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PubMed2001

Upshaw-Schulman syndrome revisited: a concept of congenital thrombotic thrombocytopenic purpura.

Upshaw-Schulman syndrome (USS) is a congenital bleeding disorder characterized by repeated episodes of thrombocytopenia and microangiopathic hemolytic anemia that respond to infusions of fresh frozen plasma. Inheritance of USS has been thought to be autosomal recessive, because 2 siblings in the same family are often affected but their parents are asymptomatic. Recently, chronic relapsing thrombotic thrombocytopenic purpura (CR-TTP), reported almost exclusively in adults, was shown to be caused by inherited or acquired deficiency in the activity of a plasma von Willebrand factor-cleaving protease (vWF-CPase). The pathogenesis of USS is unknown, and a relationship between CR-YEP and USS has not been reported. We studied 3 unrelated USS patients (ST, SY, and KI) who presented with severe indirect neonatal hyperbilirubinemia. All 3 patients had undetectable vWF-CPase activity, and the inhibitors to vWF-CPase were all negative. In their parents with no clinical symptoms, vWF-CPase activities as a percentage of control samples (mother/father) were 17/20 for ST, 60/45 for SY, and 36/5.6 for KI. Thus, USS and vWF-CPase activity appear to be coinherited as autosomal recessive traits. Transfusion of fresh frozen plasma in 2 patients (ST and SY) resulted in the expected maximal increment of approximately 7% to 8% in vWF-CPase activity at 1 to 4 hours, but the levels became less than 3% within 2 days. After this decrease, platelet counts increased, plateaued in the normal range at 10 to 12 days, and declined thereafter. Thus, the 2 to 3 weeks of therapeutic benefit from plasma infusions will be discussed in relation to the intravascular lifetime of vWF-CPase.

ADAM Proteins↗
PubMed2001

Deficient activity of von Willebrand factor-cleaving protease in patients with Upshaw-Schulman syndrome.

We identified unusually large von Willebrand factor (vWF) multimers caused by deficient activity of vWF-cleaving protease in 2 patients with Upshaw-Schulman syndrome. The autoantibodies that inhibited the protease activity were not detected in the plasma of either patient. Periodic fresh-frozen plasma transfusion was effective for management of the hemolysis and thrombocytopenia. We detected enriched enzyme activity in a particular plasma fraction, although molecular cloning of this specific protease is needed to determine a more detailed pathogenesis and to develop new therapeutic approaches.

ADAM Proteins↗
PubMed2000

Autosomal recessive inheritance of von Willebrand factor-cleaving protease deficiency.

A child with chronic relapsing thrombotic thrombocytopenic purpura (TTP/HUS) had recurrent thrombocytopenia, microangiopathic hemolytic anemia with fragmented erythrocytes, microthrombi in the lung vessels, and renal dysfunction. Assay of von Willebrand factor (vWF)-cleaving protease showed a complete protease deficiency in the patient and subnormal activities in the mother and in two asymptomatic siblings. No inhibitor of vWF-cleaving protease was detected in the patient's plasma. Periodic transfusions of fresh-frozen plasma prevented further acute episodes of TTP/HUS. Specific diagnosis of the constitutional deficiency of vWF-cleaving protease helps to provide successful prophylactic therapy.

ADAM Proteins↗
PubMed2003

The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children.

We reviewed the literature to analyze the risk of recurrence of hemolytic uremic syndrome (HUS) after renal transplantation in children. Among 118 children transplanted after post-diarrheal (D+) HUS, 1 (0.8%) had recurrence with graft loss. Among 63 children transplanted after HUS not associated with a prodrome of diarrhea (D-) of unknown mechanism, 13 (21%) had recurrence with graft loss. Of 11 patients with HUS associated with factor H deficiency who were transplanted, 5 lost the graft because of recurrence. Of 7 patients with HUS associated with normal factor H concentration but mutations in factor H gene who were transplanted, probably 2 had recurrence. Three patients with HUS associated with low serum C3, but no factor H deficiency or mutation lost their graft because of recurrence. The risk of recurrence in the autosomal recessive forms of HUS of unknown mechanism is not documented in children, but is around 60% in adults. A similar risk has been reported in the autosomal dominant forms. The only transplant patient with a constitutional deficiency of von Willebrand factor-cleaving protease had recurrence. Further efforts to document the post-transplant course of patients with D- HUS and progress in the understanding of the mechanisms and genetics of the disease are needed to allow more accurate prediction of the recurrence risk and to define therapeutic approaches.

ADAM Proteins↗
PubMed2006

[Treatment by plasmapheresis of a thrombotic thrombocytopenic purpura associated to a Still's disease: a case report].

We report the seventh published case of thrombotic thrombocytopenic purpura (TTP) associated to a Still's disease. We confirmed the secondary character of TTP using the measurement of ADAMTS 13 protease. Because of clinical and biological improvement, daily plasmapheresis was stopped after eight days of ICU treatment. Unfortunately, early (24 hours) relapse occurred resulting in daily plasmapheresis resumption for 11 more days. Main therapeutic goals and aggressive treatment duration of PTT associated with a Still's disease remain to be determined.

ADAM Proteins↗
PubMed2004

Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets.

The hemostatic activity of von Willebrand factor (vWF) is strongly dependent on its multimeric structure, with the highest activity in 'unusually large' multimers secreted from endothelial cells. The multimeric structure is regulated by a plasma protease, vWF-cleaving protease (vWF-CP, or ADAMTS-13). ADAMTS-13 mRNA is variably expressed in liver and other tissues. Because 15-25% of circulating vWF is stored in platelets, the presence and function of ADAMTS-13 in platelets are important issues. Here we report ADAMTS-13 expression in human platelets. Western blot analysis and flow cytometric analysis on permeabilized platelets revealed the presence of ADAMTS-13 protein. Real-time PCR demonstrated that ADAMTS-13 mRNA is present in platelets of six healthy volunteers, with little quantitative difference. The presence of ADAMTS-13 in platelets may imply the functional role of this enzyme in the local regulation of platelet function at the site of vascular injury or thrombus formation, and provide a useful tool for the analysis of structure and function of this enzyme.

ADAM Proteins↗
PubMed2003

Von Willebrand factor--cleaving protease activity in thrombotic microangiopathy after living donor liver transplantation: a case report.

Defective plasma activity of Von Willebrand factor (VWF)-cleaving protease (CP) and/or the inhibitors against this protease has been shown to have a pathological role in several forms of thrombotic microangiopathy (TMA). This report describes a patient for whom a diagnosis of TMA was made immediately after living donor liver transplantation. In this patient, activity of VWF-CP and its inhibitor were analyzed serially. At the onset of the disease, VWF-CP activity was quantified as 17%. Inhibitor against this protease was positive, with a titer of 0.6 Bethesda U/mL, and its inhibitory activity was quantified as 3.8 Bethesda U/mg immunoglobulin G. Laboratory parameters and clinical features were significantly improved after induction of plasma exchange (PE) with fresh frozen plasma and concurrent cessation of tacrolimus therapy. The inhibitors disappeared after one session of PE. However, VWF-CP activity after a transient increase and again decreased to subnormal levels after completion of PE. Nevertheless, this did not result in disease recurrence. In view of sustained VWF-CP activity at disease onset and the absence of definite correlations between levels of this protease and clinical features, abnormality of this enzyme system had no essential role in the pathogenesis of TMA in this case. Clinical findings suggest that TMA was tacrolimus-induced.

ADAM Proteins↗
PubMed2005

Thrombotic thrombocytopenic purpura in the setting of systemic sclerosis.

OBJECTIVES: To describe the association between thrombotic thrombocytopenic purpura (TTP) and systemic sclerosis (SSc) and the methods to distinguish TTP from scleroderma renal crisis (SRC). METHODS: A case of TTP that developed in a patient with preexisting SSc is described. Medline/PubMed was searched for literature pertaining to an association between TTP and SSc, with special attention given to distinguishing TTP from SRC. In addition, the role of von Willebrand cleaving protease in the pathogenesis of TTP is reviewed. RESULTS: Including the present case, there have been 9 reports of TTP in association with SSc in the literature. In the majority of these cases TTP presented with features compatible with SRC such as renal dysfunction, thrombocytopenia, hypertension, and microangiopathic hemolytic anemia. Von Willebrand cleaving protease activity is depressed in patients with acute TTP. CONCLUSIONS: TTP in association with SSc has been reported rarely. The diagnosis of TTP, and the distinction from SRC, may be challenging, as these cases may resemble SRC. However, the correct diagnosis is critical because treatment differs substantially for each of these life-threatening conditions. Currently, the assessment of von Willebrand factor cleaving protease activity may assist in making this distinction.

ADAM Proteins↗
PubMed2003

ADAMTS-13 activity in patients with brain and prostate tumors is mildly reduced, but not correlated to stage of malignancy and metastasis.

Impaired Von Willebrand factor cleaving activity of ADAMTS-13 was demonstrated in patients with metastasizing and malignant tumors. To investigate the relevance of ADAMTS-13 for tumor progression, we determined ADAMTS-13 activity and VWF:Ag in 80 patients with various malignancies: 30 patients with benign brain tumors, 30 patients with malignant brain tumors, 10 patients with local prostate tumors and 10 patients with metastatic prostate tumors. We found mild ADAMTS-13 deficiency in 17/80 tumor patients, but there was no significant difference in ADAMTS-13 activity between the age- and sex-matched patients with benign and malignant brain tumors nor between the age matched patients with local and metastatic prostate tumors. Patients with malignant brain tumors could only be distinguished from patients with benign tumors by elevated levels of VWF:Ag (p=0.018). Our data are hence in variance to previous studies, which found a distinct inverse correlation between ADAMTS-13 activity and level of metastasis and/or malignancy in diverse cancer-types.

ADAM Proteins↗
PubMed2004

Platelet physiology and thrombosis.

Glycoprotein (GP) Ibalpha of the GPIb-IX-V complex and GPVI bind von Willebrand factor (vWF) and collagen, respectively, and are critical for the initial interaction of circulating platelets with the injured vessel wall under high shear conditions. These interactions act together to facilitate stable thrombus formation in vivo. Ligand binding to GPIb-IX-V of the leucine-rich repeat family or GPVI of the immunoglobulin superfamily initiates platelet activation, and inside-out activation of the platelet integrin, alphaIIbbeta3, that binds vWF or fibrinogen and mediates platelet aggregation. The binding site for GPIbalpha on vWF resides in the conserved A1 domain, encompassing the disulfide bond at Cys509-Cys695. This domain may be activated to bind platelet GPIbalpha under shear stress by anchoring of the downstream A3 domain to collagen and conformational distortion of the intervening A2 domain. The N-terminal, 282 residues, of GPIbalpha contains the binding site for vWF-A1, as well as the conserved A-type domain of the leukocyte integrin alphaMbeta2 (alphaM I domain) and P-selectin expressed on activated platelets or endothelial cells. Endothelial P-selectin also supports surface expression of vWF multimers, enabling platelet vessel wall interaction by at least two mechanisms. Recent evidence suggests GPVI that binds collagen, and GPIb-IX-V that binds collagen-bound vWF are physically associated on the platelet surface. This review will focus on the structure-function of primary platelet adhesion receptors, GPIb-IX-V and GPVI, and how they act together to regulate platelet thrombus formation in pathophysiology.

ADAM Proteins↗
PubMed2006

Novel, semi-automated, 60-min-assay to determine von Willebrand factor cleaving activity of ADAMTS-13.

INTRODUCTION: The clinical entity of idiopathic thrombotic thrombocytopenic purpura (TTP) has been closely associated with a severe deficiency of the von Willebrand factor (vWF)-cleaving protease (ADAMTS-13). Levels below 5% are highly specific for TTP basically excluding hemolytic uremic syndrome (HUS). Deficiency of ADAMTS-13 can either be inherited or caused by inhibitory IgG autoantibodies to ADAMTS-13. Diagnosis of TTP is often difficult since it often manifests oligosymptomatic exhibiting only laboratory signs of thrombocytopenia and hemolysis or involving atypical organs. In such cases rapid knowledge of the ADAMTS-13 activity is very useful in helping to establish a correct diagnosis rapidly and to initiate the appropriate therapy. METHODS AND RESULTS: We have therefore designed a rapid, sensitive and simple assay for the determination of ADAMTS-13 activity and ADAMTS-13 inhibitors. The test is based on the measurement of the ristocetin-cofactor activity of purified, urea-denaturated vWF concentrate after incubation with diluted patient plasma that has been preactivated with barium chloride. While this assay has already previously been established, we have further modified and simplified the test thereby improving markedly the sensitivity, accuracy and turn-around time. A major improvement proved to be the change from buffer to heat-treated and vWF-replenished plasma as diluent for making the serial dilutions of normal pool plasma (NPP) for the calibration curve. Set up as a semi-automated assay the test is performed in only 50 to 60 min. Tested in 15 patients with ADAMTS-13 deficiency this new assay compared favorably and even more accurately with the classic electrophoretic ADAMTS-13 assay, especially in the low range below 10%. Mixing studies with patient plasma and NPP (ratio 1:1) revealed that a relatively short period of only 30 min at room temperature is sufficient for most samples to detect an inhibitor. With a single mixing experiment it is possible to discriminate inhibitor levels in the range of 0.5-4 Bethesda units. CONCLUSION: Using this novel assay, determination of ADAMTS-13 activity and ADAMTS-13 inhibitors can be performed easily, rapidly (less than 2 h), and accurately, providing rapid information about the severity of ADAMTS-13 deficiency and the presence of an inhibitor. In addition, the test is suitable for full automation enabling to screen large populations and, thus, help to get further insights into the clinical significance of ADAMTS-13 deficiency in other diseases.

ADAM Proteins↗
PubMed2005

Structure and function of snake venom toxins interacting with human von Willebrand factor.

Hemostatic plug formation is a complex event mediated by platelets, subendothelial matrices and von Willebrand factor (VWF) at the vascular injury. Snake venom proteins have an excellent potency to regulate the interaction between VWF and platelet membrane receptors in vitro. Two protein families, C-type lectin-like proteins and Zn(2+)-metalloproteinases, have been found to affect platelet-VWF interaction. Botrocetin and bitiscetin from viper venom are disulfide-linked heterodimers with C-type lectin-like motif, and modulate VWF to elicit platelet glycoprotein Ib (GPIb)-binding activity via the A1 domain of VWF leading to the platelet agglutination. The crystal structures of botrocetin and bitiscetin together with complex from the VWF A1 domain indicate the following: (1) a central concave domain formed by two subunits of botrocetin or bitiscetin provides the binding site for VWF, (2) these modulators directly bind to the A1 domain of VWF in close proximity to the GPIb binding site, (3) both modulators induce no significant conformational change on the GPIb-binding site of the A1 domain but could provide a supplemental platform fitting for GPIb. These results suggest that the modulating mechanisms of these venoms are different from those performed by either antibiotic ristocetin in vitro or extremely high shear stress in vivo. Other modulator toxins include kaouthiagin and jararhagin, chimeric proteins composed of metalloproteinase, disintegrin-like and Cys-rich domains. These toxins cleave VWF and reduce its platelet agglutinating or collagen-binding activity. Kaouthiagin from cobra venom specifically cleaves between Pro708 and Asp709 in the C-terminal VWF A1 domain resulting in the decrease of the multimer structure of VWF. Recently a plasma proteinase, which specifically cleaves VWF into a smaller multimer, has been elucidated to be a reprolysin-like metalloproteinase with thrombospondin motif family (ADAMTS). This endogenous metalloproteinase (ADAMTS-13) specifically cleaves between Tyr842 and Met843 in the A2 domain of VWF regulating its physiological hemostatic activity. These VWF-binding snake venom proteins are suitable probes for basic research on platelet plug formation mediated by VWF, for subsidiary diagnostic use for von Willebrand disease or platelet disorder, and might be potently applicable to the regulation of VWF in thrombosis and hemostasis. Structural information of these venom proteins together with recombinant technology might strongly promote the construction of a new antihemostatic drug in the near future.

ADAM Proteins↗
PubMed2005

The "cutting" edge: von Willebrand factor-cleaving protease activity in thrombotic microangiopathies.

The thrombotic microangiopathies (TMAs), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), are classically defined by constellations of clinical findings. In the late 1990's, several groups reported that a single test might be able to diagnose TTP and distinguish it from HUS. This test was an assay to detect von Willebrand factor-cleaving protease activity. Although there has been debate in the literature as to the utility of this assay, review of the available data suggests that this test can separate the idiopathic TMAs into three distinct categories: (1) patients who are protease positive with severe renal failure (similar to classic HUS), (2) patients who are protease positive without severe renal failure and (3) patients who are protease negative. While the latter two categories may appear similar to TTP at presentation, the prognosis differs in each of these groups of patients. Through use of the protease assay clinicians will be better able to diagnose, treat, predict outcome and design clinical trials.

ADAM Proteins↗