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Hemolytic Anemia: Nonimmune Defects

20. Hemolytic Anemia: Nonimmune Defects. Learning Objectives—Level I. At the end of this unit of study, the student should be able to: Define microangiopathic hemolytic anemia ( MAHA ) and list several associated disorders and the age group most commonly affected. continued on next slide.

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Hemolytic Anemia: Nonimmune Defects

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  1. 20 Hemolytic Anemia: Nonimmune Defects

  2. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Define microangiopathic hemolytic anemia (MAHA) and list several associated disorders and the age group most commonly affected. continued on next slide

  3. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Describe the general morphology and hematologic values associated with MAHA and criteria that distinguish disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS). continued on next slide

  4. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Recognize the characteristic erythrocyte morphology of MAHA on a stained blood film. • Identify organisms that can cause erythrocyte hemolysis.

  5. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Summarize the general pathophysiology for MAHA.

  6. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Compare and contrast the clinical findings, underlying cause, treatment, and characteristic findings for erythrocytes, platelet count, and coagulation tests for each of the following types of MAHA: • Hemolytic uremic syndrome (HUS) • Thrombotic thrombocytopenic purpura (TTP) continued on next slide

  7. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Compare and contrast the clinical findings, underlying cause, treatment, and characteristic findings for erythrocytes, platelet count, and coagulation tests for each of the following types of MAHA: • Disseminated intravascular coagulation (DIC) continued on next slide

  8. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Define exercise-induced hemoglobinuria. • Given a set of data and clinical history, determine whether MAHA is a probable diagnosis, identify the possible etiology, and propose follow-up tests that should be performed. continued on next slide

  9. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Compare the cause of hemolysis by the following infectious agents: • Plasmodium parasites (malaria) • Babesia parasites • Bartonella bacteria • Clostridium bacteria

  10. Hemolytic Anemias Caused by Physical Injury to RBCs

  11. Physical Injury to the RBCs • Hemolysis may be: • Intravascular • Extravascular • Results in strikingly abnormal shapes of circulating RBCs • Schistocytes • Helmet cells

  12. Table 20-1 Hemolytic Anemias Caused by Nonimmune Antagonists in the Erythrocyte Environment

  13. Microangiopathic Hemolytic Anemia (MAHA) • Hemolytic process caused by microcirculatory lesions • Damage to endothelial lining of the small vessels continued on next slide

  14. Microangiopathic Hemolytic Anemia (MAHA) • Hemolytic process caused by microcirculatory lesions • Deposition of platelets and fibrin in microvasculature • Thrombus formation within the blood vessels • RBCs forced through fibrin strands in thrombus • Fragmented by the force of flowing blood

  15. MAHA • Peripheral blood characterized by presence of • Schistocytes, keratocytes, ↑ reticulocytes • Hemolysis may be intravascular and/or extravascular

  16. MAHA • Underlying disorders associated with MAHA • Disseminated intravascular coagulation (DIC) • Infections, snake venoms, and so on • Thrombotic thrombocytopenic purpura (TTP) • Hemolytic uremic syndrome (HUS) continued on next slide

  17. MAHA • Underlying disorders associated with MAHA • Complications of pregnancy • Preeclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes and low platelet count) Syndrome • Disseminated cancer • Malignant hypertension

  18. Hemolytic Uremic Syndrome • Multisystem disorder characterized by triad of clinical features: • RBC fragmentation, thrombocytopenia, acute nephropathy (can include renal failure)

  19. Hemolytic Uremic Syndrome • Two groups • D+ HUS (diarrhea-associated) • Bloody diarrheal prodrome • 90% of cases, most in children ≤ 5 • GI infections—Shiga toxin producing E. coli continued on next slide

  20. Hemolytic Uremic Syndrome • Two groups • D– HUS (nondiarrhea-associated) • Atypical HUS (aHUS) • More likely to occur • Associated with lupus, cancer, diabetes, Streptococcus pneumoniae infections, immunosuppressive therapy • Observed in children and adults

  21. Table 20-3 Types of HUS and Associated Conditions That Can Precipitate HUS

  22. Hemolytic Uremic Syndrome • Pathophysiology • E. Coli 0157:H7, S. dysenteriae Type I • Intestinal infection • Damage to intestinal mucosa continued on next slide

  23. Hemolytic Uremic Syndrome • Pathophysiology • E. Coli 0157:H7, S. dysenteriae Type I • Shiga toxin absorbed into circulation • Endothelial cells of microvasculature of glomerulus affected • Cytotoxic damage • Release of prothrombotic vasoactive and platelet- aggregating substances • Formation of platelet-fibrin thrombi

  24. Figure 20-1 A possible mechanism for damage by Shiga-like toxin of Escherichia coli O157:H7.

  25. Hemolytic Uremic Syndrome • Clinical findings D+ HUS • Highest incidence—age 0–1 yr • Acute onset • Sudden pallor, abdominal pain, vomiting, fever • Bloody diarrhea, macroscopic hematuria continued on next slide

  26. Hemolytic Uremic Syndrome • Clinical Findings D+ HUS • Most serious complication • Acute renal failure can lead to chronic renal insufficiency • CNS symptoms can be present, lethargy, minor seizures

  27. Hemolytic Uremic Syndrome • Laboratory findings • Moderate to severe normocytic, normochromic anemia (Hb 7–9 g/dL) • Schistocytes, helmet cells, spherocytes, burr cells • Polychromasia, occasional NRBC • Leukocytosis with left shift • Platelet counts: low normal to markedly ↓ continued on next slide

  28. Hemolytic Uremic Syndrome • Laboratory findings • Hemoglobinemia, ↑ bilirubin, LD; ↓ haptoglobin • ↑ BUN, creatinine; hypokalemia; hyponatremia, metabolic acidosis continued on next slide

  29. Hemolytic Uremic Syndrome • Laboratory findings • Proteinuria, hematuria, pyuria • PT, APTT usually normal (slightly abnormal); FDP, D-dimer ↑ • Urinalysis moderate to massive amounts protein, pyuria, casts

  30. Figure 20-2 A peripheral blood smear from a patient with hemolytic uremic syndrome. The platelets are markedly decreased. Schistocytes and spherocytes are present (Wright-Giemsa stain, 1000 magnification).

  31. Hemolytic Uremic Syndrome • Therapy • > 80% of D+ HUS cases—recover continued on next slide

  32. Hemolytic Uremic Syndrome • Therapy • Mortality ↓ to 5–15% with early diagnosis and supportive care • Close observation; blood transfusion (if needed) • Control of electrolytes and hypertension • Peritoneal dialysis in anuria • Plasma exchange • D+ not indicated • D– HUS may need continued on next slide

  33. Hemolytic Uremic Syndrome • Therapy • New preventive measure in individuals with Shiga toxin E. coli • Monoclonal antibodies against Shiga toxin to provide passive immunity • Eculizamab • Recombinant, monoclonal, anti-C5 antibody effective in aHUS

  34. Thrombotic Thrombocytopenic Purpura (TTP) • Acute disorder with platelet aggregation on microvascular endothelium • Affects young adults (20–50 yrs), more females than males • Congenital or acquired • Precipitating factors • Infections (40%) • Pregnancy (10–25%)

  35. Table 20-5 Some Reported Clinical Conditions That Can Be Precipitating Factors in TTP

  36. TTP • Pathophysiology • Microthrombi • Composed of platelets and unusually large forms of VWF (von Willebrand factor) multimers • Occlude capillaries and arterioles in organs • Kidneys, heart, brain, pancreas continued on next slide

  37. TTP • Pathophysiology • Microthrombi • Deficiency in ADAMTS13 is cause of TTP • Protease that cleaves large VWF multimers • Induces platelet aggregation and platelet thrombi • RBCs fragment as pass through microthrombi

  38. TTP • Familial Form • Mutation in ADAMTS13 gene resulting in deficient /dysfunctional enzyme • Acquired Form • Autoantibodies against ADAMTS13 which block its activity

  39. TTP • Clinical findings • Similar to HUS • Occurs more often in young adults and involves more organ systems • Neurologic symptoms more prominent • Renal dysfunction less severe • Mortality rate higher than HUS

  40. Table 20-2 Comparison of Characteristics Associated with HUS and TTP

  41. TTP • Laboratory findings • Hb: 8–9 gm/dL • Normocytic, normochromic anemia • MCV variable • Polychromasia, NRBCs • ↑↑ schistocytes • Leukocytosis with left shift continued on next slide

  42. TTP • Laboratory findings • Severe thrombocytopenia • Hemoglobinemia, hemoglobinuria; • ↑ bilirubin, LD, ↓ haptoglobin • PT, APTT usually normal (or slightly prolonged)

  43. Table 20-4 Laboratory Findings in HUS and TTP

  44. TTP • Therapy • Plasma exchange with FFP • Provides ADAMTS13 protease and removes autoAb in acquired TTP • Cryosupernatant • Lacks large VWF multimers but contains VWF cleaving protease continued on next slide

  45. TTP • Therapy • Drug treatment • Monoclonal Ab—Rifuximab • Anti-platelet agents and steroids

  46. Disseminated Intravascular Coagulation (DIC) • Complex thrombohemorrhagic condition • Normal coagulation process is altered • Bacterial sepsis • Neoplasms • Immunologic disorders • Trauma

  47. Table 20-6 Causes of Disseminated Intravascular Coagulation (DIC)

  48. DIC • Damage to endothelial lining of vessels • Release of thromboplastic substances • Activate coagulation mechanism • Platelet activation and aggregation • Deposition of fibrin continued on next slide

  49. DIC • Damage to endothelial lining of vessels • Formation of microthrombi in microvasculature • RBCs fragment to form schistocytes • Complications: • Thrombotic occlusion of vessels • Bleeding and organ failure

  50. DIC • Consumptive coagulopathy • Severe thrombocytopenia and decreased coagulation factors • Serious bleeding complications • Blood smear • Thrombocytopenia and schistocytes

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