitates the formation of the inhibitory thrombin/antithrombin3 complex
301
Q

What does thrombomodulin do?

A
  • binds thrombin and sequesters its protease activity
  • thrombin/thrombomodulin complex activates protein C, which complexes with protein S to destroy coagulation cofactors
302
Q

Bivalirudin and Hirudo medicinalis

A
  • Leech that produces hirudin in its saliva that can bind and inactivate circulating and clot-bound thrombin, preventing coagulation and allowing the leech to eat a blood meal
303
Q

What encourages fibrinolysis?

A
  • serine protease plasminogen activated by tPA (tissue plasminogen activator) which then acts on fibrin to degrade the clot
304
Q

What does beta-hemolytic streptococci produce?

A
  • streptokinase which can produce an autocatalytic complex with plasminogen leading to cleavage and activation of plasmin to degrade fibrin
305
Q

What is a circulating protein that binds and inhibits plasmin?

A

alpha-2 antiplasmin

  • its role is to inactivate any plasmin that is freed from the dissolving clot after fibrinolysis
306
Q

What is a D-dimer?

A

laboratory measurement of a fibrin degradation product. D-dimers are the fragments of cross-linked delta fibers

307
Q

Hemostasis four stages

A
  1. vascular constriction limits the flow of blood to the area of injury
  2. platelets become activated and aggregate at the site of injury, forming a temporary loose platelet plug (AKA primary hemostasis)
  3. a fibrin mesh/clot forms and entraps the plug (AKA secondary hemostasis)
  4. clot is dissolved in order for normal blood flow to resume following tissue repair
308
Q

Most common therapeutic uses for anticoag drugs

A
  • venous thromboembolism
  • atrial fibrillation
  • acute coronary syndrome (angina/MI)
  • stroke
  • angioplasty/cardiopulmonary bypass surgery
309
Q

Antiplatelet drug overview:

A

1.) COX inhibitors: aspirin
2.) ADP receptor antagonists: clopidogrel, prasugrel
3.) PAR antagonist: vorapaxar
4.) GP2b/3a inhibitors: abciximab, eptifibatide, tirofiban
5.) adenosine reuptake inhibitor: Dipyridamole

310
Q

Aspirin

A
  • acetylsalicylate
  • MECH: irreversible inhibitor of COX1/2
  • SE: bleeding, GI disturbances, tinnitus at high doses
  • low dose= antiplatelet, high dose= anti-inflammatory effects
311
Q

ADP Receptor antagonists

A
  • Clopidogrel, prasugrel, ticlopidine
  • MECH: irreversible ADP receptor antagonist that prevents activation of ADP receptor
  • Oral
  • SE: BLEEDING, nausea, diarrhea, rash, severe leukopenia, thrombotic thrombocytopenic purpura (TTP, usually from ticlopidine)
312
Q

Different SE in ADP receptor antagonists

A
  • clopidogrel and prasugrel have fewer SE
  • Clopidogrel may require CYP2C19 activation
  • Prasugrel should NOT be prescribed with hx of stroke
  • irreversible drugs that last the life of the platelet
313
Q

New ADP receptor antagonists that are reversible

A
  1. Ticagrelor
  2. Cangrelor (IV)
314
Q

PAR antagonist

A
  • Vorapaxar
  • MECH: inhibits thrombin induced platelet aggregation
  • SE: risk of intracranial hemorrhage, contraindicated with Hx of stroke
315
Q

GP2b/3a receptor inhibitors

A
  • Abciximab (humanized MAB), Eptifibatide (fibrinogen analogue), tirofiban (non-peptide competitive inhibitor)
  • MECH: inhibits final common pathway for platelet aggregation, short duration of action
  • SE: bleeding, thrombocytopenia (in chronic use)
316
Q

Adenosine reuptake inhibitor

A
  • Dipyridamole
  • MECH: phosphodiesterase 3 inhibitor, inhibits platelet uptake of adenosine and thus increases adenosine interaction with adenosine 2 receptor to increase levels of cAMP and inhibit platelet activation
  • SE: headaches common because it is also a vasodilator
317
Q

What is the best treatment combination for anticoagulation?

A
  • Aspirin + clopidogrel
  • orally available
  • watch for bleeding
  • do not use prasugrel if Hx of stroke
318
Q

Anticoagulant drug overview:

A

PARENTERAL
1. indirect thrombin inhibitors (Heparin, LMWH, fondaparinux)
2. Direct thrombin inhibitors (Bivalirudin, argatroban)

ORAL
1. Direct oral anticoagulant (Rivaroxaban 10a, Dabigatran 2a)
2. Vitamin K analogue (warfarin)

319
Q

Heparin/ indirect thrombin inhibitors

A
  • mix of sulphated glycosaminoglycans at variable molecular weights and lengths
  • MECH: Binds to antithrombin and acts as an agonist for its effects resulting in inhibited Thrombin and Factor 10
  • SE: thrombocytopenia in heparin (IgG against factor 4?) , low bioavailability, check kidney fxn for LMWH and fonaparinux
320
Q

Protamine reversal drug

A
  • highly basic, positively charged peptide that combines with negatively charged heparin to form a stable complex that lacks anticoagulation activity
  • only binds long heparin molecules,/ incompletely reverses LMWH and does NOT reverse fonduaparinux
321
Q

aPTT

A
  • intrinsic pathway
  • used to monitor heparin effectiveness (normal is 2-4min)
  • normal PTT times require factors: 1, 2, 5, 7, 9, 10, 11, 12 (2 and 10 most important)
322
Q

Direct thrombin inhibitors (parenteral)

A
  • Bivalirudin, argatroban
  • MECH: bind directly to thrombin and inhibit the enzyme
  • IV, in place of heparin if hx of heparin-induced thrombocytopenia
323
Q

Direct oral anticoagulants

A
  • Rivaroxaban (factor 10 inhibitor)
  • monitoring not needed, no antidote
  • Dabigatran (factor 2/thrombin inhibitor)
  • MECH: binds directly to thrombin
  • idarucizumab is the antidote, antibody of the drug
  • SE: GI bleeding more likely
324
Q

Warfarin

A

-MECH: inhibits conversion of oxidized vitamin K epoxide into its reduced form, vitamin K hydroquinone (inhibits VKORC1 which does the gamma-carboxylation of factors)
- affects factors: 2, 7*, 9, and 10, and protein C
- SE: BLEEDING, DRUG INTERACTIONS, GI upset, cutaneous necrosis, chondrodysplasia punctata

325
Q

PT and INR

A
  • extrinsic pathway
  • recalcified plasma clots in 12-14 seconds if you add thromboplastin
  • Increased INR in warfarin pts, normal: 1.0, them >1.8
326
Q

chondrodysplasia puncta

A

Birth defect in 1st trimester exposure to Warfarin

327
Q

Which enantiomer of warfarin is more active?

A

S-enantiomer
- S and R are metabolized by different CYPs

328
Q

If too much warfarin:

A
  1. stop the drug
  2. add vitamin K/phytonadione/prothrombin complex concentrates/ recombinant factor 7a
329
Q

Fibrinolytic drugs

A
  • Alteplase, reteplase, tenecteplase
  • MECH: preferentially activate plasminogen that is bound to fibrin which confines it to the thrombus rather than systemic activation
  • only thrombolytics approved for stroke
  • IV, narrow spectrum of use
  • SE: BLEEDING, systemic lytic state, expensive
330
Q

Absolute contraindications to thrombolytic therapy

A
  • prior intracranial hemorrhage
  • cerebral vascular lesion
  • malignant intracranial neoplasm
  • Ischemic stroke within 3 months
  • aortic dissection (real or suspected)
  • active bleeding/bleeding diathesis (excluding menses)
  • significant closed-head trauma or facial trauma within 3 months
331
Q

Aminocaproic acid reversal drug

A
  • potent inhibitor of fibrinolysis
  • blocks the interaction of plasmin with fibrin
  • limited use
332
Q

Warfarin pharmacokinetics and dynamics

A

Pharmacokinetics:
• enzyme induction
• enzyme inhibition
• reduced plasma protein binding

Pharmacodynamics:
• reduced clotting factor synthesis
• competitive antagonism with vitamin K
• hereditary resistance to oral anticoagulants
• individuals varying in the magnitude of the response

IHO (6 decks)

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