Upper Extremity Deep Vein Thrombosis 4/6/10

Definition Originally described in late 19th century by Paget and von Schroetter. Originally described in late 19th century by Paget and von Schroetter. Thrombosis in any of the following veins: Thrombosis in any of the following veins: Ulnar/Radial/Interosseous Ulnar/Radial/Interosseous Brachial Brachial Axillary Axillary Subclavian Subclavian Jugular/Brachiocephalic/SVC Jugular/Brachiocephalic/SVC Basilic and cephalic are considered superficial Basilic and cephalic are considered superficial

Dark Blue: Deep vein Blue: Superficial vein

Incidence Prior to 1970, accounted for < 2% DVTs Prior to 1970, accounted for < 2% DVTs May now account for 4-8%, higher in critical care areas (up to 33% in some studies). May now account for 4-8%, higher in critical care areas (up to 33% in some studies). Male≈Female Male≈Female Idiopathic UE DVT tend to be in younger patients. Idiopathic UE DVT tend to be in younger patients.

Etiology Virchow’s Triad: Virchow’s Triad: Venous trauma (Endothelial wall) Venous trauma (Endothelial wall) Venous stasis (external compression) Venous stasis (external compression) Hypercoagulability Hypercoagulability

Dark Blue: Deep vein Blue: Superficial vein Red: “Choke” points

Risk Factors Trauma/Surgery Trauma/Surgery Malignancy/XRT Malignancy/XRT Inherited Hypercoagulable states Inherited Hypercoagulable states Anatomical deformities/Malformations (e.g. Cervical ribs) Anatomical deformities/Malformations (e.g. Cervical ribs) Hyperviscosity (Sickle cell/Polycythemia) Hyperviscosity (Sickle cell/Polycythemia) Athletes (with repetitive motions of arms)/”Effort thrombosis”/Paget-von-Schroetter syndrome Athletes (with repetitive motions of arms)/”Effort thrombosis”/Paget-von-Schroetter syndrome Thoracic Outlet Syndrome Thoracic Outlet Syndrome Previous DVT/VTE Previous DVT/VTE

Risk Factors Venous catherization Venous catherization Oral contraceptives/Hormone Replacement Therapy Oral contraceptives/Hormone Replacement Therapy Tobacco Tobacco Obesity Obesity CHF CHF Nephrotic syndrome/PNH Nephrotic syndrome/PNH Lymphedema Lymphedema Hyperhomocysteinemia Hyperhomocysteinemia Thrombophlebitis Thrombophlebitis

Symptoms Arm/Neck/Facial swelling Arm/Neck/Facial swelling Arm/Neck/Facial pain Arm/Neck/Facial pain Erythema Erythema Bluish discoloration Bluish discoloration Collateral Venous distention (including chest veins) Collateral Venous distention (including chest veins) Fever Fever

Diagnosis D-Dimer: High sensitivity/Low specificity. Measures degradation product of cross-linked fibrin D-Dimer: High sensitivity/Low specificity. Measures degradation product of cross-linked fibrin Doppler Ultrasound: High sensitivity and specificity, though operator dependent. Doppler Ultrasound: High sensitivity and specificity, though operator dependent. Venography: Gold standard. Requires contrast Venography: Gold standard. Requires contrast MRI: Relatively low sensitivity/High specificity. Limited due to time constraints/cost MRI: Relatively low sensitivity/High specificity. Limited due to time constraints/cost

Complications Pulmonary Embolism Pulmonary Embolism Historically, 1% PE were attributed to UE DVTs. Historically, 1% PE were attributed to UE DVTs. More likely 5-10%. More likely 5-10%. More centrally located the thrombosis, the higher the risk of PE (Subclavian > Brachial) More centrally located the thrombosis, the higher the risk of PE (Subclavian > Brachial)

Complications - PE

Complications Recurrent DVT/PE: Recurrent DVT/PE: Risk increases on a yearly basis Risk increases on a yearly basis 2% in 1st year 2% in 1st year 4% in 3rd year 4% in 3rd year 7% in 5th year 7% in 5th year Risk is further increased in malignancy Risk is further increased in malignancy

Complications Post-thrombotic syndrome: 15-25% of patients with UE DVT may develop PTS. Post-thrombotic syndrome: 15-25% of patients with UE DVT may develop PTS. Characterized by persistent/severe pain and persistent edema. Characterized by persistent/severe pain and persistent edema. Can often be debilitating adversely affecting quality of life. Can often be debilitating adversely affecting quality of life.

Treatment American College of Chest Physicians: American College of Chest Physicians: Recommends the UE DVT be treated the same as LE DVT. Recommends the UE DVT be treated the same as LE DVT. Treatment was shown to decrease the recurrence of DVT/PE in two prospective cohort studies. Treatment was shown to decrease the recurrence of DVT/PE in two prospective cohort studies.

Treatment Heparin (Unfractionated): Activates antithrombin III, which inactivates thrombin. Also inhibits factor Xa and factor IXa. Heparin (Unfractionated): Activates antithrombin III, which inactivates thrombin. Also inhibits factor Xa and factor IXa. Requires monitoring of the aPTT (1.5X baseline PTT) due to heparin-binding proteins (which tend to increase during illness). Requires monitoring of the aPTT (1.5X baseline PTT) due to heparin-binding proteins (which tend to increase during illness). Half-life: 60 min when given IV. Half-life: 60 min when given IV. Can be reversed with protamine sulfate. Can be reversed with protamine sulfate.

Treatment Low-molecular weight heparin (LMWH) Low-molecular weight heparin (LMWH) Less affected by heparin-binding proteins Less affected by heparin-binding proteins More active against antithrombin III More active against antithrombin III Lower rate of HIT. Lower rate of HIT. Reversal with protamine sulfate is limited Reversal with protamine sulfate is limited

Treatment Fondaparinux (Arixtra): Binds to antithrombin, which inhibits factor Xa. Fondaparinux (Arixtra): Binds to antithrombin, which inhibits factor Xa. No action against thrombin No action against thrombin Not metabolized, renally excreted. Not metabolized, renally excreted. Half-life 15 hrs Half-life 15 hrs

Treatment Direct thrombin inhibitors: Direct thrombin inhibitors: Lepirudin, renally excreted. Lepirudin, renally excreted. Argatroban Argatroban Can inhibit clot-bound thrombin Can inhibit clot-bound thrombin Not affected by circulating inhibitors of heparin (released by platelets) Not affected by circulating inhibitors of heparin (released by platelets) Does not cause HIT. Does not cause HIT.

Treatment Vitamin K antagonists: Vitamin K antagonists: Warfarin (Coumadin): Inhibits Vitamin K epoxide reductase, which recycles oxidized Vit K. Initially developed as a rodenticide (rat poison). Warfarin (Coumadin): Inhibits Vitamin K epoxide reductase, which recycles oxidized Vit K. Initially developed as a rodenticide (rat poison). Acenocoumarol: Outside US, shorter half life than warfarin. Acenocoumarol: Outside US, shorter half life than warfarin. Phenprocoumon: Outside US, longer half life than warfarin. Phenprocoumon: Outside US, longer half life than warfarin. INR goal 2-3 INR goal 2-3

Future Ximelagatran: PO Direct thrombin inhibitor. Ximelagatran: PO Direct thrombin inhibitor. Denied approval by FDA in 2004 Denied approval by FDA in 2004 Pulled from market in 2006 Pulled from market in 2006 Found to have caused severe liver damage and heart attacks. Found to have caused severe liver damage and heart attacks.

Future Rivaroxaban: PO Factor Xa inhibitor Rivaroxaban: PO Factor Xa inhibitor Compared to LMWH in orthopedic surgery patients in several trials. Compared to LMWH in orthopedic surgery patients in several trials. Reduced LE DVT/nonfatal PE/death with no significant difference in major bleeding. Reduced LE DVT/nonfatal PE/death with no significant difference in major bleeding. Approved in Europe and Canada for DVT prophylaxis in orthopedic surgery patients. Approved in Europe and Canada for DVT prophylaxis in orthopedic surgery patients. May potentially be used in HIT? May potentially be used in HIT?

Future Dabigatran: PO direct thrombin inhibitor. Dabigatran: PO direct thrombin inhibitor. RECOVER trial: End point recurrent VTE/fatal PE: RECOVER trial: End point recurrent VTE/fatal PE: 2.4% dabigatran vs 2.1% warfarin 2.4% dabigatran vs 2.1% warfarin Hazard ratio 1.1, dabigatran not inferior Hazard ratio 1.1, dabigatran not inferior 1.6% major bleeding dabigatran vs 1.9% warfarin, not significant 1.6% major bleeding dabigatran vs 1.9% warfarin, not significant Significant reduction in all bleeding with dabigatran of 29% Significant reduction in all bleeding with dabigatran of 29% Approved for DVT prophylaxis in orthopedic surgery patients in Europe and Canada. Approved for DVT prophylaxis in orthopedic surgery patients in Europe and Canada.

Treatment Duration First DVT: Provoked: 3-6 months First DVT: Provoked: 3-6 months Unprovoked: 6-12 months Unprovoked: 6-12 months DVT with cancer/antiphospholipid syndrome: Life-long therapy DVT with cancer/antiphospholipid syndrome: Life-long therapy Second DVT: Life-long therapy Second DVT: Life-long therapy

Treatment Catheter-directed thrombolysis: Infuses a thrombolytic agent (usually tPA) between two inflated balloons via a catheter. Catheter-directed thrombolysis: Infuses a thrombolytic agent (usually tPA) between two inflated balloons via a catheter. Early restoration of venous patency/improved venous return/Decreases pain/discomfort. Early restoration of venous patency/improved venous return/Decreases pain/discomfort. No change in rates of recurrent DVT/PE/bleeding/PTS. No change in rates of recurrent DVT/PE/bleeding/PTS. Contraindications include hemorrhage/recent neurosurgery Contraindications include hemorrhage/recent neurosurgery ACCP recommends against routine use (Grade 1C). With severe symptoms of recent onset with low risk of bleeding, may be used (Grade 2C) ACCP recommends against routine use (Grade 1C). With severe symptoms of recent onset with low risk of bleeding, may be used (Grade 2C)

Treatment SVC Filter SVC Filter Rates of PE 2.4% and PTS 0% in one study (n=41). Rates of PE 2.4% and PTS 0% in one study (n=41). Another study showed no episodes of PE (n=72). Another study showed no episodes of PE (n=72). ACCP recommends against routine use (Grade 1C). If anticoagulation contraindicated and DVT progression occurs, then SVC may be placed (Grade 2C). ACCP recommends against routine use (Grade 1C). If anticoagulation contraindicated and DVT progression occurs, then SVC may be placed (Grade 2C).

Treatment Graded Compression sleeves/Elastic bandages Graded Compression sleeves/Elastic bandages Useful in relieving symptoms of persistent pain/swelling such as in PTS. Useful in relieving symptoms of persistent pain/swelling such as in PTS. ACCP: Routine use not recommended (Grade 2C), except in patients with persistent pain (Grade 2C) ACCP: Routine use not recommended (Grade 2C), except in patients with persistent pain (Grade 2C)

Treatment Graded Compression sleeves/Elastic bandages Graded Compression sleeves/Elastic bandages Useful in relieving symptoms of persistent pain/swelling such as in PTS. Useful in relieving symptoms of persistent pain/swelling such as in PTS. ACCP: Routine use not recommended (Grade 2C), except in patients with persistent pain (Grade 2C) ACCP: Routine use not recommended (Grade 2C), except in patients with persistent pain (Grade 2C)

Treatment In a retrospective study of 189 Surgical ICU patients, 33% had UE DVTs, In a retrospective study of 189 Surgical ICU patients, 33% had UE DVTs, Central catheters (45%) was the highest risk factor identified Central catheters (45%) was the highest risk factor identified 6% had PE, all nonfatal, all with IJ clots 6% had PE, all nonfatal, all with IJ clots 60% were anticoagulated 60% were anticoagulated No difference in LOS/survival to 30 days, and 1 year mortality No difference in LOS/survival to 30 days, and 1 year mortality

Treatment RIETE Registry: RIETE Registry: 512 of DVTs were UE DVT (4.4%) 512 of DVTs were UE DVT (4.4%) 9% had PE (vs 29% for LE DVT) 9% had PE (vs 29% for LE DVT) 3 month outcomes of major bleeding/fatal bleeding/recurrent DVT/recurrent PE were similar between UE and LE DVTs 3 month outcomes of major bleeding/fatal bleeding/recurrent DVT/recurrent PE were similar between UE and LE DVTs Slightly higher mortality rate for UE DVTs Slightly higher mortality rate for UE DVTs Cancer patients had increased rates in recurrent DVT/PE/major bleeding. Cancer patients had increased rates in recurrent DVT/PE/major bleeding. 56% of patients had received anticoagulation. 56% of patients had received anticoagulation.

Conclusions Most studies are retrospective or cohort studies with small numbers of patients. Most studies are retrospective or cohort studies with small numbers of patients. ACCP recommends to treat UE DVTs same as LE DVTs ACCP recommends to treat UE DVTs same as LE DVTs Use heparin/LMWH, until INR therapeutic with coumadin (INR goal 2-3) Use heparin/LMWH, until INR therapeutic with coumadin (INR goal 2-3) Thrombolysis/Thrombectomy/SVC Filter not routinely indicated. Thrombolysis/Thrombectomy/SVC Filter not routinely indicated. Future PO meds may replace warfarin Future PO meds may replace warfarin

References Chest 2008; 133; 454S-545S. Chest 2008; 133; 454S-545S. Chest January 2008 vol. 133 no Chest January 2008 vol. 133 no Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM 361: Dec 10, Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM 361: Dec 10, Hingorani A, Ascher E, Lorenson E, et al. Upper extremity deep venous thrombosis and its impact on morbidity and mortality rates in a hospital- based population J Vasc Surg 1997;26:853–60. Hingorani A, Ascher E, Lorenson E, et al. Upper extremity deep venous thrombosis and its impact on morbidity and mortality rates in a hospital- based population J Vasc Surg 1997;26:853–60. Hingorani A, Ascher E, Markevich N, et al. Risk factors for mortality in patients with upper extremity and internal jugular deep venous thrombosis J Vasc Surg 2005;41:476–8. Hingorani A, Ascher E, Markevich N, et al. Risk factors for mortality in patients with upper extremity and internal jugular deep venous thrombosis J Vasc Surg 2005;41:476–8. Paget J., London: Longmans, Green & Co; Clinical lectures and essays. Paget J., London: Longmans, Green & Co; Clinical lectures and essays. Prandoni P, Polistena P, Bernardi E, et al. Upper-extremity deep vein thrombosis: risk factors, diagnosis and complications Arch Intern Med 1997;157:57–62. Prandoni P, Polistena P, Bernardi E, et al. Upper-extremity deep vein thrombosis: risk factors, diagnosis and complications Arch Intern Med 1997;157:57–62. Vascular. 2008;16(2): Vascular. 2008;16(2): von Schroetter L. Nothnagel Handbuch der Pathologie und Therapie Holder 1884 von Schroetter L. Nothnagel Handbuch der Pathologie und Therapie Holder 1884