Diagnosis of deep vein thrombosis with in vivo 99mTc-labeled red blood cells

Deep vein thrombosis (DVT) and pulmonary embolisms (PEs) are common complications after surgical procedures. The influence of prescribed blood products on the occurrence of DVT and PE was evaluated in postsurgical patients in this retrospective case–control study. The records of 286 surgical patients were analyzed: DVT (n = 52), PE (n = 92), and a control group (n = 142). The amounts of prescribed blood, blood products, and vitamin K were reviewed, together with appropriate prescribing of low-molecular-weight heparins. The influence of prescribed blood products on the occurrence of DVT or PE was analyzed using multinomial logistic regression. We demonstrated a significant difference between the test and control groups ( P < .05) in relation to receiving packed red blood cells. Treatment with red blood cells was associated with an increased risk of PE but not DVT. Patients who developed PE after surgery were hospitalized for longer (median 10 days) than patients with DVT (median 6 days). There was no difference between the test and control groups concerning treatment with fresh frozen plasma. Inadequate thromboprophylaxis significantly increased the likelihood of DVT. There is a connection between receiving packed red blood cells and occurrence of postoperative PE in surgical patients. Thus, patients receiving red blood cells should be monitored more closely after surgery, as they are more likely to develop PE postoperatively.

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THE DIAGNOSTIC VALUE OF ANGIOSCINTIGRAPHY WITH 99mTc-LABELLED RED BLOOD CELLS FOR DETECTION OF DEEP VEIN THROMBOSIS

Nuclear Medicine Communications ◽

10.1097/00006231-200803030-00007 ◽

1982 ◽

Vol 3 (3) ◽

pp. 172-181

Author(s):

J. Fogh

Keyword(s):

Deep Vein Thrombosis ◽

Red Blood Cells ◽

Blood Cells ◽

Diagnostic Value ◽

Vein Thrombosis ◽

Deep Vein

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(More than) doubling down: Effective fibrinolysis at a reduced rt-PA dose for catheter-directed thrombolysis combined with histotripsy

PLoS ONE ◽

10.1371/journal.pone.0261567 ◽

2022 ◽

Vol 17 (1) ◽

pp. e0261567

Author(s):

Samuel A. Hendley ◽

Aarushi Bhargava ◽

Christy K. Holland ◽

Geoffrey D. Wool ◽

Osman Ahmed ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Thrombolytic Therapy ◽

Red Blood Cells ◽

Blood Cells ◽

Vein Thrombosis ◽

Clinical Dose ◽

Infusion Catheter ◽

Catheter Directed Thrombolysis ◽

The Common ◽

Deep Vein

Deep vein thrombosis is a major source of morbidity and mortality worldwide. For acute proximal deep vein thrombosis, catheter-directed thrombolytic therapy is an accepted method for vessel recanalization. Thrombolytic therapy is not without risk, including the potential for hemorrhagic bleeding that increases with lytic dose. Histotripsy is a focused ultrasound therapy that generates bubble clouds spontaneously in tissue at depth. The mechanical activity of histotripsy increases the efficacy of thrombolytic therapy at doses consistent with current pharmacomechanical treatments for venous thrombosis. The objective of this study was to determine the influence of lytic dose on histotripsy-enhanced fibrinolysis. Human whole blood clots formed in vitro were exposed to histotripsy and a thrombolytic agent (recombinant tissue plasminogen activator, rt-PA) in a venous flow model perfused with plasma. Lytic was administered into the clot via an infusion catheter at concentrations ranging from 0 (control) to 4.54 μg/mL (a common clinical dose for catheter-directed thrombolysis). Following treatment, perfusate samples were assayed for markers of fibrinolysis, hemolysis, and intact red blood cells and platelets. Fibrinolysis was equivalent between the common clinical dose of rt-PA (4.54 μg/mL) and rt-PA at a reduction to one-twentieth of the common clinical dose (0.23 μg/mL) when combined with histotripsy. Minimal changes were observed in hemolysis for treatment arms with or without histotripsy, potentially due to clot damage from insertion of the infusion catheter. Likewise, histotripsy did not increase the concentration of red blood cells or platelets in the perfusate following treatment compared to rt-PA alone. At the highest lytic dose, a refined histotripsy exposure scheme was implemented to cover larger areas of the clot. The updated exposure scheme improved clot mass loss and fibrinolysis relative to administration of lytic alone. Overall, the data collected in this study indicate the rt-PA dose can be reduced by more than a factor of ten and still promote fibrinolysis when combined with histotripsy.

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99mTc labeled red blood cells versus ?-phlebography in diagnosis of deep vein thrombosis

European Journal of Nuclear Medicine ◽

10.1007/bf00251654 ◽

1982 ◽

Vol 7 (2) ◽

Author(s):

G. Jacolot ◽

P. Legendre ◽

L. Millour ◽

J.F. Morin ◽

P.P. Morin

Keyword(s):

Deep Vein Thrombosis ◽

Red Blood Cells ◽

Blood Cells ◽

Vein Thrombosis ◽

Deep Vein

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In Vivo Porcine Aged Deep Vein Thrombosis Model for Testing Ultrasound-based Thrombolysis Techniques

Ultrasound in Medicine & Biology ◽

10.1016/j.ultrasmedbio.2021.08.017 ◽

2021 ◽

Author(s):

Greyson E. Stocker ◽

Jiaqi Shi ◽

Kimberly Ives ◽

Adam D. Maxwell ◽

Paul A. Dayton ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Vein Thrombosis ◽

Thrombosis Model ◽

Deep Vein

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A Comparative Study of Prothrombinase and Thrombin Inhibitors in a Novel Rabbit Model of Non-Occlusive Deep Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642443 ◽

1994 ◽

Vol 71 (03) ◽

pp. 357-362 ◽

Cited By ~ 38

Author(s):

Stan Hollenbach ◽

Uma Sinha ◽

Pei-Hua Lin ◽

Kathy Needham ◽

Lisa Frey ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Ex Vivo ◽

Rabbit Model ◽

Thrombin Inhibitors ◽

Constant Infusion ◽

Chloromethyl Ketone ◽

Vein Thrombosis ◽

Prothrombinase Complex ◽

Deep Vein

SummaryA quantitative and non-occlusive deep vein thrombosis model was developed in rabbits. We used this model to test the antithrombotic activity of the prothrombinase complex inhibitors factor rXai and its chemical analog glutamyl-glycyl-arginyl chloromethyl ketone inactivated human factor Xa (EGR-Xai), along with the thrombin inhibitors D-phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK) and heparin. Dose dependent effects of the inhibitors during constant infusion were monitored. Measurements included thrombus weights, hemostatic parameters and both cuticle and ear bleeding times. In this model, factor rXai and EGR-Xai had comparable in-vivo efficacy, and showed 80%-93% inhibition at plasma levels of 6.5 nM (rXai) and 8 nM (EGR-Xai). Effects on ex-vivo clotting times varied among the inhibitors. At 80-100% thrombus inhibition, factor rXai and EGR-Xai had no statistically significant effect, while PPACK extended thrombin clotting time (TCT) times 2.3-fold, and heparin prolonged both activated partial thromboplastin time (APTT), prothrombin time (PT) and TCT ex-vivo clotting times 6.9-, 1.2-, and 7-fold respectively. At these dosages, cuticle and ear bleeding times were prolonged for all inhibitors and showed increases of 177%-389% (cuticle) and 45%-129% (ear). Our results demonstrate that direct inhibition of prothrombinase complex assembly is effective in arresting venous thrombosis.

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Inhibition of Prothrombinase and Not Soluble Factor Xa (fXa) Predicts Efficacy of fXa Inhibitors in an In Vivo Model of Deep Vein Thrombosis.

Blood ◽

10.1182/blood.v108.11.902.902 ◽

2006 ◽

Vol 108 (11) ◽

pp. 902-902

Author(s):

Suzanne Delaney ◽

Ann Arfsten ◽

Sherin Halfon ◽

Gail Siu ◽

John Malinowski ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Plasma Concentration ◽

Plasma Concentrations ◽

Factor Xa ◽

Vein Thrombosis ◽

Prothrombinase Complex ◽

Antithrombotic Efficacy ◽

Deep Vein

Abstract Factor Xa (fXa) inhibitors are being tested in the clinic for the prevention and treatment of deep vein thrombosis (DVT) following orthopedic surgery. The antithrombotic efficacy of these drug candidates has traditionally been established in animal models as it is not known whether fXa amidolytic activity, activated partial thromboplastin time (aPTT) or prothrombin time (PT) predict efficacious doses. The present study was designed to test the hypothesis that the potency of fXa inhibitors against fXa incorporated into the prothrombinase complex would predict in vivo antithrombotic efficacy. Eight fXa inhibitors from four structurally distinct chemical series with a range of activities against fXa were tested for their ability to inhibit the prothrombinase complex in human plasma. Thrombin generation and subsequent cleavage of a specific thrombin substrate was used as a measure of prothrombinase activity, inhibitory activity being defined by the concentration of inhibitor required to produce a 2-fold extension in the time to maximal thrombin production (2x lag). In vitro rabbit PTs were also determined. Inhibition in the rabbit DVT model was assessed as previously described (Thromb Haemost1994; 71:357) and related to plasma concentrations of drug. Agent fXa IC50 (nM) Prothrombinase 2x lag (μM) Plasma concentration in DVT (μM) Thrombosis inhibition (%) Rabbit PT 2x change (μM) PRT50034 0.5 0.18 0.06 94 7.0 PRT54681 1.3 0.22 1.14 37 2.7 PRT54676 0.7 0.24 1.65 47 1.7 PRT54004 0.4 0.25 1.04 47 1.0 PRT54456 0.8 0.34 3.39 41 1.5 PRT56848 4.4 0.92 5.2 11 4.7 PRT54955 3.5 1.35 4.6 19 8.8 PRT57106 8.2 1.66 9.2 0 64 All compounds inhibited soluble fXa by 50 % at concentrations less than 10 nM. However, the rank order of potencies for inhibition of soluble fXa differed from that required to inhibit the prothrombinase complex. There was also poor correlation between the 2x lag value for prothrombinase inhibition and the concentration required to achieve a 2x change in rabbit PT (r2 = 0.57). Neither the activities of fXa inhibition nor the change in rabbit PT predicted activity in the DVT model. In contrast, compounds could be broadly divided into 3 levels of efficacy for inhibition of in vivo thrombus growth depending on their potency in the in vitro prothrombinase assay. PRT50034 had the lowest 2x lag value of 0.18 μM and was the most potent inhibitor of in vivo thrombosis with 94 % inhibition at a plasma concentration of 65 nM. The second group of compounds, with 2x lag values in the prothrombinase assay ranging from 0.22 to 0.34 μM, inhibited in vivo thrombus formation by 37 to 47 % at plasma concentrations ranging from 1.04 to 3.39 μM. Compounds in the third category were the least potent prothrombinase inhibitors (2x lag values greater than 0.92 μM) and were unable to significantly inhibit in vivo thrombosis even at plasma concentrations of 9.2 μM. These data show that the 2x lag value obtained in the prothrombinase assay, and not inhibition of soluble fXa or extension of rabbit PT, is capable of predicting fXa inhibitor efficacy in the in vivo rabbit DVT model.

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Protein S As a Potential Treatment for FIX-Derived Deep Vein Thrombosis

Blood ◽

10.1182/blood.v126.23.2277.2277 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2277-2277

Author(s):

Vijaya Satish Sekhar Pilli ◽

Willium Plautz ◽

Rinku Majumder ◽

Paolo Simioni

Keyword(s):

Deep Vein Thrombosis ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Protein S ◽

Factor Ix ◽

Wild Type ◽

Vein Thrombosis ◽

Deep Vein

Abstract Background: Every year, 0.1-0.2% of the USA population experiences deep vein thrombosis (DVT). Two causes of DVT are increased Factor IX (FIX) levels and hyperactivating mutations in FIX (FIX Padua variant- R338L and Malmo variant T148A). In principle, inhibition of activated FIX (FIXa) should alleviate DVT. Previous in vitro studies demonstrated that the anticoagulant Protein S (PS) inhibits the intrinsic pathway mediated by wild type FIXa, making PS an attractive candidate to treat DVT. Aims: To establish Protein S as a remedy for FIX-mediated DVT/Padua/Malmo Methods: Anisotropy, clotting assays, thrombin generation assays, co-localization, co-immunoprecipitation, and bleeding assays. Results: We further explored the physiological relevance of the PS-FIXa interaction and PS-mediated inhibition of FIXa by ex vivo (co-immunoprecipitation) and in vivo (co-localization) studies. Because PS can inhibit FIXa in vivo, we used competitive, direct anisotropy assays and co-immunoprecipitation assays to measure the efficiency PS and hyperactive FIXa (R338L) interaction. Interestingly, the results demonstrated that FIXa R338L has lost its affinity towards PS compared with wild type FIXa. The same finding was obtained by ex vivo thrombin generation assays and FXa generation assays supplemented with various concentrations of PS. Thus, to be inhibited, hyperactive FIX requires a greater amount of PS compared with wild type FIXa. We are further confirming this finding with mouse models. Conclusion: Addition of PS to plasma inhibits both wild type and R338L FIXa and extends clotting time. Previous studies showed that the addition of PS has no significant negative effects. Thus, we conclude that PS supplementation potentially constitutes a novel and effective treatment for FIX-mediated DVT. Disclosures No relevant conflicts of interest to declare.

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Risk factors and coagulation parameters in relationship to phlebographic response and clinical outcome in the treatment of acute deep vein thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613442 ◽

2003 ◽

Vol 89 (02) ◽

pp. 272-277 ◽

Cited By ~ 8

Author(s):

Zbigniew Kadziola ◽

Mike Scully ◽

Roumen Nakov ◽

Frank Misselwitz ◽

Vijay Kakkar ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Oral Anticoagulants ◽

Low Molecular Weight ◽

Once Daily ◽

Coagulation Parameters ◽

Vein Thrombosis ◽

Acute Deep Vein Thrombosis ◽

Baseline Characteristics ◽

Deep Vein

SummaryPossible correlation of the effects of pharmacotherapy on the inhibition of the in-vivo generation of thrombin and on the prevention of thrombus extension in patients with deep vein thrombosis (DVT) could help to define patients at higher risk.Patients with symptomatic deep vein thrombosis confirmed by phlebography were randomised to intravenous unfractionated heparin (UFH), or a subcutaneous low-molecular-weight heparin (reviparin) twice daily for one week, or a subcutaneous reviparin once daily for four weeks. The patients were treated with oral anticoagulants for at least 3 months. Main endpoints were regression of thrombus on phlebography on Day 21 and recurrent symptomatic venous thromboembolism up to 3 months. Coagulation parameters, markers of in-vivo thrombin generation, and TFPI-release were determined at randomisation, weeks 1 and 3.Four hundred sixty six responders (reduction of at least 30 per cent in Marder score) and 419 non-responders (Marder score unchanged or changed less than ±30%) showed no significantly different baseline characteristics. The non-responder group had a higher median Marder score at baseline and after one and three weeks of treatment, and had significantly higher fibrinogen levels, TAT complexes and F1+2 values than responders. There were no significant differences in coagulation parameters between non-responders and patients with asymptomatic + symptomatic VTE with the exception of higher TAT complexes at baseline.Significant differences in Marder score and coagulation parameters at baseline were found between responders and non-responders. Non-responders have a higher risk tosuffer recurrent VTE and may need intensified treatment.

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