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The Oncologist, Vol. 9, No. 5, 561-570, September 2004; doi:10.1634/theoncologist.9-5-561
© 2004 AlphaMed Press

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Management of Bleeding in Patients with Advanced Cancer

Jose Pereira, Tien Phan

Department of Oncology, University of Calgary, Calgary, Alberta, Canada

Correspondence: Jose Pereira, MBChB, DA, CCFP, Palliative Care Office, Room 710, South Tower, Foothills Medical Centre, 1403-29th Avenue NW, Calgary, Alberta, T2N 2T9, Canada. Telephone: 403-944-2307; Fax: 403-270-9652; e-mail: pereiraj{at}ucalgary.ca


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Management: General Measures
 Management: Local Interventions...
 Management: Systemic...
 End-of-Life Considerations
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. List at least four local hemostatic agents and dressings for controlling localized bleeding in a patient with cancer.
  2. List at least four systemic therapies for controlling bleeding in a patient with advanced cancer.
  3. Describe a decision-making process related to managing bleeding in an end-of-life cancer patient.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Management: General Measures
 Management: Local Interventions...
 Management: Systemic...
 End-of-Life Considerations
 Conclusion
 References
 
Bleeding occurs in up to 10% of patients with advanced cancer. It can present in many different ways. This article provides a qualitative review of treatment options available to manage visible bleeding. Local modalities, such as hemostatic agents and dressings, radiotherapy, endoscopic ligation and coagulation, and transcutaneous arterial embolization, are reviewed in the context of advanced cancer, as are systemic treatments such as vitamin K, vasopressin/desmopressin, octreotide/somatostatin, antifibrinolytic agents (tranexamic acid and aminocaproic acid), and blood products. Considerations at the end of life are described.

Key Words. Bleeding • Hemorrhaging • Cancer • Palliative


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Management: General Measures
 Management: Local Interventions...
 Management: Systemic...
 End-of-Life Considerations
 Conclusion
 References
 
Hemorrhaging occurs in approximately 6%–10% of patients with advanced cancer [1]. When visible, it can be particularly distressing to patients and their caregivers [2, 3]. In some patients, it may be the immediate cause of death. This article focuses on hemorrhaging that is visible, as opposed to occult bleeding. It reviews treatment options in the context of advanced cancer.

Etiology and Clinical Presentation
Bleeding may result from local vessel damage and invasion or from systemic processes such as disseminated intravascular coagulopathy (DIC) or abnormalities in platelet functioning and number. The underlying causes of these abnormalities are varied and include liver failure, medications such as anticoagulants, chemotherapy, radiotherapy, surgery, and the cancer itself [4]. Occasionally, concurrent diseases, such as idiopathic thrombocytopenia, may be responsible. Hemorrhaging may manifest in a variety of ways, including hematemesis, hematochezia, melena, hemoptysis, hematuria, epistaxis, vaginal bleeding, or ulcerated skin lesions [4]. It may also present as echymoses, petechiae, or bruising. Hemorrhage may occur as an acute catastrophic event, episodic major bleeds, or ongoing low-volume oozing. These characteristics provide clues as to the underlying cause and guide management.


   MANAGEMENT: GENERAL MEASURES
Top
 Learning Objectives
 Abstract
 Introduction
 Management: General Measures
Management: Local Interventions...
 Management: Systemic...
 End-of-Life Considerations
 Conclusion
 References
 
Treatment needs to be individualized and depends on several factors, including the underlying cause(s), the likelihood of reversing or controlling the underlying etiology, and the burden-to-benefit ratio of the treatment, all in the context of the patient’s overall disease burden, life expectancy, and goals of care. If the patient’s life expectancy and overall quality of life warrants it, then management of an acute bleeding episode consists of general resuscitative measures, such as volume and fluid replacement, and specific measures to stop the bleeding. On the other hand, if the patient’s goals of care are palliative, then management may include measures to stop the bleeding without full resuscitative measures. Comfort measures only may be most appropriate for end-stage patients.

Management should focus on identifying the underlying cause(s) and, where possible, controlling the bleeding. A comprehensive history and examination is self-evident. A review of concurrent medications and other illnesses may be helpful in identifying the etiology or contributing factors, such as the concurrent use of nonsteroidal anti-inflammatory drugs, which may exacerbate or precipitate bleeding through their actions on the gastrointestinal tract and platelet functioning [5]. The burdens and risks of prophylactic anticoagulation may outweigh the benefits in patients with very advanced disease. Even when treated with appropriate therapeutic doses of anticoagulants, the incidence of bleeding complications remains higher in patients with advanced cancer than in those with earlier-stage disease [6]. Investigations may be helpful. Full blood counts and clotting profiles may reveal systemic problems, while angiography or endoscopic studies may identify the site of bleeding. Goals of care should be explored. General measures may include applying pressure over the wound, and protecting the bleeding area from trauma and from the remaining infected granulation tissue [7].

Patients at high risk for bleeding should be identified, and preventative measures should be taken before a crisis occurs. Episodic, low-volume bleeding (e.g., hemoptysis) may herald larger, catastrophic hemorrhages. Caregivers of patients at risk for major bleeds ought to be informed and prepared for such an event. However, this should be done sensitively so as not to invoke too much fear.


   MANAGEMENT: LOCAL INTERVENTIONS (Table 1Go)
Top
 Learning Objectives
 Abstract
 Introduction
 Management: General Measures
 Management: Local Interventions...
Management: Systemic...
 End-of-Life Considerations
 Conclusion
 References
 
Packing, Hemostatic Agents, and Dressings
Packing can be used with or without pressure to achieve hemostasis when bleeding originates in the nose [8, 9], vagina [10, 11], or rectum [12, 13]. Surgical swabs of varying sizes may be used. These can be coated with chemicals that facilitate hemostasis; for example, acetone in vaginal packing [10, 14] and cocaine in nasal packing. If possible, the frequency of dressing changes should be reduced, and nonadherent dressings should be used. Specially designed catheters with inflatable balloons may be used to control severe epistaxis. Foley catheters have also been used for this purpose. Such measures are temporary, since prolonged pressure may cause local ischemia.


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  		Table 1. Management of bleeding in patients with advanced cancer: local measures
 
A variety of agents and dressings, mostly designed for surgical procedures, has been reported to be of benefit for exterior, topical use in patients with advanced cancer [15]. The evidence to support this, however, is largely based on case reports. The high costs of some of these products may also be prohibitively expensive for regular usage. Thromboplastin, a natural blood-clotting agent obtained from bovine plasma, is available as a powder for topical application [16]. Systemic injection or absorption can lead to serious clotting. Absorbable gelatin is available as a sterile sponge-like dressing or sterile powder [17–19]. It can be applied dry or saturated with sterile sodium solution and is absorbed within 4–6 weeks. When applied, fibrin is deposited in the interstices of the foam, resulting in swelling of the sponge, thereby forming a large synthetic clot. When applied to nasal, rectal, or vaginal mucosa, it liquifies within 2–5 days. Other bioabsorbable topical hemostatic agents include fibrin sealants [20, 21] and oxidized cellulose [13]. Fibrin sealants are derived from human plasma and reproduce the final steps in the coagulation pathway to form a clot. They are used in a broad range of surgical procedures to assist hemostasis, including cardiovascular, hepatic, and splenic surgery. Some are impregnated with clotting factor XIII and a solution of thrombin and calcium chloride [9]. Collagen is another agent with inherent hemostatic activity. When applied as a bovine-derived mesh it comes into contact with blood, provokes the clotting cascade, and forms a clot [11, 12]. Alternatively, oxidized cellulose compounds and highly absorbent alginate dressings, derived from seaweed, are available for topical use [12, 14].

Vasoconstricting or cauterizing agents provide an alternative modality to managing localized, capillary-based bleeding. Epinephrine may be used, but its liberal use is discouraged [12]. Prostaglandins E2 and F2 have been used to control intractable hemorrhagic cystitis [22]. Bladder spasms, however, may limit their utility. Silver nitrate, an inorganic silver salt, induces a chemical cauterization and has been used to control bladder hemorrhages and epistaxis [12, 23]. Formalin, 2% or 4%, acts as a chemical cautery and has been used to control intractable rectal [24–26] and bladder [22] hemorrhaging. In one case series, topical formalin controlled bleeding in 49 of 55 patients (89%) with radiation-induced rectal bleeding. Aluminum astringents, such as 1% alum, can be delivered by continuous bladder irrigation [22]. Bladder spasms are controllable with antispasmodic medications. Sucralfate has shown some benefit in controlling cancer-related gastrointestinal bleeding and cutaneous oozing [15]. In the latter, a gel is prepared by dispersing one 1-g tablet of sucralfate in 5 ml of water soluble gel (e.g., K-Y® Jelly; McNeil-PPC, Inc.; Skillman, NJ) and is applied once or twice daily [15].

Radiotherapy
External-beam radiotherapy has been shown to decrease hemoptysis caused by lung cancer, with control occurring in up to 80% of patients [27–30]. The optimal dose and fractionation remain controversial. Hypofractionation appears to be as effective as multiple fractions (often 10 or more daily fractions) [31–33]. A single fraction of 10 Gy has been shown to be as effective as multiple fractions in patients with hemoptysis due to lung cancer [29]. Total doses of either 20 Gy (via multiple fractions) or 8 Gy (via hypofractionation) are often suggested.

Radiotherapy should also be considered for bleeding from cancerous lesions of the vagina [29, 34], skin [35], rectum, and bladder [29, 36, 37]. External-beam radiotherapy may be successful in controlling bleeding in up to 85% of cases of rectal bleeding and 60% of cases of hematuria from bladder cancer [29, 36]. One study found that a hypofractionated regimen (17 Gy in two fractions over 3 days) for patients with symptoms from advanced bladder cancer was as well tolerated as and less distressing to patients than a regimen of 12 fractions given over 26 days (45 Gy) [36].

Upper gastrointestinal hemorrhaging from malignant processes is less amenable to radiotherapy. While radiotherapy can be useful in controlling bleeding from head and neck cancers, many of these patients have already received maximal doses of radiotherapy when they present with bleeding, thereby excluding further radiation [38]. Single or reduced fraction regimens appear to be as effective as multiple fractions in controlling bleeding [29].

Endoscopy
Endoscopy-based treatments have, for a long time, been used in managing bleeding from upper gastrointestinal varices, particularly after systemic therapies such as vasopressin or somatostatin analogues have failed. This treatment method has been reported to be superior to balloon tamponade [39]. It involves the injection of sclerosing agents into the varices or ligation of the vessels.

Endoscopic interventions have also been proven to be useful for managing cancer-related hemorrhaging of the upper gastrointestinal tract [40, 41], lungs [42–44], and bladder [45]. Ethanol [46, 47], hyperosmotic saline epinephrine [41], gelatin solutions [48], and sodium tetradecyl sulfate [41] are injected into the site of bleeding. Alternatively, the vessels may be cauterized by heat [47, 49], or by polar [47, 49] or laser coagulation [50, 51].

Akhtar and colleagues reported on a series of 48 consecutive patients with esophagogastric cancer who underwent endoscopic argon-beam plasma coagulation for symptom and disease control [40]. Bleeding was well controlled in three of the five patients treated for bleeding. Hemostasis was achieved in approximately 70%–90% [41, 49] of cases treated for upper gastrointestinal bleeds. Complications occurred in 5%–15% of cases and included worsening of the bleeding and perforation of the tract. Cystoscopic-assisted cautery by either heat or laser probes has been used in the treatment of hematuria in patients with bladder cancer [45]. Its role is mainly for patients in whom continuous bladder irrigation and lavage have failed. Under direct vision, the urologist can inspect the bladder, identify the source of bleeding, and fulgurate the bleeding vessel or tumor [22, 29, 45]. In the case of hemoptysis, bronchoscopy allows for ice-cold saline lavages [44] and/or the use of balloon tamponade [44, 52], laser phototherapy [44], or topical application of thrombin or fibrinogen at the site of bleeding [44]. Endoscopic procedures have been used to control bleeds from the lower gastrointestinal tract, although these may be more challenging [53, 54]. Colonoscopic techniques vary and include bipolar electrocoagulation, heater probe, argon [55], and Nd:YAG lasers [54].

Interventional Radiology
Transcutaneous arterial embolization (TAE) may be useful in well-selected patients. The procedure is often performed via a femoral or axillary approach under local anesthetic and is generally well tolerated, requiring only mild sedation [56]. The blood vessel supplying the affected site is first identified by arteriography. This is followed by the insertion of a hemostatic agent, usually in the form of a coil. Limiting factors include the presence of a bleeding disorder and the availability of the appropriate expertise. Embolization is restricted to areas where the blood vessels are accessible by the catheter and where embolization of the blood vessel does not result in ischemia of key organs. Benefits have been reported in patients with cancers involving the head and neck [57–59], pelvis [60–64], lung [43, 44, 61, 65], liver [66], and gastrointestinal tract [67]. As with other treatment options in this setting, the majority of the evidence supporting this modality relies on case reports.

Nabi and team evaluated the efficacy of bilateral internal iliac artery embolization with permanent coils to control intractable hemorrhage from advanced pelvic urological malignancies [60]. Bleeding was controlled in all but one of six patients at the first attempt. The nonresponder was successfully treated at a second attempt. Complications were minor and included nausea, vomiting, and fever for a few days. At 22-month follow-ups, no patient had experienced bleeding recurrence.

TAE has been used to manage carotid artery rupture in cancer patients. Bates and Shamsham reported on a patient whose episodes of profuse (but self-limited) carotid hemorrhage were successfully controlled by an endovascular technique that combined placement of a flexible self-expanding stent-graft to protect the common and internal carotid artery with selective coil embolization of the affected external carotid artery branches [57]. Sakakibara and colleagues used an endoluminal balloon to control bleeding in three patients prior to undergoing surgical ligation of the arteries [58].

Transhepatic arterioembolization was used to control bleeding in five patients with inoperable hepatocellular cancer who presented with gastrointestinal bleeding from a variety of sources (esophageal varices or direct invasion of the duodenum, transverse colon, or stomach) [67]. Recordare and colleagues described four patients who underwent TAE to control spontaneous rupture of hepatocellular carcinoma [66]. Patients lived for 3–62 months following the procedure. A quality-of-life analysis was not reported. Wu and colleagues suggested that acute upper gastrointestinal bleeding is a potential complication following TAE in patients with hepatocellular cancer [68]. Thirty-one of 208 patients who underwent TAE in their service experienced upper gastrointestinal bleeding after the procedure. However, given that gastric or duodenal ulcers were found in 21 of these cases, Mallory-Weiss syndrome was found in three cases, and esophageal varices were found in two cases, the bleeding was likely the result of comorbidities and complications of the cancer rather than the treatment itself. Notwithstanding, the importance of meticulous case selection needs to be underscored.

Surgery
Surgery may be appropriate for a small group of well-selected patients who have failed conservative measures and who are deemed fit for surgery. Surgery usually consists of ligation of larger vessels [69] or the removal of bleeding tissue [70]. Two surgical approaches have been described for the management of carotid artery rupture: resection with reconstruction and ligation of the artery. Witz et al. reported on three patients with head and neck cancers who presented with acute or imminent carotid artery rupture [69]. Those patients successfully underwent ligation of the artery with no neurological sequelae. Yegappan and colleagues reported on prospectively collected data from 55 women who presented with bleeding from radiation proctitis [26]. Bleeding in six patients who did not respond to topical formalin application was controlled with surgery.


   MANAGEMENT: SYSTEMIC INTERVENTIONS (Table 2Go)
Top
 Learning Objectives
 Abstract
 Introduction
 Management: General Measures
 Management: Local Interventions...
 Management: Systemic...
End-of-Life Considerations
 Conclusion
 References
 
Vitamin K (Phytonadione, Menadiol)
Vitamin K is necessary for the hepatic production of a number of clotting factors, including factors II, VII, IX, and X. Liver disease, insufficient intake of leafy green vegetables (a source of vitamin K), small bowel disease or resection, as well as intrahepatic and extrahepatic biliary obstruction can lead to deficiencies in the clotting factors. Coagulation screening studies reveal a prolonged prothrombin time or international normalized ratio (INR) and partial thromboplastin time with normal thrombin time, fibrinogen, and serum fibrin-fibrinogen degradation products.


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  		Table 2. Management of bleeding in patients with advanced cancer: systemic interventions
 
Vitamin K treatment may be helpful if either a derangement of these factors or excessive warfarin therapy is implicated in bleeding in a patient with advanced cancer. Doses of 2.5–10 mg are recommended, depending on the severity of the situation. The jury is not out on which route of administration is best. Whitling et al. evaluated four different routes of vitamin K administration for reversing excessive anticoagulation: high-dose intravenous (1–10 mg), low-dose intravenous (≤0.5 mg), subcutaneous (1–10 mg), and oral (2.5–5 mg) [71]. Anticoagulation was achieved in all four groups. Although the high-dose intravenous method was the most effective at lowering INR levels to <5, overcorrection occurred more frequently with that method. Byrd and colleagues reported the effective and safe reversal of excess warfarin anticoagulation using subcutaneous phytonadione at doses of 1 mg for INR levels >8 but <14 (group 1) and 2 mg for levels >14 (group 2) [72]. The mean INR reductions in group 1 and group 2 after 24 hours were 49% and 67%, respectively. By 48 hours, INR levels were below 4.5 in both groups. No hemorrhagic or thrombotic complications were reported. The subcutaneous administration of phytonadione did not correct the INR as rapidly or as effectively as intravenous administration in a randomized trial [73]. Higher doses of subcutaneous phytonadione were recommended for cases where full anticoagulation reversal is required. Nee et al. suggested that subcutaneous administration along with modification of the warfarin dosing is acceptable, since all patients in their study achieved safe levels of anticoagulation within 72 hours of subcutaneous administration [74]. A recent retrospective study of 105 patients reported that only two (1.9%) patients who received intravenous phytonadione experienced adverse reactions [75]. These anaphylactoid reactions manifest as dyspnea, chest tightness, facial flushing, nausea, and, in severe cases, cyanosis, loss of consciousness, hypotension, and possibly death. However, review of the literature reveals that these are rare occurrences [76].

A randomized, double-blind, placebo-controlled study comparing oral phytonadione (2.5 mg) plus the omission of further warfarin therapy with omission alone for reversing excessive warfarin anticoagulation in 30 asymptomatic patients (INR levels of 6–10) found that the addition of oral phytonadione reduced the time to achieve a normal INR by 1 day [77]. Adverse effects did not differ between the two groups. Fondevila et al., on the other hand, reported no advantage of adding oral phytonadione (1 mg) to a regimen of simply discontinuing the warfarin in patients with excessive oral anticoagulation [78]. Oral menadiol (20 mg daily for 3 days) was found to be as effective as intravenous phytonadione (1 mg daily) in normalizing INR levels in 26 patients with cholestasis [79]. Therefore, when possible, vitamin K should be given by the subcutaneous or oral routes. When intravenous administration is considered unavoidable, the drug should be injected slowly, probably not exceeding 1 mg per minute. If, in 6–8 hours after parenteral administration, the INR is not satisfactorily lowered, the dose may be repeated. The role of prophylactic vitamin K administration for asymptomatic patients with elevated INR levels from liver involvement is unclear.

Vasopressin/Desmopressin
Vasopressin is a posterior pituitary hormone that causes splanchnic arteriolar constriction and reduction in portal pressure when injected intravenously or intra-arterially [80]. This method has been extensively used in managing variceal bleeding related to portal gastropathy [81, 82]. Its use has also been reported in oncology. In a controlled trial, vasopressin therapy stopped bleeding in about half the patients with active upper-malignancy-related gastrointestinal bleeding [83]. Doses range from 0.1–0.4 mg by continuous infusion. Vasoconstrictor effects on the myocardial, mesenteric, and cerebral circulation are the most notable potential side effects.

Somatostatin Analogues
Octreotide, an analogue of somatostatin, has been used to manage upper gastrointestinal bleeds [84]. Somatostatin reduces splanchnic flow and pressure via venous dilatation, thereby reducing portal pressure and portal venous flow. A starting dose of 50–100 µg twice daily is recommended [85]. The dose may be titrated, as needed, up to 600 µg per day. An alternative regime consists of a bolus of 50 µg given intravenously or subcutaneously, followed by a continuous subcutaneous or intravenous infusion of 50 µg/hour for 48 hours [86]. At low doses, very few side effects are reported, but at doses greater than 100 µg/hour, nausea, abdominal discomfort, and diarrhea may occur.

D’Amico et al., in a meta-analysis, concluded that emergency sclerotherapy should be used only after vasoactive drugs (octreotide, somatostatin, vasopressin, terlipressin), which are effective in approximately 83% of cases, have failed [82]. A more recent meta-analysis reported that ligation appears to be the most effective treatment for bleeding varices (effective in a mean of 91% of times, 95% confidence interval [CI] = 82%–96%): more effective than vasoconstrictive treatment (vasopressin/terlipressin, which were effective 69% of times, 95% CI = 62%–83%), vasoactive treatment (somatostatin/octreotide, 76%; 95% CI = 68%–83%), and sclerotherapy (81%; 95% CI = 72%–88%) [81]. The difference between ligation and sclerotherapy was not significant.

Except for preventing perioperative bleeding in pancreatic cancer resections [87], there are no reports related to the use of octreotide/somatostatin in controlling bleeding in cancer patients.

Antifibrinolytic Agents
Tranexamic acid (TA) and aminocaproic acid (EACA) are synthetic antifibrinolytic agents that block the binding sites of plasminogen, thereby inhibiting the conversion of plasminogen into plasmin by tissue plasminogen activator [88]. The end result is a decreased lysis of fibrin clots [89, 90]. Tranexamic acid is approximately 10 times more potent than EACA in vitro [91, 92]. Fibrinolytic inhibitors have been used successfully in a variety of nononcologic settings. These include the control of bleeding following dental extractions [93], subarachnoid hemorrhages [94], and gastrointestinal bleeds [95]. Several case reports and a few studies have been published that suggest a role for these agents in the oncology setting [88, 96–101].

TA and EACA have been administered orally and intravenously. The suggested intravenous dose of TA is 10 mg/kg three to four times a day, infused over about 1 hour. The suggested intravenous dose of EACA is 4–5 g in 250 ml over the first hour then 1 g/hour in 50 ml administered continuously for 8 hours, or until the bleeding is controlled [92]. The most common adverse effects are gastrointestinal in nature (nausea, vomiting, and diarrhea) and occur in 25% of cases [91]. Adverse effects appear to be dose dependent. Thromboembolism is uncommon [101, 102]. These antifibriolytics can also be applied topically, rectally, or by intrapleural instillation [88, 97, 103].

A systematic review of randomized trials found that hemostatic medications (TA, EACA, desmopressin, and aprotinin) used for reducing surgery-related bleeding have limited or contradictory evidence of efficacy [104]. Large controlled studies of these drugs are lacking in the cancer setting.

Blood Products
The frequency and severity of hemorrhages increases as platelet count declines below 20,000/µl [105]. The risk of severe bleeding rises only when the count is below 5–10,000/µl. Patients with chronic autoimmune thrombocytopenia can tolerate platelet counts in the 5–10,000/µl range for long periods of time. Platelet transfusion in the setting of advanced cancer should be on a case-by-case basis with the aim of controlling symptoms [106]. A single unit of platelets should increase the platelet count in an average adult by approximately 6,000–10,000/µl, assuming normal splenic pooling. Four to six units are usually required to control bleeding. There is no scientific basis for the old 20,000/µl cutoff [107–110]. The short half-life of platelets, which decreases further as their counts drop, limits their usefulness in severely thrombocytopenic patients with end-stage disease. Lassauniere and colleagues have proposed criteria for platelet transfusions in patients with advanced hematologic malignancies [106]. These criteria include continuous bleeding of the mouth or gums, epistaxis, extensive and painful hematomas, severe headaches, or disturbed vision of recent onset, as well as continuous bleeding through the gastrointestinal, gynecological, or urinary systems.

The issue of whether or not to continue platelet transfusions in thrombocytopenic patients with end-stage disease poses an ethical dilemma. While ongoing transfusions may be futile, patients and families may perceive the cessation of transfusions as withdrawal of life-sustaining therapy. Sensitive and empathic discussions among patients, their families, and the attending physician and health team are essential to explore their expectations, fears, and concerns and to engage in advanced end-of-life planning while ensuring ongoing support and commitment to providing optimal comfort care.

Fresh frozen plasma is reserved for a very select group of patients with life expectancies greater than days to weeks. These include: A) patients with specific deficiencies in certain coagulation factors; B) patients in whom the effects of warfarin need to be reversed urgently; C) patients who require urgent invasive interventions such as thoracenteses or surgery; and D) when appropriate, the treatment of DIC. Similarly, packed red cell transfusions are indicated when anemia resulting from blood loss causes or aggravates symptoms such as fatigue and dyspnea. Guidelines for red blood transfusions in palliative patients have been published elsewhere [111, 112].


   END-OF-LIFE CONSIDERATIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Management: General Measures
 Management: Local Interventions...
 Management: Systemic...
 End-of-Life Considerations
Conclusion
 References
 
The goals of care in a patient in the terminal phases of cancer should be comfort. Invasive treatments may present more burden than benefit in these patients, and comfort without invasive procedures takes precedence. In some cases, it is unclear as to whether or not a local or systemic measure will be of benefit. Time-limited or therapeutic trials (e.g., whether or not a platelet transfusion or an antifibrinolytic agent will provide benefit) may be warranted in select circumstances.

When a terminally ill patient is identified as being at risk for a major hemorrhage, family members and caregivers need to be sensitively informed and prepared, since these events can be extremely distressing. Using dark towels to absorb blood, applying pressure to the site of hemorrhaging, and placing patients in the lateral position (in the event of hematemesis or hemoptysis) are simple empowering measures. A rapid-acting sedative should be available for sedation. Midazolam, 2.5 mg or 5 mg intravenously or subcutaneously, serves this purpose well [1, 2]. If necessary, it can be repeated after 10–15 minutes. Orders for a sedative in case of such an emergency should be entered. Families/caregivers should be instructed on how to administer the medication subcutaneously. An indwelling subcutaneous butterfly facilitates administration. Families should be informed about whom to call in case of such an emergency. When patients have expressed a wish for comfort measures only, it would be inappropriate to call 911.

Anticoagulants should be reviewed, and the benefits versus burdens of continuing with these treatments should be considered. Maintaining therapeutic INR levels in terminally ill patients taking warfarin can be challenging and may require a switch to a low-molecular-weight heparin if the benefits of continuing anticoagulation outweigh the risks and burdens [113, 114]. The pharmacokinetics of these drugs are more predictable, their interactions with other drugs are less, they are not affected by liver dysfunction, and they require much less monitoring, negating the need for regular blood tests in these patients [113, 115].


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Management: General Measures
 Management: Local Interventions...
 Management: Systemic...
 End-of-Life Considerations
 Conclusion
References
 
Bleeding in patients with advanced cancer can be caused by a variety of underlying processes and presents clinically in many different ways, from chronic, low-volume bleeding to acute episodes of major hemorrhaging. Identifying the underlying cause(s) is an important first step in managing it. Whether the bleeding originates from capillaries or from larger vessels will affect the treatment plan. Several local modalities are available to manage localized bleeding. These include topical hemostatic agents and dressings, radiotherapy, endoscopic procedures, and TAE or balloon placement through interventional radiology. The use of interventional radiology is increasing. Systemic treatments are also available, particularly for more generalized bleeding or oozing. The majority of these treatments are supported only by case reports and series in the setting of advanced cancer. Comparative and controlled trials are lacking in this patient population. Patients at risk for major hemorrhages should be identified, and their families and caregivers should be prepared. End-of-life decision making should be based on comfort and the optimization of quality of life.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Management: General Measures
 Management: Local Interventions...
 Management: Systemic...
 End-of-Life Considerations
 Conclusion
 References
 

  1. Pereira J, Mancini I, Bruera E. The management of bleeding in patients with advanced cancer. In: Portenoy RK, Bruera E, eds. Topics in Palliative Care, Volume 4. New York: Oxford University Press, 2000:163–183.
  2. Gagnon B, Mancini I, Pereira J et al. Palliative management of bleeding events in advanced cancer patients. J Palliat Care 1998;14:50–54.
  3. Hoskin P, Makin W. The role of surgical and radiological intervention in palliation. In: Oncology for Palliative Medicine. Oxford, UK: Oxford University Press, 1998:229–234.
  4. Dutcher JP. Hematologic abnormalities in patients with nonhematologic malignancies. Hematol Oncol Clin North Am 1987;1:281–299.[Medline]
  5. Schafer AI. Effects of nonsteroidal anti-inflammatory therapy on platelets. Am J Med 1999;106:25S–36S.[CrossRef][Medline]
  6. Hutten BA, Prins MH, Gent M et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078–3083.[Abstract/Free Full Text]
  7. Jamjian MC. Bleeding problems in palliative care patients. Evidence based symptom control in palliative care. In: Lipman AG, Jackson KC, Tyler LS, eds. Systemic Reviews and Validated Clinical Practice Guidelines for 15 Common Problems in Patients with Life Limiting Disease. Binghamton, NY: The Haworth Press Inc., 2000:37–46.
  8. Pringle MB, Beasley P, Brightwell AP. The use of Merocel nasal packs in the treatment of epistaxis. J Laryngol Otol 1996;110:543–546.[Medline]
  9. Tisseel Kit VH. Compendium of Pharmaceuticals and Specialties. Ottawa, Canada: Canadian Pharmacists Association, 1996;31:1479–1480.
  10. Patsner B. Topical acetone for control of life-threatening vaginal hemorrhage from recurrent vaginal gynaecological cancer. Eur J Gynaecol Oncol 1993;1433–1435.
  11. Sirlak M, Eryilmaz S, Yazicioglu L et al. Comparative study of microfibrillar collagen hemostat (Colgel) and oxidized cellulose (Surgicel) in high transfusion-risk cardiac surgery. J Thorac Cardiovasc Surg 2003;126:666–670.[Abstract/Free Full Text]
  12. Atkinson LJ, Fortunato NH, eds. Hemostasis and blood loss replacement. In: Operating Room Technique, Eighth Edition. St. Louis, MO: Mosby, 1996:469–489.
  13. Schenk WG 3rd, Burks SG, Gagne PJ et al. Fibrin sealant improves hemostasis in peripheral vascular surgery: a randomized prospective trial. Ann Surg 2003;237:871–876.[CrossRef][Medline]
  14. Thomas S. Alginate dressings in surgery and wound management: Part 2. Wound Care 2000;9:115–119.
  15. Woodruff R. Haematological problems. In: Woodruff R, ed. Palliative Medicine: Symptomatic and Supportive Care for Patients with Advanced Cancer and AIDS. Melbourne, Australia: Aperula Pty Ltd., 1993:228–252.
  16. Thrombostat. Compendium of Pharmaceuticals and Specialties. Ottawa, Canada: Canadian Pharmacists Association, 1997;32:1587.
  17. Gall RM, Witterick IJ, Shargill NS et al. Control of bleeding in endoscopic sinus surgery: use of a novel gelatin-based hemostatic agent. J Otolaryngol 2002;31:271–274.[Medline]
  18. Weaver FA, Hood DB, Zatina M et al.. Gelatin-thrombin-based hemostatic sealant for intraoperative bleeding in vascular surgery. Ann Vasc Surg 2002;16:286–293.[CrossRef][Medline]
  19. Harris WH, Crothers OD, Moyen BJ et al. Topical hemostatic agents for bone bleeding in humans. A quantitative comparison of gelatin paste, gelatin sponge plus bovine thrombin, and microfibrillar collagen. J Bone Joint Surg Am 1978;60:454–456.[Abstract/Free Full Text]
  20. Shinkwin CA, Beasley N, Simo R et al. Evaluation of surgicel Nu-knit, Merocel and Vasolene gauze nasal packs: a randomized trial. Rhinology 1996;34:41–43.[Medline]
  21. Mankad PS, Codispoti M. The role of fibrin sealants in hemostasis. Am J Surg 2001;182(suppl 2):21S–28S.[CrossRef][Medline]
  22. Russo P. Urologic emergencies. In: Devita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Philadelphia, PA: JB Lippincott Co., 1993:2159–2160.
  23. Vijan SR, Keating MA, Althausen AF. Ureteral stenosis after silver nitrate instillation in the treatment of essential hematuria. J Urol 1988;139:1015–1016.[Medline]
  24. Roche B, Chautems R, Marti MC. Application of formaldehyde for treatment of hemorrhagic radiation-induced proctitis. World J Surg 1996;20:1092–1094; discussion 1094–1095.[CrossRef][Medline]
  25. Biswal BM, Lal P, Rath GK et al. Intrarectal formalin application, an effective treatment for grade III haemorrhagic radiation proctitis. Radiother Oncol 1995;35:212–215.[CrossRef][Medline]
  26. Yegappan M, Ho YH, Nyam D et al. The surgical management of colorectal complications from irradiation for carcinoma of the cervix. Ann Acad Med Singapore 1998;27:627–630.[Medline]
  27. Brundage MD, Bezjak A, Dixon P et al. The role of palliative thoracic radiotherapy in non-small cell lung cancer. Can J Oncol 1996;6(suppl 1):25–32.
  28. A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Medical Research Council Lung Cancer Working Party. Br J Cancer 1992;65:934–941.[Medline]
  29. Hoskin PJ. Radiotherapy in symptom management. In: Doyle D, Hanks GWC, Macdonald N, eds. Second Edition. New York: Oxford University Press, 1998:278–280.
  30. Langendijk JA, ten Velde GP, Aaronson NK et al. Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 2000;47:149–155.[CrossRef][Medline]
  31. Rees GJ, Devrell CE, Barley VL et al. Palliative radiotherapy for lung cancer: two versus five fractions. Clin Oncol (R Coll Radiol) 1997;9:90–95.
  32. Stevens MJ, Begbie SD. Hypofractionated irradiation for inoperable non-small cell lung cancer. Australas Radiol 1995;39:265–270.[Medline]
  33. Sundstrom S, Bremnes RM, Aasebo U et al. Hypofractionated palliative radiotherapy (17Gy/2fractions) is comparable with standard fractionation in advanced non-small cell lung cancer. Results from a national phase III trial. J Clin Oncol 2004;5:801–810.
  34. Biswal BM, Lal P, Rath GK et al. Hemostatic radiotherapy in carcinoma of the uterine cervix. Int J Gynaecol Obstet 1995;50:281–285.[CrossRef][Medline]
  35. Miller CM, O’Neill A, Mortimer PS. Skin problems in palliative care: nursing aspects. In: Doyle D, Hanks GWC, eds. Oxford Textbook of Palliative Medicine. New York: Oxford University Press, 1993:395–407.
  36. Srinivasan V, Brown CH, Turner AG. A comparison of two radiotherapy regimens for the treatment of symptoms from advanced bladder cancer. Clin Oncol (R Coll Radiol) 1994;6:11–13.
  37. Ferris FD, Bezjak A, Rosenthal SG. The palliative uses of radiation therapy in surgical oncology patients. Surg Oncol Clin North Am 2001;10:185–201.[Medline]
  38. MacDougall RH, Munro AJ, Wilson JA. Palliation in head and neck cancer. In: Doyle D, Hanks GWC, eds. Oxford Textbook of Palliative Medicine. New York: Oxford University Press, 1993:422–433.
  39. Burnett DA, Rikkers LF. Nonoperative emergency treatment of variceal hemorrhage. Surg Clin North Am 1990;70:291–306.[Medline]
  40. Akhtar K, Byrne JP, Bancewicz J et al. Argon beam plasma coagulation in the management of cancers of the esophagus and stomach. Surg Endosc 2000;14:1127–1130.[CrossRef][Medline]
  41. Loftus EV, Alexander GL, Ahlquist DA et al. Endoscopic treatment of major bleeding from advanced gastroduodenal malignant lesions. Mayo Clin Proc 1994;69:736–740.[Medline]
  42. Knott-Craig CJ, Oostuizen JG, Rossouw G et al. Management and prognosis of massive hemoptysis: recent experience with 120 patients. J Thorac Cardiovasc Surg 1993;105:394–397.[Abstract]
  43. Kvale PA, Simoff M, Prakash UB. Lung cancer. Palliative care. Chest 2003;123(suppl 1):284S–311S.
  44. Patel U, Pattison CW, Raphael M. Management of massive haemoptysis. Br J Hosp Med 1994;52:74, 76–78.[Medline]
  45. MacKinnon KJ, Norman RW. Genitourinary disorders in palliative medicine. In: Doyle D, Hanks GWC, eds. Oxford Textbook of Palliative Medicine. New York: Oxford University Press, 1993:415–422.
  46. Loscos JM, Calvo E, Alvarez-Sala JL et al. Treatment of dysphagia and massive hemorrhage in esophageal carcinoma by ethanol injection. Endoscopy 1993;25:544.
  47. Gupta PK, Fleischer DE. Nonvariceal upper gastrointestinal bleeding. Med Clin North Am 1993;77:973–992.[Medline]
  48. Tajika M, Kato T, Magaki M et al. Endoscopic injection of gelatin solution for severe hemorrhagic gastric cancer. Gastrointest Endosc 1996;43:247–250.[CrossRef][Medline]
  49. Savides TJ, Jensen DM, Cohen J et al. Severe upper gastrointestinal tumor bleeding: endoscopic findings, treatment, and outcome. Endoscopy 1996;28:244–248.[Medline]
  50. Suzuki H, Miho O, Watanabe Y et al. Endoscopic laser therapy in the curative and palliative treatment of upper gastrointestinal cancer. World J Surg 1989;13:158–164.[CrossRef][Medline]
  51. Mathus-Vliegen EMH, Tytgat GN. Analysis of failures and complications of neodymium:YAG laser photocoagulation in gastrointestinal tract tumors: a retrospective survey of 18 years’ experience. Endoscopy 1990;22:17–23.
  52. Kato R, Sawafuji M, Kawamura M et al. Massive hemoptysis successfully treated by modified bronchoscopic balloon tamponade technique. Chest 1996;109:842–843.[Abstract/Free Full Text]
  53. Bono MJ. Lower gastrointestinal tract bleeding. Emerg Med Clin North Am 1996;14:547–556.[CrossRef][Medline]
  54. Schulze S, Lyng KM. Palliation of rectosigmoid neoplasms with Nd:YAG laser treatment. Dis Colon Rectum 1994;37:882–884.[CrossRef][Medline]
  55. Schrock TR. Colonoscopic diagnosis and treatment of lower gastrointestinal bleeding. Surg Clin North Am 1989;69:1309–1325.[Medline]
  56. Broadley KE, Kurowska A, Dick R et al. The role of embolization in palliative care. Palliat Med 1995;9:331–335.[Abstract/Free Full Text]
  57. Bates MC, Shamsham FM. Endovascular management of impending carotid rupture in a patient with advanced head and neck cancer. J Endovasc Ther 2003;10:54–57.[CrossRef][Medline]
  58. Sakakibara Y, Kuramoto K, Jikuya T et al. An approach for acute disruption of large arteries in patients with advanced cervical cancer: endoluminal balloon occlusion technique. Ann Surg 1998;227:134–137.[CrossRef][Medline]
  59. Morrissey DD, Andersen PE, Nesbit GM et al. Endovascular management of hemorrhage in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 1997;123:15–19.[Abstract/Free Full Text]
  60. Nabi G, Sheikh N, Greene D et al. Therapeutic transcatheter arterial embolization in the management of intractable haemorrhage from pelvic urological malignancies: preliminary experience and long-term follow-up. BJU Int 2003;92:245–247.[CrossRef][Medline]
  61. Wells I. Internal iliac artery embolization in the management of pelvic bleeding. Clin Radiol 1996;51:825–827.[CrossRef][Medline]
  62. Yamashita Y, Harada M, Yamamoto H et al. Transcatheter arterial embolization of obstetric and gynaecological bleeding: efficacy and clinical outcome. Br J Radiol 1994;67:530–534.[Abstract/Free Full Text]
  63. Hays MC, Wilson NM, Page A et al. Selective embolization of bladder tumours. Br J Urol 1996;78:311–312.[Medline]
  64. Jenkins CN, McIvor J. Survival after embolization of the internal iliac arteries in ten patients with severe haematuria due to recurrent pelvic carcinoma. Clin Radiol 1996;51:865–868.[CrossRef][Medline]
  65. Kawaguchi T, Tanaka M, Itano S et al. Successful treatment of bronchial bleeding from invasive pulmonary metastasis of hepatocellular carcinoma: a case report. Hepatogastroenterology 2001;48:851–853.[Medline]
  66. Recordare A, Bonariol L, Caratozzolo E et al. Management of spontaneous bleeding due to hepatocellular carcinoma. Minerva Chir 2002;57:347–356.[Medline]
  67. Srivastava DN, Gandhi D, Julka PK et al. Gastrointestinal hemorrhage in hepatocellular carcinoma: management with transhepatic arterioembolization. Abdom Imaging 2000;25:380–384.[CrossRef][Medline]
  68. Wu JX, Huang JF, Yu ZJ et al. [Factors related to acute upper gastrointestinal bleeding after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma.] Ai Zheng 2002;21:881–884. Chinese.[Medline]
  69. Witz M, Korzets Z, Shnaker A et al. Delayed carotid artery rupture in advanced cervical cancer: a dilemma in emergency management. Eur Arch Otorhinolaryngol 2002;259:37–39.[CrossRef][Medline]
  70. Baum M, Breach NM, Shepherd JH et al. Surgical palliation. In: Doyle D, Hanks GWC, eds. Oxford Textbook of Palliative Medicine. New York: Oxford University Press, 1993:129–140.
  71. Whitling AM, Bussey HI, Lyons RM. Comparing different routes and doses of phytonadione for reversing excessive anticoagulation. Arch Intern Med 1998;158:2136–2140.[Abstract/Free Full Text]
  72. Byrd DC, Stephens MA, Hammann GL et al. Subcutaneous phytonadione for reversal of warfarin-induced elevation of the International Normalized Ratio. Am J Health Syst Pharm 1999;56:2312–2315.[Abstract/Free Full Text]
  73. Raj G, Kumar R, McKinney WP. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med 1999;159:2721–2724.[Abstract/Free Full Text]
  74. Nee R, Doppenschmidt D, Donovan DJ et al. Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation. Am J Cardiol 1999;83:286–288, A6–A7.[CrossRef][Medline]
  75. Shields RC, McBance RD, Kuiper JD et al. Efficacy and safety of intravenous phytonadione (vitamin K1) in patients on long-term oral anticoagulant therapy. Mayo Clinic Proc 2001;76:260–266.[Abstract]
  76. Fiore LD, Scola MA, Cantillon CE et al. Anaphylactoid reactions to vitamin K. J Thromb Thrombolysis 2001;11:175–183.[CrossRef][Medline]
  77. Patel RJ, Witt DM, Saseen JJ et al. Randomized, placebo-controlled trial of oral phytonadione for excessive anticoagulation. Pharmacotherapy 2000;20:1159–1166.[CrossRef][Medline]
  78. Fondevila CG, Grosso SH, Santarelli MT et al. Reversal of excessive oral anticoagulation with a low oral dose of vitamin K1 compared with acenocoumarine discontinuation. A prospective, randomized, open study. Blood Coagul Fibrinolysis 2001;12:9–16.[CrossRef][Medline]
  79. Green B, Cairns S, Harvey R et al. Phytomenadione or menadiol in the management of an elevated international normalized ratio (prothrombin time). Aliment Pharmacol Ther 2000;14:1685–1689.[CrossRef][Medline]
  80. Stein C, Korula J. Variceal bleeding. What are the treatment options? Postgrad Med 1995;98:143–146, 149–152.
  81. Gross M, Schiemann U, Muhlhofer A et al. Meta-analysis: efficacy of therapeutic regimens in ongoing variceal bleeding. Endoscopy 2001;33:737–746.[CrossRef][Medline]
  82. D’Amico G, Pietrosi G, Tarantino I et al. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. Gastroenterology 2003;124:1277–1291.[CrossRef][Medline]
  83. Allum WH, Brearley S, Wheatley KE et al. Acute haemorrhage from gastric malignancy. Br J Surg 1990;77:19–20.[Medline]
  84. Lin HJ, Perng CL, Wang K et al. Octreotide for arrest of peptic ulcer hemorrhage—a prospective, randomized controlled trial. Heptogastroenterology 1995;42:856–860.
  85. Lamberts SW, van der Lely AJ, de Herder et al. Octreotide. N Engl J Med 1996;334:246–254.[Free Full Text]
  86. Burroughs AK, McCormick PA, Hughes MD et al. Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding: emergency control and prevention of early variceal rebleeding. Gastroenterology 1990;99:1388–1395.[Medline]
  87. Halloran CM, Ghaneh P, Bosonnet L et al. Complications of pancreatic cancer resection. Dig Surg 2002;19:138–146.[CrossRef][Medline]
  88. Dean A, Tuffin P. Fibrinolytic inhibitors for cancer-associated bleeding problems. J Pain Symptom Manage 1997;13:20–24.[CrossRef][Medline]
  89. Garewal HS, Durie BG. Anti-fibrinolytic therapy with aminocaproic acid for the control of bleeding in thrombocytopenic patients. Scand J Haematol 1985;35:497–500.[Medline]
  90. Fricke W, Alling D, Kimball J et al. Lack of efficacy of tranexamic acid in thrombocytopenic bleeding. Transfusion 1991;31:345–348.[CrossRef][Medline]
  91. Cada DJ, ed. Drug Facts and Comparisons. St. Louis: Wolters Kluwer Health, 1997:91.
  92. Herfindal ET, Gourley DR, eds. Textbook of Therapeutics: Drug and Disease Management, Sixth Edition. Baltimore: Williams and Wilkins, 1996.
  93. Ramstrom G, Sindet-Pedersen S, Hall G et al. Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification or oral anticoagulants. J Oral Maxillofac Surg 1993;51:1211–1216.[Medline]
  94. Chandra B. Treatment of subarachnoid haemorrhage from ruptured intracranial aneurysm with tranexamic acid: a double-blind clinical trial. Ann Neurol 1978;3:502–504.[CrossRef][Medline]
  95. Biggs JC, Hugh TB, Dodds AJ. Tranexamic acid and upper gastrointestinal haemorrhage: a double-blind trial. Gut 1976;17:729–734.[Abstract/Free Full Text]
  96. De Boer WA, Koolen MGJ, Roos CM et al. Tranexamic acid treatment of haemothorax in two patients with malignant mesothelioma. Chest 1991;100:847–848.[Abstract/Free Full Text]
  97. Kaufman B, Wise A. Antifibrinolytic therapy for haemoptysis related to bronchial carcinoma. Postgrad Med J 1993;69:80–81.
  98. Cooper DL, Sandler AB, Wilson LD et al. Disseminated intravascular coagulation and excessive fibrinolysis in a patient with metastatic prostate cancer: response to epsilon-aminocaproic acid. Cancer 1992;70:656–658.[CrossRef][Medline]
  99. Shpilberg O, Blumenthal R, Sofer O et al. A controlled trial of tranexamic acid therapy for the reduction of bleeding during treatment of acute myeloid leukemia. Leuk Lymphoma 1995;19:141–144.[Medline]
  100. Avvisati G, Buller HR, ten Cate JW et al. Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet 1989;2:122–124.[CrossRef][Medline]
  101. Hashimoto S, Koike T, Tatewaki W et al. Fatal thromboembolism in acute promyelocytic leukemia during all-trans retinoic acid therapy combined with antifibrinolytic therapy for prophylaxis of hemorrhage. Leukemia 1994;8:1113–1115.[Medline]
  102. Woo KS, Tse LK, Woo JL et al. Massive pulmonary thromboembolism after tranexamic acid antifibrinolytic therapy. Br J Clin Pract 1989;43:465–466.[Medline]
  103. McElligott E, Quigley C, Hanks GW. Tranexamic acid and rectal bleeding. Lancet 1991;337:431.
  104. Erstad BL. Systemic hemostatic medications for reducing surgical blood loss. Ann Pharmacother 2001;35:925–934.[Abstract]
  105. Aderka D, Praff G, Santo M et al. Bleeding due to thrombocytopenia in acute leukemias and reevaluation of the prophylactic platelet transfusion policy. Am J Med Sci 1986;291:147–151.[Medline]
  106. Lassauniere JM, Bertolino M, Hunault M et al. Platelet transfusions in advanced hematological malignancies: a position paper. J Palliat Care 1996;12:38–41.
  107. Pisciotto PT, Benson K, Hume H et al. Prophylactic versus therapeutic platelet transfusion practices in hematology and/or oncology patients. Transfusion 1995;35:498–502.[CrossRef][Medline]
  108. Beutler E. Platelet transfusions: the 20,000/µl trigger. Blood 1993;81:1411–1413.[Free Full Text]
  109. Schiffer CA. Prophylactic platelet transfusion. Transfusion 1992;32:295–298.[CrossRef][Medline]
  110. Söhngen D, Schneider W. [Thrombocyte transfusion: clinical aspects, follow-up and complications.] Klin Wochenschr 1991;69:379–386. German.[CrossRef][Medline]
  111. Gleeson C, Spencer D. Blood transfusion and its benefits in palliative care. Palliat Med 1995;9:307–313.[Abstract/Free Full Text]
  112. Monti M, Castellani L, Berlusconi A et al. Use of red blood cell transfusions in terminally ill cancer patients admitted to a palliative care unit. J Pain Symptom Manage 1996;12:18–22.[CrossRef][Medline]
  113. Johnson MJ. Problem of anticoagulation within a palliative care setting: an audit of hospice patients taking warfarin. Palliat Med 1997;11:306–312. Erratum in: Palliat Med 1998;12:463.[Abstract/Free Full Text]
  114. Johnson MJ, Sherry K. How do palliative physicians manage venous thromboembolism? Palliat Med 1997;11:462–468.[Abstract/Free Full Text]
  115. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688–698.[Free Full Text]
Received November 19, 2003; accepted for publication March 22, 2004.





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