Thrombolytic properties of staphylokinase

Matsuo, Osamu; Okada, Kiyotaka; Fukao, Hideharu; Tomioka, Yoshiki; Ueshima, Shigeru; Watanuki, Masaaki; Sakai, Masashi

doi:10.1182/blood.v76.5.925.925

Cited by 72 publications

(1 citation statement)

References 25 publications

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“…Clot‐busting drugs are routinely administered during ischemic stroke and cardiovascular complications to break down blood clots by activating a fibrinolytic system, where inactive plasminogen (Pg) is activated into plasmin (Pm) that acts to dissolve fibrin blood clots [1, 2]. Among different thrombolytic agents available, staphylokinase (SAK) has gained wide attention as one of the most promising clot busters because of its fibrin specificity and inhibition by α2‐antiplasmin [3–5]. SAK is a ∼15‐kDa extracellular protein of Staphylococcus aureus that makes a 1:1 bimolecular complex with human Pg or Pm and results in conformational expression of new catalytic site [5] that specifically cleaves Arg 561 –Val 562 activation bond in the catalytic domain of Pg to generate Pm.…”

Section: Introductionmentioning

confidence: 99%

Integration of VEK‐30 peptide enhances fibrinolytic properties of staphylokinase

Bhando

Singh

Hade

et al. 2020

Biotech and App Biochem

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Staphylokinase (SAK), a 136 amino acid bacterial protein with profibrinolytic properties, has emerged as an important thrombolytic agent because of its fibrin specificity and reduced inhibition by α‐2 antiplasmin. In an attempt to enhance the clot dissolution ability of SAK, a 30 amino acid peptide (VEK‐30) derived from a plasminogen (Pg) binding protein (PAM), was fused at the C‐terminal end of SAK with a RGD (Arg–Gly–Asp) linker. The chimeric protein, SAKVEK, was expressed in E. coli and purified as a soluble protein. Pg activation by equimolar complexes of SAKVEK and SAK with plasmin revealed that the fusion of VEK‐30 peptide has significantly enhanced the catalytic activity of SAK. The kinetic constant, kcat/Km, of SAKVEK for the substrate Pg appeared 2.7 times higher than that of SAK and the time required for the fibrin and platelet rich clot lysis was shortened by 30% and 50%, respectively. The binary activator complex of SAKVEK with plasmin gets inhibited by α2‐ antiplasmin but remains protected in the presence of fibrin, very similar to SAK. Thus, the present study suggests that SAKVEK is more potent and effective as a thrombolytic agent due to its higher catalytic activity for Pg activation in a fibrin‐specific manner and its ability to clear platelet‐rich plasma clot faster than SAK.

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Section: Introductionmentioning

confidence: 99%

Integration of VEK‐30 peptide enhances fibrinolytic properties of staphylokinase

Bhando

Singh

Hade

et al. 2020

Biotech and App Biochem

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Effects of fibrin and α2-antiplasmin on plasminogen activation by staphylokinase

et al. 1996

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Staphylokinase obtains plasminogen activating activity by forming a complex with plas-minogen. Although the enzymatic activity of staphylokinase is enhanced by fibrin, how fibrin enhances enzymatic activity has not been determined yet. The effects of fibrin, or fibrinogen fragments, on the activation of plasminogen by staphylokinase was investigated using CNBr-digested fibrinogen fragments (FCB-2 and FCB-5) and plasmin-degraded cross-linked fibrin fragments ((DD)E complex, DD fragments and E fragments). Kinetic analysis of the activity of staphylokinase revealed that its plasminogen activating activity, which was expressed as kcatlKm, was enhanced by FCB-2 (10-fold) and FCB-5 (5-fold). These fibrin fragments caused 38-, 30-, and 8.5-fold increases in activity for the DD fragment, (DD)E complex and E fragment, respectively. Although a,-antiplasmin inhibited the activation of plasminogen by staphylokinase, FCB-2 abolished its inhibitory effects, and the plasminogen activating activity of staphylokinase was restored. The inhibitory effects of a,-antiplasmin on the activation of mini-plasminogen by staphyloki-nase were less than for Glu-or Lys-plasminogen, and the inhibitory effect of a,-antiplasmin was not altered by fibrin or EACA. These findings indicate that the staphylokinaselplasmin-(ogen) complex reacts with fibrin even in the presence of a,-antiplasmin, and efficient plasminogen activation takes place on the surface of fibrin.

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Bone marrow dysplasia in patients with newly diagnosed acute myelogenous leukemia does not correlate with history of myelodysplasia or with remission rate and survival

Ballen

Gilliland

Kalish

et al. 1994

Cancer

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Background. The records and initial bone marrow studies of 106 patients with newly diagnosed acute myelogenous leukemia (AML) were analyzed retrospectively to determine whether bone marrow dysplasia was predictive of a previous myelodysplastic disorder or correlated with remission rate and survival. Methods. Bone marrow aspirates and biopsy specimens were reviewed in a blinded fashion; dysplasia was assessed in as objective a manner as possible by numerically scoring nine specific findings: erythrocyte multinuclearity, nuclear fragmentation, megaloblastic characteristics, leukocyte granulation abnormalities and nuclear malformations, Pelger‐Huet cells, and megakaryocytic dysplasia (mononuclear megakaryocytes, micromegakaryocytes, and megakaryocytes with multiple distinct nuclei). Results. Dysplasia of the megakaryocytic line was seen in 34% of patients; 70% of the patients had erythrocyte dysplasia; and 68% had leukocyte dysplasia. Pelger‐Huet cells were seen in bone marrow of 35% of the patients. Overall dysplasia score and specific dysplastic findings such as Pelger‐Huet cells did not correlate with a known history of myelodysplasia (P = 0.47), cytogenetic abnormalities (P = 0.35), prior chemotherapy treatment with or without alkylating agents (P = 1.00), previous malignant disorders such as polycythemia vera (P = 1.00), remission rate (P = 0.93), or survival (P = 0.42). Multivariate analysis confirmed known independent risk factors for remission in this patient population, including age (P = 0.04), history of prior chemotherapy (P = 0.04), abnormalities in chromosomes 5, 7, or 8 (P = 0.02), and type of antileukemia therapy (P < 0.001). Conclusions. Bone marrow dysplasia is common in patients with AML and does not correlate with a history of myelodysplasia or predict outcome when patients are treated with standard intensive AML therapy.

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Thrombolytic properties of staphylokinase

Cited by 72 publications

References 25 publications

Integration of VEK‐30 peptide enhances fibrinolytic properties of staphylokinase

Integration of VEK‐30 peptide enhances fibrinolytic properties of staphylokinase

Effects of fibrin and α2-antiplasmin on plasminogen activation by staphylokinase

Bone marrow dysplasia in patients with newly diagnosed acute myelogenous leukemia does not correlate with history of myelodysplasia or with remission rate and survival

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