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Thrombotic Complications of Central Venous Catheters in Cancer Patients

Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: David J. Kuter, M.D., D.Phil., Hematology/Oncology Unit, Massachusetts General Hospital, 100 Blossom Street, Boston, Massachusetts 02114, USA. Telephone: 617-726-3908; Fax: 617-724-3166; e-mail: kuter.david{at}MGH.harvard.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
After completing this course, the reader will be able to:

1. Describe the mechanism of thrombosis in CVCs.
   
2. Explain the symptoms, signs, and sequelae of CVC thrombosis.
   
3. Discuss the evidence supporting the prophylaxis of CVC thrombosis.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
Central venous catheters (CVCs), such as the tunneled catheters and the totally implanted ports, play a major role in general medicine and oncology. Aside from the complications (pneumothorax, hemorrhage) associated with their initial insertion, all of these CVCs are associated with the long-term risks of infection and thrombosis. Despite routine flushing with heparin or saline, 41% of CVCs result in thrombosis of the blood vessel, and this markedly increases the risk of infection. Only one-third of these clots are symptomatic.

Within days of insertion, almost all CVCs are coated with a fibrin sheath, and within 30 days, most CVC-related thrombi arise. Aside from reducing the function of the catheter, these CVC-related thrombi can cause postphlebitic syndrome in 15%–30% of cases and pulmonary embolism in 11% (only half of which are symptomatic).

Risk factors for CVC thrombosis include the type of malignancy, type of chemotherapy, type of CVC, and locations of insertion site and catheter tip, but not inherited thrombophilic risk factors. Efforts to reduce CVC thrombosis with systemic prophylactic anticoagulation with low-molecular-weight heparin have failed. Low-dose warfarin prophylaxis remains controversial; all studies are flawed, with older studies, but not newer ones, showing benefit.

Currently, less than 10% of patients with CVCs receive any systemic prophylaxis. Although its general use cannot be recommended, low-dose warfarin may be a low-risk treatment in patients with good nutrition and adequate hepatic function. Clearly, additional studies are required to substantiate the prophylactic use of low-dose warfarin. Newer anticoagulant treatments, such as pentasaccharide and direct thrombin inhibitors, need to be explored to address this major medical problem.

Key Words. Thrombosis • Warfarin • Heparin • Catheter • DVT • Low molecular weight heparin

	INTRODUCTION

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
Almost 30 years after the description of the circulatory system by William Harvey (1578–1657) in 1625 [1], efforts began to cannulate the venous system to perform medical therapy. Credit for the first intravenous injection is often given to Christopher Wren (1632–1723) (Fig. 1), who administered various substances to animals via intravenous cannula in 1656 [2–8]. He reported his initial experiment as follows [2]:

View larger version (162K): [in this window] [in a new window]   Figure 1. Sir Christopher Wren (1632–1723). Courtesy of Dr. D. Smith, Boston, MA.

With this description, Wren described the administration of alcoholic substances, as well as opiates and purgatives to animals with their expected effect of somnolence or vomiting.

Wren’s colleagues in Oxford in the middle of the 17th century did subsequent experimentation with venous catheters. Richard Lower (1631–1691) soon used this technique to administer blood transfusions from animals, such as sheep or dogs, into humans [9]. In Germany in 1667, Johann D. Major (1634–1693) and Johann Esholtz (1623–1688) used catheters for the injection of various substances, blood products, and purgatives into the veins of animals and humans [10–12]. Unfortunately, those initial experiments resulted in the occasional death of the animal or human subject, resulting in the loss of interest in venous cannulae and their therapeutic use for some centuries.

Fortunately, in recent years, better devices have been developed for the cannulation of blood vessels and, in the past 30 years, a number of devices has been introduced for the semipermanent cannulation of the central venous system. These allow the administration of alimentation, chemotherapy, and antimicrobial therapy, as well as the withdrawal of blood samples from the central circulation. Currently a wide variety of central venous catheters (CVCs) are commonly used in medicine (Table 1). A number of short-term (1–14 days) devices are routinely used and include percutaneous internal jugular, subclavian, and femoral lines, as well as the peripherally inserted central catheters (PICCs).

	TYPES OF THROMBI ASSOCIATED WITH CVCS

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

Although the time of formation of the fibrin sheath has not been adequately studied, partial data from several studies show that the sheath develops within 24 hours of catheter insertion [13]. Furthermore, detailed studies by quantitative electron microscopy and by quantitative microbiologic testing of these fibrin sheaths over time have shown that they are always colonized by cocci [17–19].

The presence of these sheaths does not predict subsequent deep vein thrombosis (DVT) of the vessel in which the catheter is placed. In one study, only 1 of 16 patients with a fibrin sheath developed thrombosis over a median of 12.5 months [16]. Furthermore, embolization of the fibrin sheath occurs rarely and, given the small amount of embolus, is rarely symptomatic [15].

Intraluminal Thrombosis of CVCs
A very common and usually underreported event is the development of clotting within the lumen of the catheter [20–22]. This usually is uncovered when the catheter fails to allow blood to be withdrawn or fails to allow infusion through a port. The frequency of this event varies widely among different studies. Anderson et al. reported that 40 of 43 patients (93%) had this complication; whereas, in a large study by Schwarz et al., 122 of 923 (13.2%) patients had this, for a frequency of 0.81 events per 1,000 catheter days, comparable with the 0.6 per 1,000 catheter days reported by Ray et al. in 1996 [20–22]. Fortunately, these intraluminal thrombi can be lysed in most situations (80%–95%) with fibrinolytic agents such as urokinase, streptokinase, and tissue plasminogen activator (TPA) [23, 24].

The inability to withdraw blood ("ball valve effect") does not, however, predict the presence of intraluminal thrombosis. This phenomenon is of low specificity in predicting thrombosis of the catheter lumen or the blood vessel in which the catheter resides. In a study by Gould et al., 57% of thrombosed CVCs versus 27% of nonthrombosed CVCs failed to allow blood to be drawn [25]. If one analyzed by venography those CVCs that had problems with blood withdrawal, 58% had thrombosis and 42% did not have thrombosis [26]; nonthrombotic mechanical problems commonly prevent blood flow.

CVC-Related Blood Vessel Thrombosis (DVT)
The major thrombotic complication of CVCs is DVT. These mural thrombi may partially or completely block the blood vessel and, as described in greater detail below, involve 12%–74% of all CVCs. Most (~71%) are asymptomatic. In those that are symptomatic, symptoms include arm/neck/head swelling or pain, headache, numbness of the extremity, erythema of the extremity, phlegmasia, venous distention, and jaw pain.

Table 3 lists the studies in which patients with CVCs developed symptoms and then had clots in the affected blood vessel documented by venogram or ultrasound [22, 25, 27–39]. On average, 12% of all patients with CVCs developed symptomatic thrombi but there was a wide range, from 5%–41% of all CVC insertions. The cause of this wide variability is due in part to the wide variation in catheter type, position, duration of insertion, and the underlying diseases. In addition, there is a lack of uniform standards in reporting this sort of information.

	SEQUELAE OF CVC THROMBOSIS

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
Autopsy Studies
The pathologic effects of CVCs on blood vessels were studied in 74 consecutive autopsies of cancer patients with CVCs in which the cannulated vessel was compared with the contralateral vessel that was not cannulated [17]. Venous pathology (hemorrhage, thrombosis, calcification, ulceration, and inflammation) was found in 49% of the cannulated blood vessels but in only 9% of those that were not cannulated. Furthermore, mural thrombosis was seen in 30% of the cannulated vessels and in only 1% of those not cannulated; in the latter case, the one patient with mural thrombosis and no recent catheter exposure had had a cannula in that blood vessel several months earlier.

Infection of CVCs
Thrombosis is a major risk factor for infection of CVCs. This was first suggested by Press et al. in 1984, who found that bacteremia was much more common in patients with documented CVC thromboses [51]. Subsequent studies have confirmed this. In an autopsy study of patients with CVCs, 7 of 31 (23%) patients with CVCs with clots and 0 of 41 (0%) patients with CVCs without clots documented at autopsy had previously experienced an associated bacteremia [17, 18]. In a separate study, 5 of 28 (18%) patients with CVCs with clots had clinical infections versus 0 of 10 (0%) patients with CVCs without clots [40]. The odds ratio for infection related to thrombosis was 4.1 (confidence interval 1.5–11.4) [32], and prophylactic heparin/vancomycin/ciprofloxacin or heparin/vancomycin flushes resulted in a threefold lower incidence of blood infection compared with heparin alone [52]. This is not a surprising finding, since almost all cannulated blood vessels contain a fibrin sheath that is seeded with adherent cocci [17–19].

Postphlebitic Syndrome
Upon removal of CVCs from thrombosed vessels, the thrombi often persist. In a small study of 30 patients, venography was performed at variable times after the routine removal of CVCs. Nine (30%) patients had total occlusions of the blood vessel. Of these nine, only two had had prior symptoms of thrombosis [53]. Unfortunately, few other studies have looked at the long-term resolution and collateral blood vessel formation in patients with CVC-related thrombosis.

Fifteen to 35% of patients with CVC-related thromboses do develop postphlebitic syndrome (Table 2). Massoure et al. analyzed patients with upper extremity DVT and found that 14 of 40 (35%) developed postphlebitic syndrome [54]. Prandoni et al. found that 4 of 27 (15%) patients with upper extremity DVT developed postphlebitic syndrome [55]. The long-term complications of this syndrome are hard to assess in the cancer population given the, oftentimes, short survival of those affected with CVC-related thrombosis.

Pulmonary Emboli
DVT of the upper extremity has long been considered as being of trivial importance for embolization due to its location and modest size. Nonetheless, symptomatic pulmonary emboli (PE) have been reported in approximately 6% of all patients with upper extremity DVT (Table 2). Most of the patients in those studies had CVCs and most had cancer, but the studies also included some patients who lacked CVCs and some noncancer patients. The patients in the three studies, therefore, are rather heterogeneous, but 2 of 40 (5%), 3 of 22 (14%), and 2 of 63 (3%) patients, respectively, with upper extremity DVT were found to have symptomatic PE [15, 22, 54].

In studies in which ventilation/perfusion (V/Q) scans were performed on all patients with upper extremity DVT irrespective of pulmonary symptoms, the total PE rate of 11% was twice that of the symptomatic PE rate. Although usually not fatal, in four separate studies, 4 of 20 (20%), 13 of 86 (15%), 16 of 237 (7%), and 8 of 27 (30%) patients were found to have significant V/Q mismatches and diagnoses of PE [46, 55–57]. This is comparable with the rate of asymptomatic PE seen in patients with symptomatic lower extremity DVT.

	RISK FACTORS FOR CVC-RELATED THROMBOSIS

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
Patient
The patient risk factors related to CVC thrombosis are multiple. Most have not been studied in a comprehensive fashion, but some can be substantiated by a number of studies, primarily in oncology patients.

The presence of malignancy seems to result in a higher rate of CVC thrombosis than the lack of malignancy. In oncology patients, there is also some suggestion that some types of malignancy may be associated with higher rates of CVC thrombosis. Anderson et al. reported that 45% of patients with adenocarcinoma of the lung developed symptomatic CVC thrombosis, whereas only 9% of those with head and neck cancer developed CVC thrombosis [22]. This may be related to the activation of the coagulation system in these different malignancies, tumor-related changes in blood flow, or levels of tissue factor or tissue factor pathway inhibitor. It is probably related to the generally higher risk for thrombosis that occurs in oncology patients, as discussed elsewhere [58–61].

Most studies show that the inherited thrombophilia risk factors are probably not major predictors of CVC thrombosis. However, one study reported that low antithrombin III levels were associated with a greater risk for thrombosis [42]. Another study found that 32% of patients who had CVC thromboses had diagnoses of a hypercoagulable state; most had elevated anticardiolipin antibody levels, but there was no greater incidence of prothrombin 20210A mutation, Factor V Leiden, protein C deficiency, or protein S deficiency [62]. In a study in children, however, 63% of those with CVC thromboses did have an inherited risk factor, most of whom were compound heterozygotes [36]. In a related study, this higher risk for CVC thrombosis appeared to occur only in children with acute lymphoblastic leukemia [38].

Acquired thrombophilia risks may be more important in causing CVC-related thrombosis but are more difficult to prove. One component of Virchow’s triad is vessel damage. Numerous studies have documented local endothelial cell injury to blood vessels due to chemotherapy or to the CVC itself. Endothelial cell erosion in cannulated blood vessels has been reported [22]. Furthermore, there are lower thrombomodulin/higher plasminogen activator inhibitor (PAI):TPA levels in blood from patients with CVC thromboses than in blood from those without thromboses [53].

Other hematological values, such as the fibrinogen level and platelet count, have been measured in patients with CVC thromboses, but the data are conflicting [35, 41, 63]. It is, perhaps, clearer to say that most CVC thrombi are not related to elevations in fibrinogen or platelet count.

Finally, the type of chemotherapy does appear to be related to the rate of CVC thrombosis. Clotting occurred in 6 of 11 (55%) catheters through which sclerosing chemotherapy was infused, but in only 9 of 29 (31%) infused with nonsclerosing chemotherapy [41].

Device
Major design efforts have been undertaken to develop catheters that minimize trauma to blood vessels and are less thrombogenic. The catheter type and materials have undergone major design changes and continue to evolve. The substitution of silastic or flexible plastic for polyethylene has been a major change, as has the use of different plasticizers.

The position of the catheter in the vascular system is a major determinate of CVC-related thrombosis. Placement of the catheter tip high in the superior vena cava (SVC) results in a higher incidence of thrombosis than when the catheter tip is placed low in the SVC [21, 30, 33, 64, 65]. A possible explanation for this is the greater chance of damage to the blood vessel when the catheter tip is in the higher position rather than in the lower position. In addition, CVCs inserted from the left subclavian vein clotted more commonly than did CVCs inserted from the right subclavian vein [15, 25, 28, 66]. In a recent study, 14 of 16 (87%) left side CVCs versus 49 of 79 (62%) right side CVCs were reported to clot [15].

Finally, the number of catheter lumens is a major predictor of catheter thrombosis. Triple-lumen Hickman catheters failed at three times the rate of double-lumen catheters [33]. Presumably, the mechanism of action for this finding is either a stiffer catheter, more occlusion of the blood vessel, or more trauma to the blood vessel.

Overall, CVCs are a "stress test" of the coagulation system in cancer patients and can precipitate thrombosis due to multiple mechanisms related to the host and/or to the device itself.

	COSTS OF CVC-RELATED THROMBOSIS

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
Loss of function of the CVC due to thrombosis oftentimes leads to the need to replace such ports at an average cost of approximately $5,000. Furthermore, partial obstruction or complete obstruction of the port lumen leads to efforts to clear the thrombosis with fibrinolytic drugs such as recombinant TPA, urokinase, and streptokinase. A typical 1-mg TPA flush costs $27.50, and the nursing time and frustration involved in trying to clear clogged catheters may dramatically increase the cost to open an occluded port. Finally, and difficult to quantify in monetary terms, is the associated patient anxiety, discomfort, and morbidity that comes either from an occluded lumen or from an occluded blood vessel.

This has prompted major efforts to reduce CVC-related thrombosis. These efforts include the use of biomaterials, polymers, and plasticizers of low thrombogenicity. Impregnation of catheters with antithrombotic substances such as heparin-antithrombin III has been studied [67]. Early attempts to impregnate catheters with heparin resulted in rapid leaching from the catheter surface. Recent catheters, however, have a different bonding procedure, which allows the heparin to remain attached longer. In addition, catheter designs have been developed to optimize blood flow around the catheter.

The most common procedure used to reduce CVC-related thrombosis is the routine flushing of catheter ports with unfractionated heparin (UFH) or other substances. Flushing routinely occurs anywhere from once weekly to thrice weekly. Studies have shown that a 50-unit UFH flush is as effective as a 1,000-unit UFH flush [66]. Surprisingly, recent studies show that a simple saline flush is as effective as a 100-unit UFH flush in this regard [68].

The main effort to reduce CVC thrombosis, however, has been the use of low-dose systemic prophylactic anticoagulation therapy with warfarin or heparin, either UFH or low-molecular-weight heparin (LMWH).

	THE USE OF LOW DOSE WARFARIN TO PREVENT CVC-RELATED THROMBOSIS

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
The majority of studies suggest that low-dose warfarin is effective in preventing CVC-related thrombosis. In a 1990 randomized, open, prospective study of oncology patients with Port-a-Cath^® catheters, Bern et al. compared the administration of 1 mg/day of warfarin with no warfarin for 90 days [41]. All patients underwent a venogram at the time of thrombotic symptoms or at 90 days. Total thrombosis rates determined by venographic methods were 37.5% (15/40) for patients without warfarin and only 9.5% (4/42) for patients given warfarin. Symptomatic thrombi occurred in 13 of 40 (32.5%) patients without warfarin and in only 4 of 42 (9.5%) patients given warfarin (p = 0.001).

Boraks et al. obtained similar results in a nonrandomized study in which patients received 1 mg/day warfarin prophylactically and were assessed for clinically symptomatic (but venographically verified) thrombi [27]. In those patients treated prophylactically with warfarin, symptomatic thrombi occurred in 5 of 108 (5%), compared with 15 of 115 (13%) patients in an historical control group that did not receive warfarin (p = 0.03). Furthermore, the time to thrombosis was a median of 72 days in those who received warfarin but was only 16 days in those who did not receive warfarin.

Subsequently, a number of other studies have been performed to assess the utility of low-dose warfarin prophylaxis. Three have shown a probable benefit of low-dose warfarin, which was of borderline statistical significance given the small number of patients studied. In a prospective, nonrandomized study, 1 mg/day warfarin resulted in 0 of 52 (0%) patients developing CVC clots, versus 4 of 65 (6%) patients not receiving warfarin developing CVC clots (p = 0.06) [28]. In a retrospective, nonrandomized study, symptomatic CVC thrombi developed in 4 of 96 (4%) patients treated with 1 mg/day warfarin and in 24 of 209 (11%) patients who received no warfarin (p = 0.04) [37]. Of 949 patients with Quinton-type catheters who received 1 mg/day warfarin, the clinical thrombosis rate was 5.1%, and clinical complications were not apparent [64].

However, two recent studies showed no benefit of low-dose warfarin. In a nonrandomized study of 160 patients with melanoma or renal cell cancer being treated with interleukin-2, 1 mg/day warfarin did not reduce the CVC thrombosis rate [32]. In a nonblinded study of patients with hematological malignancies, Heaton et al. randomized 88 patients with double-lumen subclavian Hickman CVCs to receive either 1 mg/day warfarin or no therapy [39]. After 90 days, there was no difference in the rates of clinically significant thrombi for those treated with warfarin and those not treated: 8 of 45 (18%) patients treated with warfarin and 5 of 43 (12%) patients not treated had clinically evident thrombi.

	THE USE OF HEPARIN TO PREVENT CVC-RELATED THROMBOSIS

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
In a randomized, open-label, prospective study by Monreal et al., oncology patients with Port-a-Cath^® catheters received 2,500 units/day dalteparin or no therapy and underwent a venogram at the time of symptoms or at 90 days [46]. Of the 16 patients who received dalteparin, only one developed a thrombosis, and this thrombosis was symptomatic. Of the 13 patients who received no treatment, eight (62%) developed thromboses, and of those, seven were symptomatic. Because of the highly statistically significant difference in outcome (p = 0.002), the study was closed early to accrual.

However, similar studies done with larger numbers of patients failed to show any difference in CVC thrombosis rates. Pucheu et al. prospectively compared patients given 2,500 anti-Xa units/day dalteparin subcutaneously with untreated historical controls using ultrasonography done at months 1, 3, and 12 to screen for thrombosis [47]. Documented thrombi occurred in only 3 of 46 (6.5%) patients who received dalteparin, and all were without symptoms. In the historical control group, 11 of 72 (15%) patients developed documented clots, not a statistically significant difference. In the largest randomized, blinded, placebo-controlled study ever performed to evaluate CVC prophylaxis in cancer patients, 194 patients received placebo injections and 294 received 5,000 IU/day dalteparin s.c. for 16 weeks [48]. Clinical thrombosis occurred in 5.3% of placebo- and 5.8% of dalteparin-treated patients, not a statistically significant difference. There was no difference in infection rates.

The only other relevant data on the use of heparin to prevent CVC-related thrombosis come from a meta-analysis of 14 studies by Randolph et al. [69]. Only two of those studies were with oncology patients, and the rest were with patients who had a wide range of catheters placed for various indications and procedures. What is striking about this meta-analysis is that various prophylactic heparin doses, ranging from standard UFH to LMWH, decreased the relative rate of thrombosis to 0.43, the relative rate of bacterial colonization to 0.18, and the relative rate of bacteremia to 0.26. The lower rates of infectious complications again confirm the association of thrombosis with infection.

	USE OF ANTICOAGULATION OF CVCS IN CLINICAL PRACTICE

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
The sixth (2000) guidelines from the American College of Chest Physicians (ACCP) state that 1 mg/day warfarin or LMWH administered once a day are valid prophylactic options for CVC thrombosis [70–72]. Despite these recommendations, less than 10% of patients with CVCs receive systemic prophylaxis [28]. There are multiple reasons for this. Chief among these is the lack of convincing data from the studies mentioned above due to the small number of patients studied, the high dropout rate, and the fact that most were not placebo controlled. There is also continuing debate about the use of venographic end points instead of clinical symptom end points in many of these studies. Certainly, all of these studies are also subject to criticism over the wide range of types of tumors, patients, and CVCs.

Aside from the technical concerns about these studies, there is a genuine concern about using warfarin in potentially thrombocytopenic or anorectic chemotherapy patients. Ten percent of the patients in the study by Bern et al. [41] developed a prothrombin time (PT) greater than 15 seconds and required holding of their warfarin, and 5% of the patients in the study by Boraks et al. [27] developed a PT greater than 20 seconds and required holding of their warfarin. Ten of 45 patients in the study by Heaton et al. [39] had an international normalized ratio >1.5 and required small doses of vitamin K; there was no related bleeding. This brings into question whether there is a need for monitoring patients who are on low-dose warfarin.

The heparins also have some disadvantages. There is the major inconvenience of daily subcutaneous injections of standard heparin or LMWH. Also, in the asthenic or elderly cancer patient with a reduced glomerular filtration rate, even low prophylactic doses of LMWH may accumulate and cause bleeding. This effect is amplified in patients with reduced renal function due to disease or chemotherapy.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 
Catheter-related thrombosis is a common clinical problem that may affect nearly half of all cancer patients with CVCs. Although the thrombosis rate is high, only a third of the thrombosed CVCs become symptomatic. Nonetheless, CVC thrombosis can result in clinical symptoms, the loss of catheter function, a higher rate of infection, postphlebitic syndrome of the upper extremity, pulmonary embolus, and greater costs.

Prophylactic flushes with UFH or saline are the standard of care to maintain CVC patency but are inadequate to prevent blood vessel thrombosis. The benefit of systemic prophylaxis with LMWH or warfarin has not been well established. Despite considerable evidence for an effect of reducing the CVC thrombosis rate in nononcology patients, the failure of a large, recent study of LMWH does not support prophylaxis with LMWH in cancer patients. Low-dose warfarin prophylaxis remains controversial. Although many older studies support the use of low-dose warfarin, most recent studies do not. This controversy probably reflects the inadequate number of patients in the clinical trials, but may also be due to better catheter care or superior catheter design. The routine use of warfarin cannot be justified. However, in patients with adequate nutrition and hepatic function, the risks of this approach seem minimal.

Certainly, larger, placebo-controlled studies of low-dose warfarin prophylaxis in patients with CVCs are warranted. But it may be more fruitful to consider instead the use of newer factor Xa inhibitors, such as pentasaccharide [73–76], or direct thrombin inhibitors, such as ximelegatran [77–81]. The former appears to be a more effective prophylaxis of venous thromboembolism and is associated with less bleeding than LMWH. The latter may be a more stable oral anticoagulant than warfarin by not being affected by diet or antibiotics. Given its common occurrence, further efforts to understand and prevent CVC thrombosis are of importance. These should include not only studies of anticoagulant efficacy but also studies to determine the risk factors for CVC thrombosis, the timing of onset, and the duration of therapy. Given the fact that fibrin sheaths and occlusive or nonocclusive vessel thrombi seem to occur early on after catheter placement, early prophylaxis is probably warranted, but the duration of therapy has not been studied.

	REFERENCES

Top Learning Objectives Abstract Introduction Types of Thrombi Associated... Sequelae of CVC Thrombosis Risk Factors for CVC-Related... Costs of CVC-Related Thrombosis The Use of Low... The Use of Heparin... Use of Anticoagulation of... Conclusions References

 

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