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Thrombotic Thrombocytopenic Purpura

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THROMBOTIC THROMBOTIC THROMBOCYTOPENIC THROMBOCYTOPENIC PURPURA PURPURA DR. MUHAMMAD SHAKEEL ARIF HEMATOLOGY DEPT. SHAUKAT KHANUM MEMORIAL HOSPITAL & RESEARCH CENTRE, LAHORE, PAKISTAN.
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Page 1: Thrombotic Thrombocytopenic Purpura

THROMBOTIC THROMBOTIC THROMBOCYTOPENIC THROMBOCYTOPENIC PURPURA PURPURA

DR. MUHAMMAD SHAKEEL ARIFHEMATOLOGY DEPT.SHAUKAT KHANUM MEMORIAL HOSPITAL & RESEARCH CENTRE, LAHORE, PAKISTAN.

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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.

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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.

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CBC

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History

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

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• Reticulocyte count : 8.5% (normal 0.5-1.5%);

• absolute reticulocyte count :246,500/µl (normal 25,000-75,000/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

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Coagulation Screening Tests

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• 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

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• Electrolytes, Bun/Creatinine, Glucose

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• Liver Function Tests

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• Serum Haptoglobin• Urinalysis

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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

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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 African-

Americans• Prior to plasma exchange, mortality rate was as high as

90%, now less than 20%

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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.

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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.

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D/D of thrombocytopenia and microangiopathichaemolytic anaemia

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• 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.

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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.

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Types:

1. Congenital2. Acquired • Autoimmune forms, due to autoantibodies against

ADAMTS – 13• secondary to massive endothelial activation with

release of ultra - large VWF multimers in large amounts

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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

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• To date, more than 80 mutations have been documentedin 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 andmultiple recurrent episodes and develop progressive organfailure, others may only experience a single episode that

develops in adulthood and which is very responsive to plasma infusion,leaving no residual organ damage.

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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.

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• 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.

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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 theirrelease into plasma from endothelial cells and excessive binding to platelets, so that even defective large multimers may be present in plasma.

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Presentation

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Conditions and diseases associated with TTP

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Investigations

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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 .

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• 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

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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

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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 syndromepositive Coombs test, lack of schistocytes and the usual absence of end - organ ischaemic symptoms.

Disseminated malignancyUntil further investigations exclude or confirm the presence of metastatic cancer, it is not easy to distinguish TTP from this type of TMA.

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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 rangingfrom a single relapse to several episodes developing with

variable frequency and less severeclinical manifestations.

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The chronic recurrent forms may have a genetic basis or beassociated with autoantibodies, whereas the forms associated with malignancy or transplantation usually present as acute Episodes.

In congenital TTP, ADAMTS - 13 plasma levels are usuallyconsistently 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.

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Treatment

• Steps in the treatment of TTP .

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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 .

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Patients critically ill with TTP are often first admitted tohospitals 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.

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The immune pathogenesis of TTP may betackled 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 orprocedure. Considering that autoantibodies are a frequentpathogenetic mechanism, large doses of prednisone (1 – 2 mg/kg) are often prescribed in addition to plasma exchange duringthe acute phase of TTP, tapering this treatment when remissionis obtained.

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Treatment of acute TTP

Recommendation1. PEX should be started with 1·5 PV exchanges, using S/Dplasma in all age groups and reassessed daily (1B).

2. The volume of exchange can be reduced to 1·0 PV whenthe clinical condition and laboratory test results are stabilizing(2C).

3. Intensification in frequency and or volume of PEXprocedures should be considered in life-threateningcases (2B).

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4. Daily PEX should continue for a minimum of 2 d afterplatelet count has been >150 x 109/l and then stopped(2B).

Congenital TTPRecommendation1. 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).

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Treatment of TTP in pregnancy

• Recommendation1. If a TMA cannot be fully explained by a non-TTP pregnancy-related TMA, then the diagnosis of TTP must beconsidered and PEX should be started (2B).

2. Mothers with congenital TTP should attend a specialistcentre and receive ADAMTS13 supplementation regularlythroughout pregnancy and the post-partum period (1A).

3. Close liaison with an obstetrician with a special interestin feto-maternal medicine is required in mothers withTTP (1A).

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4 .In mothers with acquired TTP, ADAMTS13 activityshould be monitored throughout pregnancy to help predictthe need for adjuvant therapy and outcome (1B).

5. Pre-conceptual counselling is advised for subsequentpregnancies and women of child bearing age should becounselled about potential risks of pregnancy and COCP(2B).

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HIV–related TTP

Recommendation1. If a patient with TTP is found to have HIV infectionthen viral load should be measured and an HIV physicianshould be closely involved in management (1A).

2. TTP should be considered in an HIV-positive individualwith a MAHA and thrombocytopenia (1A).

3 PEX in conjunction with HAART (triple or quadrupletherapy) should be started as soon as the diagnosis ofHIV-associated TTP is made (1B).

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3. HAART should be given immediately after PEX therapyto maximize time for absorption (1A).

4. HAART should be continued after remission to preventfurther relapse (1B).

5. In resistant HIV-related TTP, rituximab could be considered(2B).

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Malignancy-associated thrombotic microangiopathy

• Recommendation1 PEX is not indicated in the management of malignancyand bone marrow transplant-associated TMA (1A).2 In cancer associated TMA, further treatment for theunderlying cancer should be considered (1A).

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Further treatments in acquired TTP

CorticosteroidsRecommendationIntravenous daily methylprednisolone (e.g. 1 g/d for threeconsecutive days – adult dose) or high dose oral prednisolone(e.g. 1 mg/kg/d) should be considered (1B).

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• Rituximab• Recommendation1 .In acute idiopathic TTP with neurological/cardiacpathology, which are associated with a high mortality,rituximab should be considered on admission, in

conjunctionwith PEX and steroids (1B).2. Patients with refractory or relapsing immune-mediatedTTP should be offered rituximab (1B).

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Ciclosporin ARecommendation

CSA may be considered as second line therapy in patientswith acute or chronic relapsing acquired TTP (1C).

Splenectomy.RecommendationSplenectomy may rarely be considered in the non-acuteperiod of immune-mediated TTP but has limited provenbenefit (2C).

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• Supportive therapyRecommendation1. Red cell transfusion should be administered according toclinical 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 unlessthere is life-threatening haemorrhage (1A).

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4. Thromboprophylaxis with LMWH is recommended onceplatelet count has reached >50 3 109/l (1B).

•Refractory TTPRecommendationIncreased frequency of PEX and addition of rituximab canbe considered in refractory TTP (1B).

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• Relapse• Recommendation1. Increased PEX and/or rituximab therapy are the agentsof choice in relapsing disease (1B).

2. Patients should be counselled about symptoms, signsand risk of relapse before discharge with verbal andwritten information (1A).In patients with a documented reduction of ADAMTS 13activity to <5%, elective therapy with rituximab can beconsidered (1B).

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