1. Heather D. Mannuel, MD, MBA March 12, 2008
Overview of ITP
Heather D. Mannuel, MD, MBA
March 12, 2008

2. Idiopathic (Immune) Thrombocytopenic Purpura
Thrombocytopenia in the absence of other blood cell abnormalities (normal RBC & WBC, normal peripheral smear)
No clinically apparent conditions or medications that can account for thrombocytopenia

3. Statistics of ITP Incidence of 22 million/year in one study
Prevalence greater as often chronic
*Segal et al 100 million/year
*age-adjusted prevalence 9.5/100,000
*1.9 :1 females / males
*incidence study = Danish study from – incidence actually rose during course of that study, probably due to asymptomatic pt detection (defined PLT count of < 50,000 as tpenia)
*2002 MD Health Care Commission supplied data on pts coded as ITP – age-adjusted prevalence was 9.5/100,000, overall 1.9/1 females/males (more males in childhood, females in mid/adult years)

4. *source – Williams Hematology 1995, Beutler et al.
*peak age in childhood is 2-5, equal dbn males/females, then female preponderance in adolescence on
*? More asymptomatic males, hence not counted?

5. Clinical Manifestations
May be acute or insidious onset
Mucocutaneous Bleeding
*petechiae, purpura, ecchymosis
*epistaxis, gum bleeding
*menorrhagia
*GI bleed, CNS bleed = RARE
*mucocutaneous = from skin/mucous mbs, as opposed to joint/organ bleeds in hemophilia
*overt GI/CNS bleed, hematuria, etc. RARE – may be increased risk in elderly pts

6. *typical picture of petechiae and purpura (small bleeds under surface)

8. Etiology of ITP : Children
Often after infection (viral or bacterial)
Theories:
*antibody cross-reactivity
*H. pylori
*bacterial lipopolysaccharides
*in one 1977 series, preceding infx seen in over 80% of pts
*Theories:
*antibodies made to viruses may x-react to PLT antigens and increase PLT clearance secondarily; *some strains of H. pylori may induce PLT aggregation;
*bacterial products like LPS, once adhered to PLTs, may induce increased phagocytosis or “clearance” of PLTs.
(note that in adults it’s generally less clear)

9. Etiology of ITP : Adults
?? Auto-antibodies?
*probably related to autoab’s that either cause PLT destruction or inhibit PLT production…but not demonstrable in all pts, so as I’ll discuss a few slides down, although it’s a convention to go looking for these autoab’s it really isn’t a factor in the dx/tx.

10. Diagnosis (of Exclusion)
Rule out other causes:
*lab error / PLT clumping
*drug / medication interaction
*infections (HIV, Hepatitis C)
*thyroid / autoimmune disease
*destructive / consumptive processes (TTP/HUS)
*bone marrow disease (leukemias, MDS)
*note both hyper- and hypothyroidism can cause tpenia; also autoimmune diseases like lupus

11. Diagnosis (of Exclusion)
Rule out other causes:
*lab error / PLT clumping
*drug / medication interaction
*infections (HIV, Hepatitis C)
*thyroid / autoimmune disease
*destructive / consumptive processes (TTP/HUS)
*bone marrow disease (leukemias, MDS)
*note both hyper- and hypothyroidism can cause tpenia; also autoimmune diseases like lupus

12. To Marrow or Not to Marrow?
Bone marrow aspiration & biopsy if…
Patient 60 yrs. or older
Poorly responsive to tx
Unclear clinical picture
*note can be an area of controversy in the community and actually between hematologists
*always need to r/o MDS, leukemias in older pts; but if you have a younger pt and the clinical picture is confusing, it’s advisable to check the marrow.

13. Anti-Platelet Antibody Testing
NOT recommended by ASH Practice Guidelines
Poor positive/negative predictive values, poor sensitivity with all current testing methods…
…and doesn’t change the management!
*ASH guidelines = published in 1996, based on 1994 study
*several studies have looked at use of antiPLT ab’s in pts with suspected ITP… and although the tests can be + in ITP, can also be + in non-immune etiologies (i.e. pregnancy, MDS, congenital tpenia)
*…despite this, it’s kind of a “knee-jerk” in the community and often among internists to order the test; but will generally still come down to clinical judgment while waiting for the test to come back.

14. Management of ITP in Adults
Emergency vs. Chronic Tx
Goal = prevention of bleeding, NOT cure!
*Note in many children ITP resolves spontaneously…not so in adults, as a large percentage of pts may remain chronically affected by ITP, either in terms of having chronic decreased PLT count or actually requiring additional/ongoing tx. (Onlly appx 9-10% spontaneous remission in one study – Stasi et al Am J Med 1995)

15. Management of ITP in Adults
Emergency vs. Chronic Tx
Goal = prevention of bleeding, NOT cure!
*Note in many children ITP resolves spontaneously…not so in adults, as a large percentage of pts may remain chronically affected by ITP, either in terms of having chronic decreased PLT count or actually requiring additional/ongoing tx. (Onlly appx 9-10% spontaneous remission in one study – Stasi et al Am J Med 1995)

16. General Principles of Therapy
Major bleeding rare if PLT > 10,000
Goal = get PLT count to safe level to prevent bleeding…
…not to specifically cure the ITP!
*again, this talk deals w/ITP in adults – and although 80%+ of children will go into a remission and likely recover normal PLT counts, only 9-10% of adults will

17. “Safe” Platelet Counts
“moderately” t-penic = 30-50,000
Probably safe if asymptomatic
Caution with elderly (CNS bleeds)
*data suggest if pts are asymptomatic at this PLT count, this is probably a safe level – fewer than 10% develop lower counts in follow up if they present at this level (although still need close f/u)
*as with all tx, need to tailor to your specific patient

18. When Planning Therapy…
Tailor therapy and decision to treat to the individual patient
Weigh bleeding vs. therapy risks
*e.g. Higher-risk pt = elderly, prone to falls, hx PUD, construction worker, etc.

19. Initial Therapy Prednisone 1 mg/kg/day
*usually response within 2 weeks
Taper off after PLT response
Duration of use = controversial
*most adults respond within 2 weeks (majority within 1 week)
*duration = often 4-6 weeks as spontaneous remissions are ususally in that time period
*no set answers even among the ITP Practice Panel of hematologists who set the ASH guidelines, as there isn’t any hard data to help determine.

20. Second-Line Therapy IV Immune Globulin (IVIg) 1 gram/kg/day x 2 days
WinRho (anti-D) – if pt is Rh+
50-75 mcg/kg/day
*winRho ->only in Rh+ patients
*Immune-mediated clearance of the sensitized erythrocytes occupies the Fc receptors in the reticuloendothelial system, minimizing removal of antibody-coated platelets
*NOTE neither tx is long-term but can provide rapid response if someone is acutely bleeding, needs to go into surgery, etc. (usually in days)

21. Treatment Side-Effects
Steroids
*bone density loss *GI effects
*muscle weakness *weight gain
IVIG/anti-D
*hypersensitivity *headache
*renal failure *nausea/vomiting
*alloimmune hemolysis

22. Splenectomy Usually reserved for treatment failure
Consider risk of bleeding, pt lifestyle
RISKS
*surgical procedure
*loss of immune function  vaccinations
*theory = that spleen is the major site of destruction of ab-coated PLTs, so removal of the site retains the PLTs
*recall you need the spleen to take care of encapsulated organisms  need pneumovax, meningococcal vaccines, Hib vaccines at least 2 weeks pre-op

23. When to do Splenectomy?
*Length of time after which the American Society of Hematology ITP Practice Guideline Panel members would recommend splenectomy when treating a hypothetical 30-year-old female who presented with a platelet count of less than 10,000/µL. The votes were stratified to reflect different platelet count responses to treatment. The figure illustrates that, in a patient with persistent severe thrombocytopenia (platelet count that remained <10,000/µL), the approaches were varied: one panelist recommended splenectomy as early as two weeks (blue curve), while another did not recommend splenectomy even after 10 weeks of unsuccessful treatment (green curve). Data from George, JN, Woolf, SH, Raskob, GE, et al. Blood 1996; 88:3.
*overall about 4-6 weeks of waiting time to “prove” tx failure, allow for spontaneous remission, etc. (this is probably average in community too)
Data from George, JN, Woolf, SH, Raskob, GE, et al. Blood 1996; 88:3.

24. Response Post-Splenectomy
Usually normalized PLTs within 2 weeks (often immediately)
Younger pts do better
Kojouri et al (Blood 2004)  65% CR
*65% CR in adults by recent review; however, 12 preop characteristics evaluated and none consistently funtioned as a predictor (f/u up to 153 mos)

25. Data from Fabris, F, et al. Br J Haematol 2001; 112:637.
The percent of patients (age <40 years, n=33, red curve; age >40 years, n=28, blue curve; p<0.005) with chronic idiopathic thrombocytopenic purpura (ITP) maintaining a platelet count >30,000/µL following splenectomy is plotted here versus time after splenectomy. Note the continuous relapse in both groups as long as six or more years post-splenectomy. Data from Fabris, F, et al. Br J Haematol 2001; 112:637.
Data from Fabris, F, et al. Br J Haematol 2001; 112:637.

26. Chronic Refractory ITP
Persistent > 3 months
PLT < 50,000
Failure to respond to splenectomy

27. When all else fails… Steroids IVIg / anti-D Rituximab (anti-CD20)
Cyclophosphamide
Danazol
Accessory splenectomy
H. pylori eradication

28. Wrapping it up… ITP is often a chronic disease in adults
Multiple therapies may be needed over time
Goal = prevention of complications
Therapy needs to be tailored to the individual patient

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