Venous thromboembolism

Venous thromboembolism Microchapters
Patient Information Deep vein thrombosis Pulmonary embolism
Overview
Classification
Epidemiology
Risk Factors
Diagnosis
Treatment Deep Vein Thrombosis Pulmonary Embolism
Prevention

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]:Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [3]

Classification

Venous thromboembolism (VTE) may be classified into:

• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE)

The following table further classifies DVT and PE:

Classification of Venous thromboembolism
Clinical diagnosis	Sub-classification	Comments
Deep vein thrombosis	Upper extremity	Uncommon and accounts for 1-5 % of all DVT Most likely due to: Central venous catheter Cardiac pacemaker Implantable cardioverter defibrillator Effort thrombosis (Paget–Schroetter disease) Cancer
	Lower extremity	Proximal: Popliteal veins Femoral veins Iliac veins Isolated distal: Calf veins (Peroneal, soleal, posterior tibial, gastrocnemial)
Pulmonary embolism (PE)	Massive PE (High risk)	Sustained hypotension (systolic blood pressure <90 mm Hg), not due to arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction, and either lasting for at least 15 minutes or necessitating the administration of inotropes OR Pulselessness OR Persistent profound bradycardia (heart rate < 40 bpm) plus findings of shock
	Sub-massive PE (Intermediate risk PE)	Right ventricular dysfunction OR myocardial necrosis AND Absence of systemic hypotension (systolic blood pressure >90 mm Hg)
	Low risk PE	Absence of hypotension, shock, right ventricular dysfunctionand myocardial necrosis

Epidemiology

Incidence

• The incidence of VTE increases with age, ranging from less than 5 cases per 100,000 people in childhood to 500 cases per 100,000 people in the elderly.
• Subjects who are more than 65 years of age are at three times higher risk for VTE compared to those who are 45-54 years old.
• In the United States, the annual incidence of VTE is estimated to be approximately 100 per 100,000 persons.

Age

• The incidence of VTE increases with age, ranging from less than 5 cases per 100,000 people in childhood to 500 cases per 100,000 people in the elderly.
• Subjects who are more than 65 years of age are at three times higher risk for VTE compared to those who are 45-54 years old.

Gender

• Studies about differences in the incidence of VTE by gender have mixed results.
  • Some reported a higher incidence of DVT among young females
  • Some reported it higher among either older females
  • Some reported it higher in men.
• In addition, the risk for DVT was reported to consistently increase with age across both genders.

Race

• There is a significant difference in the incidence of DVT as it relates to race. African Americans characteristically have the highest incidence of DVT while Caucasians rank as the second highest incidence of DVT.
• When compared to African Americans and Caucasians, the incidence of DVT is noted to be two to four times lower in Hispanics and Asian-Pacific Islanders.
• Lower incidence of thrombosis in non-Caucasians may be related to a lower prevalence of disorders like Factor V Leiden or Prothrombin 20210A mutation.

Hospitalization for VTE

• During 2007–2009, an estimated annual average of 547,596 hospitalizations had a diagnosis of VTE for adults aged ≥18 years. Estimates for DVT and PE diagnoses were not mutually exclusive. An estimated annual average of 348,558 adult hospitalizations had a diagnosis of DVT, and 277,549 adult hospitalizations had a diagnosis of PE. An estimated annual average of 78,511 adult hospitalizations (14% of overall VTE hospitalizations) had diagnoses of both DVT and PE.

• The estimated average annual number of hospitalizations with VTE was successively greater among older age groups: 54,034 for persons aged 18–39 years; 143,354 for persons aged 40–59 years; and 350,208 for persons aged ≥60 years. The estimated average annual number of hospitalizations with VTE was comparable for men (250,973) and women (296,623).

• Shown below is an image depicting the estimated average annual number of hospitalization with a diagnosis of DVT, PE, or VTE by age and sex.

Estimated average annual number of hospitalizations with a diagnosis of deep thrombosis (DVT), pulmonary embolism (PE), or venous thromboembolism (VTE), by patient sex and age group — National Hospital Discharge Survey, United States, 2007–2009 - Source:CDC

• The average annual rates of hospitalizations with a discharge diagnosis of DVT, PE, or VTE among adults were 152, 121, and 239 per 100,000 population, respectively. For VTE, the average annual rates were 60 per 100,000 population aged 18–39 years, 143 for persons aged 40–49 years, 200 for persons aged 50–59 years, 391 for persons aged 60–69 years, 727 for persons aged 70–79 years, and 1,134 for persons aged ≥80 years. The rates of hospitalization were similar for men and women, and the point estimates increased for both sexes by age.

• On average, 28,726 hospitalized adults with a VTE diagnosis died each year. Of these patients, an average of 13,164 had a DVT diagnosis and 19,297 had a PE diagnosis; 3,735 had both DVT and PE diagnoses.

Recurrence of VTE

• One-third (about 33%) of people with VTE will have a recurrence within 10 years.

• The risk of recurrence of VTE in patients diagnosed with first-time VTE is estimated to be around 7-8 percent per year during an average follow up period of 2.2 years of subsequent observation of 265 patients.

• Among patients with a first episode of VTE, the risk of recurrence of VTE is particularly elevated in the first 6 to 12 months following the first episode of VTE. The risk of recurrent VTE remains up to 10 years, with a estimated cumulative incidence of first overall VTE recurrence of 30 %. Predictors for recurrence of VTE include malignancy, neurological diseases, and paresis.

• In recent years, the increase in thrombosis incidence may be related to improved diagnostic modalities and increased awareness by clinicians.

Complications of VTE

• Estimates suggest that 60,000-100,000 Americans die of VTE, 10 to 30% of which will die within one month of diagnosis.

• Among people who have had a DVT, one-half will have long-term complications (post-thrombotic syndrome) such as swelling, pain, discoloration, and scaling in the affected limb.

Risk Factors

Shown below is a list of predisposing factors for VTE. The risk factors are classified as moderate or weak depending on how strongly they predispose for a VTE.

Moderate risk factors	Weak risk factors
❑ Chemotherapy ❑ Obesity ❑ Chronic heart failure ❑ Respiratory failure ❑ Hormone replacement therapy ❑ Cancer ❑ Oral contraceptive pills ❑ Stroke ❑ Pregnancy ❑ Postpartum ❑ Prior history of VTE ❑ Thrombophilia ❑ Hospitalization	❑ Advanced age ❑ Laparoscopic surgery ❑ Prepartum ❑ Varicose veins

Risk factors of VTE may be categorized in to modifiable, non-modifiable, temporary and other risk factors.

Modifiable Risk Factors	Non-Modifiable Risk Factors	Temporary Risk Factors	Other Risk Factors
❑ Modifiable risk factors are reversible based upon lifestyle/behavior modification. ❑ Obesity is defined as a body-mass index (BMI) above 30 kg/m2. ❑ Smoking: Smoking significantly increases the risk of DVT, particularly among women who are taking oral contraceptive pills as well as among obese people. ❑ Use of oral contraceptives ❑ Hyperhomocysteinemia: Hyperhomocysteinemia can be reduced with vitamin B supplementation.	❑ Advanced age ❑ Heart failure ❑ Thrombophilia or hypercoagulable state ❑ Polycythemia vera ❑ Factor V Leiden ❑ Prothrombin G20210A mutation ❑ Protein C deficiency ❑ Protein S deficiency ❑ Activated protein C resistance ❑ Antithrombin III deficiency ❑ Factor VIII mutation ❑ Antiphospholipid syndrome ❑ Heparin induced thrombocytopenia ❑ Nephrotic syndrome ❑ Paroxysmal nocturnal hemoglobinuria	❑ Pregnancy and the peri-partum period ❑ Active cancer ❑ Central venous catheterization	❑ Other possible factors associated with VTE include: ❑ Nutrition low in fish ❑ Psychological stress ❑ Cardiovascular risk factors such as diabetes and hypercholesterolemia

Diagnosis

Suspected pulmonary embolism

D-dimer

Negative

Positive

Stop

CXR

Ultrasound If signs of DVT present

Normal PE unlikely with positive D-dimer or PE likely

Abnormal PE unlikely with positive D-dimer or PE likely

V/Q scan

CTPA

Nnormal

Non diagnostic

High probability

PE present

PE absent

Stop

Treat

Treat

Stop

PE unlikely

PE likely

Serial ultrasound

CTPA or serial ultrasound

Prevention

Patient population	Sub-population	Scoring criteria for risk assessment					Major predisposing risk factors and their score	Prophylaxis recommendations
		Padua score (Score≥ 4: High risk for VTE Score< 4: Low risk for VTE)	IMPROVE score (0 0.5% 1 1.0% 2 1.7% 3 3.1% 4 5.4% 5-8 11%)	IMPROVE bleeding risk score (Score ≥7: Elevated risk of bleeding Score <7: Not elevated risk of bleeding)	IMPROVE Associative score (Score 0-1: Low risk for VTE Score 2-3: Intermediate risk for VTE Score 4-10: Hight risk for VTE)	Caprini score (Score 0-1: Low risk of VTE Score 2: Moderate of VTE Score 3-4: High risk of VTE Score ≥ 5: Highest risk for VTE)
Non-surgical patients	Acutely ill patients	✔	✔	✔	-	-	IMPROVE: Active cancer: 3 Previous VTE: 3 Decreased mobility: 3 Thrombophilia: 3 Previous trauma or surgery within that last month: 2 Age≥ 70: 1 Heart and/or respiratory failure: 1 Ischemic stroke or acute myocardial infarction: 1 Acute rheumatologic disorder and/or acute infection: 1 Obesity: 1 Hormonal therapy	Hospitalized medical patients: Increased risk of thrombosis Anticoagulant thromboprophylaxis with low-molecular-weight heparin [LMWH], low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux Low risk of thrombosis Use of pharmacological prophylaxis or mechanical prophylaxis is not recommended Bleeding or at high risk of bleeding Anticoagulant thromboprophylaxis is not recommended Increased risk of thrombosis who are bleeding or at high risk for major bleeding Optimal use of mechanical thromboprophylaxis with graduated compression stockings (GCS) or intermittent pneumatic compression (IPC) Note: When bleeding risk decreases, and if risk persist, pharmacologic thromboprophylaxis be substituted for mechanical thromboprophylaxis. Who receive an initial course of thromboprophylaxis extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay is not recommended.
							IMPROVE bleeding risk: Active gastric or duodenal ulcer: 4.5 Prior bleeding within the last 3 months: 4 Thrombocytopenia (<50x109/L): 4 Age ≥ 85 years: 3.5 Liver failure (INR>1.5): 2.5 Severe kidney failure (GFR< 30 mL/min/m2): 2.5 Admission to ICU or CCU: 2.5 Central venous catheter: 2 Rheumatic disease: 2 Active malignancy: 2 Age: 40-84 years: 1.5 Male: 1 Moderate kidney failure (GFR: 30-59 mL/min/m2): 1
	Cancer in outpatient						Does the patient have a solid tumor  AND  Additional risk factors for VTE? Previous VTE Hormonal therapy Immobilization Angiogenesis inhibitors Thalidomide Lenalidomide
	Chronically immobilized patients	-	-	-	-	-	-	Not indicated
	Long travel						Prior VTE episode  Recent trauma  Recent surgery  Active cancer  Advanced age  Immobility Severe obesity  Estrogen intake Thrombophilia	Frequent ambulation Calf muscle excercise Sitting in an isle seat Below knee compression stockings (15-30 mm Hg pressure at ankle)
	Asymptomatic thrombophilia	-	-	-	-	-	-	Not indicated
Surgical patients	Orthopedic surgery patients
	General and abdominal pelvic surgeries	-	-	-	-	✔	Caprini: 5 points: Stroke (in the previous month)  Fracture of the hip, pelvis, or leg  Elective arthroplasty  Acute spinal cord injury (in the previous month) 3 points:  Age≥ 75 years  Prior episodes of VTE  Positive family history for VTE  Prothrombin 20210 A  Factor V Leiden  Lupus anticoagulants  Anticardiolipin antibodies High homocysteine in the blood  Heparin induced thrombocytopenia  Other congenital or acquired thrombophilia 2 points:  Age: 61-74 years  Arthroscopic surgery  Laparoscopylasting more than 45 minutes  General surgerylasting more than 45 minutes  Cancer  Plaster cast  Bed bound for more than 72 hours  Central venous access 1 point: Age 41-60 years  BMI > 25 Kg/m2  Minor surgery  Edema in the lower extremities  Varicose veins  Pregnancy  Post-partum  Oral contraceptive Hormonal therapy  Unexplained or recurrent abortion  Sepsis (in the previous month)  Serious lung disease such as pneumonia (in the previous month)  Abnormal pulmonary function test  Acute myocardial infarction Congestive heart failure (in the previous month)  Bed rest  Inflammatory bowel disease	Low risk of VTE: Early ambulation No mechanical VTE prophylaxis  No pharmacological VTE prophylaxis Mechanical VTE prophylaxis  (Intermittent pneumatic compression is preferred) Moderate risk of VTE: If no bleeding risk: LMWH  OR  LDUH  OR  Mechanical VTE prophylaxis  (Intermittent pneumatic compression is preferred) If high bleeding risk: Mechanical VTE prophylaxis  (Intermittent pneumatic compressionis preferred) High risk of VTE: If no bleeding risk: LMWH  OR  LDUH  OR  Mechanical VTE prophylaxis  Extended treatment with LMWH for 4 weeks  PLUS mechanical VTE prophylaxis (in case of cancer) If high risk of bleeding: Mechanical VTE prophylaxis  (Intermittent pneumatic compression is preferred)
	Cardiac surgery	-	-	-	-	✔		Non-hemorrhagic post-op complications: LDUH  OR  LMWH PLUS Mechanical VTE prophylaxis Un-complicated post-op period: Mechanical VTE prophylaxis  (Intermittent pneumatic compression is preferred)
	Thoracic surgery	-	-	-	-	✔
	Craniotomy	-	-	-	-	✔
	Spinal surgery	-	-	-	-	✔
	Trauma	-	-	-	-	✔

Non-surgical patients

(i) Prevention in acutely ill hospitalized patients

Risk assessment in acutely ill patients

The following scoring systems can be used to assess the risk of VTE, based on risk factors:

(a) Padua prediction score for VTE

Shown below is a table depicting Padua predictive score for VTE among hospitalized medical patients. The interpretation of the score is as follows:

• Score≥ 4: High risk for VTE
• Score< 4: Low risk for VTE

Variable	Score
Active cancer	3
Previous VTE	3
Decreased mobility	3
Thrombophilia	3
Previous trauma or surgery within that last month	2
Age≥ 70	1
Heart and/or respiratory failure	1
Ischemic stroke or acute myocardial infarction	1
Acute rheumatologic disorder and/or acute infection	1
Obesity	1
Hormonal therapy	1

(b) IMPROVE predictive score for VTE

Calculation of the IMPROVE predictive score

Variable	Score
Prior episode of VTE	3
Thrombophilia	3
Malignancy	1
Age more than 60 years	1

Interpretation of the IMPROVE predictive score

Score	Predicted VTE risk through 3 months
0	0.5%
1	1.0%
2	1.7%
3	3.1%
4	5.4%
5-8	11%

(ii) Preventive approach in acutely ill hospitalized patients based on risk assessment

Abbreviations: LDUH: low dose unfractionated heparin; LMWH: low molecular weight heparin; VTE: Venous thromboembolism

What is the risk of thrombosis in the acutely ill patient?

High

Low

Is the patient bleeding or at high risk of bleeding?

No VTE prophylaxis

Yes

No

Mechanical VTE prophylaxis For the period of immobilization or hospital stay only ❑ Graduated compression stocking ❑ Intermittent pneumatic compression

Pharmacological VTE prophylaxis For the period of immobilization or hospital stay only ❑ LMWH ❑ LDUH, BID ❑ LDUH, TID ❑ Fondaparinux

Did the bleeding or bleeding risk subside AND the patient is still at increased risk of thrombosis?

Yes

No

❑ Substitute mechanical prophylaxis by pharmacological prophylaxis

❑ Continue mechanical prophylaxis

(iii) Prevention in critically ill hospitalized patients

Risk assessment in critically ill patients

(a) IMPROVE bleeding risk score

Shown below is a table depicting the IMPROVE risk score for bleeding among hospitalized medical patients. The scores can be interpreted as such:

• Score ≥7: Elevated risk of bleeding
• Score <7: Not elevated risk of bleeding

Variable	Score
Active gastric or duodenal ulcer	4.5
Prior bleeding within the last 3 months	4
Thrombocytopenia (<50x109/L)	4
Age ≥ 85 years	3.5
Liver failure (INR>1.5)	2.5
Severe kidney failure (GFR< 30 mL/min/m2)	2.5
Admission to ICU or CCU	2.5
Central venous catheter	2
Rheumatic disease	2
Active malignancy	2
Age: 40-84 years	1.5
Male	1
Moderate kidney failure (GFR: 30-59 mL/min/m2)	1

(iv) Preventive approach in critically ill hospitalized patients

Abbreviations: LDUH: low dose unfractionated heparin; LMWH: low molecular weight heparin; VTE: Venous thromboembolism

Is the critically ill patient bleeding or at risk for major bleeding?

Yes

No

Mechanical VTE prophylaxis ❑ Graduated compression stocking ❑ Intermittent pneumatic compression

Pharmacological VTE prophylaxis ❑ LMWH ❑ LDUH

Did the bleeding or bleeding risk subside?

Yes

No

❑ Substitute mechanical prophylaxis by pharmacological prophylaxis

❑ Continue mechanical prophylaxis

Shown below is an algorithm depicting VTE prophylaxis among cancer patients. Note that, cancer patients with indwelling central venous catheters do not require VTE prophylaxis with neither low molecular weight heparin, low dose unfractionated heparin or vitamin K antagonists.

Abbreviations: LDUH: low dose unfractionated heparin; LMWH: low molecular weight heparin; VTE: Venous thromboembolism

❑ Does the patient have a solid tumor AND ❑ Additional risk factors for VTE? ❑ Previous VTE ❑ Hormonal therapy ❑ Immobilization ❑ Angiogenesis inhibitors ❑ Thalidomide ❑ Lenalidomide

Yes

No

Pharmacological VTE prophylaxis ❑ LMWH ❑ LDUH

❑ No VTE prophylaxis