Sickle Cell Anemia/Hemophilia Flashcards
What are sickle cell syndromes caused by?
Inherited disorder of of the B-globin gene
(HbA is normal)
-the alpha chains are normal but there is a substitution of valine for glutamic acid on the beta chains.
What is HbF?
Fetal hemoglobin
- 2 alpha chain and 2 gamma chains
- it is less likely to sickle
What is sickle cell trait?
Heterozygous =HbAS
- usually asymptomatic (sometimes can see symptoms at times of high stress or at high altitudes)
- carriers
If both mother and father have SCT, what are the changes their child will have SCD, SCT, or normal
25% SCD
50% SCT
25% normal
How is SCD distributed racially and geographically?
- more common in blacks and hispanics
- common worldwide but especially in Africa, India, Saudi Arabia and Mediterranean countries
What is the genotype of sickle cell disease (SCD)?
Homozygous HbSS
What are genral long term complications of SCD?
- chronic organ damage
- cognitive impairment
- frequent hospitalizations
- school and work difficulties
How do RBCs differ in SCD and what problems does this cause?
RBCs are bioconcave
- problem because RBC cannot get through microvasculature=impair circulation
- causes clotting and sludging
- sickled hemoglobin polymerization-fibrin=hard edges
- causes membrane damage
- abnormal shape=marked for destruction
- stasis of blood flow
What the clinical manifestations of SCD?
- impaired circulation
- destruction of RBCs
- stasis of blood flow
How is hemoglobin solubility affected by SCD?
In the oxygenated state it is the same, but in the deoxygenated state-the HbS is less soluble= see fibrin deposition
What is the cause of sickled RBCs?
In the deoxygenated state, the solubility of HbS is lowered and the RBC becomes unstable and goes into the sickled state
- for a while it will cycle between the two shapes but eventually becomes damaged and looses its flexibility and the cell becomes permanentally sickled
- this is when you start to see obstruction of blood flow
What is an irreversibly sickled cell? What happens when cells become irreversibly sickled?
- continual replications of shape causes loss of membrane flexability and fibrin deposits and eventually the cell becomes permanently sickled
- this leads to slow blood flow through microcirculation and causes the sickled cells to adhere to endothelial cells= tissue damage=release of tissue factor=release of platlets= clotting cascade=further complicates circuation problems
- this further increases blood flow obstruction
How does SCD affect the RBC life span and how will this show up on labs?
The lifespan is much shorter (goes from a few months to 16-20 days)
- low Hb on labs
- body recognized not normal and markers for destruction
How does SCD affect the spleen and what is the result of this?
Obstruction of blood to spleen causes functional asplenia
- this increases susceptibility to infection
- spleen is generally what cleans out RBCs marked for destruction so it can get very large = spleen not working as well=increased risk for infection
- too busy destorying marked RBCs
Why do people with SCD tend to have coagulation abnormalities and bleeding events
- as sickle cells cause damage to microvasculature, tissue factor is being release and overconsumption of clotting factor
- at risk for bleeding events
What types of infection are those with SCD especially susceptible to?
-encapsulated organisms
(pneumococcal bacteria)
-group B strep
-Haemophilis influenzae
When does SCD present and what does it present as?
Within first year of life= Typically 4-6 months after birth (that’s how long HbF takes to change to S)
- labs=hemolytic anemia- continually drop
- vaso-occlusion=pain and swelling in hands and feet
How are children typically diagnosed with sickle cell disease?
genetic screening at birth
- typically don’t have to present with problems
- get on therapies early
What symptoms will someone with SCD present with if not previously screened
- pallor
- fever
- arthralgia
- abdominal pain
- weakness/fatigue (hemolytic anemia)
- anorexia
What are some clinical findings you would see in SCD?
- enlargement of liver, spleen and hear from sequestered blood cells
- hematuria (blood in urine)
- low Hb
- elevated reticulocytes-body trying to make up
- elevated WBC/platlets from stress
- will see sickled RBC in peripheral blood
How is SCD generally treated?
- no cure except bone marrow transplant-but most don’t do it
- disease modifying therapies
- preventive medical interventions
- supportive care-role of pharmacist- pain meds
What are the goals of SCD therapy?
-important to start early and to see specialists
-reduce hospitalizations and complications
-increase life span
(average=42-48)
What are important immunizations for those with SCD?
Pneumococci (prevnar-PCV13 between age 6-18 and pnuemovax-PPSV23 at age 2 and every 5 years)
-Influenza-pulmonary problems
What pneumococci vaccine is recommended for functional asplenia?
Pneumovax
- PPPSV23
- every 5 years
When is pnumovax (PPSV23) given and why?
At age 2 and every 5 years because it induces a poor antibody response
When is penicillin prophylaxis given to those with SCD and what is the dosing regimen?
- PCN 125mg BID until age 3
- PCN 250mg BID though age 5
- No benefits at age 6 and above unless history of invasive pneumococcal infection or surgical splenectomy
What disease modifying agents are available for SCD and what do they do?
- fetal hemoglobin inducers
- increase HbF which correlates with decreased sickling
What is the goal HbF levels in disease modifying therapy?
levels of greater than 20% reduce risk of complications
-low HbF=more frequent pain and mortality
What agents can be used to induce fetal hemoglobin?
hydroxyurea=most common
decitabine-for hydroxyurea non-responders
How does hydroxyurea stimulate HbF production?
Exact mechanism unknown
- possible cytotoxic effect on bone marrow (also used for leukemia) stimulates stress erythropoiesis triggering HbF production?
- nitric oxide released from metabolism may contribute to vasodilation= more room for sickle cells
- increases RBC size and improves cellular deformability
What are important points from the MSH trial and other trials of hydroxyurea use in SCD?
- reduced painful episodes, ACS (acute chest syndrome) , need for blood transfusion and mortality
- really showed importance because patient felt better and lived longer
- if you start it early (after 9 months) can even prevent some end organ damage
What are the indications for hydroxyurea?
- frequent pain episodes
- severe anemia
- history of ACS
What should patients diagnosed with SCD be started on no matter how many pain crisis they are having?
hydroxyurea
Is hydroxyurea safe to use in children?
Yes, does not appear to impact growth and development
- may start at 9 months
- may even preserve splenic function
Can hydroxyurea be used for stroke prevention?
Yes, has shown some effectiveness if patient doesn’t tolerate transfusion therapy
What side effects should you keep in mind about hyroxyurea?
- bone marrow suppression (recover within 2 weeks of holding therapy)
- abndmial pain
- elevated LFTs-liver function tests
- Alopecia (patchy hair loss and thinning)
- reproductive-teratogenic- but has been done-talk to doctor
- WATCH contamination
What monitoring is required by hydroxyurea?
- check CBC monthly (weekly for first month) and hold doses for bone marrow suppression seen as decrease in WBC, hemoglobin and platlets
- renal and liver function tests-hold dose for greater than 50% decrease in SrCr or 100% increase in liver function tests
What should you do if you notice low WBC (AN less than 500) and platelets in a patient on hydroxyurea?
-hold hydroxyurea for about 2 weeks
Why is chronic blood transfusion therapy given to SCD patients?
- to prevent stroke
- reduced frequency of vaso-occulsive pain and ACS if they don’t tolerate hydroxyurea or it doesn’t work
What is the goal of chronic transfusion therapy?
Maintain HbS levels of less than 30%
How often are transfusions given in chronic transfusion therapy?
Every 3-4 weeks, adjusted to maintain less than 30% HbS cells
What are the risks of chronic transfusion therapy?
Alloimmunization-antibodies to RBCs that destory them
- Iron overload=end organ damage
- hyper-viscosity-blood thicker-risk for clots
- viral transmission-more safe now
- volume overload
What are patients on chronic transfusion therapy counseled to avoid extra iron?
there is a risk for iron overload-which can cause end organ damage
What is used to treat iron overload?
- iron chelators
- desferal- SC or IV infuson (falling out of favor)
- deferasirox (Exjade)- oral- dissolved in OJ, apple juice, water-does have REMS control
Why are SCD patients at higher infection risk?
-functional asplenia and impaired antibody production
How can infections be prevention in SCD?
vacinations and PCN prophylaxis
When does a person with SCD need to be evaluated to determine if they have an infection?
If they have a fever of greater than 101
- can get really sick, really fast
- need IV antibiotics quickly
What are the criteria for hospitalization of patients with SCD for infection if fever over 101
- fever over 104
- infant less than 1
- WBC over 30,000
- history of bactremia/sepsis
What infections are SCD patients at higher risk for?
encapsulated organisms such as streptococcus pneumonia, haemophilus influezae, neisseria meningitidis, salmonela
What are good antibotic options for infections in SCD?
ones that cover encapsulated organisms such as ceftriaxone, ceotaxime or clindamycin if PCN allergy
What are acute complications of SCD?
infection, neurologic, acute chest syndrome, splenic sequestration, pain crisis
What is the cause of neurologic SCD complications?
cerebrovascular occlusion
-can cause overt stroke, headache, paralysis, aphasia, visual disturbances, facial droop and seizure
Who is at highest risk for neurologic SCD complications?
- increased risk with increasing age
- highest risk when very young
- high risk of recurrence
Treatment for cerebrovasucalr occusion as a result of SCD?
- hospitalization
- transfusions to maintain HbS below 30%
- children-start chronic tranfusions
- need to check with CT scans and MRIs every 2 hours in hospital
What is the causes of acute chest syndrome (ACS) in SCD?
vaso-occlusive crisis in pulmonary vasculature
- tissue damage
- can cause secondary infection
What does ACS present as?
=pumonary infiltrate
cough, shortness of breath dyspnea, tachypena=increased respitory rate (35-50) chest pain, fever, wheezing, new onset hypoxia (low O2)
Why start antibiotic therapy when a patient presents with ACS?
Risk for infection secondary to the pulmonary occlusion
What are risk factors for ACS in SCD?
young age (typically less than 5) , higher Hb, higher leukocytes, history of asthma, smoke exposure
What should be done to treat ACS in SCD?
- pain management (without analgesic induced hypoventilation)
- use broad spectrum antibiotics early (macrolide or quinolone) for secondary infection
- oxygen in hypoxic or acute stress
- transfusion if severe with worsening hypoxia and increased work of breathing
What happens during splenic sequestration in SCD?
sudden massive enlargement of spleen
- sickled RBCs sequestered in parenchyma (a lot of RBC’s to destroy)
- Hb falls quickly
- decrease in circulating blood= hypotension and hypovolemia shock
What can repeated splenic infarction causes?
autospenectomy- spleen there but doesn’t function-called functionally asplenic
-generally really young patients
Who is at most risk for splenic sequestration?
Infants and children
- declines in adolescence
- spleen don’t really function anymore so the blood doesn’t go there
Treatment of splenic sequestration?
- RBC transfusion to correct hypovolemia and high HbS
- broad spectrum antibiotics to prevent infection from precipitating sequestration
- splenectomy in life threatening or repetitive episodes
What is the cause of pain crisis in SCD?
-vaso-occulusion leading to bone and muscle infarctions at single or multiple sites
What is the most common reason for hospitalization from SCD?
pain crisis
What are risk factors for pain crisis?
fever, infection, dehydration, hypoxia, acidosis
-stressful times in life can trigger
How do you treat mild pain crisis from SCD?
mild-outpatient-oral analgesics (NSAIDS, acetaminophen), fluids, rest- if persistent add opioid combo (Norco, Percocet)
How do you treat moderate to severe pain crisis from SCD?
hospitalization, transfusions, fluids if dehydrated
How do you treat moderate pain crisis from SCD?
combo therapy with opioid (Norco, Percocet)
How do you treat severe pain crisis from SCD?
aggressively with opioids (morphine, hydromorphone, fentanyl, methadone-helps with neuropathic pain)
Why do patients with SCD need high dose opioids long term?
tolerance develops
- in severe pain
- NOT opoid navie
- can try a different
- talk to the patient about what works with them
What is PCA or patient controlled analgesia?
for severe pain for pain crisis
Advantage of PCA in pain crisis
better monitoring of patient’s drug use
less risk of over/under dosing
Disadvantage of PCA in pain crisis
cost
continuous narcotic
Controllable elements in PCA
- drug chosen
- basal rate
- PCA interval
- PCA bolus dose
What are the complications from pain crisis?
- may develop neuropathic pain- doesn’t respond to traditional opiods (methadone will work)
- may miss school for days (watch for kids wanting this)
- develop drug familiarity and can be mistaken for drug seekers
Chronic pulmonary and cardiac complications of SCD?
- pulmonary hypertension
- cardiac enlargment
- LVEF (left ventricular ejection fraction) decreased
Chronic skeletal complications of SCD?
osteonecrosis and osetomyelitis
Chronic ocular and GI complications of SCD?
- retinal hemorrhage
- cholelithiasis
Chronic renal complications of SCD?
- sickle cell nephropathy
- chronic renal failure in 30%
Chronic growth and psychiatric complications of SCD?
- depression and anxiety
- delayed growth and development
What patients may be appropriate for a allogenic stem cell transplant?
- younger than 16
- severe form of SCD with a lot of complications
- available sibling dono
What is the only cure for SCD? Why don’t more patients do it?
- allogeneic stem cell transplant
- significant toxicities- high dose chemo, 40% mortality
- giving a new immune system, have graft vs host problems
What is a mab in the works for SCD? How does it work?
Crizanlizumab
- binds P selection and blocks gp ligand 1
- decrease number of pain crisis
What is hemophilia?
group of related bleeding disorders that are inherited
vWD, hemophilia A/B
Is von Willebrand disease, Hemophilia A or B more common?
von willebrand disease
Where is hemophilia most found?
evenly distributed geographically and racial groups
Who does vWD affect?
1% of population
males = females
Who does hemophilia A affect?
1/5000 male births
factor VIII deficiency
hemophilia A
factor IX deficiency
hemophilia B
Who does hemophilia B affect?
1/30,000 male births
Etiology of hemophilia
X linked inherited disorder
Females obligate carriers
Spontaneous mutation in 33% of males
Symptomatic female carriers of hemophilia
mild disease
Role of vWF
platelet adhesion (site of vascular injury)
What happens in defects in vWF?
decreased platelet adhesion
bleeding of mucous membranes/soft tissues
role of factor VIII carrier protein
increases half life: minutes to hours
Type I vWD
reduction in normally functioning vWF
Type 2 vWD
dysfunctional vWF
Type 3 vWD
complete absence of vWF
Severe hemophilia
<1% factor activity or <0.01 IU/mL
spontaneous bleeding more common
Moderate hemophilia
> 1 and <5% factor activity
Mild hemophilia
> 5% to <40% factor activity
At what age do you start to see initial presentation of hemophilia?
3 months to 2 years
- later onset with mild/moderate
Initial presentation of hemophilia
suspicious bleeding events (bleeding with circumcision)
Common bleeding sites in initial presentation of hemophilia
- CNS
- hemarthrosis
- skeletal muscle
- GI tract
- GEN tract
- post traumatic bleeding
Hemarthrosis in infants in hemophilia
irritability
decreased use of limb
hemarthrosis in children in hemophilia
prodromal stiffness
warm sensation
acute pain and swelling
CNS bleeding site in hemophilia
- intracranial hemorrhage
- HA, vomiting, lethargy
- seizure in perinatal period
Skeletal muscle bleeding site in hemophilia
- quadriceps, forearm
- severe = loss of limb
GI tract bleeding site in hemophilia
- lesions anywhere along GI tract
- hematoma of bowel wall (pseudo appendicitis)
Post traumatic bleeding in hemophilia
delayed bleeding common
may persist for weeks
GEN tract bleeding in hemophilia
hematuria: benign
Prognosis of hemophilia if no treatment
severe disease premature death
Prognosis of hemophilia if standard factor replacement therapy
life expectancy approaches general population
Long term complications of hemophilia
- joint abnormalities
- transmission of inaction
- development of inhibitors
Join destruction in hemarthrosis
- tissue deposition of iron
- dense fibrosis/contractures
- limitation of motion
risk factors of hemarthrosis
- older age
- non-Caucasian
- increased BMI
number and severity of bleeding with hemarthrosis
- correlate with function and QOL
- chronic pain and disability
Additional therapy for hemarthrosis
- GC burst (reduce synovial inflammation)
- joint aspiration (factor replacement)
- rest and splinting of joint (followed by ROM)
Infection and hemophilia
- reduced with donor screening and virucidal techniques
Older factor VIII/IX products are at high risk for
hep B and C
HIV
hepatocellular carcinoma
Current infectious risks of factor VIII/IX
parvovirus B19
CJD
Goal of therapy for bleeding episodes in hemophilia
- replace deficient endogenous protein
Management strategies for bleeding episodes in hemophilia
PRN treatment
prophylaxis
Desmopressin can be used for what hemophilia type?
vWD
- bleeding episodes and prevention
T/f you can give desmopressin more than every 24 hours
false
- tachyphylaxis occurs if more than 24 hours
depletion of vWF from endothelial stores
ADE of desmopressin
- dose and age related
- facial flushing
- HA
- HTN
- retention of free water
Factor VIII concentrates can be used for what diseases?
hemophilia A
vWD
Factor IX concentrates can be used for what diseases?
hemophilia B
How do factor concentrates work?
provide deficient protein allowing for hemostasis
Where do factor concentrates come from?
plasma source
recombinant product
What do you consider with dosing factor concentrates?
- site and severity of bleed
- type of hemophilia
- presence of inhibitor
What do you consider with target concentration with factor concentrates?
depends on bleed
- less severe lower concentrations for shorter periods than severe bleeding events
How else can you give factor concentrates?
bolus therapy
VIII: 8-24 hours
IX: 12-24 hours
Factor concentrate monitoring
- after admin of factor
- immediately before surgery
- daily to achieve target concentrations
goal of prophylactic therapy in hemophilia
- maintain factor levels >1%
factor 25-40 units/kg 3 times per week
Primary prophylactic therapy in hemophilia
- regular replacement starting at 2 years
- done before bleeding event
Secondary prophylactic therapy in hemophilia
- started >1 bleed into target joint
- prevent further joint/organ damage
Intermittent prophylactic therapy in hemophilia
- moderate/mild deficiency
- based on activity and factor level
Concerns with prophylactic therapy in hemophilia
- cost $$$$
- central venous access
- thrombosis risk
- infection
- commitment
- unnecessary treatment
Plasma products
factor purified from humans with monoclonal antibodies
factor product selection
- risk of viral transmission
- categorized based on purity
Recombinant products
genetically engineered proteins produced in animal or human cell lines
- made from modified VIII gene
What cells can you get modified factor VIII?
- baby hamster kidney (BHK)
- chinese hamster ovary (CHO)
- human embryonic kidney cells (HEK)
First gen factor selection
- contain bovine/human proteins in culture medium AND final product
second gen factor selection
bovine or human proteins in culture medium, NOT in final product
- stabilized with sucrose
third gen factor selection
NO bovine or human proteins
What have factor VIII and vWF products?
- Humate-P
- Koate-DVI
- Alphanate
- Wilate
What have factor IX plasma source?
PMonoNine
AlphaNine
What have factor IX third gen recombinant?
BeneFIX
Ixinity
Rixubis
What factor VIII products are long acting?
Adynovate
Eloctate
**10-22 half life
What factor IX products are long acting?
Alprolix
Idelvion
***66-93 half life
Inhibitors in hemophilia
development of antibodies to neutralize factor
30% severe hem A
3-5% severe hem B
Clinical manifestations of inhibitors in hemophilia
increase in bleeding frequency
difficulty treating bleeding episodes
How are inhibitors measured in hemophilia?
bethesda units
1BU = amount of inhibitor needed to inactivate 50% of FVIII in equal volume of pooled plasma
Treatment of acute bleeding with inhibitors in hemophilia
- high dose factor replacement (low inhibitor)
- recomb VIIa
- FEIBA
- Obizur
- immunotherapy
Obizur is only for what hemophilia?
A
Immune tolerance induction (ITI) in inhibitor hemophilia
60-80% effective
- repetitive doses of VIII
- maintained by continued exposure to factor VIII
Alternative agent for hemophilia
emicizumab
Prophylaxis with emicizumab
- with or w/o inhibitors
- helpful in ITI ineffective
NOT FOR ACUTE BLEEDS
HAVEN 1 trial
emicizumab: prophylaxis with inhibitors
HAVEN 3 trial
emicizumab: prophylaxis without inhibitors
BBW for emicizumab
thrombotic events and thrombotic microangiopathy
**patients with inhibitors receiving bypassing agent
