13,,,,Thrombotic thrombocytopenic Purpura (TTP) and Hemolytic-uremic.pptx

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1. Thrombotic thrombocytopenic P urpura (TTP) and Hemolytic-uremic syndrome (HUS)

2. Thrombotic Microangiopathies : T he term thrombotic microangiopathies comprise a spectrum of clinical syndromes that includes TTP HUS They are caused by insults that lead to excessive activation of platelets, which deposit as thrombi in small blood vessels

3. Etiology/classification TTP Congenital Acquired - Idiopathic - Autoimmune - Malignancy - Medications - Pregnancy - Infection HUS Typical ( associated with bloody diarrhea) Atypical (not associated with bloody diarrhea)

4. Acquired Thrombotic Thrombocytopenic Purpura Pathophysiology TTP is characterized by microthrombi composed of platelets and unusually large forms of von Willebrand factor (VWF) Occlude capillaries and arterioles in a number of organs -kidneys, heart, brain, and pancreas. (VWF is a plasma protein secreted from vascular endothelial cells needed for platelets to adhere to collagen.)

5. Ultralarge multimers of VWF normally are cleaved into smaller forms by the protease ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 motif, member 13) Deficiency in ADAMTS13 is the cause of TTP As a result these ultralarge VWF multimers remain attached to the endothelial cells and adhere to platelets, inducing platelet aggregation and formation of platelet thrombi. As erythrocytes are forced through the thrombi, fragmentation occurs .

6. The familial form of TTP occurs because of a mutation in the ADAMTS13 gene, resulting in a deficient/dysfunctional enzyme The acquired type is caused by autoantibodies against ADAMTS13, which block its activity

7. ADAMTS13 is also decreased in conditions such as - Sepsis - DIC - Liver diseases These results are controversial. The significance of decreased ADAMTS13 levels without autoimmune inhibitors or gene mutations remains uncertain

8. Pathology Widespread hyaline thrombi in the terminal arterioles and capillaries In older lesions, hyaline deposits may be seen in the subendothelial layers of capillaries and between the endothelium and muscular layers of arterioles In chronic cases, the thrombi may be infiltrated by fibroblasts or converted to subendothelial deposits by proliferating endothelial cell lesions

9. Preocclusive pseudoaneurysmal dilatation may also be present . Fibrinoid necrosis and vascular or perivascular inflammatory cell infiltration are characteristically absent or minimal

10. Small amounts of fibrin may be present surrounding or sometimes penetrating the amorphous or granular material . Glomerular microthrombi are usually spotty, and cortical necrosis of the kidney is uncommon

11. Clinical Features TTP is uncommon, but not rare Adolescents and adults, with a peak incidence between the ages of 30 and 50 years . M/C in females

12. Pentad of signs- 40% of cases Thrombocytopenia Microangiopathic hemolytic anemia Fleeting neurologic deficits Fever R enal abnormalities

13. weakness , dizziness, and headache Purpura is common at presentation but serious external or internal bleeding is rare except toward the terminal stage Abdominal pain or other gastrointestinal symptoms due to visceral ischemia or pancreatitis

14. Laboratory Findings B lood smear show polychromasia , basophilic stippling, nucleated red cells, and schistocytes Anemia P latelet counts below 20,000/ μ l The reticulocyte count is usually increased. Moderate neutrophilia with some increase in immature forms may be present .

15. Bone marrow studies are infrequently performed E rythroid hyperplasia, increased numbers of megakaryocytes, and occasionally microvascular hyaline thrombi C oagulation profile usually are normal. Fibrin degradation products may be slightly elevated

16. Serum lactic dehydrogenase (LDH ): Elevated Unconjugated bilirubin : Elevated H aptoglobin levels are reduced Hemoglobinemia , hemoglobinuria and hemosiderinuria Proteinuria and microscopic hematuria are present

17. Blood urea nitrogen and creatinine are normal or mildly elevated. Liver function tests are usually normal Analysis of CSF show an increased protein concentration and xanthochromia .

18. Skin, gingiva, and bone marrow may be biopsied and examined for hyaline thrombi within arterioles and capillaries Biopsies are diagnostic in <50% of cases

19. ADAMTS13 Measurement ADAMTS13 activity levels are <10 % of normal (or <5%, depending on the assays used ) Enzyme immunoassays is used to measure ADAMTS13 antigen levels. The ADAMTS13 inhibitors of TTP are primarily immunoglobulin G ( IgG ),with IgA and IgM Abs detectable less frequently : false-positive results in 5 to 15%

20. V on Willebrand Factor Multimers and Antigen Levels Large multimers are depleted in most patients presenting with acute TTP Ultra-large multimers are detected during the early stage of recovery or during remission

21. Differential Diagnosis Disseminated intravascular coagulation Systemic lupus erythematosus Active autoimmune connective tissue disease Pregnancy Malignancy Bone marrow transplantation Pneumococcal or other infection D rugs or chemicals (e.g., mitomycin C, gemcitabine, calcineurin inhibitors, quinine, cocaine)

22. Management and Prognosis 80–90 % of patients who are treated aggressively with exchange plasmapheresis survive the initial episode of TTP Plasma exchange with fresh frozen plasma of at least one plasma volume should be performed daily until several days after the platelet count is normal and there is minimal hemolysis

23. Platelet transfusion should be avoided because bleeding complications are uncommon in TTP, and marked deterioration in neurologic status is noted with platelet transfusions Cryoprecipitate-depleted plasma, a more effective treatment option because this blood product lacks large vWF multimers

24. Without treatment, acute TTP is almost always fatal, often within 10 to 14 days

25. Hereditary Thrombotic Thrombocytopenic Purpura (Schulman-Upshaw syndrome or chronic relapsing TTP) Rare disorder, <1% of cases Neonatal period, recognized later in life Mutations of the ADAMTS13 gene on chromosome 9q34 .

26. Clinical Manifestations N eonate is born with meconium stain or presents within a few hours after birth with neonatal distress, jaundice, and thrombocytopenia Hemolysis with schistocytes Seizures I mprove immediately after blood transfusion or exchange transfusion

27. Diagnosis ADAMTS13 activity levels are <10% of normal, but may be slightly higher in milder cases Inhibitory antibodies of ADAMTS13 are not detectable Ultra-large vWF multimers are detected during remission

28. Treatment Responds to fresh frozen plasma administered every 2 to 3 weeks

29. Hemolytic Uremic Syndrome Is a multisystem disorder first characterized by a triad of clinical findings: Hemolytic anemia with erythrocyte fragmentation Thrombocytopenia Acute nephropathy, which can include renal failure Typical HUS, now more appropriately known as shiga toxin–associated HUS (STX-HUS)

30. Shiga Toxin–associated Hemolytic-Uremic Syndrome Characterized by bloody diarrhea with >90% of the cases associated with GI infections by specific serotypes of Escherichia coli, which produce Shiga toxin ( Stx ) M/C serotype of Shiga toxinproducing E. coli (STEC), is E. coli O157:H7 Most other cases are associated with infection by Shigella dysenteriae Type 1.

31. Enteropathogenic E. coli has a bovine reservoir and generally is transmitted by undercooked meat, unpasteurized milk, or food and water contaminated by bovine feces Person-to-person transmission may occur during the acute diarrheal phase Occasionally, urinary infection with E. coli may also lead to the development of HUS Renal failure: 100% cases

32. C ongested renal glomeruli , capillary wall thickening, and endothelial cell swelling or necrosis Hyaline thrombi are common in glomerular loops and hilum and may be seen extending into small and medium-sized arteries, including the interlobular arteries Cortical infarcts with extensive thrombosis Pathology

33. Neutrophils are often present. Severe cases :heart , pancreas, or brain, thrombosis Thrombi in the renal glomeruli of Shiga toxin–associated HUS are enriched in fibrin and contain no or little vWF

34. Pathophysiology Injury of the kidney and other organs is due to thrombosis induced by exposure to Shiga toxins Globotriaosylceramide (Gb3 ) receptor, of endothelial or other target cells such as renal endothelial cells Shiga toxin via its B-subunit binds this receptor This binding is followed by internalization of A-subunit via endocytosis .

35. After proteolysis by a furin -like protease a small fragment of the A-subunit is generated that is capable of disrupting large subunit of ribosomes inhibition of protein synthesis cytotoxic to the target cells Endothelial cell injury expose the underlying thrombogenic glomerular basement membrane activation of platelets with subsequent formation of thrombi

36. Although damage primarily occurs in the renal microvasculature, other organ systems (CNS, heart, liver) can be affected. The resulting thrombotic microangiopathy that traps erythrocytes and causes fragmentation is responsible for the schistocytes commonly seen in HUS

37. Clinical Manifestations Symptomatic E nteropathogenic E. coli infection leads to HUS in up to 15% of cases Diarrhea and other gastrointestinal symptoms develop between 2 and 12 days Bloody diarrhea develops 1 to 3 days later. Symptoms and signs of HUS begin to manifest as the diarrhea improves

38. Risk factors: Young or old age L ong duration of diarrhea Elevated leukocyte count Antimicrobial or antimotility drug use, and B loody diarrhea

39. S udden pallor, abdominal pain, vomiting, A ppearance of dark-red or nearly black urine. O liguria or even anuria.

40. Extrarenal complications: 50% of patients Neurological complications: Serious Pancreatitis Colonic necrosis and perforation M yocardial infarction C ongestive heart failure P ericardial or pleural effusion A cute respiratory distress syndrome

41. Laboratory Findings T hrombocytopenia variable severity A nemia often is severe M oderate polymorphonuclear leukocytosis Hemoglobinemia may be marked

42. Prothrombin time and partial thromboplastin time: Normal or minimally prolonged Fibrin degradation products or D-dimers: Elevated Serum haptoglobin levels: Low or absent. Bilirubin level: Elevated . The liver transaminases and amylase: Elevated

43. The blood urea nitrogen and serum creatinine levels may be quite high . The urine usually contains hemoglobin and hemosiderin, albumin. Microscopically, erythrocytes, leukocytes, and casts are seen

44. Diagnosis and treatment E. coli O157:H7 is detected by plating fresh feces on sorbitol–MacConkey agar.

45. No specific treatment is available Early and careful management of acute renal failure and hypertension and cautious use of packed red cell transfusions Dialysis: 50% of the patient require Plasma therapy is of no or little benefit

46. Atypical Hemolytic-Uremic Syndrome Refers to the syndrome of acute renal failure, MAHA, and thrombocytopenia in children without a prodrome of hemorrhagic diarrhea or another apparent cause. Children, familial , noninfectious form of HUS R ecurs and is associated with worse renal outcome

47. Etiology and Pathophysiology Mutations in one of three proteins involved in regulation of complement activation , complement factor H (CFH ), membrane cofactor protein (MCP, or CD46) factor I (IF) are detected in 30 to 50% of familial and sporadic cases of atypical HUS

48. Excessive complement activation endothelial cell injury, exposing the underlying thrombogenic tissues microvascular thrombosis leads to fragmentation of red blood cells and hemolysis microangiopathic hemolysis

49. Excessive complement activation directly cause injury of renal parenchymal cells without microvascular thrombosis,

50. Clinical Manifestations 3 per million population of age < 18 years M=F E arly in childhood or during young or middle adulthood S pontaneously or be triggered by stress conditions such as acute infections, diarrhea, or pregnancy

51. Pallor, weakness, and tachypnea: Common H ypertension , fluid overload, and lethargy. Ascites , pleural effusions, and pericardial effusions may be noted . In severe cases, seizures and coma

52. Laboratory Findings Thrombocytopenia may be less severe Biochemical findings are those of hemolysis, renal dysfunction, and occasionally liver injury Electrolyte abnormalities and acid-base imbalance

53. Diagnosis M icroangiopathic hemolysis, renal failure, and thrombocytopenia Renal biopsy may show mesangial cell proliferation with expansion of the matrix with or without thrombosis in the renal glomeruli, arterioles, or small arteries C3 level: decreased

54. C omplement factor H deficiency: high rate of relapse, progression to end-stage renal failure, and recurrence after transplantation Membrane cofactor protein mutations are associated with a lower risk of end-stage renal failure

55. Treatment T reatment of any infection or inflammation , C orrection of fluid and electrolyte imbalance C ontrol of hypertension Cautious transfusion for anemia, and dialysis T he need for platelet transfusion is infrequent, but platelets may be required for bleeding complications

56. F resh frozen plasma Plasma exchange P lasma infusion Combined liver–kidney transplant

57. Comparison of Characteristics Associated with HUS and TTP TTP Adults ages 20–50 Hemolytic anemia with red cell fragmentation Renal dysfunction (mild to moderate) Thrombocytopenia Severe CNS symptoms Fever HUS Children <5 years old Hemolytic anemia with red cell fragmentation Acute renal failure Thrombocytopenia Mild CNS symptoms

58. Summary

59. Reference Greer P. John et al. Wintrobe’s clinical hematology. 14 th edition. Philadelphia, Wolters Kluwer publ.2019.p3434-58. Kumar V, Abbas AK, Aster JC, et al. Robbins and Cotran Pathologic Basis of Disease. 10 th edition. Philadelphia. Elsevier Publ. 2021. p 937-39. Shirlyn B. McKenzie, J. Lynne Williams,et al. Clinical laboratory hematology . 3 rd edition. Julie Levin Alexander publ.2015. p 372-80 Singh Tejindar . Atlas and text of Hematology. 4 th edition. New Delhi. 2018. p 115-18. Kawthalkar M S. Essentials of Hematology. 1 st edition. New Delhi. Jaypee brothers. 2006. p 453-54.

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