1. THROMBOTIC
THROMBOCYTOPENIC
PURPURA
DR. MUHAMMAD SHAKEEL AR
IF
HEMATOLOGY DEPT.
SHAUKAT KHANUM MEMORIAL HOSPITAL & RESEARCH
CENTRE, LAHORE,
PAKISTAN.

2. Case:
• A 32-year-old woman comes to the ER complaining of
episodic orbital headaches, difficulty moving her tongue,
difficulty speaking, and intermittent numbness of her
extremities for the last week.

3. Examination
•Vital signs are normal, except for a temperature of 100 °F.
•The patient’s exam is unremarkable.
•The patient has no detectable splenomegaly which can be
associated with thrombocytopenia.
•The Neuro exam is non-focal. The patient has another
neurologic episode while in the ER, causing a left facial
droop and mild dysarthria.

4. CBC

5. History
•How long anemic
•Bruising or bleeding
•recent signs or symptoms of infection
•Drug history
•Joint pain
•Skin rashes
•Dirrhea or abdominal pain
•jaundice

6. • Reticulocyte count : 8.5% (normal 0.5-1.5%);
• absolute reticulocyte count :246,500/µl (normal 25,00075,000/µl)
• Blood Cultures
• This patient has a temperature of 100 °F without any
localizing signs. DIC and sepsis might cause
thrombocytopenia, so obtaining several blood cultures
early in the hospitalization is not inappropriate.
PATIENT RESULTS: No growth at 48 hours

7. Coagulation Screening Tests

8. • Coomb's Test
• This patient could have an autoimmune hemolytic
anemia, and a positive direct Coomb’s Test is the
diagnostic finding in these patients.
PATIENT RESULT: Negative Direct and Indirect

9. • Electrolytes, Bun/Creatinine, Glucose

10. • Liver Function Tests

11. • Serum Haptoglobin
• Urinalysis

13. DIFFERENTIAL DIAGNOSIS
•
•
•
•
Thrombotic Thrombocytopenic Purpura (TTP)
Disseminated Intravascular Coagulation (DIC)
HUS
Evan's Syndrome: Autoimmune Hemolytic Anemia and
Thrombocytopenia
• Megaloblastic Anemia Due to Vitamin B12 or Folic Acid
Deficiency

14. Epidemiology
•
•
•
•
Suspected TTP-HUS- 11 cases/million/yr
Idiopathic TTP-HUS- 4.5 cases/million/yr
Severe ADAMTS13 deficiency- 1.7 cases/million/yr
Incidence rates were greater for women and AfricanAmericans
• Prior to plasma exchange, mortality rate was as high as
90%, now less than 20%

15. Terminology
• TTP and HUS (hemolytic uremic syndrome) are both
acute syndromes with abnormalities in multiple organ
systems and evidencing microangiopathic hemolytic
anemia and thrombocytopenia.
• Although some studies appear to distinguish these two
entities the presenting features are essentially the same
in most adult patients. Furthermore, the pathologic
changes are the same and so is the initial treatment.

16. Definitions and Diagnosis
• The Classic Pentad of TTP
• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Renal insufficiency or abnormalities
• Neurologic abnormalities that can be fluctuating
• Fever
• Most common symptoms at presentation are nonspecific
and include abdominal pain, nausea, vomiting and
weakness.

17. D/D of thrombocytopenia and microangiopathic
haemolytic anaemia

18. • MAHA
• nonimmune hemolysis (negative coombs) with
prominent red cell fragmentation (schistocytes) on
peripheral blood smear. Will exhibit increased LDH and
indirect bilirubin.
• Schistocytes
• in the appropriate clinical setting schistocyte count>1%
was strongly suggestive of TTP-HUS, ie 2 or more schistos
in microscopic field at 100x magnification.

19. Definitions Continued…
• Neurologic symptoms
• most are subtle, such as transient confusion or severe
headache. Focal, objective abnormalities are less
common, but grand mall seizures and coma can occur.
• Fever
• less frequent finding, but the presence of chills and high
spiking fever should suggest dx of sepsis or DIC.
• Cardiac involvement
• incidence is difficult to determine, but diffuse platelet
thrombi and associated hemorrhage in cardiac tissues
can lead to arrythmias, MIs, sudden death, shock, or
heart failure.

20. Types:
1. Congenital
2. Acquired
• Autoimmune forms, due to autoantibodies against
ADAMTS – 13
• secondary to massive endothelial activation with
release of ultra - large VWF multimers in large amounts

21. Congenital TTP
• Congenital TTP is very rare (1 in 1 million) and represents
5% of all TTP cases.
• usually occurs immediately after birth or during
childhood, although may present later in life
• Congenital TTP is caused by homozygous or double
heterozygous mutations in the ADAMTS13 gene (located
on chromosome 9q34) that affect protein secretion or
function; it is inherited in autosomal recessive manner

22. • To date, more than 80 mutations have been
documented
in patients with familial TTP.
• the majority cause severe ADAMTS - 13 deficiency by
decreasing its biosynthesis, intacellular trafficing and
secretion and/or proteolytic activity.
• While some patients have neonatal disease onset and
multiple recurrent episodes and develop progressive organ
failure, others may only experience a single episode that
develops in adulthood and which is very responsive to
plasma infusion,leaving no residual organ damage.

23. Acquired TTP
• The acquired form accounts for >99% of the adolescent
and adult cases.
• Pathophysiology
• von Willebrand factor, a glycoprotein secreted from
vascular endothelial cells in very large polymeric forms,
supports platelet adhesion and aggregation at sites of
vessel injury.
• ADAMTS13, a metalloprotease in plasma, cleaves von
Willebrand factor when it is conformationally unfolded
by shear stress.
• By cleaving vWF before it is fully activated by shear
stress, ADAMTS13 prevents vWF-mediated platelet
aggregation.

24. • Autoimmune TTP is due to anti - ADAMTS - 13 antibodies
that inhibit the proteolytic activity of ADAMTS - 13
and/or bind the protease to accelerate its clearance
from plasma through opsonization and/or other yet
unclear mechanisms.
• Anti - ADAMTS – 13 antibodies are usually of IgG type,
although in few cases autoantibodies of IgA and/or IgM
isotype were also found.
• The higher incidence of autoimmune idiopathic TTP in
specific ethnic groups such as Afro – Caribbeans.

25. Ultra - large VWF multimers, pivotal players in the
presently accepted model of TTP, are not constantly
detected in patient plasma.
In some instances, there is an imbalance between their
release into plasma from endothelial cells and excessive
binding to platelets, so that even defective large multimers
may be present in plasma.

27. Presentation

28. Conditions and diseases associated with
TTP

29. Investigations

32. Differential diagnosis
HUS
•diarrhoeal prodromes
•more severe and persistent symptoms of renal
impairment.
difficult to distinguish TTP from atypical HUS, except for
the paradigmatic prevalence of neurological symptoms in
the former and of renal failure in the latter .

33. • DIC
• markedly increased levels of fibrin degradation
• products and D-dimer and, in decompensated cases, by
the presence of hypofibrinogenaemia and prolonged PT,
APTT
• pre - eclampsia and eclampsia,
• Tests of coagulation and fibrinolysis are usually abnormal
in pre - eclampsia or eclampsia

34. Malignant hypertension
is less frequent, renal damage is not as severe and the
degrees of anaemia and thrombocytopenia are more
severe in TTP.
HELLP syndrome
(haemolysis, elevated liver enzymes and low platelets)
Abnormally high serum transaminases

35. Connective tissue disorders
(systemic lupus erythematosus and severe scleroderma)
symptoms and signs are usually less severe, and laboratory
tests such as antinuclear antibodies and lupus - like
anticoagulant give positive results.
Evans syndrome
positive Coombs test, lack of schistocytes and the usual
absence of end - organ ischaemic symptoms.
Disseminated malignancy
Until further investigations exclude or confirm the
presence of metastatic cancer, it is not easy to distinguish
TTP from this type of TMA.

36. Clinical Course
• In approximately two - thirds of cases, TTP occurs only
once(acute sporadic TTP).
• In more than one - third of patients, the disease tends to
recur after periods of remission of the acute episode.
• Recurrence, has a spectrum of presentations ranging
from a single relapse to several episodes developing with
variable frequency and less severe
clinical manifestations.

37. The chronic recurrent forms may have a genetic basis or
be
associated with autoantibodies, whereas the forms
associated with malignancy or transplantation usually
present as acute Episodes.
In congenital TTP, ADAMTS - 13 plasma levels are usually
consistently below the limit of sensitivity of the assays
available at present and patients remain asymptomatic for
prolonged periods of time (usually from 3 weeks to 3
months) and then thrombocytopenia and schistocytic
anaemia herald the appearance of new symptoms of end organ ischaemia.

38. Treatment
• Steps in the treatment of TTP .

39. Plasma therapy
Plasma exchange may help by removing anti - ADAMTS 13 autoantibodies, the most frequent mechanism of acute
sporadic TTP.
also helps to replace the deficient protease, infusion alone
being probably sufficient in congenitally deficient cases
with no associated autoantibody.
Treatment with plasma should be initiated as soon as the
clinical diagnosis is suspected .

40. Patients critically ill with TTP are often first admitted to
hospitals without facilities for plasma exchange; in such
circumstances, daily infusion of large amounts of fresh - frozen
plasma (FFP) (30 mL/kg) should be started promptly, taking
measures to avoid volume overload .
At least 1 plasma volume should be exchanged daily until
platelets rise to 150 × 10 9 /L or more, LDH is normal and
schistocytes are no longer present on blood films. Daily
treatment with plasma exchange must be continued for at least
3 days after remission has been obtained.

41. The immune pathogenesis of TTP may be
tackled by using immunomodulating agents such as
corticosteroids, cyclophosphamide, azathioprine, intravenous
immunoglobulins
Splenectomy has also been attempted.
In general, it is diffi cult to recommend a useful agent or
procedure. Considering that autoantibodies are a frequent
pathogenetic mechanism, large doses of prednisone (1 – 2 mg/
kg) are often prescribed in addition to plasma exchange during
the acute phase of TTP, tapering this treatment when remission
is obtained.

42. Treatment of acute TTP
Recommendation
1. PEX should be started with 1·5 PV exchanges, using S/D
plasma in all age groups and reassessed daily (1B).
2. The volume of exchange can be reduced to 1·0 PV when
the clinical condition and laboratory test results are stabilizing
(2C).
3. Intensification in frequency and or volume of PEX
procedures should be considered in life-threatening
cases (2B).

43. 4. Daily PEX should continue for a minimum of 2 d after
platelet count has been >150 x 109/l and then stopped
(2B).
Congenital TTP
Recommendation
1. S/D plasma infusion or intermediate purity Factor VIII should
be used to treat congenital TTP (1C).
2. Treatment regimens for congenital TTP should be
individualized according to the patient’s phenotype (1A).

44. Treatment of TTP in pregnancy
• Recommendation
1. If a TMA cannot be fully explained by a non-TTP pregnancyrelated TMA, then the diagnosis of TTP must be
considered and PEX should be started (2B).
2. Mothers with congenital TTP should attend a specialist
centre and receive ADAMTS13 supplementation regularly
throughout pregnancy and the post-partum period (1A).
3. Close liaison with an obstetrician with a special interest
in feto-maternal medicine is required in mothers with
TTP (1A).

45. 4 .In mothers with acquired TTP, ADAMTS13 activity
should be monitored throughout pregnancy to help predict
the need for adjuvant therapy and outcome (1B).
5. Pre-conceptual counselling is advised for subsequent
pregnancies and women of child bearing age should be
counselled about potential risks of pregnancy and COCP
(2B).

46. HIV–related TTP
Recommendation
1. If a patient with TTP is found to have HIV infection
then viral load should be measured and an HIV physician
should be closely involved in management (1A).
2. TTP should be considered in an HIV-positive individual
with a MAHA and thrombocytopenia (1A).
3 PEX in conjunction with HAART (triple or quadruple
therapy) should be started as soon as the diagnosis of
HIV-associated TTP is made (1B).

47. 3. HAART should be given immediately after PEX therapy
to maximize time for absorption (1A).
4. HAART should be continued after remission to prevent
further relapse (1B).
5. In resistant HIV-related TTP, rituximab could be
considered
(2B).

48. Malignancy-associated thrombotic
microangiopathy
• Recommendation
1 PEX is not indicated in the management of malignancy
and bone marrow transplant-associated TMA (1A).
2 In cancer associated TMA, further treatment for the
underlying cancer should be considered (1A).

49. Further treatments in acquired TTP
Corticosteroids
Recommendation
Intravenous daily methylprednisolone (e.g. 1 g/d for three
consecutive days – adult dose) or high dose oral
prednisolone
(e.g. 1 mg/kg/d) should be considered (1B).

50. • Rituximab
• Recommendation
1 .In acute idiopathic TTP with neurological/cardiac
pathology, which are associated with a high mortality,
rituximab should be considered on admission, in
conjunction
with PEX and steroids (1B).
2. Patients with refractory or relapsing immune-mediated
TTP should be offered rituximab (1B).

51. Ciclosporin A
Recommendation
CSA may be considered as second line therapy in patients
with acute or chronic relapsing acquired TTP (1C).
Splenectomy.
Recommendation
Splenectomy may rarely be considered in the non-acute
period of immune-mediated TTP but has limited proven
benefit (2C).

52. • Supportive therapy
Recommendation
1. Red cell transfusion should be administered according
to
clinical need especially if there is cardiac involvement (1A).
2. Folate supplementation is required during active
haemolysis
(1A).
3. Platelet transfusions are contra-indicated in TTP unless
there is life-threatening haemorrhage (1A).

53. 4. Thromboprophylaxis with LMWH is recommended once
platelet count has reached >50 3 109/l (1B).
•Refractory TTP
Recommendation
Increased frequency of PEX and addition of rituximab can
be considered in refractory TTP (1B).

54. • Relapse
• Recommendation
1. Increased PEX and/or rituximab therapy are the agents
of choice in relapsing disease (1B).
2. Patients should be counselled about symptoms, signs
and risk of relapse before discharge with verbal and
written information (1A).
In patients with a documented reduction of ADAMTS 13
activity to <5%, elective therapy with rituximab can be
considered (1B).