Sickle Cell Disease, feat Dr. David Abel
/Here’s the RoshReview Question of the Week:
Which of the following is a precipitating factor for a painful crisis in a pregnant woman with sickle cell disease?
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Today we’re joined once again by Dr. David Abel, an assistant professor in the Department of Obstetrics and Gynecology at Oregon Health Sciences University. Dr. Abel has previously joined us to talk about thalassemias and von Willebrand’s disease — he shares his passion for blood disorders again with us today to talk more on sickle cell!
Listen to our last sickle podcast here.
Epidemiology of Sickle Cell Disease (HbSS)
Most common inherited hemoglobinopathy in the United States, and in fact is the most common inherited disease worldwide.
Autosomal recessive fashion — both parents need to be carriers.
Affects approximately 10 million people worldwide and approximately 100,000 people in the United States.
This translates into a prevalence of about 1 in 375 who have the disease.
Predominantly affects people of African ancestry
Two thirds of those that are affected reside in West Africa.
50% of children born with sickle cell disease are born in Nigeria.
Sickle Cell Trait: 1 in 12 are carriers.
In the United States, approximately 7% to 9% of the African American population.
As the gene is widely distributed, other populations may be affected including those residing in the areas of the Mediterranean, Caribbean, South and Central America, as well as East India.
More than 90% of children with sickle cell disease in the United States survive into adulthood.
Compared to the general population, however, their lifespans are two or threedecades shorter and limited by both acute and chronic morbidity.
Sickle cell trait confers a survival advantage in malaria-endemic regions such as in sub-Saharan Africa where almost 80% of individuals with sickle cell anemia live — resulting in “positive screening” with respect to human evolution.
Hemoglobin Structure in Sickle Cell and Pathophysiology
Remember: thalassemias represent quantitative defects globin synthesis. By contrast, hemoglobin S is characterized by a qualitative defect of the beta globin gene.
HbS results from a single nucleotide substitution, an adenine- to-thymine substitution in the sixth codon of the beta globin polypeptide which replaces glutamic acid with valine.
From this one amnio acid change, rather than forming tetramers, under conditions of low oxygen tension, this hemoglobin S forms long inflexible chains or fibers.
They distort the red blood cell membrane, resulting in this sickled shape.
These distorted red blood cells are destroyed by the reticuloendothelial system, resulting in a moderate to severe anemia.
Compared to the normal life span of a red blood cell of 120 days, the life span of these sickled red blood cells is reduced to an average of 15 days.
These distorted red blood cells clog up the microvasculature —> obstruction and local ischemia which clinically manifests as a vasoocclusive crisis.
Repeated vasoocclusive crises can lead to interruption of normal perfusion of multiple organs, including the spleen, lungs, kidneys, heartand brain.
Adults with sickle cell disease are essentially functionally asplenic — increased incidence and severity of infection in patients with sickle cell disease.
Sickled red cells are also prone to lysis which releases free hemoglobin.
Damages the endothelium and may also lead to thrombosis.
Also consumes nitric oxide, an important vasodilator and thus can lead to an exacerbation of the ischemia.
Testing for Sickle Cell Disease and Trait
Foundation of screening: CBC, Hb electrophoresis. High suspicion in patients with family history / ancestry and MCV < 80.
HbSS (disease) electrophoresis:
85-95% hemoglobin S
Remaining mostly hemoglobin F, small component of hemoglobin A2
HbSB (trait) electrophoresis (assuming normal second beta gene):
50-60% hemoglobin A (normal adult Hb)
35-45% hemoglobin S
Small amounts hemoglobin F, hemoglobin A2
There are many other sickle genotypes:
Homozygous hemoglobin SS constitutes about 70% of these genotypes.
Hemoglobin C, which differs from hemoglobin S only in that the amnio acid lysine instead of a valine replaces glutamic acid in the beta globin gene, can exist in combination with hemoglobin S, thus is called hemoglobin SC disease.
Hemoglobin S may coexist with beta-thalassemia.
Hemoglobin S beta thalassemia zero is also identified as sickle cell anemia and is just as severe as hemoglobin SS.
Hemoglobin S beta thalassemia plus is not as severe as there is some hemoglobin A that is preserved.
Maternal and Fetal Considerations with Sickle Cell
During pregnancy, the increase in red blood cell mass that normally occurs does not in those with sickle cell anemia.
50%–70% of pregnancies with sickle cell disease require at least one hospitalization
30%–40% will require a transfusion.
In the United States, the maternal mortality rate is approximately 10 times higher than it is for patients without sickle cell disease.
Vasoocclusive Crisis / Pain Crisis is most common cause of recurrent morbidity.
Can be precipitated by such factors as cold, physical exertion, dehydration and stress.
Opioids are a mainstay of treatment for a pain crisis — it is important not to withhold treatment for these patients.
Acute chest syndrome severe life-threatening form of a vasoocclusive crisis
Presents similarly to pneumonia.
Fever, tachypnea, chest pain, hypoxia and infiltrates noted on chest x-ray.
In addition to infectious agents, acute chest syndrome may also result from fat emboli, intrapulmonary aggregates of sickled red blood cells, atelectasis or pulmonary edema.
Patients with a history of frequent hospitalizations and/or episodes of acute chest syndrome correlate with increased risks during pregnancy.
The treatment of acute chest syndrome typically consists of antibiotics, usually ceftriaxone and azithromycin, pain control, and if needed oxygen and transfusion.
Other complications
Stroke: occurs in almost 25% by the age of 25
Splenic sequestration / asplenia
Acute renal failure
Acute cholecystitis
Pulmonary hypertension: 6 to 11% of patients with sickle cell disease
Venous thromboembolism: ocurs in 10-25% of those with sickle cell disease by age 40
In pregnancy risk elevates: 2x increased risk of stroke, 5x increased risk of cerebral vein thrombosis, 2x increased risk of pulmonary embolism, 2.5x increased risk of deep vein thrombosis.
Maternal infection complications: asymptomatic bacteriuria, pyelonephritis, sepsis and an almost ten-fold increased risk of pneumonia.
Placental Consequences:
Placental hypoperfusion with endothelial damage is the main contributor to adverse pregnancy outcomes.
Increased risk of preeclampsia and eclampsia, placental abruption, antepartum bleeding and alloimmunization.
Fetal consequences:
2x increased risk of preterm birth
3x risk of small-for-gestational age
4x increased risk of stillbirth.
Serial fetal growth assessments and antepartum testing are needed.
Possible increased risk of neonatal abstinence syndrome due to the use of opioids to treat pain crises.
Should transfusion be used prophylactically?
2015 meta-analysis of 12 observational studies with almost 1300 patients demonstrated a reduction in both maternal and perinatal mortality as well as a reduction in pain events and preterm birth.
2016 Cochrane review that included only randomized controlled trials did not demonstrate a benefit with prophylactic when compared with selective transfusion.
Management strategy:
CBCs should be checked frequently, and a goal of maintaining a hemoglobin around 10 (same might say up to 12) and a percentage of hemoglobin S less than 35 to 40% is reasonable.
It is important to avoid iron overload when considering transfusion therapy which may lower target Hb for some individuals.
Treating Sickle Pain Beyond Opioids
Amitriptyline
Gabapentin
Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs)
Complementary (CAM) therapies
Hydroxyurea
Mainstay of treatment in the non-pregnant patient, as it reduces the risk of a vasoocclusive crisis and acute chest syndrome, thereby leading to improved survival and quality of life.
Patients with sickle cell disease who have higher amount of fetal hemoglobin tend to do better, and hydroxyurea increases fetal hemoglobin as well as reduces red blood cell adhesion and increases nitric oxide, the vasodilator we discussed earlier.
Has been found to cause birth defects in animals, although it has not been found to increase the risk of birth defects in humans. Still, it is generally avoided during pregnancy.
Preconception Counseling for Sickle Cell
Discuss the increased risk of both maternal and fetal complications, though many can have a successful pregnancy.
Know history — past need for transfusions, the frequency of hospitalizations due to vasoocclusive crises and if there is a history of acute chest syndrome.
Due to the possibility of iron overload due to multiple transfusions, it is important to check a ferritin prior to prescribing iron.
ACOG recommends 4 mg of folic acid daily.
Screen for hypertension and treat if warranted to maintain a blood pressure less than 140/90.
A dilated eye examination performed by an ophthalmologist should be performed if not done within the past year.
If there are any concerns for nephropathy, refer to nephrology — screen for proteinuria.
If there are any concerns for pulmonary hypertension, an echocardiogram is recommended with cardiology referral if needed.
As most patients are functionally asplenic, pneumococcus, haemophilus influenza type b, and meningococcus immunizations are recommended.
Check antibody screen — possible risk of alloimmunization.
Cure for Sickle Cell Disease?
Have been accomplished with hematopoietic stem cell transplantation.
In this case, the donor may be related or unrelated.
Stem cell transplantation offers a cure, but can result in death, graft rejection, graft versus host disease, and sterility due to chemotherapy.
Gene therapy for sickle cell disease, where patients receive their own genetically modified hematopoietic stem cells, is still experimental and there are several clinical trials underway.
Final Important Points on Managing Sickle Disease in Pregnancy
Hydroxyurea should be discontinued if it has not been already.
There are some who might consider restarting this after the fetal anatomical survey shows no evidence of abnormalities.
Chelation agents should also be discontinued.
Low-dose aspirin for preeclampsia risk reduction is recommended.
Monthly urinary cultures monitoring for asymptomatic bacteriuria and watching for any signs or symptoms of pyelonephritis.
Also reasonable to do in patients with sickle trait as risk is also increased in that population.
Frequent CBC monitoring, usually monthly is reasonable.
Interval fetal growth assessments every 3-4 weeks are recommended.
Antepartum testing starting at 32 weeks is indicated, with a delivery goal of 37 to 39 weeks.
Watch for preeclampsia is very important.
If a cesarean delivery is required, a preoperative transfusion may be prudent to increase hemoglobin levels to 8 to 10 g/dl.
Thromboprophyalxis: SCDs definitely; anticoagulation should be individualized.
Assuming the patient did not have a thromboembolic event during the pregnancy, could consider prophylactic low-molecular weight heparin for six weeks postpartum.