Classic Thrombotic Thrombocytopenic Purpura Research Articles

Von Willebrand factor-cleaving protease (ADAMTS-13) activity in thrombotic microangiopathies: diagnostic experience 2001/2002 of a single research laboratory.

Severe deficiency of von Willebrand factor-cleaving protease (ADAMTS-13) activity (<5% of normal) is specific for classical thrombotic thrombocytopenic purpura (TTP), a disorder presenting with thrombocytopenia, microangiopathic haemolytic anaemia and often with organ dysfunction such as neurological symptoms, renal failure, and fever. A certain, though according to several case series, variable percentage of patients with clinically diagnosed TTP and most patients with other forms of thrombotic icroangiopathies (TMA) do not show severe ADAMTS-13 deficiency. We determined ADAMTS-13 activity in 508 plasma samples of 309 patients referred to our laboratory in 2001 and 2002. Plasma samples with ADAMTS-13 activity <5% were additionally tested for the presence of inhibitory antibodies. Patients were assigned to ten predefined clinical categories according to information provided in the referral letter (TMA not specified; TMA associated with neoplasia or chemotherapy; TMA following haematopoietic stem cell transplantation; TMA with additional disorder; idiopathic TTP; haemolytic-uraemic syndrome (HUS) not specified; HUS with diarrhoea prodrome; atypical HUS; other haematological disorder; no clinical information available). We detected 50 (16%) patients with severe ADAMTS-13 deficiency. Forty-four (88%) of these patients had been classified as idiopathic TTP, 2 as neoplasia- or chemotherapy-associated, and 4 as non-specified TMA. Among the patients labelled as acute idiopathic TTP, the prevalence of severe ADAMTS-13 deficiency was 63% (44/70). Inhibitory antibodies were found in 31 (62%) patients with ADAMTS-13 activity <5%. Of the 44 patients with acute idiopathic TTP, at initial presentation or at relapse, with ADAMTS-13 activity <5%, 11 were identified to have (probable) constitutional severe ADAMTS-13 deficiency. Severe ADAMTS-13 deficiency is found in about 60% of patients diagnosed with idiopathic TTP but in none of 111 diagnosed with HUS. Plasma ADAMTS-13 activity <5%, however, does not identify all patients clinically diagnosed with TTP. Detection of inhibitory antibodies against ADAMTS-13 helps to differentiate between acquired and constitutional forms of TTP, which may be important for treatment strategies.

Von Willebrand factor-cleaving protease (ADAMTS-13) activity in thrombotic microangiopathies: diagnostic experience 2001/2002 of a single research laboratory.

Severe deficiency of von Willebrand factor-cleaving protease (ADAMTS-13) activity (<5% of normal) is specific for classical thrombotic thrombocytopenic purpura (TTP), a disorder presenting with thrombocytopenia, microangiopathic haemolytic anaemia and often with organ dysfunction such as neurological symptoms, renal failure, and fever. A certain, though according to several case series, variable percentage of patients with clinically diagnosed TTP and most patients with other forms of thrombotic icroangiopathies (TMA) do not show severe ADAMTS-13 deficiency. We determined ADAMTS-13 activity in 508 plasma samples of 309 patients referred to our laboratory in 2001 and 2002. Plasma samples with ADAMTS-13 activity <5% were additionally tested for the presence of inhibitory antibodies. Patients were assigned to ten predefined clinical categories according to information provided in the referral letter (TMA not specified; TMA associated with neoplasia or chemotherapy; TMA following haematopoietic stem cell transplantation; TMA with additional disorder; idiopathic TTP; haemolytic-uraemic syndrome (HUS) not specified; HUS with diarrhoea prodrome; atypical HUS; other haematological disorder; no clinical information available). We detected 50 (16%) patients with severe ADAMTS-13 deficiency. Forty-four (88%) of these patients had been classified as idiopathic TTP, 2 as neoplasia- or chemotherapy-associated, and 4 as non-specified TMA. Among the patients labelled as acute idiopathic TTP, the prevalence of severe ADAMTS-13 deficiency was 63% (44/70). Inhibitory antibodies were found in 31 (62%) patients with ADAMTS-13 activity <5%. Of the 44 patients with acute idiopathic TTP, at initial presentation or at relapse, with ADAMTS-13 activity <5%, 11 were identified to have (probable) constitutional severe ADAMTS-13 deficiency. Severe ADAMTS-13 deficiency is found in about 60% of patients diagnosed with idiopathic TTP but in none of 111 diagnosed with HUS. Plasma ADAMTS-13 activity <5%, however, does not identify all patients clinically diagnosed with TTP. Detection of inhibitory antibodies against ADAMTS-13 helps to differentiate between acquired and constitutional forms of TTP, which may be important for treatment strategies.

Thrombotic Microangiopathy in the Cancer Patient

Thrombotic microangiopathy, manifesting as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome, is a common complication in cancer patients. It shares the pathogenic microvascular occlusive lesion and many clinical manifestations as the classical TTP, but the spectrum of complications varies widely. Several subsets are seen, including a microangiopathic hemolytic anemia in advanced cancer, chemotherapeutic drug-associated microangiopathy and those with the transplant setting. The prognosis is not as favorable as in classical TTP. Anecdotal reports indicate that responses are seen with plasma exchange and with immunoadsorption.

Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease

Thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) are today often regarded as variants of one syndrome denoted as TTP/HUS, characterized by thrombocytopenia caused by intravascular platelet clumping, microangiopathic haemolytic anaemia, fever, renal abnormalities and neurological disturbances. Unusually large von Willebrand factor multimers have been observed in plasma from patients with chronic relapsing forms of TTP. Their appearance in patients with classic TTP is caused by deficiency of a specific von Willebrand factor-cleaving protease. A constitutional deficiency of this protease has consistently been found in familial cases of TTP, whereas in acquired TTP the protease deficiency is caused by the presence of an inhibiting autoantibody. A normal activity of von Willebrand factor-cleaving protease has been established in patients with HUS. In this chapter, we report 23 cases with severe constitutional protease deficiency: about one half of these patients had their first acute episode as children, whereas the other half had their first TTP event at an adult age, several of them during their first pregnancy. Two of these 23 individuals with congenital protease deficiency, both older than 35 years, have never had an acute TTP event. These results indicate that a deficiency of von Willebrand factor-cleaving protease alone is not sufficient to cause acute TTP. Patients with long-lasting dormant protease deficiency have been found to experience multiple relapses of TTP after having had their first acute episode. In one protease-deficient, plasma-dependent patient with chronic relapsing TTP, we estimated that 5% of normal protease activity is sufficient to remove the most adhesive von Willebrand factor multimers and prevent the formation of platelet microthrombi. The deficiency of von Willebrand factor-cleaving protease is a very strong risk factor for TTP, but the development of an acute bout requires a trigger, possibly causing the activation or apoptosis of endothelial cells in the microcirculation. It is unclear whether anti-endothelial cell antibodies, cytokines or other agents are involved in triggering thrombotic microangiopathy. The release of platelet calpain (and/or other proteases), leading to a degradation of von Willebrand factor and to platelet aggregation, has been reported in patients during their acute TTP episode. It is unknown whether calpain directly triggers an acute event or whether it merely reflects its release during the aggregation of platelets by the unusually large von Willebrand factor multimers. With regard to the heterogeneous aetiology of thrombotic microangiopathies, requiring distinct therapeutic measures, a new classification of thrombotic microangiopathy should replace the current, frequently inappropriate clinical discrimination between TTP and haemolytic uraemic syndrome.

Von Willebrand Factor Proteolysis Is Deficient in Classic, but not in Bone Marrow Transplantation–Associated, Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT) differs from classic TTP in its clinical course and therapy. A characteristic of classic TTP is the inhibition of a plasma protease that specifically cleaves von Willebrand factor (vWF), thus reducing its multimeric size. We investigated whether this protease was also inhibited in BMT-associated TTP. Plasma from patients with classic or BMT-associated TTP was incubated with recombinant vWF R834Q, a vWF mutant with enhanced sensitivity to the protease. The proteolysis of vWF multimers was analyzed and quantified on Western blot. Metalloprotease activity was strongly inhibited in the classic TTP patient group. However, metalloprotease activity was normal in the BMT-associated TTP patient group. The difference in activity between the two patient groups was highly significant (P = .0016). The results indicate that the etiologies of classic and BMT-associated TTP are indeed different and provide an explanation for the lack of success of plasma exchange in BMT-associated TTP.

Treatment of plasma refractory thrombotic thrombocytopenic purpura with protein A immunoabsorption.

The objective of this study was to assess the effect of protein A immunoabsorption in terms of response rate and toxicities in patients with classical thrombotic thrombocytopenic purpura (TTP) refractory to therapeutic plasma exchange. The study included nine females and one male with a diagnosis of classical TTP treated at multiple university hospital centers with protein A immunoabsorption (PAI) after having failed plasma exchange. The 10 patients had an age range 17-62 years. Prior to PAI, the patients had failed to respond to a mean of 15 (range 6-39) therapeutic plasma exchanges. Three patients had previous episodes of TTP. Evaluation for response to PAI included serial measurements of serum creatinine, lactate dehydrogenase (LDH), hemoglobin, hematocrit, and platelet count before, during, and up to 18 months post-PAI treatment. Seven of 10 study patients had resolution of their TTP. Six of the patients required six or fewer therapeutic PAIs and one required 12 treatments. All responding patients had evidence of improvement by the third PAI treatment. Three patients demonstrated no response to PAI, with two patients expiring from complications of TTP and one patient demonstrating a complete response to a subsequent therapy. No significant toxicity was noted with the use of PAI in this setting. Protein A immunoabsorption in patients with classical TTP refractory to plasma exchange can produce durable complete remissions and warrants comparative studies.

Thrombotic thrombocytopenic purpura following coronary artery bypass graft surgery: prospective observations of an emerging syndrome.

Thrombotic thrombocytopenic purpura (TTP) is a rapidly progressive syndrome of thrombocytopenia, microangiopathic hemolysis, and organ dysfunction. While most TTP is idiopathic, we have observed four cases following coronary artery bypass graft (CABG) surgery in a 2-year period. We have studied these cases prospectively to define the natural history, and potentially unique characteristics, of a post-CABG TTP syndrome. On average, the onset occurred 4.75 days postoperatively (post-op), but the diagnosis was made 8.5 days post-op. All four patients exhibited microangiopathic hemolysis, thrombocytopenia, mental status changes, and severe renal failure. Three also had unexplained fever. All patients received therapeutic plasma exchange for 5, 6, 8, and 11 days, respectively, and all achieved complete hematological remission. Three patients required dialysis for 7, 15, and 16 days, respectively, but were restored to baseline renal function if they survived. One patient with severe pre-existing peripheral vascular disease died of Candida sepsis. None of the surviving patients have relapsed at a median follow-up of 19 months. These cases appear distinguished by a delay in diagnosis despite intensive medical supervision, a florid presentation with most, or all, of the components of the classic TTP pentad, an excellent and rapid response to plasma exchange, and a tendency not to relapse. As such, they may represent a subgroup characterized by a more rapid and severe onset, but also a rapid response to therapy and earlier recovery than the typical idiopathic form of TTP. An aggressive approach to management is warranted.

Resolution of refractory, classic thrombotic thrombocytopenic purpura after staphylococcal protein A immunoadsorption

Multiple therapeutic interventions are available for treatment of thrombotic thrombocytopenic purpura. Resolution of thrombotic thrombocytopenic purpura may require use of several of these interventions. A patient presenting with classic (non-cancer chemotherapy-associated) thrombotic thrombocytopenic purpura had an initial response to intensive, daily plasma exchange with fresh-frozen plasma and cryosupernatant. Multiple attempts over a period of 2 months to decrease the frequency of plasma exchange resulted in exacerbations of disease activity, indicated by increased schistocytosis, decreased hematocrit, increased serum lactate dehydrogenase, and decreased platelet counts. After a total of 39 plasma exchanges, the patient was begun on immunoadsorption therapy utilizing a staphylococcal protein A immunoadsorption treatment column. After six 2000-mL protein A immunoadsorption treatments, the patient's platelet count, lactate dehydrogenase, and peripheral smear normalized, and they have remained normal over nearly 4 months of follow-up. Treatment by protein A immunoadsorption may be of benefit in patients with classic thrombotic thrombocytopenic purpura who are not achieving a sustained remission with conventional plasma exchange therapy.

The treatment of thrombotic thrombocytopenic purpura: plasma infusion or exchange?

Classic thrombotic thrombocytopenic purpura has substantial mortality and, because the pathogenesis is uncertain, multiple therapies are often used. These include corticosteroids and antiplatelet drugs, with plasma infusion or exchange most dramatically influencing outcome. To compare the relative efficacy of these latter two options, the records of 20 patients were retrospectively analysed. The groups were well matched for size and disease severity and received equivalent volumes of plasma. No significant difference in response rate or survival was demonstrated, although plasmapheresis may be preferable in the presence of impaired renal function with fluid overload.