DR V PHILIP CLINICAL HAEMATOLOGY UNIT CHRIS HANI BARAGWANATH ACADEMIC HOSPITAL

Transcription

1 DR V PHILIP CLINICAL HAEMATOLOGY UNIT CHRIS HANI BARAGWANATH ACADEMIC HOSPITAL

2 Rare but fatal disease if unrecognized and untreated Incidence about 1: 1 million in the USA Female preponderance of 2:1 Part of the group of Thrombotic microangiopathies (TMA) which include 1)acquired TTP 2)hereditary TTP 3) drug induced TMA 4) ST-HUS 5) complement mediated TMA

3 Pentad of features ANAEMIA: microangiopathic, severe THROMBOCYTOPAENIA: severe, but bleeding uncommon CONSIDER TTP IN EVERY PATIENT WITH SEVERE ANAEMIA AND THROMBOCYTOPAENIA Renal dysfunction : commonly mild, not requiring dialysis Neurological manifestations including confusion, seizures, headache and coma Fever

4 Anaemia with Hb less than 6g/dl Thrombocytopaenia less than 20x10ˆ9/l Numerous fragments (schistocytes) in peripheral blood Elevated LDH levels: to be used more for monitoring purposes rather than diagnosis Renal dysfunction with elevated urea and creatinine Hypocalcaemia especially once treatment has been initiated HIV and ANA should be tested to elicit a possible cause Certain labs can measure levels of ADAMTS13

5

6 Initiation of platelet microthrombi occurs when ultralarge multimers of von Willebrand factor are not cleaved by a disintegrin and metalloprotease with a ThromboSpondin type 1 motif enzyme ADAMTS 13. These large multimers are released in small vessels under sheer stress and remain attached to endothelial cells until cleaved. This leads to micro-infarctions of tissue especially in the brain and kidney As blood passes through the microthrombi haemolysis occurs as a mechanical phenomenon leading to fragmentation of red cells

7 HIV Auto-immune conditions : SLE Pregnancy Drugs: antiviral (acyclovir); quinine; platelet aggregation inhibitors (ticlopidine, clopidogrel, prasugrel) Immune suppressants: cyclosporine, tacrolimus, mitomycin Hormone altering drugs : oestrogens, hormone replacement therapy

8 TTP DIC ANAEMIA SEVERE MODERATE THROMBOCYTOPAENIA SEVERE MODERATE FRAGMENTS NUMEROUS MILD INR NORMAL PROLONGED PTT NORMAL PROLONGED

9 Other primary TMA s MAHA and thrombocytopaenia: Pre-eclampsia and HELLP, DIC, systemic malignancy, accelerated hypertension, SLE Evans syndrome: Coombs positive Megaloblastic anaemia Myelodysplastic syndromes Heparin induced thrombocytopaenia Vascular lesions such as Kaposiform capillary haemangioendotheliomas, cardiac valves etc

10 NEED INTENSE AND URGENT THERAPY Depends on individual patients: All patients have to be put onto steroids either prednisone 1 to 1.5 mg/kg/day or methylprednisolone 125 mgs 3 times a day Patients without neurological manifestations can be put onto a trial of FFP 40mls/kg body weight in 2 daily doses. May need to be given diuretics to prevent fluid overload. If no response or detioraration in physical state initiate plasma exchange Therapeutic plasma exchange for all ill and pregnant patients. This has a dual purpose of removing antibodies and infusing cleavase enzyme

11 Continue treatment until platelet count more than 100 and LDH levels less than 1000 U/l Seizures can occur on treatment because of the infusion of citrate in plasma and blood. Calcium supplements should be given Transfuse Hb upto 8g/dl If no response within 4 to 5 days add other immune suppressants such as azathioprine or Rituximab. Start treatment of the underlying cause such as ARV s in HIV+ individuals Platelet transfusion can be given if significant bleeding occurs but not otherwise.

12 YEAR TOTAL TTP HIV NEG FFP PREG 1 2 PROSTATE 2 ANA ADENOCA QUININE DEATH

13 27 males from a total of 113 TTP patients of whom 4 were HIV negative with female preponderance of 4:1 Most patients required 8 to 10 days of plasma exchange One was ANA+, 2 with malignancies and 1 with accelerated hypertension. More than 90% of our patients are HIV+ Rituximab was given in 1 patient and vincristine in another for refractory TTP 3 patients had relapses Death in most patients occurred in the first 48 hours after diagnosis

14 Recombinant ADAMTS13: mainly for hereditary TTP Anti-VWF (caplacizumab) is a monoclonal antibody-based fragment that binds to vwf and blocks its interaction with GP1b-1X-V on platelets. Decreases time to remission but complicated by increased bleeding and relapse after stopping therapy.

15 From a disease with >90% mortality in the eighties to more than an 80% chance of survival with appropriate therapies In patients with anaemia and thrombocytopaenia TTP must always be considered. Phone the haematopathologist to review the smear urgently. TTP can develop after the initial smear and a smear review must be done if indicated Intense and urgent management is an absolute and ideally these patients should be managed in a high care setting Consider TTP in all HIV+ patients with severe anaemia and thrombocytopaenia

16 Brynes, JJ & Moake, JL (1986) thrombotic thrombocytopenic purpura and the haemolytic-uremic syndrome: evolving concepts of pathogenesis and therapy, Clinical Haematology,15, Novitsky,N, Thomson J, Abrahams, L, du Toit,C, Mcdonald, A thrombotic thrombocytopenic purpura in patients with retroviral infection is highly responsive to plasma infusion therapy, British Journal of Haematology,128, Coppo,P & Froissart,A Treatment of thrombotic thrombocytopenic purpura beyond plasma exchange, American Society of Haematology, 2015 George, JN, How I treat patients with thrombotic thrombocytopenic purpura:2010 Blood ; George, JN, Cuker, A, Acquired TTP from UpToDate 2016