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Venous Thromboembolism (VTE) in ICU

Chee M. Chan, MD Pulmonary and Critical Care Medicine

Washington Hospital Center Washington, D.C.

Slide 2

VTE in ICU

• Pathophysiology of thrombosis • Prophylaxis and DVT • Pathophysiology of pulmonary embolism • Pulmonary embolism diagnostics • Pulmonary embolism therapeutics Slide 3

VTE Overview

Primary Presentation Secondary Development

Risk Factors Prophylaxis

Hemodynamic Instability Respiratory Failure Diagnostics Cardiac Echo Doppler US Angiogram UF Heparin Spiral CT D-dimer Therapeutics Thrombolytics Warfarin Argatroban LMWH Lepirudin

Slide 4

Pathophysiology of Thrombosis

Slide 5

Venous Thromboembolism

“ The detachment of larger or smaller fragments from the end of the softening thrombus are carried along by the current of blood and driven in remote vessels. This gives rise to the very frequent process upon which I have bestowed the name EMBOLIA.”

Virchow, 1846 Vessel Injury Acquired Stasis Hyper-coagulability Inherited

Slide 6

Virchow’s Triad

• Hypercoagulable (25%) • Stasis • Vessel damage Slide 7

Intensivists’ General Paradigm

Pipes Stuff Flow

Slide 8

Hematology 101 for Intensivists

Clot Bleed Stuff Pipe = Biologically Active Conduit Stuff Flow Coagulation Fibrinolysis

Slide 9

Hematology 101 for Intensivists

Bleed Clot Stuff Pipe = Biologically Active Conduit Stuff Coagulation Fibrinolysis Flow (stasis)

Slide 10

Pathogenesis of VTE Thrombogenic Stimuli

• Endothelial damage – Exposure of tissue factor/subendothelial matrix – Hypoxia  receptors for leukocytes – Activation by inflammatory cytokines (IL-1, TNF) • Express tissue factor • Internalize thrombomodulin (  Protein C activation) • Release PAI-1

Clot

• Activation of coagulation – Inflammation (IL-1, TNF) • Monocytes  tissue factor and tethered leukocytes • Internalize thrombomodulin • Shedding endothelial protein C receptor – Coagulation cascade activation Slide 11 2003

Bleed

Pathogenesis of VTE Thrombogenic Stimuli

• Blood flow (stasis) – Systemic

Clot

• Immobilization pools blood in calf venous sinuses • Increased blood viscosity

Bleed

– Local • Hypoxia of valve cusps produces tissue factor and activates coagulation • Accumulation of clotting factors in venous sinuses of calf or valve cusp pockets Slide 12

Adapted from Wertz Lung Biology Health Disease 2003

ICU VTE Risk Factors

ICU Risk Factors

Major Surgery Trauma MI/CHF Stroke Burns Sepsis Catheter

Hypercoag

X X X X Adopted from Dalen. CHEST 2002; 122:1440-1456.

Slide 13

Stasis

X X X X X X X

Vessel

X X X

DVT Prophylaxis in ICU

• Most preventable cause of hospital associated death in medical patients  PE DVT • Valvular damage Recurrence PE Post-phlebitic syndrome • Symptomatic proximal DVT can be an extension of distal DVT that was previously asymptomatic • Significant number of fatal PEs NOT preceded by symptomatic DVT Slide 14

ICU Issues and VTE

• VTE are frequently unrecognized in critically ill patients – High risk – Unable to express symptoms – Physical signs masked by critical illness • Pulmonary embolism can result in: – Failure to wean from the ventilator – Increased ICU length of stay – Death Slide 15

Asymptomatic DVT ICU Admit

Patient Population

Surgical ICU Respiratory ICU MICU-Resp fail/vent MICU-Resp fail/vent

% DVT

7.5% Harris.

J Vas Surg.

1997;26:734-739.

10.7% Schonhster.

Respiration

1998;65:173-177.

19% Goldberg.

AJRCCM.

1996; 153:A94.

6.3% Fraisse.

AJRCCM.

2000; 161:1109-1114.

Slide 16

Prospective Eval DVT Critically Ill Non-Prophylaxed

Study

Moser 1981 Cade 1982 Hirsch 1995 Kapoor 1999 Fraisse 2000

Control

Respiratory General Medical Medical Vent COPD

Screen

Fib LS Fib LS US US Venogram

#

23 60 104 390 85

% DVT

13% 29% 32% 31% 28% Slide 17

Natural History of DVT

132 surgical patients, no prophylaxis 70% No DVT (92) 30% DVT (40) 35% calf with spontaneous lysis (14) 42% calf only (17) 23% propagation Popliteal/femoral (9)

Kakkar. Lancet. 1969; 6:230-232.

56% No PE (5) 44% PE (4)

Slide 18

Incidence of VTE Major Trauma W/out Prophylaxis

• Lower leg DVT 58%, proximal DVT 18% • Vast majority clinically not apparent

• 50% face, chest, abdomen • 54% major head injury • 62% spinal injury

Incidence

• 69% lower extremity ortho • 61% pelvic fractures • 80% femoral fractures • 77% tibial fractures Geerts. N Engl J Med. 1994;331:1601-1606.

Slide 19

DVT Prophylaxis Trials in Critically Ill

Study Control

Cade ’82 Placebo Kapoor ’99 Fraisse ’00 Cook ‘05 Placebo Placebo None Geerts. J Crit Care. 2002;17:95-104.

% DVT

29% 31% 28% Slide 20

Treatment % DVT

UF Heparin UF Heparin Nadroparin UF Heparin 13% 11% 15% 9.6%

Femoral Catheter-associated DVT

Study

Meredith ’93 Trottier ’95 Durbec ’97 Durbec ’97 Jogut ’00 Ibrahim ‘02

Population

Trauma 8.5 Fr Med/Surg Med/Surg Med/Surg Med/Surg Medical

Screen

US US Venogram Venogram US US

% DVT

14% 25% 7% Femoral 17% Tibial 9% Femoral 26% Tibial 11% 15.4% Slide 21

Pulmonary Embolism in Patients with Upper Extremity Catheter DVT

• 86 consecutive patients catheter DVT • 15% high probability (PE) V/Q scan (13/86) • 31% PE patients symptomatic (4/13) • 15% PE patient mortality (2/13) despite full anticoagulation   DVT polyvinyl chloride or polyethylene Monreal. Thromb Haemost. 1994;72:548-5.50

Slide 22

Autopsy Studies PE Critically Ill

Study

Neuhaus 1978 Moser 1981 Pingleton 1981 Cullin 1986 Blosser 1998 Willemsen 2000

ICU Setting

Med/Surg Respiratory Medical Surgical Medical Surgical Geerts. J Crit Care. 2002;17:95-104.

Slide 23

PE Autopsy Present

27% 20% 23% 10% 7% 8%

Fatal

12% 0% - 1% 2% 3%

VTE Prophylaxis

Pharmacologic Unfractionated heparin Low molecular weight heparin Vitamin K Antagonists Mechanical Graduated compression stockings Intermittent pneumatic compression devices

Slide 24

IVC filters

Thromboembolism Risk Surgical Patients



Prophylaxis

Low Risk Minor surgery; age<40; no risk factors Moderate Risk Minor surgery risk factors Surgery; age 40-60; no risk factors

Calf

2% 10-20 %

DVT, % Proximal

0.4% 2-4%

Clinical

0.2%

PE, % Fatal

<0.01% 1-2% 0.1-0.4% High Risk 20-40% 4-8% 2-4% 0.4-1.0% Surgery; age>60 or 40-60 with additional risk factors (prior VTE, cancer, hypercoagulability) Highest Risk 40-80% 10-20% 4-10% 0.2-5% Surgery with multiple risk factors (age>40, cancer, prior VTE) Hip or knee arthroplasty, HFS Major trauma, SCI Geerts. Chest. 2004;126 Suppl:338S-400S.

Slide 25

70 60 50 40 30 20 10 0 60.5

Relative risk reduction 67% 20.3

C ontrol Heparin Relative risk reduction 68% Screening DVT 1.9

Collins. N Engl J Med. 1988;318:1162-1173.

0.6

Fatal PE

Slide 26

Trauma and VTE

• Patients recovering from major trauma have the highest risk for developing VTE among all hospitalized patients. (Geerts. N Engl J Med. 1994;331:1601-1606.) • Without prophylaxis, multisystem or major trauma patients have a DVT risk exceeding 50%. (Kudsk. Am J Surg. 1989;158:515-519.) • PE is the third leading cause of death in trauma patients who survive beyond the first day. (Acosta. J Am Coll Surg. 1998;186:528-533.) Slide 27

Risk Factors for VTE

The following display the significant risk factors and odds ratios for VTE developed from the National Trauma Data Bank.

Risk Factor (Number at Risk) N Odds Ratio (95% CI)

*Age  40 y 178,851 2.29 (2.07

–2.55) Pelvic fracture *Lower extremity fracture 2,707 63,508 Spinal cord injury with paralysis *Head injury (AIS score  3) *Ventilator days >3 *Venous injury Shock on admission (BP <90 mm Hg) 2,852 52,197 13,037 1,450 18,510 *Major surgical procedure Knudson. Ann Surg. 2004;240:490-498.

Slide 28 73,974 2.93 (2.01

–4.27) 3.16 (2.85

–3.51) 3.39 (2.41

–4.77) 2.59 (2.31

–2.90) 10.62 (9.32

–12.11) 7.93 (5.83

–10.78) 1.95 (1.62

–2.34) 4.32 (3.91

–4.77)

INJURED PATIENT High Risk Factors (Odds ratio for VTE = 2 –3)

•

Age



40

• •

Pelvic fx Lower extremity fx

• • •

Shock Spinal cord injury Head injury (AIS



3)

• • • •

Very High Risk Factors (Odds ratio for VTE = 4 –10) Major operative procedure Venous injury Ventilator days >3 2 or more high risk factors Does the patient have contraindication for heparin?

Does the patient have contraindication for heparin?

No Yes No Mechanical compression LMWH* * Prophylactic dose

Knudson. Ann Surg. 2004;240:490-498.

Slide 29

LMWH* and mechanical compression Yes Mechanical Compression and serial CFDI OR temporary IVC filter

Critical Care Patient

Assess Bleeding Risk

• • •

High

Mechanical prophylaxis – Graduated compression stockings (GCS) – Intermittent pneumatic compression devices (IPC) Delayed prophylaxis until high risk bleeding abates Screen for proximal DVT with Doppler US in high risk patients

Low

• Low dose unfractionated heparin (LDUH) • Low molecular weight heparin (LMWH) • Combination of LMWH and mechanical prophylaxis for high risk patients Adapted from Albers. Chest. 2008;133 Suppl:381S-453S.

Slide 30

Critical Care Patient

Bleeding Risk

Low Low High High

Thrombosis Risk

Moderate High Moderate High

Prophylaxis Recommendation

LDH 5000 units SC bid LMWH • Dalteparin • Enoxaparin GCS or IPC  LDUH when bleeding risk subsides GCS or IPC  LMWH when bleeding risk subsides Adapted from Albers. Chest. 2008;133 Suppl:381S-453S.

Slide 31

Anti-Xa Activity After Enoxaparin 40 mg SQ

1.0

0.8

0.6

Ward (Group 2), n=13 ICU patients (Group 1), n=16

0.4

0.2

0 0 3 6

Time (hours)

Priglinger. Crit Care Med. 2003; 31:1405-1409.

Slide 32 9 12

Vena Caval Filters

• 5 filter types -- all equal efficacy • Pulmonary embolism 2.6%-3.8% • Deep venous thrombosis 6%-32% • Insertion site thrombosis 23%-36% • Inferior caval thrombosis 3.6%-11.2% • Postphlebitic syndrome 14%-41% Streiff. Blood. 2000; 95:3669-3677.

Slide 33

ACCP Recommendations

• ACCP recommendations for thromboprophylaxis in ICU patients • All ICU patients -> assessed for VTE prophylaxis • All ICU patients -> routine thromboprophylaxis • Moderate risk -> LMWH or LDUH prophylaxis • High risk -> LMWH prophylaxis • Bleeding risk high -> mechanical prophylaxis • When bleeding risks decreases -> chemical Adopted from Albers. Chest. 2008 Slide 34

Pulmonary Embolism in ICU

Chee M. Chan, MD Pulmonary and Critical Care Medicine Washington Hospital Center Washington, D.C.

Pulmonary Embolism (PE)in ICU

• Pathophysiology of pulmonary embolism • Pulmonary embolism diagnostics • Pulmonary embolism therapeutics

Major Pulmonary Embolism

Incremental Resistance Pulmonary Artery Pressure Mean Closing Pressure P 2 - P 1 Q = R CO = mPAP - LVEDP PVR PVR = mPAP - LVEDP CO Q = Flow = Cardiac Output

Major Pulmonary Embolism

Effect of Pulmonary Embolism Incremental Resistance Pulmonary Artery Pressure Mean Closing Pressure Q = Flow = Cardiac Output

Epidemiology

Total Incidence 630,000 Survival > 1 hr 563,000 Death within 1 hr 67,000 Diagnosis not made 400,000 Diagnosis made 163,000 Survival 280,000 Death 120,000 Survival 150,000 Death 13,000

Risk Factors for PE

Non-modifiable (permanent)

Spinal cord injury Paralytic stroke Congestive heart failure Chronic lung disease Irritable bowel disease Malignancy Prior venous thromboembolism Thrombophilia Age > 60 Varicose veins Obesity

Modifiable (transient)

Hip or leg fracture Hip or knee replacement Major general surgery Major trauma Central venous lines Chemotherapy Hormone replacement therapy Oral Contraceptives Pregnancy Sedentary Laparoscopic surgery Albers. Chest. 2008; 133: 381S-453S

VTE in ICU Pulmonary Embolism Diagnostics

Diagnostics

Massive Pulmonary Embolism Diagnostics

• • • • • • •

History Physical CXR ABG EKG BNP troponin Echo Angio Helical CT MRI Angio

Risk Stratification in PE

Mortality

65% 25% 15% 8.1% 0-1%

Clinical State

Cardiac Arrest Shock Hypotension without hypoperfusion

High Risk Predictions History/Physical Diagnostic

•

EKG

•

CXR

•

ABG

•

Troponin

•

BNP

•

Echo Confirmatory

Normal BP RV dysfunction

Low Risk

Normal BP and RV Data from MAPPET – Kasper. J Am Coll Cardiol. 1997; 30:1165-1171.

•

V/Q

•

CT Angio

•

Angio

EKG Manifestations

• Normal EKG – UPET 14% (6% massive and 23% submassive) – PIOPED 30% • Rhythm disturbances rare – Atrial fibrillation/flutter 0-5% – Blocks or ventricular dysrhythmias non-existent – PEA cardiac arrest • Electrocardiographic cor pulmonale – Right axis, RBBB, SIQIIITIII – Related to embolism size • Non-specific ST-T segment changes – UPET 42% – PIOPED 49%

Chest X-Ray (CXR)

• UPET – Normal CXR 34% – Parenchymal abnormalities 67% • Elevated hemidiaphragm 46% • Consolidation 39% • Pleural effusion 30% • Atelectasis 28% – Vascular abnormalities 37% • Diminished vascularity 22% • Prominent central PA 86% • PIOPED – Normal 16% – Atelectasis/parenchymal abnormality 68% – Pleural effusion 48%-blunting 86%

Arterial Blood Gas (ABG)

• Hypoxia not uniform – PaO2  80 • 12% UPET • 19% PIOPED • Normal A-a gradient does NOT exclude PE – PIOPED (PaO2>80,PaCO2>35) • 38% without cardiopulmonary disease • 14% with cardiopulmonary disease

D-Dimer

• Elevated in clinical conditions where fibrin crosslinks are cleaved by plasmin • High sensitivity and negative predictive value • Low specificity • ELISA – Accurate quantitative measurement – Expensive and labor intensive • Semi-quantitative latex assay – Faster and less expensive – Unacceptably low sensitivity

Signs & Symptoms for PE Nonspecific

Symptoms

Dyspnea Chest pain (pleuritic) Chest pain (substernal) Cough Hemoptysis Syncope

Signs

Tachypnea (≥ 20/min) Tachycardia (> 100/min) Signs of DVT Cyanosis

PE confirmed (n=219)

80% 52% 12% 20% 11% 19% 70% 26% 15% 11% Torbicki et al. Eur Heart J 2008

PE excluded (n=546)

59% 43% 8% 25% 7% 11% 68% 23% 10% 9%

Estimating Pre-test Probability of PE

• Implicit (empiric) – Uses clinician knowledge and experience – Frequent disagreement – Experience level influences assessment – Estimates trend towards middle, few to low or high probability groups – Inaccurate low risk assessment • Explicit criteria – Scoring systems – Prediction rules – Clinical decision rules

Canadian PE Pre-test Probability

Creating the Score Criteria

Suspected DVT Alternative diagnosis is less likely than PE Heart rate >100 beats/min Immobilization or surgery in the previous 4 weeks Previous DVT/PE Hemoptysis Malignancy (on treatment, treated in the past 6 mo, or palliative)

Score Range

0-2 points 3-6 points >6 points

Interpretation of the Score Mean Probability of PE, % Patients with this score, %

3.6

20.5

66.7

40 53 7 Wells. Thromb Haemost. 2000;83:416-420.

Points

3.0

3.0

1.5

1.5

1.5

1.0

1.0

Interpretation of Risk

Low Moderate High

Wells’ Score + D-dimer

Clinical Probability (2 levels) PE unlikely PE likely Wells’ Score 0-4 > 4 Mortality if D-dimer negative 2.2% 16.1% Mortality if D-dimer positive 18.3% 57.7% Wells. Thromb Haemost. 2000;83:416-420.

Geneva Pretest Score for PE

Geneva Score

for Assessment of Pretest Probability for Pulmonary Embolism

Criteria

Age 60-79 years Age >79 years Prior DVT/PE Recent surgery Heart rate >100 beats/min PaCO 2 , mm Hg <36 36-39 PaO 2 , mm Hg <49 49-60 60-71 71-82 Chest radiograph Platelike atelectasis Elevation of hemidiaphragm

Score

1 2 2 3 1 2 1 4 3 2 1 1 1

Interpretation of Criteria Score Range

0-4 points 5-8 points 9-12 points

Mean Probability of PE %

10 38 81

Patients with this score %

49 44 6

Interpretation of risk

Low Moderate High

Clinical Gestalt vs. Prediction Rules

Clinical Gestalt Prediction Rules

Pretest Prob Rate Pulmonary Embolism Rate Pulmonary Embolism Low Moderate High 8% - 19% 26% - 47% 46% - 91% 3% - 28% 16% - 46% 38% - 98%

“Clinical gestalt of experienced clinicians and prediction rules used by physicians of varying experience have shown similar accuracy in discriminating among patients who have a low, moderate or high pretest probability of PE.”

Chandilal. JAMA, 2003; 290:2849-2858.

Diagnostic Approach to Pulmonary Embolism

High Clinical Probability CT Angio Positive CT Negative CT Diagnosis Confirmed Duplex Ultrasound Negative Positive Pulmonary Angiography Negative Diagnosis Excluded Positive Diagnosis Confirmed Diagnosis Confirmed

Fedullo. N Engl J Med. 2003; 349:1247-1256.

Diagnostic Strategies

Diagnostic Strategies for Excluding Pulmonary Embolism with Upper 95% Confidence Limit of 3% or Less and 3 Month Risk

Diagnostic Strategy Initial Evaluation 3-Month Risk for VTE Complications (upper 95% CL)

Normal pulmonary angiogram Normal lung scan Normal lung scan, normal legs Normal D-dimer Normal D-dimer low clinical probability 0.8 (2.1) 0.9 (2.3) 0.6 (1.2) 0.0 (1.8) 0.2 (0.8) Marieke. Ann Intern Med. 2003;138:941-951.

Negative CT Scan

Clinical Validity of a Negative CT Scan in Suspected Pulmonary Embolism Overall negative likelihood ratio of VTE after negative chest CT Overall negative predictive value Negative likelihood ratio of VTE after a negative single slice spiral CT chest Negative likelihood ratio of VTE after negative multidetector row CT chest Overall negative likelihood ratio of mortality attributable to PE Overall negative predictive value 0.07 (CI, 0.05-0.11) 99.1% (CI, 98.7-99.5%) 0.08 (CI, 0.05-0.13) 0.15 (CI, 0.05-0.43) 0.01 (CI, 0.01-0.02) 99.4% (CI, 98.7-99.9%)

“Clinical validity of using a CT scan to rule out PE is similar to that reported for angiography.”

Quiroz. JAMA. 2005; 293: 2012-2017.

BNP and Troponins

Complementary Biomarkers for Risk Stratification Future Directions?

Hemodynamically Stable PE

  

BNP Stretch RV Dysfxn BNP <50 detects low risk And

  

Troponin Ischemia RV damage TnT >0.01 detects high risk Both Normal Both Elevated Floor Low risk Heparin Outpatient High risk Echocardiogram Heparin vs Medical or surgical embolectomy

BNP and Troponins

Konstantinides et al Konstantinides et al Glannitsis et al Janata et al Pruszczyk et al ten Wolde et al Kucher et al Kucher et al Pruszczyk et al n 106 106 56 106 64 110 73 73 79 biomarker cTnI cTnT cTnT cTnT cTnT BNP NT-proBNP BNP NT-proBNP Cut-off 0.07 μg/mL 0.04 μg/mL 0.10 μg/mL 0.09 μg/mL 0.01 μg/mL 21.7 pmol/L 500 pg/mL 50 pg/mL 153-334 pg/mL Kucher et al. Circulation 2003;108:2191- 2194 NPV, % 98 97 97 99 100 99 100 100 100 PPV, % 14 12 44 34 25 17 12 12 23

Major Pulmonary Embolism Echo Findings

• • • • • • • •

Pulmonary Embolism

Right-sided thrombi Correlation with obstruction RV dilatation/hypokinesis Pul art dilatation  LV size;  RV/LV ratio Tricuspid regurgitation Abnormal/paradoxical septum Loss of inspiratory collapse IVC • • • •

Alternative Diagnosis

AM I Tamponade Aortic dissection Valvular disease

Major Pulmonary Embolism

Transthoracic Echo PE bilateral RV Dilatation PE 50%-90% central/proximal Transesophageal Echo

• TEE sensitivity 80%-97%, specificity 84%-100% • Comparable sensitivity to spiral CT attributed to TEE ability to visualize proximal extending mobile portions of distally impacted emboli • Low sensitivity beyond proximal Pruszczyk. Chest. 1997;112:722-728.

Wittlich. J Am Soc Echo. 1992;5:515-524.

PE in ICU Pulmonary Embolism Therapeutics

Goals of Treatment

• Stabilization of clot • Revascularization of occluded pulmonary vasculature – 2/3rd will have complete resolution of thrombus – 1/3rd will have partial resolution – 5% will develop chronic thromboembolic pulmonary hypertension • Immediate treatment => decreased mortality

Therapeutics

Massive Pulmonary Embolism Therapeutics Heparin Thrombolytics Embolectomy Vena caval filters Standard Bolus Catheter Surgical

ACCP Recommendations

• High suspicion PE – anticoagulate during eval period • Non-massive PE – LMWH, UFH, Fondaparinux • Non-massive PE – LMWH over UFH • Non-massive PE – initial LMWH/UFH/Fondaparinux for at least 5 days • Renal failure – IV UFH over LMWH • UFH – aPTT prolongation that corresponds to plasma heparin level 0.3 to 0.7 IU/mL anti-Xa activity • Inability to achieve therapeutic aPTT – measure anti-Xa • Initiate VKA on day 1 and discontinue heparin when INR is stable and greater than 2.0

Chest. 2008;133:454S-545S.

Long Term ACCP Recommendations

• Transient reversible risk - VKA 3 months • First idiopathic PE - VKA ≥ 3 months (consider indefinite treatment) • Two or more idiopathic PE – VKA indefinite treatment • PE and cancer - LMWH 3-6 months (consider indefinite treatment) • Antiphospholipid antibodies or two or more thrombophilic conditions - 12 months • First episode with deficiency of protein C, protein S, prothrombin 20210 gene mutation, homocysteinemia, or high factor VIII levels 6-12 months • INR target 2.5 (range 2.0-3.0) Chest. 2008;133:454S-545S.

Benefits of Thrombolytic Therapy

• Eliminate venous thrombi  decrease recurrent PE • Prevent chronic vascular obstruction and pulmonary HPT • Reduction of morbidity and mortality

Rapid Clot Lysis Enhance pulmonary perfusion Early hemodynamic improvement Improve gas exchange

Thrombolytic Therapy-Trials

Heparin Lysis Study

UPET 1970 Tibbutt 1974 Ly 1978 Marini 1988 PIOPED 1990 Levine 1990 Goldhaber 1993 Sanchez 1995 Konstantinides 2002

#

160 30 20 30 13 58 101 8 256

Mortality

7% 8% 9% 0% 0% 0% 4% 100% 2.2%

Recurrent

19% - - 0% - 0% 9% - 2.9%

Mortality

9% 0% 0% 0% 11% 3% 0% 0% 3.4%

Recurrent

15% - - 0% - 0% 0% 0% 3.4%

Thrombolytic Therapy

Pooled analysis – 748 patients (11 studies):

Thrombolytics Recurrent PE

2.7%

All cause mortality Major bleeding

4.3% 9.1%

UFH

4.3% 5.9% 6.1%

OR (CI)

0.67 (0.33 – 1.37) 0.70 (0.37 – 1.30) 1.42 (0.81 – 2.46) Subset with hemodynamic instability – 254 patients (5 trials):

Mortality Major bleeding Thrombolytics

6.2% 21.9%

UFH

12.7% 11.9%

OR (CI)

0.47 (0.20 – 1.10) 1.98 (1.0 – 3.92) Wan et al. Circulation 2004; 110:744-749

PE Therapy Facts

• Heparin better than placebo – Barritt. Lancet. 1961;1:729.

• 12 hr urokinase = 24 hr urokinase  24 streptokinase  heparin – UPET II. JAMA. 1974;229:1606-1613.

• 2 hr TPA>12/24 hr urokinase – Goldhaber. Lancet 1988;2:293-298.

– Meyer. J Am Coll Cardiol. 1992;19:239-245.

• 2 hr TPA = 2 hr short infusion urokinase – Goldhaber. J Am Coll Cardiol. 1992;20:24-30.

PE Therapy Facts

• IV = intrapulmonary TPA – Verstraete. Circulation. 1988;77:353-360.

• Bolus TPA = 2 hr TPA – Levine. Chest. 1990;98:1473-1479.

– Goldhaber. Chest. 1994;106:718-724. – Sors. Chest. 1994;106:712-717.

• 2 hr TPA>12 hr streptokinase – Meneveau. Eur Heart J. 1997;18:1141-1148.

• 2 hr TPA = 2 hr streptokinase – Meneveau .J Am Coll Cardiol. 1998;31:1057-1063.

PE Complications of Thrombolytic Therapy

• Major hemorrhage (12%) – TPA 13.7% – UK 10.2% – SK 8.8% • Intracranial hemorrhage (1.2%) – Fatal in 50% – SK - none reported – UK 1.3% – TPA 1.6% – Elevated diastolic BP as risk Fatal Intracranial Requiring transfusion/surgery Arcasoy. Chest. 1999;115:1695-1707.

Major Pulmonary Embolism Surgical or Catheter Embolectomy

• Diagnostic confirmatory studies can delay definitive treatment and contribute to mortality; angio 14%-67% • Cardiopulmonary bypass > venous inflow occlusion • Mortality decreasing but variable (16%-46%) • 1960s 57% 1990s 26% • Highest mortality with cardiac arrest (60%) • Catheter fragmentation an option if no arrest

• •

Heparin-induced Thrombocytopenia Hypercoagulable Paradox

Thrombosis risk  degree of thrombocytopenia – Mild thrombocytopenia 50% – Severe thrombocytopenia 90% Isolated “HIT”  50% thrombosis post dx/stop heparin

Venous

• DVT 50% • PE (25%) • Cerebral vein thrombosis • Adrenal hemorrhagic infarct

Arterial

• Aortic or iliofemoral thrombosis acute limb ischemia infarct (5%-10%) • Acute thrombotic stroke (3%-5%) • Myocardial infarction (3%-5%) Warkentin. Heparin Induced Thrombocytopenia. 2001.

PE in the ICU Summary

• PE risk stratification is crucial to determine optimal treatment • Risk/benefit ratio must be carefully considered before administration of thrombolytic therapy in massive PE • Early and aggressive treatment decreases mortality

Hemostasis Problems in Critical Illness

Per Thorborg, MD, PhD, FCCM

Director, Adult Critical Care Medicine @ OHSU Professor of Anesthesiology/CCM Dept. of Anesthesiology and Perioperative Medicine

Lynn Boshkov, MD

Assoc Director, Transfusion Medicine and Director, Hemostasis & Thrombosis Associate Professor of Pathology, Medicine and Pediatrics Oregon Health & Science University Portland, Oregon

Introduction

• • • • While coagulation-associated problems in critical care medicine include both hyper- and hypocoagulable states, venous thromboembolism (VTE) is addressed in another module.

In the ICU, acquired hypocoagulable states are much more common than congenital states [such as vWD (types I, II, III); hemophilia A, B, C; Bernard Soulier and Glanzmann’s thrombasthenias; inborn platelet abnormalities; isolated coagulation factor deficiencies; dysfibrinogenemias; alpha2 antiplasmin deficiency, other rare disorders]. Of these disorders, vWD is by far the most common. (1%) In the following teaching module, due to space restrictions, only some of the most common acquired coagulation problems seen in the ICU patient are addressed. It is recommended to involve hematology and blood bank early in the management course of a severely bleeding patient.

The order in which the material will be presented is 1. An updated view of the coagulation cascade; 2.Critical illness coagulopathies and treatment; 3.Uncontrolled bleeding and massive transfusion; 4. Anticoagulation associated problems; 5.Case scenarios; and 6. References.

The Three Stages of Hemostasis

• In primary hemostasis, a platelet plug is formed within 5 minutes to seal the site of injury. • In secondary hemostasis, fibrin is formed (coagulation) and a fibrin mesh reinforces the frail platelet plug (timescale hours).

• The third part is (secondary) fibrinolysis, which dissolves the clot but takes place first after tissue repair (timescale days).

• The coagulation cascade for fibrin formation, described in the early 1960s by Davie, Ratnoff, and MacFarlane, was based on in vitro data. While its extrinsic and intrinsic pathways setup explained many PT and APTT abnormalities, it failed to explain other clinical observations. • Newer data from the 1990s have replaced this older model with a cell-based model where interactions among endothelial cells, platelets, and thrombin have taken center stage.

The Platelet Plug Formation

• • • • Primary hemostasis is initiated by endothelial damage exposing subendothelial collagen. Platelets adhere to collagen via their GPIb receptor using vWF as a bridging ligand. Platelets activate changing from discoid (2 μm) to irregular shape with pseudopods.

Granular contents are released (which include bridging molecules and platelet agonists such as vWF, fibrinogen, FV, FVIII, Ca 2+ , 5-HT, ADP, TxA 2 ).

Activation also changes the conformation of the GPIIb/IIIa receptor promoting fibrinogen binding and platelet aggregation.

The activated platelet exposes a phospholipid surface domain, PF3, which will become the catalytic center for the next part, the secondary hemostasis

Cell-Based Coagulation 2005

• With injury, tissue factor (TF) becomes exposed to blood and combines with free-circulating FVII initiating fibrin clot formation.

• This complex activates FX, which, with FV, can form small amounts of thrombin, enough to activate local platelets (see next slide).

• The surface of the activated platelet becomes the catalytic center for a larger amount of thrombin production, which produces enough fibrin to stabilize the platelet clot.

• Thrombin has both pro-coagulatory and pro-modulatory, as well as antifibrinolytic, activities. • Three major modulating systems act to inhibit coagulation activation: – Tissue factor pathway inhibitor (TFPI) rapidly inhibits the TF/FVIIa pathway once activated; – The protein C and S system will inactivate FVa and FVIIIa; and – Antithrombin will inactivate thrombin (FIIa), as well as FXa, FIXa, FXIa, FXIIa.

Normal Hemostasis

X TF VIIa Xa Va TF-Bearing Cell II IIa VIII/vWF VIIIa TF VIIa IX V IXa X II VIIa IX VIIIa Xa IXa Va Activated Platelet IXa VIIIa X Xa II Va Va Platelet

IIa IIa

Reproduced with permission from: Hoffman M et al.

Blood Coagul Fibrinolysis.

1998;9(suppl 1):S61-S65.

Fibrinolysis

• Secondary (normal physiological) fibrinolysis occurs by activation of plasminogen to plasmin by tPA. This happens normally within the clot. • Plasmin degrades fibrin (and fibrinogen) to fibrin degradation products (FDP); its activity is controlled by alpha2-antiplasmin. When fibrin has been cross-linked (by FXIII), small segments, known as D-dimers, can be measured.

• Plasminogen activator inhibitor (PAI-1) inactivates tPA, thereby controlling fibrinolysis.

• Abnormally activated (primary) fibrinolysis can cause or contribute to bleeding. It is most commonly seen after therapy with tPA, streptokinase, and urokinase and can also complicate liver disease, prostate and neurosurgery, CPB, and burns.

• Laboratory clues to possible abnormal fibrinolysis are unexpectedly low fibrinogen and a shortened euglobulin clot lysis time.