ADAMTS‐13 assays in thrombotic thrombocytopenic purpura

Peyvandi, Flora; Palla, Roberta; Lotta, Luca A.; Mackie, Ian; Scully, Marie; Machin, Samuel J.

doi:10.1111/j.1538-7836.2010.03761.x

Cited by 103 publications

(114 citation statements)

References 65 publications

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“…One possible explanation for this heterogeneity in human congenital TTP is that numerous ADAMTS13 mutations may result in diverse plasma ADAMTS13 activities below the detection limit of currently available assays (ϳ 5%), 34 which would still be sufficient to prevent spontaneous recurrent TTP. 20,35 This is substantiated by the observation that women with a specific hereditary ADAMTS13 deficiency get acute TTP only on pregnancy, although their equally deficient brothers remain asymptomatic.…”

Section: Discussionmentioning

confidence: 99%

Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus)

Feys

Roodt

Vandeputte

et al. 2010

Blood

104

130

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Thrombotic thrombocytopenic purpura (TTP) is the prototypical microangiopathy characterized by disseminated microthromboses, hemolytic anemia, and ultimately organ dysfunction. A link with deficiency of the von Willebrand factorcleaving protease (ADAMTS13) has been demonstrated, but additional genetic and/or environmental triggers are thought to be required to incite acute illness. Here we report that 4 days of ADAMTS13 functional inhibition is sufficient to induce TTP in the baboon (Papio ursinus), in the absence of inciting triggers because injections with an inhibitory monoclonal antibody (mAb) consistently (n ‫؍‬ 6) induced severe thrombocytopenia (< 12 ؋ 10 9 /L), microangiopathic hemolytic anemia, and a rapid rise in serum lactate dehydrogenase. Immunohistochemical staining revealed the characteristic disseminated platelet-and von Willebrand factor-rich thrombi in kidney, heart, brain, and spleen but not lungs. Prolonged inhibition (14 days, n ‫؍‬ 1) caused myocardial ischemic damage and asplenia but not death. Control animals (n ‫؍‬ 5) receiving equal doses of a noninhibitory anti-ADAMTS13 mAb remained unaffected. Our results provide evidence for a direct link between TTP and ADAMTS13 inhibition and for a mild disease onset. Introductionvon Willebrand factor (VWF) is a multimeric glycoprotein that bridges platelets to injured arterial vessels through interactions with both subendothelial collagen and platelet membrane receptors. Unusually large VWF multimers (UL-VWFs) are released as VWF precursors into the bloodstream by stimulated endothelial cells. 1 These high-molecular-weight proteins are abnormally adhesive, being able to bind and cross-link platelets in circulation even in the absence of endothelial injury. 2 Normally, UL-VWFs are rapidly cleaved by circulating VWF-cleaving protease (AD-AMTS13), 3 which generates VWF multimers of sizes seen in normal plasma. 4 The inability to process UL-VWF in cases of ADAMTS13 deficiency can cause disseminated platelet-rich thrombi, which block terminal arterioles, 1,5 leading to hemolytic anemia with ischemic organ failure and ultimately death in patients with thrombotic thrombocytopenic purpura (TTP). Diagnosis is based on signs of concurrent thrombocytopenia with hemolytic anemia and fragmented red blood cells (schistocytes) in the absence of other identifiable primary causes. 6 ADAMTS13 deficiency can be hereditary by mutations in the ADAMTS13 gene 3 or acquired by inhibiting autoantibodies to ADAMTS13. 7 The former is currently treated by infusion of fresh frozen plasma, which contains donor ADAMTS13 to overcome the deficiency. The latter often requires plasma exchange to both replenish the diminished proteolytic activity and remove inhibitors.These plasma therapies could effectively reduce mortality to approximately 20%, 8 but morbidity still is considerable and not seldom as a consequence of the plasma therapy. 9,10 Safer therapeutic strategies are therefore required 11 and could focus on the inhibition of the platelet-VWF interaction 12 or on the reconst...

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Section: Discussionmentioning

confidence: 99%

Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus)

Feys

Roodt

Vandeputte

et al. 2010

Blood

104

130

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“…[8][9][10][11] Thus, a detection of ADAMTS13 deficiency is routinely used to support clinical suspicion of TTP and to help clinicians to timely and effectively treat patients. [12][13][14] Most cases of TTP are acquired TTP patients in whom autoimmune production of antibody causes ADAMTS13 deficiency, leading to clinical manifestation of the disorder. 8 The standard therapy for TTP is immediate plasma exchange (PE), which effectively reduces disease mortality from more than 90% to less than 20%.…”

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confidence: 99%

Diagnostic and prognostic values of ADAMTS13 activity measured during daily plasma exchange therapy in patients with acquired thrombotic thrombocytopenic purpura

Liu

Yang

et al. 2014

Transfusion

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BACKGROUND:Thrombotic thrombocytopenic purpura (TTP) requires immediate treatment with plasma exchange (PE) to prevent disease mortality and/or morbidity. Frequently, PE is initiated before blood sample is collected to confirm ADAMTS13 deficiency. However, the effect of PE treatments on the evaluation of ADAMTS13 is uncertain. Moreover, the pertinence of ADAMTS13 activity during PE therapy to prediction of treatment outcomes is unclear. Thus, clarification of the diagnostic and prognostic values of ADAMTS13 activity obtained during PE treatment is an unmet clinical need. STUDY DESIGN AND METHODS:A total of 212 sequential samples were obtained during the course of daily PE treatment from 19 patients with acquired TTP. ADAMTS13 activity levels were determined in these longitudinal samples for analysis. RESULTS: After the initial three daily PE procedures, the sensitivities of ADAMTS13 activity in diagnosis of TTP (<10%) were 89, 83, and 78%, respectively. To determine prognostic value, patients with (n = 7) and without (n = 12) a recovery of ADAMTS13 activity to more than 10% within seven sessions of daily PE treatment were compared. Recovery of ADAMTS13 activity to more than 10% within 7 days is significantly associated with a timely achievement of clinical response (p < 0.01). In contrast, the patients without more than 10% ADAMTS13 within 1 week appear at risk for worse treatment outcomes manifested as TTP exacerbation, treatment refractoriness, or death. CONCLUSION: The data suggest that ADAMTS13 activities measured during the initial period of PE therapy offer both diagnostic and prognostic values in acquired TTP.T hrombotic thrombocytopenic purpura (TTP) typically presents as an acute episode with platelet (PLT) thrombosis, anemia, and evidence of organ tissue damage. The routine laboratory abnormalities for TTP include thrombocytopenia, increased serum lactate dehydrogenase (LDH), decreased hemoglobin, and presence of schistocytes on blood smear.1-3 Although these laboratory findings are characteristically associated with TTP, they are not diagnostic. Many other forms of thrombotic microangiopathies (TMAs), such as atypical hemolytic uremic syndrome, often present with similar clinical manifestations but have different underlying pathophysiology and require different treatment strategy. 4-7The primary risk factor for TTP is deficiency of ADAMTS13 protease. 8,9 Physiologically, ADAMTS13 cleaves VWF multimers, limits excessive formation of unusually large VWF multimers, and therefore prevents PLT thrombosis. [8][9][10][11] Thus, a detection of ADAMTS13 deficiency is routinely used to support clinical suspicion of ABBREVIATIONS: OSUMC = Ohio State University Medical Center; PE = plasma exchange; TMA(s) = thrombotic microangiopathy(-ies); TTP = thrombotic thrombocytopenic purpura. The standard therapy for TTP is immediate plasma exchange (PE), which effectively reduces disease mortality from more than 90% to less than 20%. 15,16 The test for ADAMTS13 in most hospitals is not offered locally, but rather as a sen...

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“…For example, ADAMTS13 is low in about 16% of cases of DIC. ADAMTS13 activity and inhibitor assays are limited in the setting of hyperbilirubinemia, resulting in falsely low activity and elevated titers, respectively [5]. TTP in the setting of positive DAT has been shown, often resulting in the incorrect diagnosis and patient morbidity [6].…”

Section: Discussionmentioning

confidence: 99%

Fatal Hematologic Alphabet Soup: A Complicated Case with Overlapping Features of TTP, AIHA, and HLH

Aledort¹

2015

J Hematol Thrombo Dis

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Here we describe the case of an unfortunate 26 year old woman who developed a fatal combination of autoimmune hemolytic anemia (AIHA), hemophagocytic lymphohistiocytosis (HLH), and thrombotic thrombocytopenic purpura (TTP). Her initial clinical picture looked that of typical autoimmune hemolytic anemia but when she was refractory to standard therapy and her course progressed, alternative diagnoses were evaluated despite the lack of schistocytes on her peripheral smear. The case highlights consideration of TTP in severe hemolysis in absence of schistocytes and investigation of HLH in severe multiorgan dysfunction even after a primary diagnosis, in this case AIHA, has been made.

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ADAMTS‐13 assays in thrombotic thrombocytopenic purpura

Cited by 103 publications

References 65 publications

Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus)

Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus)

Diagnostic and prognostic values of ADAMTS13 activity measured during daily plasma exchange therapy in patients with acquired thrombotic thrombocytopenic purpura

Fatal Hematologic Alphabet Soup: A Complicated Case with Overlapping Features of TTP, AIHA, and HLH

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