1. A Man with Abdominal Pain, Petechiae, Anemia and Thrombocytopenia Mahmoud Barazi, M.D. Nephrology Fellow Texas Tech University Health Science Center

2. The Case 26 y.o WM with PMH of Alcoholism and prior Pancreatits presented to ED with 3 day hx of abdominal pain amd n/v Recently married, spent his honeymoon in Jamaica

3. The Case Admitted that he was drinking heavily everyday. Denies any diarrhea Denies any fever, chills Stated that his symptoms started while he arrived to Texas

4. The Case PMH: Prior Pancreatitis in 2007, Hx of Alcoholism Medication: None. No OTCs use including NSAIDs Family Hx: Brother has Juvenile Pancreatits Social Hx: Works as an insurance agent, No hx of smoking/Illicit drugs. ROS: Negative for Fever/chills, weight loss, HA, blurry vision, muscle weakness, CP, SOB, cough, hemoptysis, Hematoemesis, Hematochezia, Hematuria or dysuria.

5. Physical Exam Gen: Alert & Oriented X 3, in mild distress due to pain VS: Tmp 96.2BP 154/98HR96 SaO299 on RAWeight 225lbsBMI28 NECK: No JVD, Supple Chest: CTAB, No additional breathing sounds CVS: S1, S2 normal, No M/R/G, NSR Abdomen: Soft, Tender in the periumblical area Ext: small Petechiae in both lower extremities

6. WBCs

7. Hgb

8. Platelets

9. Reticulocyte %

10. PT, PTT, Fibrinogen & D-Dimer

11. BUN/Cr

12. Amylase

13. LD

14. Peripheral Blood Smear The observed findings of thrombocytopenia along with scattered schistocytes and microspherocytes is suggestive of a hemolytic/microangiopathic process (TTP, HUS, DIC)

15. Other Labs TG139 CK181 Urine Na92 Urine Cr105 Urine Amylase6898 Protein/24 hr19251 VWF PROTEASE ACTIVITY: 320 L >530 ng/ml

16. Urinalysis GlucoseNegative BloodLarge pH6.0 Protein300 NitriteNegative Leukocyte EstTrace ColorDark Brown RBC12-20 WBC10-15 EosinophilsNegative MyoglobinA Positive

17. Imaging Ct-Abdomen: Pancreatitis with enlargement and edema of the pancreatic head and proximal portion of the body of the pancreas. Surrounding the inflammatory changes in the right upper quadrant with moderated amount if fluid seen within the true bony pelvis Bilateral pleural effusions and bilateral lower lobe atelectasis

18. Imaging Abdominal US Within normal limits Liver measures 16.07 cm Spleen is 11.66 x 3.92 x 11.43 cm Right kidney is 12.57 cm Left kidney is 11.57 cm

19. Diagnosis Acute Pancreatitis and TTP Cases Reported: - Eur J Med Res. 2008 Oct 27;13(10):481-2 - Eur J Gastroenterol Hepatol. 2008 Dec;20(12):1226-30 - Br J Haematol. 2009 Feb;144(3):430-3. Epub 2008 Nov 19

20. History of TTP Initially described by Dr Eli Moschcowitz at the Mount Sinai Hospital in 1925 Ascribed the disease to a toxic cause Noted that his patient, a 16 year-old girl, had anemia, Petechiae, microscopic hematuria, and at autopsy, disseminated microvascular thrombi In 1966, a review of 16 new cases and 255 previously reported ones led to the formulation of the classical pentad of symptoms

21. History mortality rates were found to be very high (90%) In 1978 report and subsequent studies showed that blood plasma was highly effective in improving the disease process In 1991 it was reported that plasma exchange provided better response rates compared to plasma infusion In 1982 the disease had been linked with abnormally large von Willebrand factor multimers late 1990s saw the identification of a missing protease activity from people with TTP In 2001, ADAMTS13 was identified on a molecular level

22. The Clinical Problem Prompt recognition is important because the disease responds well to plasma-exchange treatment associated with a high mortality rate when untreated 90 percent of patients with thrombotic thrombocytopenic purpura died from systemic microvascular thrombosis that caused cerebral and myocardial infarctions and renal failure

23. The Clinical Problem recognition of thrombotic thrombocytopenic purpura can be difficult because of the variety of presentations and lack of specific diagnostic criteria only consistent abnormalities are microangiopathic hemolytic anemia, characterized by red-cell fragmentation and thrombocytopenia, features that can also occur in other conditions

24. The Clinical Problem Before the availability of effective therapy, the diagnosis of TTP was based on the progressive appearance of the following pentad of clinical features: - microangiopathic hemolytic anemia - thrombocytopenia - neurologic - renal abnormalities - fever

25. The Clinical Problem recognition of the efficacy of plasma-exchange therapy meant that less stringent diagnostic criteria were required to allow a more rapid initiation of treatment In a randomized trial demonstrating the efficacy of plasma-exchange therapy, only microangiopathic hemolytic anemia and thrombocytopenia, without an apparent alternative cause, were required for the diagnosis of thrombotic thrombocytopenic purpura; the frequency of neurologic and renal abnormalities and fever was less than in previous reports N Engl J Med 1991;325:393-397

26. The Clinical Problem This change in diagnostic criteria has resulted in an increase by a factor of seven in the number of patients treated for thrombotic thrombocytopenic purpura Nonetheless, the disease remains uncommon, with the annual incidence in the United States estimated at 4 to 11 cases per million people

27. The Clinical Problem TTP occurs primarily in adults Children with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure were originally said to have the hemolytic–uremic syndrome Childhood hemolytic–uremic syndrome, typically preceded by abdominal pain and diarrhea, was recognized in 1983 as a complication of infection caused by bacteria that produce Shiga toxins, such as Escherichia coli O157:H7

28. The Clinical Problem Currently, 91 percent of children with typical hemolytic–uremic syndrome survive with supportive care, without plasma-exchange treatment These observations suggested that TTP and the HUS were two discrete syndromes Was supported by reports describing severe deficiency (<5% activity) of a von Willebrand factor–cleaving protease, termed "ADAMTS 13” in patients with a diagnosis of TTP but not in patients with a diagnosis of the HUS Lancet 2005;365:1073-1086

29. The Clinical Problem ADAMTS 13 cleaves the large von Willebrand factor multimers that are synthesized and secreted by endothelial cells When ADAMTS 13 is not present, the resulting abnormally large von Willebrand factor multimers in plasma have a greater ability to react with platelets and cause the disseminated platelet thrombi characteristic of TTP

30. The Clinical Problem TTP and HUS are not distinct syndromes Essential diagnostic criteria — microangiopathic hemolytic anemia and thrombocytopenia — are the same Although neurologic abnormalities are commonly considered characteristic of TTP and renal failure characteristic of the HUS patients with these syndromes may have neither abnormality or both Br J Haematol 2003;120:556-573

31. The Clinical Problem TTP is used to describe microangiopathic hemolytic anemia and thrombocytopenia occurring in adults without an apparent alternative cause, with or without neurologic or renal abnormalities, and regardless of the cause or associated condition. Children in whom microangiopathic hemolytic anemia, thrombocytopenia, and renal failure develop, typically after diarrhea, are described as having the HUS

32. The Clinical Problem Plasma exchange is not standard treatment for these children Thrombotic microangiopathy is a term describing the pathological morphology of TTP and the HUS This abnormality can also be present in other conditions such as malignant hypertension and autoimmune disorders

33. Evaluation The most common symptoms at presentation are nonspecific and include: - abdominal pain - nausea/vomiting - weakness The diversity of the clinical features is related to the presence of microvascular thrombi in many organs

34. Evaluation

35. Approximately half of patients with TTP have severe neurologic abnormalities at presentation or during the course of the disease, such as seizures and fluctuating focal deficits many patients may have no or only minor neurologic abnormalities, such as transient confusion Fever is uncommon. A temperature above 102°F (38.9°C) and chills suggest infection rather than thrombotic thrombocytopenic purpura Blood 2003;102:60-68

36. Evaluation TTP is often described as acute, one fourth of patients have symptoms for several weeks before diagnosis The importance of considering the possibility of TTP is emphasized by the frequent misdiagnosis of the symptoms The key diagnostic clues are from the laboratory evaluation. The presence of both anemia and thrombocytopenia (in the absence of leukopenia) suggests the diagnosis

37. Evaluation evidence of microangiopathic hemolytic anemia provides support (but is not specific) for the diagnosis Increased serum levels of lactate dehydrogenase and indirect- reacting bilirubin, and a negative direct Coombs' testExamination of the blood smear is critical. Observation of two or more schistocytes in a microscopic field with a magnification of 100 suggests microangiopathic hemolysis

38. Evaluation Many patients have normal serum creatinine levels Transient high levels may occur in one third of patients, and acute renal failure occurs infrequently Blood 2003;102:60-68 Kidney Int 75: S52-S54; doi:10.1038/ki.2008.622

39. Evaluation It is critical to rule out other potential causes of the presenting signs and symptoms, including sepsis, disseminated cancer, and malignant hypertension Rarely, disseminated intravascular coagulation may be present in patients with thrombotic thrombocytopenic purpura, presumably the result of tissue ischemia

40. Evaluation Br J Haematol 2003;120:556-573

41. Evaluation Evaluation of women during pregnancy is especially difficult Although pregnancy is associated with thrombotic thrombocytopenic purpura, especially near term or post partum, signs characteristic of thrombotic thrombocytopenic purpura may also occur in patients with severe preeclampsia, eclampsia, and the HELLP syndrome

42. Evaluation The circumstances of the presentation are important. Patients in ICU commonly have anemia and thrombocytopenia, and TTP is unlikely in these patients even if fragmented red cells are present TTP is rare in children; among adults it occurs predominantly in women Black race and obesity are associated with an increased risk of TTP

44. Evaluation The value of measurements of ADAMTS 13 activity and inhibitors remains uncertain There are discrepancies among assay techniques, and in vitro measurements may not always correlate with in vivo activity In nine cohort studies, the frequency of severe ADAMTS 13 deficiency among patients with idiopathic thrombotic thrombocytopenic purpura was 33 to 100 percent J Thromb Haemost 2005;3:1663-1675

45. Evaluation Clinical manifestations of severe ADAMTS 13 deficiency, either congenital or acquired are heterogeneous They range from no or minimal symptoms and signs to progressive multiorgan failure suggesting that many factors contribute to acute episodes Severe ADAMTS 13 deficiency may also occur in disorders other than TTP whereas patients with normal levels of ADAMTS 13 activity may have the characteristic features and clinical course of TTP J Clin Invest 2005;115:2752-2761

46. Evaluation Even after a diagnosis of TTP is made, continuing evaluation is important In the Oklahoma (TTP–HUS) Registry, 10 percent of patients with an initial diagnosis of idiopathic thrombotic thrombocytopenic purpura were subsequently found to have sepsis or systemic cancer Semin Hematol 2004;41:60-67

47. Management/Plasma Exchange Treatment the only treatment for which there are firm data on its effectiveness The clinical trial included 102 patients randomly assigned at the time of diagnosis to receive either daily plasma exchange (exchanging 1.0 to 1.5 times the predicted plasma volume of the patient) or plasma infusion (30 ml per kilogram of body weight for one day, then 15 ml per kilogram per day) NEngl J Med 1991;325:393-397

48. Plasma Exchange Treatment demonstrated significantly improved survival at six months among patients receiving plasma exchange as compared with patients receiving plasma infusion (40 of 51 [78 percent] vs. 32 of 51 [63 percent], P=0.04) Twelve of the 51 patients assigned to plasma infusion were subsequently treated with plasma exchange because of clinical deterioration N Engl J Med 1991;325:393-397

49. Plasma Exchange Treatment Initial response rates were also higher with plasma exchange; within seven days after randomization, 24 patients treated with plasma exchange (47 percent) had a normal platelet count (i.e., >150,000 per cubic millimeter) and no new neurologic events, as compared with 13 patients in the plasma-infusion group (25 percent, P=0.02)

50. Plasma Exchange Treatment Twenty-four patients with renal failure who were not eligible for the trial (because they would have been unable to tolerate plasma infusion) were treated with plasma exchange; 20 (83 percent) survived Recurrent thrombocytopenia within 30 days after the discontinuation of plasma-exchange treatment indicates an exacerbation of a continuing episode of TTP A plasma-exchange procedure typically requires several hours and costs $1,500 to $3,000.

51. Plasma Exchange Treatment Before effective therapy was available, most survivors of thrombotic thrombocytopenic purpura were children which may reflect their inherent resistance to thrombosis, as suggested by observations that venous and arterial thromboses are rare in children rather than different etiologic factors For example, among patients whose illness follows E. coli O157:H7 infection, the mortality rate among adults (45 percent) is five times as high as that among children Thromb Haemost 2002;88:900-911 Lancet 1999;354:1327-1330

52. Plasma Exchange Treatment The effectiveness of plasma exchange has been attributed to the removal of ADAMTS 13 autoantibodies and replacement of ADAMTS 13 activity However, plasma exchange also seems to be effective for patients who do not have a severe deficiency of ADAMTS 13 activity In a cohort of patients with idiopathic thrombotic TTP, plasma- exchange treatment resulted in a normal platelet count in 24 of 32 patients who did not have a severe deficiency of ADAMTS 13 activity (75 percent), as compared with 14 of 16 patients who had a severe deficiency (88 percent) Blood 2003;102:60-68

53. Plasma Exchange Treatment Although a case series suggested that cryosupernatant plasma, which is deficient in von Willebrand factor, may be superior to fresh-frozen plasma as a replacement product in plasma exchange, a small, randomized trial failed to confirm this Among 27 patients treated at the time of initial diagnosis with either cryosupernatant plasma or fresh-frozen plasma, there was no significant difference in the time to response (5.5 and 6.0 days, respectively) or in survival (79 percent and 77 percent) Therefore, fresh-frozen plasma is an appropriate replacement product Transfusion 2006;46:74-79

54. Plasma Exchange Treatment On the basis of observational data, daily plasma exchange should be continued until the platelet count is normal Lactate dehydrogenase levels, which reflect tissue ischemia as well as hemolysis are also a marker of response to treatment J Clin Apher 1998;13:16-19

55. Plasma Exchange Treatment Risks of plasma exchange should be recognized In a nine-year cohort study of 206 consecutive patients treated for TTP, 5 (2 percent) died of complications attributed to the plasma- exchange treatment (3 from hemorrhage related to the insertion of a central venous catheter and 2 from catheter-related sepsis) Fifty-three other patients (26 percent) had major complications attributed to plasma-exchange treatment, including systemic infection, venous thrombosis, and hypotension requiring dopamine However, the benefits of therapy outweigh the risks Transfusion 2006;46:154-156

56. Plasma Infusion remains appropriate for patients with TTP when there may be a delay until plasma exchange is available

57. Immunosuppressive Agents In patients who have idiopathic TTP, exacerbations when plasma exchange is stopped, or a relapse after a remission is achieved (suggestive of acquired deficiency of ADAMTS 13 activity) glucocorticoid therapy is often prescribed in addition to plasma exchange (e.g., 1 to 2 mg of prednisone per kilogram daily until remission is achieved; or 1 g of methylprednisolone per day for three days administered intravenously)

58. Immunosuppressive Agents The rationale is that plasma exchange will have only a temporary effect on the presumed autoimmune basis of the disease and additional immunosuppressive treatment may cause a more durable response The use of glucocorticoids in such patients is based on clinical experience and case series although other case series have reported similar outcomes without the use of glucocorticoids Br J Haematol 2003;120:556-573

59. Immunosuppressive Agents For patients who require additional treatment to have a remission, small case series have suggested a benefit with more intensive immunosuppressive therapy with rituximab, cyclophosphamide, vincristine, or cyclosporine Clinical trials are lacking to guide the use of immunosuppressive agents

60. Remission and the Risk of Relapse Relapses are rare in patients with TTP, except in those with a severe deficiency of ADAMTS 13 activity; half of such patients may have a relapse, most within a year Long-term follow-up data suggest a diminished frequency of relapses over time, though a relapse can occur years after the initial episode American Society of Hematology, 2004:407-23

61. Remission and the Risk of Relapse Small case series have suggested lower rates of relapse after splenectomy or the use of rituximab, but it is unclear whether these observations reflect the efficacy of these therapies or the natural history of disease The current recommended approach to patients in remission is only to ensure prompt medical attention, including a complete blood count, in the event of any systemic symptoms that may suggest relapse, such as abdominal pain, nausea, vomiting, or diarrhea Ann Intern Med 1996;125:294-296

62. Remission and the Risk of Relapse the risk of relapse with a future pregnancy is an important concern Although many case reports and small case series have described recurrences of thrombotic thrombocytopenic purpura in pregnant women who had a previous episode of TTP a follow-up study involving 30 pregnancies among 19 women who had recovered from TTP (including women whose initial episode was idiopathic, pregnancy associated, or preceded by bloody diarrhea) revealed that most subsequent pregnancies were unaffected TTP was diagnosed during one pregnancy in each of five women; all five women and two of the infants survived Transfusion 2004;44:1149 - 1158

63. Areas of Uncertainty It may be difficult to distinguish TTP from other conditions with similar manifestations Plasma exchange efficacy for some categories of patients (e.g., those who have undergone allogeneic hematopoietic stem-cell transplantation) is uncertain or unlikely. In adults who have TTP after a prodrome of bloody diarrhea or acute, immune-mediated drug toxicity, evidence of any benefit of plasma-exchange treatment is limited to case series the optimal duration of therapy is unknown. the efficacy of any treatment to prevent relapses is uncertain

64. Guidelines The American Association of Blood Banks, the American Society for Apheresis, and the British Committee for Standards in Haematology recommend daily plasma exchange with replacement of 1.0 to 1.5 times the predicted plasma volume of the patient as standard therapy for TTP The British guidelines recommend that plasma-exchange therapy be continued for a minimum of two days after the platelet count returns to normal they also recommend the use of glucocorticoids for all patients with TTP Br J Haematol 2003;120:556-573

65. Conclusions and Recommendations Because TTP is uncommon, a high index of suspicion is required for rapid diagnosis and prompt initiation of plasma-exchange treatment The unexplained occurrence of thrombocytopenia and anemia should prompt immediate consideration of the diagnosis and evaluation of a peripheral-blood smear for evidence of microangiopathic hemolytic anemia

66. Conclusions and Recommendations Other conditions (e.g., malignant hypertension, severe preeclampsia, sepsis, and disseminated cancer) that are likely to cause the same clinical findings as thrombotic thrombocytopenic purpura should be ruled out glucocorticoids for: - patients who have idiopathic TTP - whose condition worsens when plasma exchange is stopped - who have a relapse after remission although the use of this therapy is not supported by data from randomized trials

67. Conclusions and Recommendations Measurement of ADAMTS 13 activity is not necessary for decisions about diagnosis and initial management, although a severe deficiency indicates an increased risk of relapse

68. References Thrombotic Thrombocytopenic Purpura/James N. George, M.D. N Engl J Med 2006; 355:630, Aug 10, 2006 Blood 2003;102:60-68 Br J Haematol 2003;120:556-573