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PubMed2006

ADAMTS-13 levels in fresh, stored, and solvent detergent treated plasma.

BACKGROUND: ADAMTS-13 is implicated in the pathophysiology of thrombotic thrombocytopenic purpura (TTP). Plasma exchange is thought to be effective through removal of a harmful substance or provision of a required material such as ADAMTS-13. As various methods are used to prepare plasma we determined the effects of storage and solvent detergent treatment on the ADAMTS-13 levels in plasma. METHODS: Samples from fresh plasma and fresh frozen plasma (FFP) were stored at 22 degrees C and ADAMTS-13 levels were measured at 0, 12, 24, 48 and 72 h. Samples were also taken from solvent detergent treated plasma (SDP) and cryosupernatant plasma (CSP). Total protein, albumin, fibrinogen and immunoglobulins were also measured. RESULTS: In fresh plasma, the levels of both the 175 and 140 Kd subunits of von Willebrand factor were consistent at 1.38 and 1.35 OD units from 0 to 48 h indicating normal ADAMTS-13 activity. The Vitex SDP produced slightly more of the 140 Kd subunit than did Octapharma SDP which gave equivalent fragments. Cryosupernatant plasma was the same as normal plasma. None of these values changed over 48 h. There was a 28% decrease in FVIII in fresh plasma over 24 h. Fibrinogen and albumin were unchanged. CONCLUSION: ADAMTS-13 levels are not significantly decreased by storage of plasma at room temperature for up to 48 h. Both CSP and SDP also contained essentially normal levels of ADAMTS-13 and therefore could be used for treatment of patients with TTP.

ADAM Proteins↗
PubMed2001

Are increased levels of von Willebrand factor in chronic coronary heart disease caused by decrease in von Willebrand factor cleaving protease activity? A study by an immunoassay with antibody against intact bond 842Tyr-843Met of the von Willebrand factor protein.

Low levels of von Willebrand factor (VWF) in von Willebrand's disease type 2A (VWD 2A) result from increased cleavage of the bond 842Tyr-843Met in the VWF protein by VWF cleaving protease. On the other hand, decreased levels of this protease result in unusually large VWF in thrombotic thrombcytopenic purpura with thrombotic complications. In the present study, we designed an enzyme-liked immunosorbent assay of VWF cleaving protease activity to be used to assess whether the high levels of VWF in coronary heart disease (CHD) relate to a deficiency of this protease. Plasma samples with added Pefabloc and CaCl(2) were incubated with purified VWF coated on a microtiter plate. The remaining undigested multimers were quantified by an antibody directed against the intact 842Tyr-843Met bond of the VWF protein. Phosphate-buffered saline (PBS), instead of plasma, was used to obtain the initial level of coated undigested VWF. The reduction in absorbance at 492 nm between PBS and the unknown sample was taken as a measure of the protease activity. The assay was applied to plasma samples from 21 senior women with chronic CHD (cases) and 34 age-matched controls, as well as to samples from three patients with VWD 2A. The protease activity was similar in the two women groups (P>.05), although the VWF antigen levels were higher in the cases (P<.01). The VWD 2A patients had similar plasma levels of the protease to that in normal pooled plasma (NPP). In the senior controls, the protease activity correlated with the subject age (r's=-.61, P<.01, n=34). In conclusion, the developed method is specific for evaluating the protease function on VWF cleavage. The moderate increase of VWF antigen in chronic CHD may not depend on the protease activity. The age influence on the protease levels supports earlier findings of higher VWF levels in healthy older subjects. A high sensitivity of the mutated protein of VWF for the protease effect rather than increases in activity or quantity of the enzyme is probably involved in the pathogenesis of VWD 2A.

ABO Blood-Group System↗
PubMed2002

Deficiency of von Willebrand factor-cleaving protease activity in the plasma of malignant patients.

von Willebrand factor (vWF) multimeric pattern and von Willebrand factor-cleaving protease activity (vWF-cp) were studied using plasmas from patients with advanced stage- and limited stage-malignant tumors. Deficiency of highly polymeric forms of vWF was observed in plasmas from 7 of 11 patients tested. vWF-cp activity was deficient in plasma samples of six patients with advanced stage-malignant tumors (ranging from 6% to 30% activity of normal plasma), whereas an essentially normal vWF-cp activity was observed in samples taken from patients with limited stage-malignant tumors. Inhibitor of vWF-cp was not detected in any plasma samples tested. To further analyze the relevance of this enzymatic activity in metastatic diagnosis, a study of vWF-cp activity was conducted in 17 patients with colon cancer, and it was shown that deficiency of vWF-cp was associated with the progression of the disease.

ADAM Proteins↗
PubMed2002

Cancer-related thrombotic microangiopathy secondary to Von Willebrand factor-cleaving protease deficiency.

Cancer-related thrombotic microangiopathy (TM) is a serious complication with a short-term life-threatening prognosis. This complication shares certain similarities with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, both characterized by circulating platelet aggregates containing ultralarge multimers of Von Willebrand factor (VWF). We report a case of cancer-related thrombotic microangiopathy secondary to disseminated metastatic cancer with undetectable serum Von Willebrand factor-cleaving protease activity and no evidence of serum inhibitory antibody. A concomitant decrease of Ca 19-9 level and hemolysis was observed during chemotherapy, in parallel with normalization of Von Willebrand factor-cleaving protease activity. The role of ultralarge multimers of Von Willebrand factor in platelet aggregation in the context of metastatic disease is discussed with respect to our findings in this case of cancer-related thrombotic microangiopathy.

ADAM Proteins↗
PubMed2000

[Idiopathic thrombotic thrombocytopenic purpura or Moschowitz syndrome: current physiopathologic and therapeutic perspectives].

INTRODUCTION: The objective of this work was to review current data about the physiopathology, clinical features, and treatment of thrombotic thrombocytopenic purpura (Moschowitz's syndrome). CURRENT KNOWLEDGE AND KEY POINTS: Thrombotic thrombocytopenic purpura is a rare disorder characterized by widespread thrombotic injuries of platelets in the microcirculation. Its physiopathology has been elucidated recently. Evidence of a deficiency of Von Willebrand's factor-cleaving protease would be due to either IgG antibodies in the acute form of the disease or constitutional deficiency in the chronic form of the disease. FUTURE PROSPECTS AND PROJECTS: Plasma exchange is the current reference treatment. However, in the light of recent publications, either infusions of concentrates of purified enzyme or more intensive immunosuppressive therapy would be more specific.

ADAM Proteins↗
PubMed2002

Control of von Willebrand factor multimer size and implications for disease.

Plasma von Willebrand factor (vWF) is a multimeric protein that mediates adhesion of platelets to sites of vascular injury, however only the very large vWF multimers are haemostatically competent. Plasma vWF derives predominantly from the vascular endothelium and is of a smaller average multimer size to that found in the sub-endothelial matrix. The existence of plasma factors that control the size of vWF multimers and account for this difference has long been suspected. vWF cleaving protease (vWFCP), a metalloproteinase that regulates vWF multimer size by proteolytic cleavage, and thrombospondin-1 (TSP-1), a trimeric glycoprotein that uncouples multimers by reducing the disulfide-bonds which link individual subunits, are two such factors that have recently been identified. The large and ultra large vWF multimers play a central role in arterial thrombosis and agents that regulate their size hold promise as novel anti-thrombotic drugs.

ADAM Proteins↗
PubMed1998

Deficiency of von Willebrand factor-cleaving protease in familial and acquired thrombotic thrombocytopenic purpura.

Excessive intravascular platelet agglutination in patients with thrombotic thrombocytopenic purpura (TTP) appears to be associated with excessive release from endothelial cells of unusually large von Willebrand factor (vWF) multimers and/or impaired degradation of these multimers by a 'depolymerase' cleaving vWF to smaller, non-agglutinating molecular forms. We studied the activity of a recently described vWF-cleaving protease in four patients, including two brothers, with chronic relapsing TTP. All four patients had lacking or strongly reduced vWF-cleaving protease activity. In another patient with chronic relapsing TTP, the protease deficiency was due to the presence in the patient plasma of an inhibitor that was found to be an IgG. We conclude that constitutional as well as acquired deficiency of vWF-cleaving protease may predispose to clinical manifestation of TTP.

ADAM Proteins↗
PubMed2002

Thrombotic thrombocytopenic purpura (TTP)--an enigmatic disease finally resolved?

Thrombocytopenic thrombocytopenic purpura (TTP), characterized by hemolytic anemia, thrombocytopenia and fluctuating neurological abnormalities, was almost universally fatal until in the 1970s, when it was discovered that remissions could usually be achieved by exchanging plasma from patients with that of donors. For the following 25 years, this therapy was routinely used without any real understanding of why it was effective. Three recent papers published almost simultaneously offer insights into the molecular basis of TTP, a rationale for why plasma exchange is helpful, and avenues for development of new and highly specific therapeutic agents.

ADAM Proteins↗
PubMed2001

Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy.

INTRODUCTION: Thrombotic microangiopathy (TM) of the fulminant type occurring in patients following bone marrow transplant (BMT) has clinical manifestations that are similar to thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome, but the outcome is generally fatal despite conventional therapy. Idiopathic acquired TTP has been associated with IgG inhibitors to the cleaving protease of von Willebrand factor (vWF) in plasma. In this study, we investigated the role of the vWF protease and vWF proteolysis in the pathogenesis of BMT-associated TM of the fulminant type. METHODS: vWF antigen level, vWF multimeric pattern, and vWF metalloprotease activity were investigated in the plasma samples of six consecutive patients with acute BMT-associated TM. Histologic and immunohistochemical studies were also performed on autopsy kidney specimens from four of the patients. All six patients had the fulminant type of the disorder with a fatal outcome and none of the patients responded to plasma infusion. RESULTS: The vWF-cleaving protease activity in plasma was normal in all patients. However, analysis of the vWF multimeric pattern showed a decrease of high molecular weight multimers. The decrease of large multimers may be caused by vWF-platelet binding as well as shear enhanced proteolysis of vWF. In the four patients who had an autopsy, a pattern of arteriolar thrombosis, distinct from that of TTP, was detected in the kidneys. CONCLUSION: These findings suggest that BMT-associated TM of the fulminant type is a heterogeneous process and distinct from TTP in pathogenesis. Analysis of vWF protease and vWF multimeric distribution are valuable tools in making the distinction between BMT-associated TM and TTP.

ADAM Proteins↗
PubMed2002

von Willebrand factor-cleaving protease inhibitor in a patient with human immunodeficiency syndrome-associated thrombotic thrombocytopenic purpura.

Antibodies that inhibit von Willebrand Factor (VWF)-cleaving protease activity occur in patients with acute thrombotic thrombocytopenic purpura (TTP) and often persist in the chronic phase. A deficiency of this protease is likely to be responsible for the generation of ultrahigh VWF multimers and influence the formation of intra-arterial platelet aggregates that result in microangiopathic haemolytic anaemia, thrombocytopenia and end in organ failure. This report demonstrates complete deficiency of VWF-cleaving protease and the presence of a concentration-dependent IgG1 inhibitor in the plasma of a patient with acquired immunodeficiency syndrome (AIDS). These data may contribute to understanding the pathophysiology of human immunodeficiency syndrome (HIV)-related TTP.

ADAM Proteins↗
PubMed2000

Von Willebrand factor--cleaving protease activity in congenital thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, fluctuating neurological impairment, renal dysfunction and fever. Both acquired and congenital forms are recognized. Recurrent episodes, which may be predictable (occurring every 21-28 d), are seen in congenital disease and may be treated by infusion with fresh-frozen plasma (FFP). Congenital TTP has recently been associated with deficiency of a novel von Willebrand factor (VWF)-cleaving protease. To investigate whether residual protease activity dictates clinical manifestations, we determined protease activity in three patients with congenital TTP of varying severity. Intrinsic VWF-cleaving protease activity of a range of plasma-derived products was also assessed as one patient had been successfully maintained for many years, initially using an intermediate-purity factor VIII concentrate (Kryobulin) and then cryoprecipitate. All three patients had a severe absolute deficiency of VWF-cleaving protease activity (< 3%) up to 5 months after clinical symptoms. Three relatives were also found to have a mild reduction in protease activity (25-50%). Nevertheless, the intrinsic VWF-cleaving protease activity of plasma-derived products correlated with their clinical efficacy: significant (100%) protease activity was found in FFP, cryosupernatant, solvent-detergent-treated plasma, cryoprecipitate and Kryobulin. Two clinically ineffective factor VIII products (Fahndi and Haemate P) possessed only low protease activity (6.25% and 12.5% respectively). Although this suggests that VWF-cleaving protease activity is central to the pathogenesis of congenital TTP, either small differences in protease activity below 3% or hitherto unknown factors have a profound influence on clinical phenotype. The possible use of factor VIII concentrates in the treatment of this condition also warrants further investigation.

ADAM Proteins↗
PubMed2001

Microangiopathic haemolytic anaemia in metastasizing malignant tumours is not associated with a severe deficiency of the von Willebrand factor-cleaving protease.

Complete deficiency of von Willebrand factor-cleaving protease (VWF-cp) has recently been identified as a pathogenetically important factor for thrombotic thrombocytopenic purpura (TTP). Microangiopathic haemolytic anaemia (MAHA) with thrombocytopenia in patients with metastasizing neoplasms is clinically similar to TTP, however, the pathogenesis of the condition is unclear. Partial deficiency of VWF-cp in metastasizing malignancy has recently been reported in patients without MAHA. Our study shows normal or subnormal VWF-cp activity in four patients with metastasizing neoplasia-associated MAHA but, in contrast to classical TTP, no complete deficiency of VWF-cp despite the full clinical picture of MAHA.

ADAM Proteins↗