To understand the pathophysiologic significance of abnormal serum prostacyclin (PGI2) binding activities in thromboticthrombocytopenicpurpura (TTP), we evaluated the PGI2 binding characteristics in three chronic TTP sera and 19 normal sera. PGI2 binding by serum was rapid and reversible. The binding activity in TTP sera (22.1 +/- SD, 4.4%) was significantly lower than that of normal sera (42.2 +/- 6.2%). Moreover, the antiaggregating activity and 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) content in the gel filtrates
Thromboticthrombocytopenicpurpura (TTP) is a rare, life-threatening, thrombotic microangiopathy (TMA) characterized by severe deficiency in A Disintegrin And Metalloprotease with ThromboSpondin type 1 domain 13 (ADAMTS-13). This von Willebrand factor (vWF) cleaving protease deficiency is due either to autoantibodies directed against the protein in the acquired form of the disease, or to biallelic mutations of the encoding gene in the inherited form (also termed Upshaw-Schulman syn- drome) . In TTP, vWF and platelet-rich thrombi in small arterial vessels lead to mechanical haemolytic anaemia and thrombocytopenia with ischaemic injury of organs, prefer- entially in the brain and heart, which determines severity of the disease [1, 2]. Pregnancy is a known trigger of TTP; one precipitant might be that ADAMTS-13 activity physio- logically decreases during pregnancy, while its substrate, vWF, increases [3–5]. Within pregnancy-related diseases, TTP can mimic other TMA such as Haemolysis Elevated Liver enzymes Low Platelet (HELLP) syndrome [6, 7]. It is critical to distinguish TTP from HELLP syndrome as TTP does not necessarily require pregnancy discontinuation [8–10] but does require urgent treatment based on plasma exchange . The annual incidence of ADAMTS- 13 deficiency TMA is less than 2 per million, and is more common in females . Overall, the estimated incidence of TTP associated with pregnancy is less than 1 per 100,000 pregnancies , and before the era of ADAMTS- 13 assays, it was found at a rate of 1 per 25,000 births . The obstetrical incidence of TTP, as defined by a TMA with a severe ADAMTS-13 deficiency (activity <10 %) , has not been addressed in women during pregnancy or post-partum because the assay for ADAMST-13 activity has only recently become available. However, the identifi- cation of TTP during pregnancy is crucial, since it is asso- ciated with poor prognosis of both mother and foetus [5, 15]. To date, the assessment of ADAMTS-13 activity in pregnant women with thrombocytopenia has not been performed systematically, and the prevalence of TTP in pregnant women with thrombocytopenia remains uncer- tain. We conducted a two-year retrospective study at the Bordeaux University Hospital tertiary obstetrical unit. We assessed the incidence of TTP based on ADAMTS-13 ac- tivity in all consecutive pregnant or post-partum women presenting with thrombocytopenia less than 75 G/L. TTP patients were identified and followed through their subse- quent pregnancies.
Abstract: Thromboticthrombocytopenicpurpura (TTP) is a rare, life-threatening thrombotic microangiopathy which causes significant morbidity and mortality unless promptly recognized and treated. The underlying pathogenesis of TTP is a severe deficiency in ADAMTS13 activity, a metalloprotease that cleaves ultralarge von Willebrand factor multimers. This deficiency is either autoantibody mediated (acquired TTP) or due to deleterious mutations in the gene encoding ADAMTS13 (congenital TTP). The elucidation of this disease mechanism has reinforced the rationale and place of current therapies (eg, plasma exchange) as well as providing a basis for the prospective evaluation of immunotherapy with rituximab in addition to classic immunosup- pression (eg, corticosteroid) in autoantibody-mediated TTP. This review discusses the current evidence base for therapeutic interventions in acquired and congenital TTP as well as provid- ing a practical approach to the other aspects of investigation and management for which a firm evidence base is lacking. Novel agents that are currently being evaluated in prospective trials and future directions of therapy are also discussed which are expected to make an important contribution to improving outcomes in patients with TTP.
Thromboticthrombocytopenicpurpura and the hemo- lytic uremic syndrome are rare, closely-related disorders characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Thrombotic thrombocy- topenic purpura was first reported by Moschowitz in 1925 and is classically described as a pentad of hemolytic ane- mia, thrombocytopenia, neurological symptoms, renal involvement, and fever [1-3], although only a minority of patients present with the complete pentad[4,5]. Hemo- lytic uremic syndrome, first described by Gasser et al. in 1955, is often preceded by a diarrheal illness and presents with MAHA and thrombocytopenia and a clinical picture dominated by renal insufficiency. Significant insights into the pathophysiology of these disorders have recently been described. In the early 1980s, ultra large multimers of von Willebrand factor (ULVWF) were found in the plasma of thromboticthrombocytopenicpurpura patients. The presence of ULVWF was ultimately found to be due to a lack of von Willebrand cleaving protease activity, due either to congenital deficiency or an IgG inhibitor [8-10]. This protease has been identified[11,12] and designated ADAMTS13 (A disintegrin and metallo- proteinase family with thrombospondin-like motifs) and processes the ULVWF by proteolytic cleavage. Though there are conflicting data, TTP is most often associated with severe deficiencies of ADAMTS13 activity, whereas in HUS activity of this protease is relatively preserved. Fur- ther, pathologic differences have been observed between malignancy and chemotherapy associated TTP-HUS as compared to idiopathic/HIV-linked TTP and sporadic HUS [13,14]; the former characterized by both micro and macrovascular fibrin thrombi, as opposed to the microv- ascular, platelet-rich angiopathy seen in the latter. Without treatment, thromboticthrombocytopenic pur- pura is often a fatal disease, with a mortality rate in excess of 95%. Plasma exchange (PE) has been shown in sev- eral case series to produce response rates of approximately 80% and survival rates greater than 90% [16-20]. The effectiveness of plasma exchange was confirmed in a pro- spective randomized clinical trial by the Canadian Apher- esis Study Group, which demonstrated that PE was more effective than simple plasma infusion in the treatment of thromboticthrombocytopenicpurpura. While the role of plasma exchange in malignancy and chemother- apy associated TTP is limited[1,14] the utility of PE in patients with HUS is controversial, given common clinical features and high morbidity of untreated TTP-HUS, with- holding PE may be inappropriate[5,18,21]. Present prac- tice at our institution and others is to treat TTP and HUS in a similar fashion.
41. Yomtovian R, Niklinski W, Silver B, Sarode R and Tsai HM. Rituximab for chronic recurring thromboticthrombocytopenicpurpura: a case report and review of the literature. Br J Haematol. 2004 Mar;124(6):787–795. 42. Ojeda-Uribe M, Federici L, Wolf M, Coppo P and Veyradier A. Successful long-term rituximab maintenance for a relapsing patient with idiopathic thromboticthrombocytopenicpurpura. Transfusion. 2010 Mar;50(3):733-5. DOI: 10.1111/j.1537-2995.2009.02497.x. 43. Zheng X, Pallera AM, Goodnough LT, et al. Remission of chronic thromboticthrombocytopenicpurpura after treatment with cyclophosphamide and Rituximab. Ann Intern Med 2003;138:105–108. 44. Ahmad A, Aggarwal A, Sharma D, et al. Rituximab for Treatment of Refractory/Relapsing ThromboticThrombocytopenicPurpura (TTP). Am J Hematol. 2004;77:171–176.
Case presentation: We report the case of a 17-year-old Caucasian woman with widespread hematomas and headache. Due to hemolytic anemia, thrombocytopenia, and schistocytosis, thromboticthrombocytopenicpurpura- hemolytic uremic syndrome was suspected and plasma exchange therapy was initiated immediately. Since her thrombocyte level did not increase during the first week of therapy, plasma treatment had to be intensified to a twice-daily schedule. Further diagnostics showed markedly reduced activities of both ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 - also known as von Willebrand factor-cleaving protease) and factor H. Test results for antibodies against both proteins were positive. While plasma exchange therapy was continued, rituximab was given once weekly for four consecutive weeks. After the last dose, thrombocytes and activities of ADAMTS-13 and factor H increased into the normal range. Our patient improved and was discharged from the hospital.
microangiopathic hemolytic anemia, and absence of al- ternative etiology are sufficient to diagnose TTP [6, 7]. This allows physicians to diagnose TTP rapidly, which can be of lifesaving importance. Incidences of TTP are also in- creasingly associated with pregnancy . TTP can com- mence at any time in pregnancy. In a study, out of 13 pregnancies complicated by thrombotic microangiopathies (TMA), three patients had onset before mid-pregnancy, eight had onset during peripartum, and two several weeks postpartum . In our case, thrombocytopenia was de- tected during the third trimester while TTP was symp- tomatologically evident (by ecchymosis) at second day after delivering the baby by caesarean section. In our case, even though thrombocytopenia was present during the third trimester of gestation, the hemolytic anemia precipi- tated on second postoperative day. With the exception of the recurrent attacks of headache and proteinuria, her renal function and nervous system were normal without any episodes of fever. Because TTP typically does not have a bleeding tendency, the possibility of a migrating sub- cutaneous hematoma after the caesarean section with spinal anesthesia, which could have been facilitated by the single dose of LMWH, was excluded by a normal U/S scan of her abdominal wall, abdominal cavity, and pelvis.
All the 25 TTP-SLE patients had decreased platelet count and microangiopathic hemolytic anemia. Fever (n = 20, 80%) was the most common clinical symptom observed, followed by rash (n = 10, 40%) and gastro- intestinal symptoms (n = 10, 40%). Other clinical pre- sentations include edema (n = 9, 36%), nervous system symptoms (n = 9, 36%), and joint pain (n = 5, 20%) (Table 1). Blood smear and Coombs test were performed in 17 patients; all of these patients had fragmentation of erythrocytes and 4 of them had Coombs positive. The increase of LDH was found in all patients (median = 528 U/L, range 265–2511 U/L). Nineteen patients (76%) had impaired renal function. The median of serum creatinine level was 115 umol/L (range 38–366.8 umol/L).
The differential diagnosis for TTP includes other thrombotic microangiopathies (TMAs) importantly dis- seminated intravascular coagulopathy (DIC) and haemo- lytic uraemic syndrome (HUS) . The diagnosis of TTP and TTP-like syndrome in our unit is made on the basis of severe thrombocytopaenia, elevated LDH levels and schistocytes on the peripheral smear in the correct clinical setting (including the presence of HIV infection). DIC is generally excluded when the coagulation parameters (with the exception of the D-dimers) are normal . HUS would only be considered in patients with current or his- torical diarrhoea and severe renal dysfunction. In our co- hort, only 1 patient presented with any significant renal dysfunction. The absence of a single highly sensitive and specific marker for TTP in HIV infection is a significant impediment to early diagnosis and care, since other TMAs cannot always be excluded with certainty. Of note, the Coombs test may be non-specifically positive in HIV-infected patients and the clinical and diagnostic sig- nificance of this is uncertain .
Effective use of rituximab, a monoclonal antibody directed against CD20 receptors on the surface of B cells, has been increasingly reported in the treatment of TTP associated with the presence of ADAMTS13 inhibitor in patients who have been resistant to treatment with plasma exchange. It is well tolerated and has few serious side effects. Among the most serious side effects of rituximab are infectious complications related to re-activation of latent viral infections, including HCV  . Therefore all risks and benefits should be considered very carefully before its
Atypical hemolytic syndrome is an extremely rare, life threatening, progressive disease. Approximately one to two cases per million are seen annually in the US. 3.4 It is known to be associated with variety of conditions including infections, drugs, autoimmune conditions, vaccination, malignancy, organ transplantation, pregnancy, and metabolic conditions. 11,13 We hereby describe a case of atypical hemolytic uremic syndrome associated with CABG surgery. A 58 year old female presented to the emergency department (ED) with three days of worsening shortness of breath and cold like symptoms including nausea, vomiting and rhinorrhea. Twenty six days prior to presentation she had undergone Coronary Artery Bypass Graft (CABG) for three vessel disease. The physical examination was unremarkable. Labs showed anemia, acute renal injury and thrombocytopenia. A peripheral smear demonstrated over 10 per high-power field of schistocytes. She was presumptively diagnosed with ThromboticThrombocytopenicPurpura (TTP) and started on plasmapheresis. ADAMSTS-13 was normal and autoimmune workup was negative. After an extensive workup she was diagnosed with Atypical Hemolytic Uremic Syndrome (aHUS). To our knowledge this is the first case of aHUS associated with CABG. In fact, there has been only one other case of aHUS related to cardiac surgery which was found in a child who underwent Tetralogy of Fallot repair. 1
Thrombotic microangiopathy (TMA) is characterized by haemolytic anaemia, thrombocytopenia and organ injury due to platelet thrombosis in the microcirculation. Depend- ing on predominantly kidney or CNS location, it is classi- fied as haemolytic-uremic syndrome (HUS) or thromboticthrombocytopenicpurpura (TTP). HUS may be typical HUS or atypical HUS (aHUS) including the pregnancy induced form. The incidence of acquired TMA is 17.5/mil- lion/year, 17% occur during pregnancy or postpartum . aHUS has defects in complement regulation causing increased alternative pathway activation in glomerular ves- sels. The causes are disabling mutations in the genes of