A clot (possibly) due to loss of TNF a suppression

Jennifer Broussard Matthew Berlinger Dean Lauret Dept of Internal Medicine LSU Baton Rouge

Case Presentation

34-year-old African American female

PMH of multiple DVTrsquos miscarriages amp reported Crohnrsquos

Noncompliant with TNF a inhibitor amp lovenox ~6 mths

Presented with shortness of breath and pleuritic chest pain

Case Presentation

Vital Signs T 981 BP 12498 HR 87 Pulse Ox 94

433

143 72 227

PT 151 INR 118 PTT 227 ESR 22 CRP 554 UPT negative HIV (AntAb) negative

CTA Thorax Acute pulmonary thromboembolism involving the main lobar and segmental pulmonary arteries bilaterally

141 109

42 22

91

9

079

Case Presentation

Develops severe

abdominal pain

CTA reveals thrombosis of infra-

renal abdominal aorta proximal left

common iliac artery and right renal artery

Loses sensation and pulses of left

lower extremity

Emergent vascular

surgery to restore

blood flow

Case Presentation

CTA AbdPelvis Partially occlusive thrombus in the infrarenal abdominal aorta amp proximal left common iliac artery

Case Presentation

Working differential diagnosis for venous and arterial thrombosis

1 Antiphospholipid Syndrome bull Highly suspicious on first glance

2 Heparin Induced Thrombocytopenia and Thrombosis

bull Immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications

3 Paroxysmal Nocturnal Hemoglobinuria bull Rare acquired nonmalignant disorder of hematopoietic stem cells characterized by

hemolysis diminished hematopoiesis and thrombophilia

4 Malignancy bull 34 yo with no overt symptoms or risk factors (non-smoker no family history)

Antiphospholipid Syndrome

Sydney Criteria 2006 bull Must meet at least one of the clinical and one of the laboratory criteria

bull Clinical criteria bull Vascular thrombosis

bull Pregnancy morbidity

bull Laboratory criteria (two or more occasions at least 12 weeks apart) bull Lupus anticoagulant

bull Anticardiolipin antibody

bull Anti-β2 glycoprotein-I antibody

Case Presentation

Post surgery anticoagulated amp treated for APS

4 days of plasma exchange and high

dose steroids

Anti-β2 glycoprotein-I antibody negative

Lupus anticoagulant negative

Anti-cardiolipin negative

Phosphatidylserine IgMIgGIgA negative

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Case Presentation

34-year-old African American female

PMH of multiple DVTrsquos miscarriages amp reported Crohnrsquos

Noncompliant with TNF a inhibitor amp lovenox ~6 mths

Presented with shortness of breath and pleuritic chest pain

Case Presentation

Vital Signs T 981 BP 12498 HR 87 Pulse Ox 94

433

143 72 227

PT 151 INR 118 PTT 227 ESR 22 CRP 554 UPT negative HIV (AntAb) negative

CTA Thorax Acute pulmonary thromboembolism involving the main lobar and segmental pulmonary arteries bilaterally

141 109

42 22

91

9

079

Case Presentation

Develops severe

abdominal pain

CTA reveals thrombosis of infra-

renal abdominal aorta proximal left

common iliac artery and right renal artery

Loses sensation and pulses of left

lower extremity

Emergent vascular

surgery to restore

blood flow

Case Presentation

CTA AbdPelvis Partially occlusive thrombus in the infrarenal abdominal aorta amp proximal left common iliac artery

Case Presentation

Working differential diagnosis for venous and arterial thrombosis

1 Antiphospholipid Syndrome bull Highly suspicious on first glance

2 Heparin Induced Thrombocytopenia and Thrombosis

bull Immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications

3 Paroxysmal Nocturnal Hemoglobinuria bull Rare acquired nonmalignant disorder of hematopoietic stem cells characterized by

hemolysis diminished hematopoiesis and thrombophilia

4 Malignancy bull 34 yo with no overt symptoms or risk factors (non-smoker no family history)

Antiphospholipid Syndrome

Sydney Criteria 2006 bull Must meet at least one of the clinical and one of the laboratory criteria

bull Clinical criteria bull Vascular thrombosis

bull Pregnancy morbidity

bull Laboratory criteria (two or more occasions at least 12 weeks apart) bull Lupus anticoagulant

bull Anticardiolipin antibody

bull Anti-β2 glycoprotein-I antibody

Case Presentation

Post surgery anticoagulated amp treated for APS

4 days of plasma exchange and high

dose steroids

Anti-β2 glycoprotein-I antibody negative

Lupus anticoagulant negative

Anti-cardiolipin negative

Phosphatidylserine IgMIgGIgA negative

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Case Presentation

Vital Signs T 981 BP 12498 HR 87 Pulse Ox 94

433

143 72 227

PT 151 INR 118 PTT 227 ESR 22 CRP 554 UPT negative HIV (AntAb) negative

CTA Thorax Acute pulmonary thromboembolism involving the main lobar and segmental pulmonary arteries bilaterally

141 109

42 22

91

9

079

Case Presentation

Develops severe

abdominal pain

CTA reveals thrombosis of infra-

renal abdominal aorta proximal left

common iliac artery and right renal artery

Loses sensation and pulses of left

lower extremity

Emergent vascular

surgery to restore

blood flow

Case Presentation

CTA AbdPelvis Partially occlusive thrombus in the infrarenal abdominal aorta amp proximal left common iliac artery

Case Presentation

Working differential diagnosis for venous and arterial thrombosis

1 Antiphospholipid Syndrome bull Highly suspicious on first glance

2 Heparin Induced Thrombocytopenia and Thrombosis

bull Immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications

3 Paroxysmal Nocturnal Hemoglobinuria bull Rare acquired nonmalignant disorder of hematopoietic stem cells characterized by

hemolysis diminished hematopoiesis and thrombophilia

4 Malignancy bull 34 yo with no overt symptoms or risk factors (non-smoker no family history)

Antiphospholipid Syndrome

Sydney Criteria 2006 bull Must meet at least one of the clinical and one of the laboratory criteria

bull Clinical criteria bull Vascular thrombosis

bull Pregnancy morbidity

bull Laboratory criteria (two or more occasions at least 12 weeks apart) bull Lupus anticoagulant

bull Anticardiolipin antibody

bull Anti-β2 glycoprotein-I antibody

Case Presentation

Post surgery anticoagulated amp treated for APS

4 days of plasma exchange and high

dose steroids

Anti-β2 glycoprotein-I antibody negative

Lupus anticoagulant negative

Anti-cardiolipin negative

Phosphatidylserine IgMIgGIgA negative

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Case Presentation

Develops severe

abdominal pain

CTA reveals thrombosis of infra-

renal abdominal aorta proximal left

common iliac artery and right renal artery

Loses sensation and pulses of left

lower extremity

Emergent vascular

surgery to restore

blood flow

Case Presentation

CTA AbdPelvis Partially occlusive thrombus in the infrarenal abdominal aorta amp proximal left common iliac artery

Case Presentation

Working differential diagnosis for venous and arterial thrombosis

1 Antiphospholipid Syndrome bull Highly suspicious on first glance

2 Heparin Induced Thrombocytopenia and Thrombosis

bull Immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications

3 Paroxysmal Nocturnal Hemoglobinuria bull Rare acquired nonmalignant disorder of hematopoietic stem cells characterized by

hemolysis diminished hematopoiesis and thrombophilia

4 Malignancy bull 34 yo with no overt symptoms or risk factors (non-smoker no family history)

Antiphospholipid Syndrome

Sydney Criteria 2006 bull Must meet at least one of the clinical and one of the laboratory criteria

bull Clinical criteria bull Vascular thrombosis

bull Pregnancy morbidity

bull Laboratory criteria (two or more occasions at least 12 weeks apart) bull Lupus anticoagulant

bull Anticardiolipin antibody

bull Anti-β2 glycoprotein-I antibody

Case Presentation

Post surgery anticoagulated amp treated for APS

4 days of plasma exchange and high

dose steroids

Anti-β2 glycoprotein-I antibody negative

Lupus anticoagulant negative

Anti-cardiolipin negative

Phosphatidylserine IgMIgGIgA negative

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Case Presentation

CTA AbdPelvis Partially occlusive thrombus in the infrarenal abdominal aorta amp proximal left common iliac artery

Case Presentation

Working differential diagnosis for venous and arterial thrombosis

1 Antiphospholipid Syndrome bull Highly suspicious on first glance

2 Heparin Induced Thrombocytopenia and Thrombosis

bull Immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications

3 Paroxysmal Nocturnal Hemoglobinuria bull Rare acquired nonmalignant disorder of hematopoietic stem cells characterized by

hemolysis diminished hematopoiesis and thrombophilia

4 Malignancy bull 34 yo with no overt symptoms or risk factors (non-smoker no family history)

Antiphospholipid Syndrome

Sydney Criteria 2006 bull Must meet at least one of the clinical and one of the laboratory criteria

bull Clinical criteria bull Vascular thrombosis

bull Pregnancy morbidity

bull Laboratory criteria (two or more occasions at least 12 weeks apart) bull Lupus anticoagulant

bull Anticardiolipin antibody

bull Anti-β2 glycoprotein-I antibody

Case Presentation

Post surgery anticoagulated amp treated for APS

4 days of plasma exchange and high

dose steroids

Anti-β2 glycoprotein-I antibody negative

Lupus anticoagulant negative

Anti-cardiolipin negative

Phosphatidylserine IgMIgGIgA negative

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Case Presentation

Working differential diagnosis for venous and arterial thrombosis

1 Antiphospholipid Syndrome bull Highly suspicious on first glance

2 Heparin Induced Thrombocytopenia and Thrombosis

bull Immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications

3 Paroxysmal Nocturnal Hemoglobinuria bull Rare acquired nonmalignant disorder of hematopoietic stem cells characterized by

hemolysis diminished hematopoiesis and thrombophilia

4 Malignancy bull 34 yo with no overt symptoms or risk factors (non-smoker no family history)

Antiphospholipid Syndrome

Sydney Criteria 2006 bull Must meet at least one of the clinical and one of the laboratory criteria

bull Clinical criteria bull Vascular thrombosis

bull Pregnancy morbidity

bull Laboratory criteria (two or more occasions at least 12 weeks apart) bull Lupus anticoagulant

bull Anticardiolipin antibody

bull Anti-β2 glycoprotein-I antibody

Case Presentation

Post surgery anticoagulated amp treated for APS

4 days of plasma exchange and high

dose steroids

Anti-β2 glycoprotein-I antibody negative

Lupus anticoagulant negative

Anti-cardiolipin negative

Phosphatidylserine IgMIgGIgA negative

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Antiphospholipid Syndrome

Sydney Criteria 2006 bull Must meet at least one of the clinical and one of the laboratory criteria

bull Clinical criteria bull Vascular thrombosis

bull Pregnancy morbidity

bull Laboratory criteria (two or more occasions at least 12 weeks apart) bull Lupus anticoagulant

bull Anticardiolipin antibody

bull Anti-β2 glycoprotein-I antibody

Case Presentation

Post surgery anticoagulated amp treated for APS

4 days of plasma exchange and high

dose steroids

Anti-β2 glycoprotein-I antibody negative

Lupus anticoagulant negative

Anti-cardiolipin negative

Phosphatidylserine IgMIgGIgA negative

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Case Presentation

Post surgery anticoagulated amp treated for APS

4 days of plasma exchange and high

dose steroids

Anti-β2 glycoprotein-I antibody negative

Lupus anticoagulant negative

Anti-cardiolipin negative

Phosphatidylserine IgMIgGIgA negative

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Case Presentation

bull Patient ultimately discharged on lifelong anticoagulation due to life threatening clot however reason for her clot remained undetermined

bull Speculations of Antiphospholipid Syndrome were unable to be confirmed and outpatient flow cytometry was negative for Paroxysmal Nocturnal Hemoglobinuria

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Case Presentation

Could this be a clot due to

IBD

Colonoscopy report obtained

Negative pathology

Protein losing enteropathy

Systemic inflammatory

state

Could this be a clot due to loss of TNF a suppression

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Endothelium

1628

Harvey-

Description of blood

17th century

Malphigi-

Network of vessels which blood flows through

17th century

Von Recklinghausen-

Vessels are lined by cells

18th century

Palade amp Gowan-

Endothelium interacts with lymphocytes

Endothelial cells are dynamic

heterogeneous and make up a

disseminated organ that possess vital

secretory synthetic metabolic and immunologic

functions

Blood vol 91 NO 10 1998

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Endothelium

A crucial function of endothelium is to facilitate blood flow by providing an antithrombotic surface that inhibits platelets and clotting

VASODILATION (leukocyte inhibition

platelet disaggregation)

VASOCONSTRICTION

(promotes leukocyte adhesion)

PAF

Endothelin

PGI2

Nitric Oxide

Perturbation of the endothelial surface results in its transformation into a thrombotic surface

Pivotal step in transforming the endothelial surface from an anticoagulant to a procoagulant surface is the induction of tissue factor

Blood vol 91 NO 10 1998

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Inflammation Activates Endothelium

bull Thrombosis and inflammation have been closely associated

bull Endothelial cells express membrane bound pro-inflammatory molecules leukocyte-endothelial cell adhesion molecules (CAM) bull Tethering and rolling and ultimate recruitment of more WBCrsquos and platelets bull ldquoCytokine milieurdquo including TNF a

bull Inflammation results in an activated endothelium PROTHROMBOTIC

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Tumor Necrosis Factor a

bull TNF-a is a low molecular weight peptide with a broad range of biological and immunologic effects

bull ldquoPotent inducer of pro-coagulant activityrdquo

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Tumor Necrosis Factor a

bull Naworth at Oklahoma Medical Research Foundation in 1986

bull Cultured bovine aortic endothelial cells and incubated with TNF

bull TNF exposure resulted in dose-dependent induction of tissue factor

Nawroth et al The Rockefeller University Press Vol 163 March 1986

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

TNF-a Tissue Factor Expression

CLOT

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Lagniappe hellip

bull Anti- TNF a agents are being increasingly used in Behcetrsquos syndrome bull Used in situations of pulmonary artery involvement- most lethal complication

Seminars in Arthritis and Rheumatism 45 (2015) 369- 373

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Lagniappehellip

bull Experimental data has proven that low molecular weight heparin has ability to decrease TNF a

Ann Vasc Surgery 2007 21 5mdash55

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

ldquoTake- Awayrdquo Points

bull The endothelium is a heterogeneous organ that functions in concert with local factors resulting in either an anticoagulant or procoagulant state

bull TNF a plays a crucial role in the activation of procoagulant state likely through its ability to enhance tissue factor expression

bull Suppression of TNF a through monocolonal antibody therapy may act to down regulate the inflammatory state of endothelial cells that results in clot formation

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Special thanks to

bull Matthew Berlinger MD

bull Lee Engel MD

bull Dean Lauret MD

bull Diana Hamer PhD

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44

Resources

bull Bevilacqua MP et al Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium characterization and comparison with the actions of interleukin 1 Proc Natl Acad Sci U S A 1986 Jun83(12)4533-7

bull Cines et al Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders The Journal of The American Society of Hematology Blood vol 91 NO 10 1998

bull Carr et al Low Moleuclar Weight Heparin Suppresses Tumor Necrosis Factor Expression from Deep Vein Thrombosis Ann Vasc Surgery 2007 21 5mdash55

bull Crawford JD et al Paroxysmal nocturnal hemoglobinuria a red clot syndrome Ann Vasc Surg 2014 Jan28(1)122e5-10 doi 101016javsg201307003 Epub 2013 Nov 5

bull Gan To Kagaku Ryoho Definition of tumor-necrosis factor and its production mechanism 1984 Jul11(7)1356-68

bull Hamuryudan et al Pulmonary artery involvement in Behcetrsquos syndrome Effects of anti-Tnf Treatment Seminars in Arthritis and Rheumatism Volume 45 Issue 3 Dec 2015 369-373

bull Lejeune et al Clinical applications of TNFa in cancer Current Opinion in Immunology 1998 10573-580

bull Myakis et al International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome(APS) Journal of Thrombosis and Haemostasis 4 295ndash306

bull Nawroth et al Modulation of Endothelial Cell Hemostatic Properties by Tumor Necrosis Factor J Exp Med The Rockereller University Press Vol 163 March 1986 740-745

bull Rosenblum MG1 et al Tumor necrosis factor alpha a multifaceted peptide hormone Crit Rev Immunol 19899(1)21-44