Sickle Cell Disease Pathophysiology

Sickle Cell Disease Pathophysiology

  1. Type of anemia in this case:

Sickle cell anemia is the diagnosis that is most consistent with this clinical scenario. A differential diagnosis would be hemolytic anemia.

  1. The following data in the clinical scenario supports the diagnosis of sickle cell anemia:
  • Sodium 139 mEq/L —> Normal (Range 135 to 145 mEq/L)
  • Potassium 5.0 meq/l —> Normal (Range 3.5 to 5.3 mEq/L)
  • Creatinine 0.47 mg/dl —-> Low (Range: 0.5 to 1.1 mg/dL for females)
  • Total bilirubin 10 mg/dl —-> High (Range: 0.3 to 1 mg/dL)
  • BUN 7 mg/dl —-> Normal (Range: 5-20 mg/dL)
  • WBC 15,200 —–> High (Range: 4500 to 11000 cells/mm3)
  • Haematocrit 19% —-> Low (Range: 37-47%)
  • Haemoglobin 6.5 g/dl —–> Low (Range 13-15 g/dL)
  • Ferritin 3155 ng/ml —-> High (Range: 12-150 ng/mL)

Sickle Cell Disease Pathophysiology

The presenting complaints that include severe pain, especially in the joints, and the fact that she is a known sickler, are all characteristics of a sickle cell crisis. Joint pains result from the occlusion of blood vessels by the sickled red blood cells that are rigid and cannot pass through the vessels.

The cells adhere together, obstructing blood flow and consequently leading to pain in the joints. This is one of the characteristic symptoms observed, especially during a sickle cell crisis (Hoffbrand & Steensma, 2020).

The above lab findings, along with the presenting symptoms, and past medical history, indicate that the type of anemia is Sickle Cell Anemia (Hemolytic anemia).

  1. Risk factors that caused the exacerbation of the anemia:
  • Infection: Diarrhoea and fever are indicative of infection, and in this case, could have resulted in exacerbation of sickle cell crisis.
  • Dehydration: Dehydration secondary to profuse diarrhea also serves as a risk factor.
  • Stress: Stress due to infection and the resulting diarrhea can serve as a potential risk factor for exacerbation of anemia.
  • Race: People of African-American descent are highly predisposed to sickle cell anemia. (Mougianis, 2020)
  • Low hemoglobin count: Reduced hemoglobin count reduces oxygen supply, causing the formation of rigid non-liquid strands in the red blood cells resulting in change in cell shape thereby causing sickle cells.
  • High altitudes: The resultant decrease in oxygen saturation following an ascend to a higher altitude can trigger the sickle cell crisis.
  • Excess workout: This may trigger a sickle cell crisis due to reduced oxygen concentrations, especially during strenuous exercises in a known sickler.
  • Pregnancy: Pregnancy is one of the triggers of the sickle cell crisis. The woman, who is of child-bearing age, may have been pregnant, and this may have resulted in triggering the sickle cell crisis.
  • Alcohol consumption and cigarette smoking: These are some other factors that may have caused the sickle cell crisis in the patient.
  • Chronic illnesses: Some common chronic illnesses such as diabetes, which may be underlying in the patient, may cause the sickle cell crisis observed.
  1. Pathophysiological concepts involved in sickle cell anemia:

Genetic alteration that results in sickle cell anemia:

Sickle cell disease is caused by mutations in the HBB gene. This gene is responsible for giving instructions for making hemoglobin. Hemoglobin is made up of four protein units; two alpha-globins and two beta-globins. HBB gene is responsible for making the beta-globin chain.

A mutation in the HBB gene results in the formation of an abnormal beta-globin chain known as hemoglobin S. Substitution of Thymine for Adenine in the sixth codon of the beta-globin gene leads to the substitution of the glutamic acid residue by a valine residue (Ribeil, 2017).

In this condition, one of the beta-globin chains is substituted with hemoglobin S. In sickle cell anemia, both beta-globin units are replaced with hemoglobin S. (Ribeil, 2017). Deoxygenation of the hemoglobin S (HbS) leads to the formation of HbS polymers causing red blood cell sickling and damage to the membrane. It is inherited as an autosomal recessive disorder.

The pathological process responsible for joint pain:

  • Joint pain (referred to as hand-foot syndrome of sickle cell anemia) occurs due to obstruction of blood flow due to the accumulation of sickle cells in micro-capillaries supplying the joints. Some of the triggers of the sickle cell crisis causing joint pain include infections, hypoxia, dehydration, acidosis, cold, among others (Pivkin, 2017). This results from a change in the shape of the red blood cells in sickle cell anemia. The red blood cells become stiff and lose the ability to pass through capillaries. This results in the occlusion of the blood vessels by the red blood cells. (Pivkin, 2017).
  • Due to the tortuous nature of these capillaries in the joints, sickle cells stack up, resulting in tangled masses, which in turn causes vasospasm, thrombosis, and infarction due to occlusion of blood capillaries.
  • This results in symmetric pain in the joints of hands and feet in sickle cell anemia patients. The pain crisis is especially exacerbated when the individual is dehydrated, stressed, or cold.
  • Low oxygen is responsible for decreased solubility, increased viscosity, and polymer formation leading to the formation of a gel-like substance comprising of hemoglobin crystals referred to as tactoids. This plays a role in the vaso-occlusive crisis that results in joint pains.

Reason for having a stroke 16 years.

Large arteries supplying the brain are the main source of strokes in sickle cell anemia. Clumping of the rigid red blood cells along the walls of the arteries causes damage to the vessels, further exposing the tissue causing further aggregation of the sickled red blood cells that in turn result in further narrowing of the vessels (Bray, 2020).

Subsequently, the abnormal sickle shape of hemoglobin and decreased oxygen-carrying capacity leads to occlusion of micro-capillaries of the brain. As the sickle cells do not flow smoothly in the capillaries due to their asymmetric shape, they occlude the blood vessels and damage the endothelium.

They also induce vasospasm by invoking inflammatory mediators, cytokines, etc. This, according to Bray (2020), results in thrombotic events in the capillaries of the brain, which in turn leads to thrombosis, hemorrhage, cerebrovascular accidents (CVA). These events could have been responsible for stroke in the given client

Rationale for splenic infarct:

Splenic infarction is a condition where blood flow to the spleen is compromised, leading to partial or complete tissue death in the spleen (tissue ischemia and consequent necrosis). Splenic infarction is a common condition, especially in children with sickle cell anemia. In adults, it can have an acute onset or can be precipitated by factors such as acute chest syndrome and exposure to high altitudes characterized by reduced oxygen saturation.

As the spleen is responsible for the destruction of red blood cells, sickle cells enter into the spleen for destruction after the completion of their life span. Splenic infarction may involve a small portion of the spleen or may affect the whole spleen. The severity of the effect on the spleen is determined by the vessel occluded.

Due to their abnormal shape, sickle cells are trapped in the sinusoids of the spleen, forming rigid and tangled masses in the red pulp. Accumulation of more and more sickle cells in the spleen causes obstruction (vaso-obstructive crisis), resulting in ischemia and splenic infarct formation (Kumar et al., 2019). Altered hemolysis and macrophage response to sickle cells also contribute to the formation of a splenic infarct

Reasons for icteric sclera and elevated bilirubin:

Increased destruction of the sickled red blood cells at a faster rate than they can be cleared results in increased circulating bilirubin levels. Inflammation of the gall bladder and cystic duct occurs due to hemolysis of sickle cells.

The inflammatory mediators infiltrate the gall bladder and cystic duct, which causes obstruction of the cystic duct, thereby elevating the risks of formation of gall stones. Bile flow is obstructed, which is then reabsorbed into the systemic circulation resulting in icteric sclera and elevated bilirubin, as seen in the given case.

Acute Chest Syndrome:

Acute chest syndrome is a complication of sickle cell anemia resulting from infections or blood flow blockade to the chest and lungs. Clinical presentation varies from mild respiratory complications to acute respiratory distress syndrome.

Acute chest syndrome is characterized by fever, rapidly decreasing hemoglobin, bilateral pulmonary infiltrates on chest x-ray, and increased heart rate (De Luna et al., 2020). Infection and increased phospholipase A2 activity in sickle cell anemia (crisis) can result in increased permeability of pulmonary capillaries. This leads to the entry of free fatty acids into the pulmonary capillaries.

This results in the formation of an embolus and acute chest syndrome, which can cause lung injury, difficulty in breathing, reduced oxygen supply to the rest of the body, and consequent death (Jain, Bakshi, & Krishnamurti, 2017).

Another mechanism of acute chest syndrome in sickle cell disease is heightened sticking together of the sickled red blood cells to the pulmonary microvasculature in reduced oxygen supply leading to blockage and consequent reduction of blood flow to the lungs.

Does she or does she not have this?

The client in the given case does not have acute chest syndrome. This is evidenced by the absence of bilateral infiltrates, adventitious lung sounds, normal oxygen saturation, and negative chest X-ray from the primary assessment data. The patient also does not mention any difficulty in breathing, cough, or any other respiratory symptoms.

  1. Actual or potential complications related to the diagnosis of sickle cell anemia:

Some of the potential complications that might be related to the diagnosis of sickle cell anemia include

  • Hypoxia,
  • Ischemia and infection
  • skin breakdown and ulcers due to poor wound healing,
  • a stroke or a cerebrovascular accident
  • heart failure that may lead to pulmonary hypertension
  • renal impairment due poor perfusion
  • acute chest syndrome
  • substance abuse due to increased pain severity
  • organ damage which results from blocked blood flow. This deprives the organs of both oxygen and blood. This can cause damage to organs such as the liver and spleen
  • blindness resulting from blockage of circulation to the eyes
  • leg ulcers
  • Gallstones due to increased bilirubin levels from the increased breakdown of red blood cells
  • Pregnancy complications due to heightened risk of elevated blood pressure. This predisposes the mothers to miscarriages and premature births.

Sickle Cell Disease Pathophysiology References

Bray, M. A., Sartain, S. E., Gollamudi, J., & Rumbaut, R. E. (2020). Microvascular thrombosis: experimental and clinical implications. Translational Research : The Journal of Laboratory and Clinical Medicine225, 105–130. https://doi.org/10.1016/j.trsl.2020.05.006

De Luna, G., Habibi, A., Deux, J. F., Colard, M., Pham Hung d’Alexandry d’Orengiani, A. L., Schlemmer, F., Joher, N., Kassasseya, C., Pawlotsky, J. M., Ourghanlian, C., Michel, M., Mekontso-Dessap, A., & Bartolucci, P. (2020). Rapid and severe Covid-19 pneumonia with severe acute chest syndrome in a sickle cell patient successfully treated with tocilizumab. American Journal of Hematology95(7), 876–878. https://doi.org/10.1002/ajh.25833

Hoffbrand, A. V., & Steensma, D. P. (2020). Haemolytic anaemias & Genetic disorders of haemoglobin . In Hoffbrand’s essential haematology (8th ed., pp. 64–96). Wiley Blackwell.

Jain, S., Bakshi, N., & Krishnamurti, L. (2017). Acute Chest Syndrome in Children with Sickle Cell Disease. Pediatric Allergy, Immunology, and Pulmonology30(4), 191–201. https://doi.org/10.1089/ped.2017.0814

Kumar, R., Kapoor, R., Singh, J., Das, S., Sharma, A., Yanamandra, U. & Nair, V. (2019). Splenic infarct on exposure to extreme high altitude in individuals with Sickle trait: A single center experience. High Altitude Medicine & Biology, 20(3), 215-220. https://doi.org/10.1089/ham.2018.0120

Mougianis, I., Cohen, L. L., Martin, S., Shneider, C., & Bishop, M. (2020, May 29). Racism and Health-Related Quality of Life in Pediatric Sickle Cell Disease: Roles of Depression and Support. Journal of Pediatric Psychology, 45(8), 858-866. https://doi.org/10.1093/jpepsy/jsaa035.

Pivkin, I. V., Peng, Z., Karniadakis, G. E., Buffet, P. A., Dao, M., & Suresh, S. (2017). Biomechanics of red blood cells in human spleen and consequences for physiology and disease. (2017). Proceedings of the National Academy of Sciences, 114(22). https://doi.org/10.1073/pnas.1706577114

Ribeil, J.-A., Hacein-Bey-Abina, S., Payen, E., Magnani, A., Semeraro, M., Magrin E., Caccaveli, L., Neven, B., Bourget, P., El Nemer, W., Bartolucci, P., Weber, L., Puy, H., Meritet, J.- F., Grevent, D., Beuzard, Y., Chretien, S., Lefebvre, T., Ross, R. W., … Cavazzana, M. (2017). Gene therapy in a patient with Sickle Cell disease. The New England Journal of Medicine, 376(), 848-855. https://www.nejm.org/doi/full/10.1056/NEJMoa1609677.

Sickle Cell Disease Pathophysiology Instructions

 NURS 6501 Module 8 Week 11 Concepts of Pediatrics Knowledge Check

Learning Resources

Required Readings (click to expand/reduce)

McCance, K. L. & Huether, S. E. (2019). Pathophysiology: The biologic basis for disease in adults and children (8th ed.). St. Louis, MO: Mosby/Elsevier.
•	Chapter 14: Cancer in Children, including Summary Review
•	Chapter 20: Alterations of Neurologic Function in Children (stop at Childhood tumors); Summary Review
•	Chapter 34: Alterations of Cardiovascular Function in Children (stop at Defects decreasing pulmonary blood flow); Summary Review
•	Chapter 37: Alterations of Pulmonary Function in Children (stop at Congenital malformations); Summary Review
•	Chapter 40: Alterations of Renal and Urinary Tract Function in Children, including Summary Review
•	Chapter 43: Alterations of Digestive Function in Children, including Summary Review
•	Chapter 46: Alterations of Musculoskeletal Function in Children (stop at Avascular diseases); (start at Cerebral palsy) (musculoskeletal tumors in children); Summary Review
•	Chapter 48: Alterations of the Integument in Children, including Summary Review
•	Chapter 50: Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children, including Summary Review

•	Analyze concepts and principles of pathophysiology across the lifespan 

QUESTION 1
1.	Scenario 1: Acute Lymphoblastic Leukemia (ALL)
An 11-year-old boy is brought to the clinic by his parents who states that the boy has not been eating and listless. The mother also notes that he has been easily bruising without trauma as he says he is too tired to go out and play. He says his bones hurt sometimes. Mother states the child has had intermittent fevers that respond to acetaminophen. 
Maternal history negative for pre, intra, or post-partum problems.
PMH: Negative. Easily reached developmental milestones. 
PE: reveals a thin, very pale child who has bruises on his arms and legs in no particular pattern.
LABS: CBC revealed Hemoglobin of 6.9/dl, hematocrit of 19%, and platelet count of 80,000/mm3. The CMP demonstrated a blood urea nitrogen (BUN) of 34m g/dl and creatinine of 2.9 mg/dl.
DIAGNOSIS: acute leukemia and renal failure and immediately refers the patient to the Emergency Room where a pediatric hematologist has been consulted and is waiting for the boy and his parents.
CONFIRMED DX: acute lymphoblastic leukemia (ALL) was made after extensive testing.  
Question
1.     Explain what ALL is?  

QUESTION 2
1.	Scenario 1: Acute Lymphoblastic Leukemia (ALL)
An 11-year-old boy is brought to the clinic by his parents who states that the boy has not been eating and listless. The mother also notes that he has been easily bruising without trauma as he says he is too tired to go out and play. He says his bones hurt sometimes. Mother states the child has had intermittent fevers that respond to acetaminophen. 
Maternal history negative for pre, intra, or post-partum problems.
PMH: Negative. Easily reached developmental milestones. 
PE: reveals a thin, very pale child who has bruises on his arms and legs in no particular pattern.
LABS: CBC revealed Hemoglobin of 6.9/dl, hematocrit of 19%, and platelet count of 80,000/mm3. The CMP demonstrated a blood urea nitrogen (BUN) of 34m g/dl and creatinine of 2.9 mg/dl.
DIAGNOSIS: acute leukemia and renal failure and immediately refers the patient to the Emergency Room where a pediatric hematologist has been consulted and is waiting for the boy and his parents.
CONFIRMED DX: acute lymphoblastic leukemia (ALL) was made after extensive testing.  
Question
1.     Why does ARF occur in some patients with ALL? 

QUESTION 3
1.	Scenario 2: Sickle Cell Disease (SCD)
A 15-year-old male with known sickle cell disease (SCD) present to the ER in sickle cell crisis. The patient is crying with pain and states this is the third acute episode he has had in the last 10-months. Both parents are present and appear very anxious and teary eyed. A diagnosis of acute sickle cell crisis was made. 
Question
1.     Explain the pathophysiology of acute SCD crisis. Why is pain the predominate feature of acute crises?  

QUESTION 4
1.	Scenario 2: Sickle Cell Disease (SCD)
A 15-year-old male with known sickle cell disease (SCD) present to the ER in sickle cell crisis. The patient is crying with pain and states this is the third acute episode he has had in the last 10-months. Both parents are present and appear very anxious and teary eyed. A diagnosis of acute sickle cell crisis was made. 
Question
1.     Discuss the genetic basis for SCD.

QUESTION 5
1.	Scenario 3: Hemophilia
8-month infant is brought into the office due to a swollen right knee and excessive bruising. The parents have noticed bruising about a month ago but thought the bruising was due to the attempts to crawl. They became concerned when the baby woke up with a swollen knee. Infant up to date on all immunizations, has not had any medical problems since birth and has met all developmental milestones. 
FH: negative for any history of bleeding disorders or other major genetic diseases. 
PE: within normal limits except for obvious bruising on the extremities and right knee. Knee is swollen but no warmth appreciated. Range of motion of knee limited due to the swelling.
DIAGNOSIS: hemophilia A.    
Question
1.     What is the pathophysiology of Hemophilia