Thrombotic Thrombocytopenic Purpura

British J of Hematology 2000

History

• In 1924, Dr.Eli Moschcowitz described a 16- year old girl with abrupt onset of petechiae, pallor, followed by paralysis, coma, and death.

• Autopsy showed ‘hyaline’ thrombi occluding terminal arterioles and capillaries.

Rock GA, Br J Hematology 2000

Definition

• Syndrome of Coomb’s negative microangiopathic hemolysis and thrombocytopenia in the absence of an alternative explanation for these manifestations.

• Presence of Fever, Neurological and renal abnormalities : classic Pentad.

Shumak KH, Ann Intern Med 1995

Clinical Presentation• Approximately 1000 new cases occur each year

• Common in middle aged group,median age-40

• Female:male (2:1).

• Acute onset and fulminant course

• Mortality rate >90% in pre-pheresis era.

• Relapse rates, 10-40% ranging from months to years have been reported.

Clinical Features

• Renal abnormalities– Proteinuria/hematuria > oliguria/ARF

• Neurological abnormalities– Mental status changes> focal abnormalities.

• Profound weakness related to anemia.

• Abdominal pain,nausea, vomiting & diarrhea

• Fever without chills.

• Primary/idiopathic TTP vs. secondary

George, Blood Aug 2000

Secondary TTP• Drug-induced

– Acute immune mediated: Ticlopidine & plavix.– Dose-related: mitomycin, tacrolimus, pencillin,

cyclosporine, cisplatin, bleomycin, OCP– Quinine: HUS like illness.

• Pregnancy and post-partum.• Allogenic bone marrow transplant.• Autoimmune disorders (SLE,scleroderma)• HIV infection.

Pathogenesis

• Deficiency of VWF-cleaving protease– Termed ADAMTS13 ( “a disintegrin-like and

metalloprotease with thrombospondin type I repeats– Corresponding gene : chromosome 9q34.– Familial recurrent TTP: constitutional deficiency– Acquired/Idiopathic : transient auto-antibodies– HUS : normal levels of enzyme

http://www.asheducationbook.org/content/vol2002/issue1/images/large/George_fig1.jpeg

ULVWF Model

                                                                                                                                 

George,Blood Aug 2000

Diagnosis

• Primary diagnostic criteria– Thrombocytopenia ( often below <20,000)– Microangiopathic hemolytic anemia

• Negative Coomb’s test.

• Fragmented red cells (schistocytes) on peripheral smear

• LDH elevation is the hallmark of RBC destruction and tissue injury related to ischemia.

• Presence of above criteria is sufficient to establish presumptive diagnosis & begin PE

                                                                                                                                  

                                    

                                                                                                                                 

                                                                                                                                 

                                                                                                                                 

Diagnosis

• At present there are no confirmatory test.

• Other features in pentad support the diagnosis.

• Tests for ADAMTS13 deficiency or inhibitors are not readily available and lack standardization.

Differential Diagnosis

• Disseminated intravascular coagulation.

• Sepsis: cytomegalovirus, rocky mountain spotted fever, meningococcemia.

• Preeclampsia/eclampsia, HELLP.

• Disseminated malignancy.

• Hemolytic-uremic syndrome

• Evans syndrome

• Malignant hypertension.

Treatment

• Plasma exchange:– Untreated TTP has 80-90% mortality.– Removes ULvWF multimers, autoantibody and

replaces metalloproteinase.– Randomized controlled trial (Rock et al, 1991)– FFP as the replacement fluid is most widely

used and cost effective.

Treatment

• Cryosupernatant plasma (Rock et al 2000)– Theoretically superior to FFP in refractory

disease– Removal of cryoprecipitate from donor plasma

results in removal of vWF ( only 18%), with no change in metalloproteinase concentration.

• Solvent-detergent plasma (Moake et al 1998)– Lacks high molecular weight forms of VWF– Inactivates lipid-enveloped viruses.– Drawback: parvovirus & hep A not inactivated.

Response To Treatment

• MS changes improve dramatically.

• Thrombocytopenia require several days.

• Parameters of hemolysis improve promptly, yet anemia may continue to worsen.

• Recovery from renal failure is unpredictable and often slow.

• Prolonged courses of PE, with frequent exacerbations is characteristic of idiopathic TTP

American Society of Hematology 2002

Complications of Plasma Exchange

• Central venous catheter-related  Insertion procedure

• 4%    Sepsis

• 15%    Thrombosis

• 10%• Plasma-related

    Allergic• 4%

    Infection• 0

• Instrument-related Unintentional plateletpheresis

Duration of treatment.

• No studies precisely determine optimal schedule

• AABB extracorporeal therapy committee: daily PE until plt ct > 150k for 2-3 days.

• American Society for Apheresis: daily PE until Plt > 100k, complete normalization of LDH.

• Tapering schedule to 3 times per week after sustained response is highly recommended.

Conn's current therapy ;2004

Treatment

• Avoid prophylactic platelet transfusion (Gordon et al , 1987; Harkness et al 1981)– Unless life-threatening bleeding is present.– Provide additional substrate for thrombus

formation.– MI and strokes have reportedly occurred after

transfusion.

British J of Hemat 2000

Adjuvant Therapy

• Antiplatelet agents:– Aspirin (325mg), dipyrimadole ( 400mg)– Ticlopidine maintenance for 1 year.

• Corticosteroids– Presence of auto antibodies to ADAMTS13

supports the autoimmune disease.– Reserved for patients refractory to PE.

British J of Hematology 200

Treatment

• Splenectomy (Crowther et al, 1996)

• Chemotherapy: Cytoxan, Vincristine, Rituxan, CHOP.

• High- dose IV IgG

• Protein A immunoadsorption columns.