Venous Thromboembolism

This chapter presents the current practices for the prevention, diagnosis, and treatment of venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). The major focus is on prevention, because VTE is considered the leading cause of preventable deaths in hospitalized patients (1).

I. Risk Factors

A. Major Surgery

Major surgery (i.e., performed under general or spinal anesthesia that lasts longer than 30 minutes) is the leading source of VTE in hospitalized patients (2,3,4). Con-tributing factors include vascular injury and thromboplastin release during the surgical procedure.
The highest incidence of postoperative VTE occurs after major procedures involving the hip and knee (3,4).

B. Major Trauma

Victims of major trauma have a greater than 50% chance of developing VTE, and pulmonary embolism is the third leading cause of death in those who survive the first day (3). Contributing factors in trauma-related VTE are vascular injury and thromboplastin release from damaged tissues (similar to surgery-related VTE).
Traumatic injuries with the highest risk of VTE include spinal cord injuries and fractures of the spine, hip and pelvis (3,4).

C. Acute Medical Illness

Hospitalization for acute medical illness is associated with an 8-fold increase in the risk of VTE (5).
Conditions with the highest risk of VTE include acute stroke, neuromuscular weakness syndromes, severe sepsis, cancer, and right-sided heart failure.
The risk of VTE is lower in acute medical illness than in major surgery or trauma (2,3,4), but the majority (70–80%) of deaths from VTE occur in medical patients (3).

D. ICU-Related Risks

ICU-related risk factors for VTE include prolonged mechanical ventilation (>48 hrs), central venous cath-eters, vasopressor infusions, drug-induced paralysis, and prolonged immobility.
ICU patients often have one of the high-risk conditions mentioned previously, in addition to the ICU-related risk factors for VTE; as a result, all ICU patients are considered to have a high risk of VTE (3), and are therefore candidates for thromboprophylaxis (see next).

II. Thromboprophylaxis

Prophylaxis for VTE is a standard measure for all ICU patients (except those that are fully anticoagulated), and is started on the day of admission. Appropriate preventive measures can vary in different high-risk conditions, as indicated in Table 4.1.

Table 4.1 Thromboprophylaxis for Selected Conditions

Conditions	Regimens
Acute Medical Illness	LDUH or LMWH
Major Abdominal Surgery	(LDUH or LMWH) + (GCS or IPC)
Thoracic Surgery	(LDUH or LMWH) + (GCS or IPC)
Cardiac Surgery with Complications	(LDUH or LMWH) + IPC
Craniotomy	IPC
Hip or Knee Surgery	LMWH
Major Trauma	LDUH or LMWH or IPC
Head or Spinal Cord Injury	(LDUH or LMWH) + IPC
Any of the above + active bleeding or high risk of bleeding	IPC
From Reference 3. Abbreviations: LDUH = low-dose unfractionated heparin; LMWH = low-molecular weight heparin; GCS = graded compression stockings; IPC = intermittent pneumatic compression.

A. Unfractionated Heparin

Standard or unfractionated heparin is a heterogeneous mix of mucopolysaccharide molecules that vary in size and anticoagulant activity.

1. Actions

Heparin is an indirect-acting drug that must bind to a cofactor (antithrombin III or AT) to produce an anticoagulant
effect. The heparin-AT complex inactivates several coagulation factors, and inactivation of factor IIa (antithrombin effect) is 10 times more sensitive than the other anticoagulant reactions (6).
Heparin also binds to a specific protein on platelets to form an antigenic complex that induces the formation of IgG antibodies. These antibodies can cross-react with the platelet binding site and activate platelets, which promotes thrombosis and a consumptive thrombocytopenia. This is the mechanism for heparin-induced thrombocytopenia, which is described in more detail in Chapter 12.

2. Prophylactic Dosing

The potent antithrombin activity of the heparin-AT complex allows low doses of heparin to inhibit thrombogenesis without producing systemic anticoagulation.

The standard regimen of low-dose unfractionated heparin (LDUH) is 5000 units by subcutaneous injection every 12 hours. There is a more frequent dosing regimen (5000 units every 8 hours), but there is no evidence of superiority over twice daily dosing (2,7).
Studies in ICU patients (8) and postoperative patients (9) have shown a 50–60% reduction in the incidence of leg vein thrombosis with LDUH.
The standard LDUH regimen may be less effective in obese patients because of the increased volume of drug distribution in obesity. The recommended dosing for LDUH in obesity is included in Table 4.2 (10).

3. Complications

The risk of major bleeding with LDUH is <1% (7), and anticoagulation monitoring is not necessary.
Heparin-induced thrombocytopenia has been reported in 2.6% of patients receiving LDUH (11).

4. Indications

LDUH is suitable for thromboprophylaxis in all high-risk conditions except hip and knee surgery (see Table 4.1) (3).

Table 4.2 Anticoagulant Regimens for Thromboprophylaxis

Unfractionated Heparin
	Usual Dose:	5000 Units SC every 12 hrs
	High-Risk Dose:	5000 Units SC every 8 hrs
	Obesity:	5000 Units SC every 8 hrs (BMI<50)
		7500 Units SC every 8 hrs (BMI≥50)
Enoxaparin (LMWH)
	Usual Dose:	40 mg SC once daily
	High-Risk Dose:	30 mg SC twice daily
	Obesity:	0.5 mg/kg SC once daily (BMI>40)
	Renal Failure:	30 mg once daily (for CrCL<30 mL/min)
Dalteparin (LMWH)
	Usual Dose:	2500 Units SC once daily
	High-Risk Dose:	5000 Units SC once daily
	Renal Failure:	No recommended dose adjustment
From References 2, 10, 13,14,15, and 16. CrCL = creatinine clearance, SC = subcutaneous.

B. Low-Molecular-Weight Heparin

Low-molecular-weight heparin (LMWH) is produced by enzymatic cleavage of heparin molecules, which produces smaller molecules of more uniform size. This results in more potent and predictable anticoagulation than occurs with unfractionated heparin. LMWH must still bind to anti-thrombin III, and the major anticoagulant reaction is inactivation of Factor Xa.

1. Advantages

LMWH has the following advantages over unfraction-ated heparin:

A more predictable dose-response relationship, and no routine monitoring of anticoagulant activity (5).
Less frequent dosing due to a longer duration of action.
A much lower risk of heparin-induced thrombocytopenia (0.2% for LMWH vs. 2.6% for LDUH) (11).

2. Disadvantages

The major disadvantage of LMWH is its clearance by the kidneys, which creates the need for dosage adjustments in patients with renal failure. However, the tendency to accumulate in renal failure varies with individual LMWH preparations (see later).

3. Relative Efficacy

LMWH is equivalent to LDUH for all high-risk conditions encountered in the ICU (11), and is superior to LDUH for prophylaxis of VTE in hip and knee surgery (3,4).

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