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?

• Cold environment

• Consumption of sugar

• Mild physical exertion

• Overhydration

Check out the answer at the links above and get a sweet deal on RoshReview!

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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.

Thalassemias, feat. Dr. David Abel

Here’s the RoshReview Question of the Week!

A 31-year-old G1P1 woman of Southeast Asian descent with a history of intrauterine fetal demise presents to your office for preconception counseling. She also reports a history of mild anemia due to alpha-thalassemia. You order DNA testing. Which of the following is most likely her genotype?

• α-/--

• α-/α-

• α-/αα

• αα/–

Check if you got the right answer and get a special deal on the CREOG Q-Bank at link above!

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The Basics of Hemoglobin

• The major oxygen carrying pigments of the body. Carries oxygen from the lungs to the tissues to meet the needs of cells for oxidative metabolism.

  • We carry almost two pounds of hemoglobin at any given time!

• The hemoglobin molecule is a tetramer.

  • Typically, this tetramer is composed of two alpha chains and two non-alpha globin chains.

  • The molecular mass of a hemoglobin tetramer is large, approximately 64,000 daltons. 

  • The primary structure of a particular hemoglobin is determined by its covalent bonds between the amino acids that form these polypeptide globins, and it is this primary structure that determines the behavior of a particular hemoglobin.

• Hemoglobin synthesis is controlled by two multigene clusters, the alpha and beta globin genes.

  • The alpha genes are on chromosome 16.

    • Both genes for alpha globin are duplicated, thus there are four genes at the alpha globin locus, with two genes inherited from each parent.

  • The beta genes are on chromosome 11.

    • The beta globin gene consists of two genes, one inherited from each parent. 

  • Each of these two gene clusters also contain other genes!

Common Hemoglobin Molecules and Embryology of Hemoglobin

• Hemoglobin changes during fetal development.

  • The switch from embryonic to fetal to adult hemoglobin synthesis is a major mechanism by which the developing fetus adapts from the hypoxic intrauterine environment, as each hemoglobin has its own oxygen dissociation curve.

• In the embryonic stage of development, there exists both zeta and epsilon globin chains that are synthesized by yolk sac erythroblasts.

  • The zeta gene is part of the alpha globin gene cluster, and the epsilon gene is part of the beta globin gene cluster.

    • Hb Gower-1: two zeta and two epilson chains

    • Hb Gower-2: two alpha and two episilon chains

    • Hb Portland: two zeta and two gamma chains. 

• After the first trimester, the zeta and epsilon globin chains are replaced by hemoglobin F, the dominant hemoglobin in-utero.

  • Hb F is composed of two fetal gamma globin chains and two alpha globin chains.

    • The gamma gene is a fetal gene that is part of the beta globin gene cluster.  

• Hemoglobin F declines in the third trimester of pregnancy and is slowly replaced by hemoglobin A, which consists of two alpha and two beta chains.

  • Also keep in mind that expression of delta globin begins near birth. The delta gene is also part of the beta globin cluster, and contributes to hemoglobin A2 (two alpha, two delta globins).

• At birth, hemoglobin F accounts for approximately 75-80 percent of hemoglobin and hemoglobin A accounts for 20-25 percent.

  • Postnatally, hemoglobin F is slowly replaced by hemoglobin A so that infants do not rely heavily on normal amounts and function of hemoglobin A until they are between 4 and 6 months old. 

• In adults, hemoglobin A makes up approximately 97%, hemoglobin A2 approximately 2.5% and less than 1% consists of hemoglobin F. 

The Basics of Hemoglobinopathy and Thalassemias

• Hemoglobinopathies arise when a change occurs in the structure of a peptide chain or a defect compromises the ability to synthesize a specific polypeptide chain.

  • Can be qualitative or quantitative defects.

    • Thalassemias are quantitative disorders. 

• Thalassemia is derived from a Greek term that roughly means “the sea” (Mediterranean) in the blood.  

  • It was first applied to the anemias frequently encountered in people from the Italian and Greek coasts and nearby islands. 

  • Individual syndromes are named according to the globin chain whose synthesis is adversely affected.

    • Alpha thalassemia represents either a reduction or complete absence of production of alpha globin chains

    • Beta thalassemia is a reduction or complete absence of beta globin production. 

  • Among the most common autosomal recessive disorders worldwide. More than 100 genetic forms of alpha thalassemia have been identified. 

• By contrast, conditions such as sickle cell anemia represent a structural hemoglobinopathy, a qualitative defect.

Beta Thalassemias

• Hemoglobin electrophoresis can be used to diagnose beta thalassemia. This can reveal:

  • Reduction in the expression of beta globin (b+) or

  • Complete absence of beta globin expression (b0).

• Complete absence of beta globin expression is referred to as beta thalassemia major, aka Cooley’s anemia or transfusion-dependent thalassemia.

  • Little to no beta globin chain production and thus minimal to absence of hemoglobin A.

  • Symptoms usually manifest 6-12 months of life.

  • Since there is no hemoglobin A due to the lack of beta globin, hemoglobin F persists.

    • On a hemoglobin electrophoresis, you will see at least 95% of hemoglobin F, and  hemoglobin A2 will usually range between 3.5 and 7%.

    • The circulating red blood cells are very hypochromic, abnormal in shape, and the hemoglobin is markedly reduced, somewhere around 3-4 g/dl. 

  • Anemia of beta thalassemia major is so severe that long-term blood transfusions are usually required for survival.

    • The severe anemia results in extramedullary erythropoiesis, delayed sexual development and poor growth.

    • Death may occur by age 10 unless treatment with periodic blood transfusions is initiated.

• Beta thalassemia intermedia, now referred to as non-transfusion dependent beta thalassemia, presents as a less severe clinical phenotype.

  • A moderate microcytic anemia is present.

    • On hemoglobin electrophoresis, up to 50% of hemoglobin F will be noted and just as in beta thalassemia major, hemoglobin A2 will usually range between 3.5 and 7%.

  • May result from different mechanisms:

    • I.e., inheriting both a mild and severe beta thalassemia mutation, or

    • The inheritance of two mild mutations, or,

    • The inheritance of complex combinations of mutations.

• Beta thalassemia minor, also referred to as beta thalassemia trait, is caused by the presence of a single beta-thalassemia mutation and a normal beta globin gene on the other chromosome.  

  • Significant microcytosis with hypochromia on the blood smear but a mild anemia.

  • In general, thalassemia minor has no associated symptoms.

    • On hemoglobin electrophoresis, hemoglobin F is present up to 5%, and hemoglobin A2 at 4% or more. 

Alpha Thalassemias

• The alpha thalassemias are more difficult to diagnose because the typical elevations in hemoglobin F and A2 that are seen in the beta-thalassemias we have just discussed do not occur. This makes hemoglobin electrophoresis difficult to use for diagnosis.

  • Instead, molecular testing (DNA sequencing) is required for diagnosis.

  • More than 100 genetic forms of alpha thalassemia have been identified, with phenotypes ranging from asymptomatic to lethal.

  • The severity of this disorder is usually well correlated with the number of non-functional copies of the alpha globin genes (a one, two, three, or four-gene deletion).

• Silent Carrier: one alpha globin gene deletion.

  • Essentially has no clinical consequences.

  • On the CBC, the MCV is usually normal or perhaps mildly decreased.

• Alpha Thalassemia Minor: two gene deletion.

  • If two genes on the same chromosome are deleted, this is known as a cis deletion.

    • More commonly seen in those of southeast Asian ancestry.

    • If both parents carry a cis deletion, their offspring will have a 25% chance of having no functional alpha globin genes.

  • If the two deleted genes are on different chromosomes, this is trans deletion.

    • More common in those of African descent

    • If both parents have a two gene deletion in trans, their offspring will always have the same two gene deletion in trans.

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• Hemoglobin H: three gene deletion, which results in a moderate microcytic anemia.

  • When the alpha chains are reduced, the beta chains pair together and form beta globin tetramers, which is what this hemoglobin H represents.

  • In some cases, instead of the three gene deletion, a two gene deletion occurs with a mutant (i.e., non-functional) alpha globin mutation, such as hemoglobin Constant Spring.

    • This is referred to as nondeletional hemoglobin H.

    • Individuals with this nondeletional hemoglobiin H have a higher percentage of hemoglobin H, more splenomegaly and more advanced disease.

  • Most individuals with hemoglobin H don’t require regular transfusions. The anemia is typically mild; however, the phenotype is variable

    • With the dilutional anemia that occurs during pregnancy, the need of a transfusion may be increased. 

• Alpha thalassemia major, or hemoglobin Barts: Four gene deletion that results in a gamma tetramer.

  • Normal Hb A and Hb F are totally absent.

  • Hemoglobin Barts is incompatible with life and results in hydrops in-utero and stillbirth.

    • Its oxygen dissociation curve is markedly shifted to the left, so it holds onto oxygen and very little is released to the tissues.

    • Usually, the fetus or newborn will have marked anasarca and hepatosplenomegaly, with a hemoglobin level of 3-10 g/dL.

  • If a fetus is known to have alpha thalassemia major, multiple intrauterine transfusions can help these fetuses survive.  

    • Prenatal diagnosis of the thalassemias can be performed using either chorionic villi from CVS or using cultured amniocytes obtained from an amniocentesis.

  • A study at the University of California at San Francisco is looking at the use of in utero stem cell transplantation during pregnancy to essentially cure the fetus before birth. 

Take Home: When to Work Up for Thalassemia

• If the MCV is decreased (<80), a hemoglobin electrophoresis is very reasonable.

  • Ferritin to assess for iron deficiency is also something that can be performed at the same time.

    • Hemoglobinopathy and iron deficiency can coexist!

• If the MCV is decreased, and both a ferritin and hemoglobin electrophoresis are normal, molecular studies to assess for alpha thalassemia would be appropriate. 

Anemia in Pregnancy

Be sure to check out the new ACOG Practice Bulletin #233 on anemia — first time it’s been updated in a while! And while you’re at it, check out our old episode on sickle cell anemia.

Physiologic Changes in Pregnancy to Blood Volume 

• Definitions

  • Remember that anemia in pregnancy is defined as: 

    • Hgb <11 g/dL in the first and third trimester 

    • Hgb <10.5 g/dL in the second trimester 

    • Previously, ACOG had discussed a lower threshold for certain people based on race, but one important study found that this lower threshold likely contributes to the perpetuation of racial disparities in medicine without a scientific reason for lower Hgb 

• What happens in pregnancy? 

  • Physiologic

    • Plasma volume expands by 40-50%

    • Erythrocyte mass expands by 15-25% 

    • So even though there is increased red cell mass, it seems overall that HCT % goes down 

  • There is also increased iron requirement, so it is more likely for people to become iron deficient 

Causes of Anemia in Pregnancy 

• Acquired 

  • Deficiency 

    • Iron deficiency - by far the most common 

    • B12 deficiency 

    • Folic acid deficiency 

  • Hemorrhagic 

  • Anemia of chronic disease 

  • Acquired hemolytic anemia 

  • Aplastic anemia 

• Inherited 

  • Thalassemias 

  • Sickle cell 

  • Hemoglobinopathies 

  • Inherited hemolytic anemias 

Work-up of Anemia in Pregnancy 

• Screening 

  • All pregnant people should be screened for anemia with CBC in the first trimester and again right before third trimester (usually 24-28 weeks) 

  • Also, should have discussion with everyone about screening for hemoglobinopathies if they have not been screened before 

• Work up of asymptomatic with mild to moderate anemia: 

  • Anemia type: microcytic vs normocytic vs macrocytic 

    • Microcytic (MCV < 80 fl) 

      • Most commonly: iron deficiency 

      • But can also be caused by thalassemias, anemia of chronic disease, sideroblastic anemia, etc. 

    • Normocytic (MCV 80-100fL) 

      • Hemorrhagic or early iron deficiency = common 

      • Others: anemia of chronic disease, bone marrow suppression, chronic renal insufficiency, hemolytic anemia 

    • Macrocytic (MCV > 100 fL) 

      • Folic acid deficiency, B12 deficiency = most common 

      • Others: Reticulocytosis, liver disease, alcohol abuse, drug-induced hemolytic anemia 

• Iron studies with measurement of red blood cell indices, serum iron levels, ferritin levels 

  • Some places also include a total iron-binding capacity 

  • In someone with iron deficiency, iron levels and ferritin will be low, while TIBC will be high 

• Peripheral blood smear 

• Can also look at vitamin B12 and folate levels if macrocytic 

• Other work-up: 

  • If not responding to treatment with iron, folate, or B12, then further workup should be done 

  • Ie. is there a reason for malabsorption (gastric bypass?) 

  • Is there a reason for blood loss? 

Treatment of Anemia in Pregnancy 

• Iron deficiency 

  • Can start with oral iron, unless there is a reason for malabsorption 

    • Usual requirements: 27 mg daily during pregnancy, and usual diet will live 15 mg of elemental iron/day 

    • Most oral forms of iron will exceed this 

    • If unable to tolerate oral iron or has reasons for malabsorption, can do IV iron, which can come in the form of iron dextran, ferric gluconate, or iron sucrose 

• Folate or B12 deficiency

  •  MCV > 115 is almost exclusively seen in people with folate or B12 deficiency 

  • Give folate or B12! 

  • Folic acid: 400 mcg/day unless there are other indications for increased folate (ie. history of neural tube defect affecting child, on anti-epileptics) 

  • B12: usually only seen in people with gastric resection or Crohn disease 

    • Usually given IM every month, 1000 mcg/injection 

• Other causes 

  • Depending on the cause, may need to work with colleagues from other specialties 

  • Or your friendly neighborhood MFM 

• A word on transfusion 

  • Hgb <6 g/dL have been associated with abnormal fetal oxygenation 

  • Usually recommend transfusion if Hgb <7 or if symptomatic 

  • However, can consider higher threshold if other co-morbidites (ie. sickle cell anemia with known crises if Hgb <7)