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.

Sickle Cell Disease & Pregnancy

What is sickle cell disease?

• Sickle hemoglobin (HbS) results from a point mutation in the beta hemoglobin gene. 

• Sickle hemoglobin disease results from inheritance of at least one sickle mutation, and co-inheritance of another beta-hemoglobin modifying gene.

  • Classically, this is homozygosity for HbS genes (HbSS); however, sickle disease also manifests with co-inheritance of hemoglobin C (HbSC); beta-thalassemia; and others.

• The disease causes significant pain crises and multi-system disease, thought to arise primarily from hemolytic anemia as well as vaso-occlusion.

  • Importantly from an infection perspective, splenic infarction is common early in life and thus results in a hyposplenic, immunocompromised state. 

  • Manifestations of disease can be seen in:

    • Infection, particularly a susceptibility to pneumonia and a related but indistinguishable complication known as acute chest syndrome

    • Anemia

    • Pain from vaso-occlusive crisis

    • Stroke and myocardial infarction

    • Renal disease

    • Retinopathy (particularly with HbSC disease)

    • Pregnancy complications, including growth restriction, preeclampsia, stillbirth, and maternal mortality. 

Who should be screened, and how?

• Screening for sickle trait and sickle cell disease is now part of universal newborn screening in all 50 US states. 

• Screening in adults is done via hemoglobin electrophoresis.

• Screening should be offered if:

  • A partner is known to have sickle cell disease, and the other partner does not know their carrier status, or;

  • A patient does not know their carrier status and wishes to know.

    • IMPORTANT: race/ethnicity-based screening is ineffective and problematic in identifying at-risk individuals, and thus anyone who desires testing should be offered it! 

      • ACOG PB 78 on hemoglobinopathies in pregnancy, updated in 2007, notes that “ethnicity is not always a good predictor of risk,” though focuses to a large degree on observed ethnic group differences.

      • Similarly, ACOG CO 691 endorses hemoglobinopathy screening via CBC for all women, and electrophoresis for women “suspected of hemoglobinopathy based on at risk ethnicity” 

      • Other ACOG guidance now endorses offering hemoglobinopathy screening universally, including the ACOG FAQ document for patients on carrier screening. 

    • However, there are risks to screening that your patients should be made aware of, particularly with respect to genetic discrimination. 

      • Health insurance markets and employer-based plans are prohibited from this through the Genetic Information Non-Discrimination Act (GINA).

      • These protections do not extend into: 

        • life, disability, or long-term care insurance markets,

        • employers with fewer than 15 employees

        • US military and the TRICARE health system

        • the Indian Health Service

        • the Veterans Health Administration

        • Federal employees Health Benefits Program. 

  • A quick plug here for licensed genetic counselors – they are awesome and know lots of things, as well as when your patients may benefit from different types of screening! If you have access, we totally recommend listening in on a counseling session with them! 

What should be done to optimize pregnancy in the preconception period for those with sickle cell disease?

• Most pregnancies can be managed successfully and result in live birth, with proper surveillance and preparation. 

• Partner screening is recommended if status is not known, as we previously mentioned, as the likelihood of the fetus having a hemoglobinopathy can be 0% (if partner is not a carrier) or 50% (if the partner is a carrier). 

  • This can also help to inform approach to prenatal genetic testing and subsequent decisions for the pregnancy, if desired. 

• Baseline preeclampsia screening 

  • Hypertension may be present due to renal disease in pregnant patients, and sickle nephropathy can result in significant proteinuria. 

  • Baseline 24 hour urine protein, in addition to LFTs, BUN, and creatinine, are useful. 

• Ophthalmologic screening for retinal disease, which has a tendency to worsen in pregnancy

•  Hemoglobin and iron studies 

  • Frequently, due to hemolysis, those with sickle disease are severely iron-overloaded and should potentially delay pregnancy until they receive chelation therapy (which cannot be given in pregnancy).

    • Prenatal vitamins with iron should be avoided in this particular group.

• Baseline urine culture as asymptomatic bacteriuria and UTIs are more common in sickle disease, and are often more difficult to treat due to renal disease. 

• Pulmonary function tests can be considered, as those with particularly severe sickle cell disease are at higher risk of pulmonary embolus and reactive airway disease, in addition to having a baseline to reference for acute concern for acute chest syndrome. 

  • Echocardiography may also be useful in severe cases to assess for underlying pulmonary hypertension. 

• Type and screen is often one of the most important tests:

  • Often due to a history of transfusion, multiple antibodies may be present on screening, which can be significant for alloimmunization of the fetus and hemolytic disease of the fetus/newborn (HDFN).

    • If the patient is positive for an offending antibody, this will allow for partner testing to occur to determine if a fetus may be at risk for HDFN.

• Medication Management:

  • Hydroxyurea: is generally a mainstay of sickle cell disease management in the nonpregnant patient which works by increasing Hemoglobin F production. Gamma globulin is not affected by sickling, so decreased overall concentration of HbS  

    • Regrettably in the peri-conception period, there is not much data regarding its use – but guidelines recommend discontinuing in the three months prior to conception, though the limited data that exists suggest there is no increase in major anomalies. 

  • Folic acid: due to increased red cell turnover, generally there is consensus that folate supplementation should be higher in those with sickle cell disease; 4mg daily is recommended (versus the 0.4mg – 0.8mg/day recommended universally).

  • Iron chelators: should be discontinued for conception, as they are associated with some risk of anomalies.

  • Antihypertensive medications: often patients with SCD may be taking ACE-Is or ARBs, as they are renal protective. However, these are teratogenic and should be replaced with agents that are safe in pregnancy. 

  • Pain medication: opioids are standard of care for management of severe pain in sickle cell disease. Patients who are on standing doses of opioids should be counseled with regards to risk of neonatal abstinence syndrome but should not routinely discontinue their pain medications.

    • Acetaminophen, non-medicinal strategies for pain control are also appropriate.

    • Short courses of NSAIDs may be appropriate in some circumstances, but generally are avoided in pregnancy. 

    • Aspirin in low dose should be considered in pregnancies of patients affected by sickle cell disease to help reduce preeclampsia risk.

  • Anticoagulation: patients with sickle cell disease are not typically on anticoagulants just for sickle disease; though with a history of DVT/PE, they might be, and in those cases you should treat them like other patients with that history. 

    • Absent a high-risk DVT/PE history, pharmacologic thromboprophylaxis should just be considered with any hospitalization given the high risk of clotting. 

• Immunizations: should be up to date, and also remember due to functional hyposplenism, additional vaccines should be considered: meningococcal, pneumonia, and H. influenzae type b are all recommended for patients with sickle cell disease. 

• Breastfeeding: should still be encouraged! Resumption of hydroxyurea use may be delayed with breastfeeding, as its not well studied in terms of its effects on infants. 

Pain crises in pregnancy – how to manage them?

• Avoid triggers for pain crises as best as possible – dehydration, hypoxia, acidosis, infection, and cold temperatures are all common triggers. 

  • Termination of pregnancy and delivery/postpartum are two common times for pain crisis development – so appropriate hydration and monitoring are key at those time points!

  • With crisis, one key management point is reversal/correction of the trigger – and in or out of pregnancy, hydration is often key to that.

  • Oxygen therapy is often also needed due to inadequate oxygen delivery during vaso-occlusive crisis. 

• In crisis, pain control should be aggressive!

  • Opioids are the therapy of choice, if acetaminophen is not satisfactory.

  • The patient’s experience, and their hematologist’s knowledge of the patient, are often of significant benefit in these situations! 

• Keep your diagnostician hat on!

  • Pain crises can often be part of, or proceed significant events for patients with sickle cell disease – including DVT/PE, acute chest syndrome, or stroke. 

    • Each complication of sickle cell disease could be a podcast of management on its own – so a multidisciplinary approach is often required to ensure good patient outcomes. 

    • If patient or family is telling you the pain is different – listen! This can be a clue that something else is going on than usual pain crisis.

    • Use your hematology colleagues to guide, but often management will consist of at least CBC, chemistry panel with LFTs, and a chest xray. 

Acute Chest in Pregnancy - ACS is the leading cause of death in SS disease 

• Often preceded by a vaso-occlusive pain episode, present with chest, arm, and leg pain consistent with a pain crisis, and follow a much more severe clinical course, often requiring mechanical ventilation, and sometimes resulting in death

• Dx = radiographic evidence of consolidation + one of the following: 

  • Temperature >38.5C 

  • >2% decrease in O2 sat 

  • Tachypnea 

  • Intercostal retractions, nasal flaring, or use of accessory muscles 

  • Chest pain 

  • Cough 

  • Wheezing 

  • Rales 

• Treatment: a lot of this overlaps with pain crisis:

  • Treat pain 

  • Fluids - prevent hypovolemia 

  • O2

  • Blood transfusion - discuss with heme about simple vs exchange transfusion 

  • Bronchodilators 

  • Antibiotics - usually empiric to cover things like C. trachomatis, strep, and H.flu. Usually a third gen cephalosporin with a macrolide (ie. CTX + azithromycin) 

  • Escalation of care - may need to go to the ICU!