Sickle Cell Disease Overview
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Questions and Answers

What are the common sites of painful crises associated with vaso-occlusive symptoms?

Common sites include joints, extremities, and lower back.

What are the respiratory signs associated with acute chest syndrome?

Respiratory signs include chest pain, fever, dyspnea, and cough.

What are the leading causes of hospitalization for individuals experiencing vaso-occlusive symptoms?

The leading causes are hypoxia, infection, fever, acidosis, dehydration, and various triggers.

What are the main consequences of strokes as noted in the provided content?

<p>Infection, fat embolism, and possibly pulmonary infarction are major consequences.</p> Signup and view all the answers

What major health concerns contribute to morbidity and mortality associated with acute chest syndrome?

<p>Transient ischemic attack, low steady-state hemoglobin level, and a high rate of acute chest syndrome contribute to morbidity and mortality.</p> Signup and view all the answers

What is the significance of tissue factor (TF) in the hypercoagulable state, particularly in the context of sickle cell disease (SCD)?

<p>Tissue factor (TF) is abnormally expressed on circulating endothelial cells, and its expression increases during pain episodes, contributing to coagulation activation in SCD.</p> Signup and view all the answers

Identify two biomarkers of coagulation that are elevated in a hypercoagulable state.

<p>Thrombin-Antithrombin complexes and D-dimer are two biomarkers that are elevated in a hypercoagulable state.</p> Signup and view all the answers

How does the exposure of phosphatidylserine on red blood cells affect coagulation?

<p>The exposure of phosphatidylserine on RBC surfaces acts as a docking site for enzymatic complexes involved in coagulation, enhancing thrombin generation.</p> Signup and view all the answers

What is the rationale for targeting protein S in the treatment of sickle cell disease?

<p>Targeting protein S may help to restore balance in the coagulation pathway, reducing the risk of thrombosis in patients with sickle cell disease.</p> Signup and view all the answers

What findings were reported in the PROSICK study regarding the role of coagulation activation in SCD?

<p>The PROSICK study indicated a significant activation of the coagulation pathway in sickle cell disease, highlighting the need for effective management strategies.</p> Signup and view all the answers

What percentage of RBC in SCD patients does protein S bind to?

<p>Protein S binds to 6% of RBC in SCD patients.</p> Signup and view all the answers

What effect does the addition of calcium have on protein S binding?

<p>The addition of calcium removes the binding of protein S.</p> Signup and view all the answers

What is one role protein S plays in relation to phosphatidylserine?

<p>Protein S binds to phosphatidylserine, which exposes red blood cells.</p> Signup and view all the answers

How does protein S contribute to phagocytosis?

<p>Protein S aids phagocytosis by binding its SHBG domain to the TAM receptor on macrophages.</p> Signup and view all the answers

Is protein S implicated in clearing procoagulant RBC or microparticles that expose phosphatidylserine?

<p>Yes, protein S is involved in the clearance of phosphatidylserine exposing RBC or microparticles.</p> Signup and view all the answers

What are the primary cell types from which microparticles (MP) are derived?

<p>Endothelial cells and monocytes are the primary cell types that derive microparticles.</p> Signup and view all the answers

What is the incidence of venous thromboembolism (VTE) in patients with SCD according to the data?

<p>The incidence of VTE in patients with SCD can be as high as 25%.</p> Signup and view all the answers

What are the 1-year recurrence and bleeding rates for venous thromboembolism (VTE) in patients with SCD?

<p>The 1-year recurrence rate for VTE is 13.2%, and the bleeding rate is 7.9%.</p> Signup and view all the answers

Explain the fatality rates linked to VTE and bleeding based on the provided cohort study.

<p>The fatality rate for VTE is 3.1%, while for bleeding it is 7.4%.</p> Signup and view all the answers

In the coagulation pathway described, which factors are activated by tissue factor (TF)?

<p>Factors FVIIa, FIXa, and FXIa are activated by tissue factor (TF).</p> Signup and view all the answers

What is the significance of targeting protein S with antibodies like PS003biv?

<p>Targeting protein S with antibodies like PS003biv enhances the cofactor activity of activated protein C (aPC), which is crucial in regulating thrombin generation.</p> Signup and view all the answers

What role do microparticles play in the coagulation process as inferred from the context?

<p>Microparticles enhance coagulation and are linked to coagulation activation biomarkers.</p> Signup and view all the answers

How does PS003biv differ from conventional low molecular weight heparin (LMWH) in therapeutic administration?

<p>PS003biv is administered intravenously at a dose of 10 mg/kg, whereas LMWH is administered subcutaneously at a dose of 200 UI/kg.</p> Signup and view all the answers

What role does protein S deficiency play in sickle cell disease based on the PROSICK study?

<p>Protein S deficiency contributes to the pathogenesis of sickle cell disease by promoting thrombosis in compromised circulatory conditions.</p> Signup and view all the answers

What does the high recurrence rate of VTE suggest about management in SCD patients?

<p>The high recurrence rate suggests that careful monitoring and management of VTE is essential in SCD patients.</p> Signup and view all the answers

In the context of the FeCl3-induced murine thrombosis model, what are the main outcomes monitored when using PS003biv?

<p>The main outcomes monitored are the efficacy of thrombin generation and the overall anticoagulant effect compared to controls.</p> Signup and view all the answers

Which immunoglobulin is referenced in the context of anti-TF antibodies, and what is its role?

<p>The immunoglobulin referenced is IgG, which acts as a control in assessing the activity of anti-TF antibodies.</p> Signup and view all the answers

What experimental methods might be used to study the effects of protein S in both murine models and humans?

<p>Cellular approaches and ex-vivo assays are used to study the effects of protein S in sickle cell disease in both settings.</p> Signup and view all the answers

What was the effect of PS003biv on vaso-occlusion in the liver for the SCD model?

<p>PS003biv decreased vaso-occlusion in the liver.</p> Signup and view all the answers

How many mice were used in each group for the SCD PS003biv experiment?

<p>Four mice were used in each group.</p> Signup and view all the answers

What type of microscopy was used to evaluate the SCD steady state?

<p>Light sheet microscopy was used.</p> Signup and view all the answers

What was the dosage of heme administered to induce vaso-occlusion in the study?

<p>The dosage of heme administered was 50 µmol/kg.</p> Signup and view all the answers

In addition to the liver, which other organ showed decreased vaso-occlusion as a result of PS003biv treatment?

<p>The lungs also showed decreased vaso-occlusion.</p> Signup and view all the answers

What role does heme injection play in the vaso-occlusive crisis model?

<p>Heme injection provokes the vaso-occlusion crisis in the model.</p> Signup and view all the answers

What specific outcomes did PS003biv affect aside from vaso-occlusion?

<p>PS003biv decreased hemolysis and coagulation activation.</p> Signup and view all the answers

What types of mice were used as a model in this study?

<p>Townes sickle mice with human α-globine and β-globine S were used.</p> Signup and view all the answers

Study Notes

Sickle Cell Disease Overview

  • Sickle cell disease (SCD) is a global health problem.
  • Approximately 3 million people are affected worldwide.
  • It's one of the most common genetic diseases.
  • The prevalence varies geographically. High prevalence in regions with high malaria risk.

Sickle Cell Disease: Definition

  • A single base change (GAG to GTG) in the beta chain of human haemoglobin results in sickle cell disease.
  • This genetic mutation causes the production of hemoglobin S (HbS).
  • HbS has unique polymerisation properties, causing long, rigid fibres to form in red blood cells.
  • These fibres distort the red blood cells, leading to various complications.
  • Inheritance is autosomal recessive.

Sickle Cell Disease: Pathophysiology

  • A self-perpetuating cycle of sickling, vaso-occlusion, and inflammation leads to acute and chronic complications.
  • Sickled red blood cells cause vaso-occlusion (blockage of blood vessels)
  • This leads to painful crises, acute chest syndrome, stroke, and other complications.
  • Inflammation plays a key role in the pathophysiology of SCD.

Major Acute Symptoms

  • Vaso-occlusive painful crises: Sudden, throbbing, sharp pain in joints, extremities, and lower back, leading to hospitalizations. Triggers include hypoxia, infection, fever, acidosis, dehydration, pregnancy, menstruation, and obstructive sleep apnea
  • Acute chest syndrome: Presence of a new pulmonary infiltrate, respiratory symptoms, and fever, leading to hospitalization and in some cases, death.
  • Stroke: Blockage or rupture of blood vessels in the brain, resulting in ischemic or hemorrhagic stroke.
  • These conditions frequently lead to severe morbidity and mortality.

Sickle Cell Disease: Symptoms

  • Almost all organs can be affected due to microvascular involvement.
  • Life expectancy is decreased by 30 years on average.
  • Quality of life is significantly reduced due to complications.

Treatments

  • Hematopoietic stem cell transplantation: A curative treatment that replaces bone marrow.
  • Hydroxyurea: A supportive drug that increases production of fetal hemoglobin.
  • L-glutamine: Prevents oxidative damage to red blood cells (RBCs) and decreases endothelial cell adhesion.
  • Voxelotor: Modulates hemoglobin-oxygen affinity and reduces HbS polymerization.
  • Crizanlizumab: Blocks interactions between endothelial cells, platelets, RBCs, and leukocytes, which improves anemia symptoms.
  • Blood transfusions: Alleviate anemia and prevent complications.

Coagulation in SCD Pathophysiology

  • SCD patients have a hypercoagulable state.
  • Biomarkers include increased thrombin-antithrombin complexes, and D-dimers.
  • Tissue factor expression is increased during pain episodes.
  • Reduced natural anticoagulant proteins such as protein C and protein S has been found in SCD
  • Activation of coagulation mechanisms plays a crucial role in inflammation and endothelial damage.

Targeting Protein S in SCD

  • Protein S deficiency is frequent in SCD patients.
  • This is associated with resistance to activated protein C.
  • The rationale for targeting S is to improve hemolysis, reduce vaso-occlusion, and alleviate acute and chronic complications.
  • The PROSICK study examines the effects of targeting protein S on sickle cell disease.

PS003biv Treatment

  • PS003biv reduced vaso-occlusion and hemolysis.
  • This agent improved the survival and reduced the duration of the pain crisis.

Conclusion

  • A continuing activation of coagulation is evident in SCD
  • Coagulation activation triggers inflammation increasing the risk for several complications (e.g., vasoocclusion).
  • Inhibition of coagulation shows conflicting results.
  • Protein S enhancement is a potentially innovative treatment strategy in the treatment of SCD.

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SCD Coagulation 2024 PDF

Description

This quiz explores the critical aspects of sickle cell disease, including the painful crises associated with vaso-occlusive symptoms and respiratory complications like acute chest syndrome. Additionally, it dives into biomarkers, coagulation factors, and the implications for morbidity and mortality in affected individuals. Test your knowledge on significant findings related to this condition.

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