A Man with Abdominal Pain, Petechiae, Anemia and Thrombocytopenia

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 96.2 BP 154/98 HR 96 SaO2 99 on
  RA Weight 225lbs BMI 28
• 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

• TG 139
• CK 181
• Urine Na 92
• Urine Cr 105
• Urine Amylase 6898
• Protein/24 hr 19251
• VWF PROTEASE ACTIVITY 320 L gt530 ng/ml

16
Urinalysis

• Glucose Negative
• Blood Large
• pH 6.0
• Protein 300
• Nitrite Negative
• Leukocyte Est Trace
• Color Dark Brown
• RBC 12-20
• WBC 10-15
• Eosinophils Negative
• Myoglobin A 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 2713(10)481-2
• - Eur J Gastroenterol Hepatol. 2008
  Dec20(12)1226-30
• - Br J Haematol. 2009 Feb144(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 1991325393-397

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 hemolyticuremic
  syndrome
• Childhood hemolyticuremic 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 O157H7

28
The Clinical Problem

• Currently, 91 percent of children with typical
  hemolyticuremic 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 (lt5 activity) of a von Willebrand
  factorcleaving protease, termed "ADAMTS 13 in
  patients with a diagnosis of TTP but not in
  patients with a diagnosis of the HUS
• Lancet 20053651073-1086

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 2003120556-573

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
Evaluation

• 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 102F
  (38.9C) and chills suggest infection rather than
  thrombotic thrombocytopenic purpura
• Blood 200310260-68

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 200310260-68
• Kidney Int 75 S52-S54 doi10.1038/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 2003120556-573
• Br J Haematol 2003120556-573

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

43
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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 200531663-1675

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 20051152752-2761

46
Evaluation

• Even after a diagnosis of TTP is made, continuing
  evaluation is important
• In the Oklahoma (TTPHUS) 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 20044160-67

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 1991325393-397

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, P0.04)
• Twelve of the 51 patients assigned to plasma
  infusion were subsequently treated with plasma
  exchange because of clinical deterioration
• N Engl J Med 1991325393-397

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., gt150,000 per cubic millimeter) and no new
  neurologic events, as compared with 13 patients
  in the plasma-infusion group (25 percent, P0.02)

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 O157H7 infection, the mortality rate
  among adults (45 percent) is five times as high
  as that among children
• Thromb Haemost 200288900-911 Lancet
  19993541327-1330

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 200310260-68

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 20064674-79

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 19981316-19

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 200646154-156

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 2003120556-573

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, 2004407-23

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 1996125294-296

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 2004441149-1158

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 2003120556-573

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 355630, Aug 10,
  2006
• Blood 200310260-68
• Br J Haematol 2003120556-573

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