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Coagulation Abnormalities in Malignancy: A Review

Defects of hemostasis in patients with cancer have long been recognized; Trousseau,1 in 1865, was the first to note this association, and Morrison2 studied altered coagulation in patients with malignancy as early as 1932. Abnormalities of hemostasis in patients with cancer are remarkably complex and present major clinical challenges. Many instances of hemorrhage or thrombosis in patients with malignancy are by obscure mechanisms;3 however, often the mechanisms are now definable. Changes of hemostasis secondary to malignancy are multifaceted and the development of clinically significant hemorrhage or thrombosis in cancer patients often represents a total clinical expression of many changes in hemostasis.4,5 This review describes the major changes of hemostasis developing in patients with malignancy, with particular emphasis on those thought to be most clinically significant for morbidity and mortality, and an approach to diagnostic problems and management is presented. The subsequent authors contributing to this issue of Seminars focus on particular problems with hemostasis and malignancy.

HYPERCOAGULABILITY AND THROMBOSIS Pathophysiology The first described abnormality of hemostasis in malignancy was that of hypercoagulability and thrombosis and the first large survey of blood changes in cancer

From the Division of Hematology Oncology, Department of Medicine, University of California, Los Angeles Center for the Health Sciences, Los Angeles, California. Reprint requests: Dr. Bick, Department of Oncology, Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231.

patients showed "accelerated bleeding times" in over 60% of patients studied.1,2 Following these classic descriptions, many authors have reported hypercoagulability and thrombosis in association with many malignancies. 5-15 Many have found elevated clotting factors in patients with malignancy and the factors most commonly elevated, and formerly implicated in causing hypercoagulability have been Factors I, V, VIII:C, IX, and XI. 6,7,12,16 Also, many patients with malignancy have shortened activated or nonactivated partial thromboplastin times, accelerated prothrombin times, and accelerated clotting times. 5,12,16 Although these parameters have usually been assumed to be indicative of hypercoagulability, there is no proof of this3,5 and none of these laboratory parameters correlate with the development of a clinical thrombotic episode in an individual patient.3,4 Increased fibrinogen and platelet catabolism (increased turnover and decreased survival) happen in many patients with disseminated malignancy.17 Also, increased titers of fibrin(ogen) degradation products (FDP), D-dimer, fibrinopeptide A and B, cryofibrinogens, fibrin monomer, B-ß 15-42 and related peptides, platelet factor 4, ß-thromboglobulin, and altered fibronectin and antithrombin levels are seen in many individuals with disseminated malignancy.7,17-27 These laboratory findings vividly imply that many patients with cancer have a low-grade disseminated intravascular clotting process.28,29 The shortened survival of fibrinogen, platelets, and other coagulation proteins is often followed by an overcompensatory increase in coagulation factors and fibrinolytic enzymes, although these latter proteins may be decreased in some myeloproliferative disorders.30 Also, these changes are frequently accompanied by significant decreases in major coagulation inhibitors, including antithrombin III protein C and protein S, although the exact mechanisms of decreases in antithrombin III and proteins C and S are controversial and may be because of consumption, or may result from defective

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hepatic synthesis. 10,12,30,31 However, this sequence of changes disrupts the balance between coagulation, fibrinolysis, and inhibition of the clotting and fibrinolytic system and may make patients more susceptible to a significant clinical event secondary to only minor changes in the complete hemostatic system. This may then predispose the patient to localized intravascular coagulation (thrombosis/thromboembolism) or a classic disseminated intravascular coagulation (DIC)-type syndrome associated with hemorrhage or thrombosis. 28,29,32 Thrombus formation is the more common of the two expressions of intravascular coagulation in patients with solid tumors and may approach 40 to 50% in some cancer patient populations.5,33 Sometimes, changes in coagulation factors have been correlated with bulk of tumor present and overall patient survival. Some coagulation abnormalities tend to normalize following initiation of therapy for the particular malignancy; this phenomenon may be noted following surgery, radiation therapy, chemotherapy, and biotherapeutic or hormonal manipulation.5-7,17 It has recently been noted, however, that hormonal therapy may also lead to decreases in antithrombin III and make the patients more susceptable to thrombosis.34 The mechanism or mechanisms by which malignant tissues may initiate localized intravascular coagulation or DIC are highly complex; however, many malignant tissues can release procoagulant materials, and sometimes fibrinolytic materials as well, into the systemic circulation. This topic is addressed in the review by Gordon in this issue of Seminars. Despite the mechanisms, when compared with normal tissue, most malignant tissue can begin the clotting process via many multifaceted processes, and many pathologic tumor specimens are commonly noted to be associated with encircling fibrin formation. Many malignant tissues can initiate fibrin formation without apparent later activation of the fibrinolytic system. 35,36 Many malignant tissues are also capable of releasing a "thromboplastin-like" activity and may provide this activity either systemically or locally to start a clotting process; the amount released will most probably dictate whether a localized intravascular coagulation event (thrombus) or a systemic DIC-type syndrome happens. Low levels of antithrombin III, despite its cause, will allow this process to start more readily and to proceed without normal inhibition once it has begun, 512 for example, in the patient with significant liver metastases and later decreased or defective antithrombin III synthesis.31 DIC in malignancy is discussed in later sections. Mucinous adenocarcinomas are tumors commonly associated with thrombus formation; in these malignancies the sialic acid moiety of secreted mucin can initiate coagulation by the nonenzymatic activation of Factor X

to Factor Xa. 5,8,16,37 In pancreatic carcinoma, the release of systemic trypsin triggers intravascular coagulation events. 5,38 Also, it has been shown that trypsin release is correlated with the magnitude of disseminated thrombi; patients with carcinoma of the body or tail of the pancreas have minimal ductal obstruction, and large amounts of trypsin release and far more thrombotic and thromboembolic episodes than patients with carcinoma of the head of the pancreas with maximal ductal obstruction, and minimal trypsin release. 5,32 DIC represents the "coagulopathy" of adenocarcinoma of the prostate;39,40 however, malignant prostatic tissue not only activates the procoagulant system, but also independently activates the fibrinolytic system. In this instance, both a DIC and secondary fibrinolysis in association with inordinantly excessive fibrino(geno)lysis from both primary activation and activation secondary to DIC happens. This coagulopathy is more often manifested as hemorrhage instead of thrombosis, showing the wide variability of clinical expression in DIC depending on the balance between activation of the procoagulant system versus activation of the fibrino(geno)lytic system. Therapy of prostatic carcinoma is often followed by an alleviation of general hemostasis abnormalities, including changes of the procoagulant and fibrinolytic system. This is noted particularly with administration of estrogens, whereas testosterone has been noted to enhance coagulation abnormalities in many patients. 19,41,42 Hypercoagulability in cancer patients may also arise from platelet abnormalities. The role of platelets in contributing to thrombosis in malignancy was suspected many years ago, and the first large study of this phenomenon was initiated by Moolten et al in 1949,43 which showed abnormal increases in platelet numbers and abnormal morphology, platelet lysis, and defective adhesion to glass wool. Also, a correlation was noted between platelet adhesiveness and the development of thrombosis; increased platelet adhesion was better correlated with thrombosis in malignancy than was thrombocytosis. Increased platelet adhesion, as measured by shortened bleeding times, accelerated thromboplastin generation, shortened prothrombin consumption, and increased adhesion to glass has been studied in many cancer patient populations and appears to be a uniform abnormality in a variety of solid tumors. 2,6,7,12,44 However, it is unclear whether these changes are primary disturbances caused by the malignancy or whether these platelet abnormalities are because of initial earlier changes in the coagulation system that activate platelets and make them hyperaggregable.5 Thrombocytosis is a well-recognized accompaniment of malignancy and most commonly is associated with carcinoma of the pancreas, lung, gastrointestinal

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TABLE 1. Malignancies Often Associated with Thrombosis Colon

Myeloproliferative syndromes

Gallbladder

Ovary

Gastric

Pancreas

Lung (any cell type)

Paraprotein disorders

Management of Thrombosis and Thromboembolus in Patients with Malignancy Antineoplastic therapy is associated with some correction of abnormal hemostasis, and this is especially appreciated in prostatic carcinoma. Because of this, treated patients are less susceptible to thrombosis and thromboembolus and when thrombotic episodes develop in untreated patients, consideration should be given to antineoplastic therapy. The use of both warfarin and heparin or antiplatelet agents is associated with some correction of altered coagulation factors and normalization of both fibrinogen and platelet consumption (increased turnover and decreased survival). 3,4,7,17,41 Despite these findings, however, cancer patients are notoriously resistant to anticoagulant therapy, and thrombotic events commonly continue after initiation of antithrombotic therapy. 3-5,48 Warfarin and less commonly intravenous heparin are not only often ineffective, but may be associated with significant bleeding problems in patients with malignancy, probably resulting from large areas of necrotic tumor surface.3-5,48 This has also been experienced by others, noting a high chance of fatal hemorrhage associated with the use of intravenous heparin in patients with malignancy.17 Also, many patients with malignancy have decreased antithrombin III levels5,31 and responses to heparin may be less than optimal; this is especially frequent in patients with liver metastases. Experience with antiplatelet agents in patients with malignancy has been reasonable.5 I commonly use aspirin (enteric coated) 300 to 600 mg twice daily to be taken with 30 cc of liquid antacid in combination with dipyridamole at a dose of 50 to 75 mg four times a day in patients with cancer and thrombosis. 3-5,29,48 This is often effective for the immediate prophylaxis of extension of thrombi and for long-term prophylactic therapy in cancer patients with recurrent thrombosis. Warfarin and heparin are generally contraindicated in patients with malignancy and thrombosis or thromboembolus if central nervous system (CNS) metastases, abcesses, or infection are present.3,4,48 Low-dose subcutaneous heparin can safely be used in most preoperative patients with malignancy as prophylaxis for postoperative thrombosis or pulmonary embolus; however, intravenous or high-dose heparin therapy should probably not be used in this instance.5,29 When the patient with malignancy has life-threatening thrombosis and has adequate levels of antithrombin III, low-dose heparin is most useful and appears to be as equally effective as large doses of heparin and is not often associated with bleeding from tumor surfaces, as frequently happens with intravenous heparin. Important

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tract, ovary, breast, and myeloproliferative syndromes, and patients undergoing bone marrow suppressive chemotherapy have less thrombocytosis than patients not being so treated. 2,5,7,12,44 The most pronounced instances of thrombocytosis are usually noted in the myeloproliferative disorders.5,45 As with coagulation protein abnormalities and hypercoagulability, thrombocytosis and increased platelet aggregability generally correlate poorly with the actual development of a clinical thrombotic event in an individual patient and so the significance of these laboratory findings is unclear. As outlined before, there are various mechanisms enabling malignant tissue to induce changes in coagulation factors and platelets to create a hypercoagulable state, that is, an increased predisposition to thrombosis, as an expression of an underlying intravascular clotting process, which may be systemic or may stay localized.5,29 The difficult and evolving subject of cancer cell procoagulant activity leading to intravascular coagulation is discussed in detail by Gordon, an authority on this difficult subject. Intravascular coagulation may be mild and manifested only by abnormal laboratory tests of hemostasis, such as elevated levels of FDP, D-dimer, B-ß 15-42 and related peptides, fibrinopeptide A or B, circulating fibrin monomer, and other tests generally interpreted as representing hypercoagulability.46 However, intravascular coagulation may proceed to more than a laboratory phenomenon and become expressed clinically as localized thrombosis or thromboembolus, or in more extreme cases may be manifested as a systemic (or disseminated) intravascular coagulation event associated with hemorrhage and thrombosis. The malignancies most commonly associated with thrombosis are depicted in Table 1. The general incidence of thrombosis in malignancy is about 15%, but may be higher in specific tumors, such as pancreatic carcinoma where this may be seen in more than 50% of patients. 3-5,10,14 Patients with malignancy are likelier to develop postoperative deep vein thrombosis than are patients without cancer. For cancer of the gastrointestinal tract, the chance of postoperative thrombosis and thromboembolus approaches 40%. 3,4,8,16,37,47

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clinical aspects of thrombosis in cancer patients is further discussed in the article by Scates in this issue of Seminars.

HEMORRHAGE Leukemias Hemorrhage may precede the overt clinical diagnosis of leukemia by several months; this is frequently noted in acute leukemias. 49-52 Petechiae, purpura, and ecchymoses are the most common prediagnostic manifestations and petechiae, purpura, ecchymoses, or other less commonly noted sites of hemorrhage are present in about 40 to 70% of patients with acute leukemia at the time of diagnosis. 5,53-55 The most prevalent sites of hemorrhage in patients with acute leukemia are the skin, eye, and mucosal membranes, including epistaxis, gingival bleeding, and gastrointestinal bleeding;5,50,51 however, retinal bleeding can be found in about 15% of patients at presentation and in 50% of patients with acute leukemia as the disease progresses. 5,52,53,56 In acute leukemia, hemorrhage is a common cause of death and is the mechanism of death in about 40% of patients. 52,53,57 During the past three decades, infection has surpassed hemorrhage as the most common cause of death in patients with acute leukemia, probably resulting from more intensive chemotherapy and attendant immunosuppression, and the major impact of the development of platelet concentrate therapy to help control thrombocytopenia, the most common cause of fatal hemorrhage in acute leukemia. 5,50-52,58 Clinical bleeding manifestations in acute leukemias are summarized in Table 2. Hemorrhage is less commonly a problem in the chronic myeloid or lymphoid leukemias. 3-5,50-52,59 However, in both chronic myelogenous leukemia (CML) or chronic lymphocytic leukemia (CLL) local or diffuse thromboses or thromboembolism frequently happens. 3,4,48,60 Many patients with chronic leukemia have bothersome bleeding, usually manifested as petechiae, purpura, ecchymoses, or oozing from mucosal mem-

TABLE 2. Clinical Hemorrhage in Acute Leukemias

branes, including the gastrointestinal and genitourinary tracts.5 Only rarely do these patients have retinal bleeding or other serious life-threatening bleeding unless severe thrombocytopenia (usually drug-induced) or thrombocytosis/thrombocythemia develops.5 As with chronic myelogenous leukemias, CLL is also more commonly associated with thrombosis or thromboembolus in the early course of the disease. 3,4,60 Hemorrhage, however, becomes a problem later during the disease as thrombocytopenia from chemotherapy or marrow infiltration, liver infiltration, or other hemostasis defects, including DIC, secondary to the leukemia itself, sepsis, transfusions, or other causes may become manifest 3-5,28,29,32,48,61 Hemorrhage may happen in any of the leukemias but is most common in acute promyelocytic (FAB M3) leukemia, acute myelomonocytic (FAB M4) leukemia, and acute granulocytic (FAB M1 and M2) leukemia. Life-threatening or severe hemorrhage is less commonly seen in chronic myelogenous leukemia and chronic lymphocytic leukemia and is less commonly seen in pure monocytic leukemia. 3,4,50-52,62-64 Propensity to hemorrhage in leukemias is depicted in Table 3. There are many mechanisms for development of significant or life-threatening hemorrhage in all leukemias and these will be discussed as categories of defects, including platelets, the coagulation proteins, mechanisms for the development of DIC, abnormalities of the vasculature, and the leukemia cell as a source of various clot-promoting materials, fibrino(geno)lytic materials, and other products that may change or disrupt the hemostasis system.5,52 Platelets The most common single cause of serious or lifethreatening hemorrhage in acute or chronic leukemias is thrombocytopenia.3,4,50,51 Thrombocytopenia is most common because of chemotherapy or marrow infiltration. However, less common causes of thrombocytopenia in patients with leukemia are the development of DIC with consumption of platelets, infection-induced immune or nonimmune thrombocytopenia, or the development of TABLE 3. Propensity to Hemorrhage in Leukemia*

1. Hemorrhage may precede diagnosis by months; petechiae, purpura, and ecchymoses most common

Acute promyelocytic leukemia

2. Up to 70% have petechiae and purpura at diagnosis

Acute myelomonocytic leukemia

3. Retinal hemorrhage in 15% at diagnosis

Acute myeloblastic leukemia

4. Retinal hemorrhage in 50% during course of disease

Chronic myelogenous leukemia

5. Most patients will have hemorrhage of skin, and/or mucosal membranes during course

Chronic lymphocytic leukemia

6. Hemorrhage is the cause of death in 40%

Monocytic leukemia *In descending order of probability.

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splenomegaly and associated Hypersplenism with increased platelet sequestration. In clinical practice when seeing severe thrombocytopenia in patients with leukemia, these mechanisms must be recalled because, although the most common cause of thrombocytopenia is drug-induced or from marrow infiltration, any combination of several or many of the previously mentioned mechanisms may be operative and must be corrected if life-threatening hemorrhage is to be successfully treated. Mechanisms of thrombocytopenia in leukemia are summarized in Table 4. In patients with actue myelogenous leukemia the platelet count commonly drops below 10,000/mm3 during remission induction therapy;5,52,65,66 bleeding is uncommon with a platelet count of greater than 10,000/ mm3 in patients undergoing remission induction. However, when the platelet count drops below 5000/ mm3, severe hemorrhage is frequent. During remission induction, a daily urine examination for red blood cells and a daily stool guaiac should be obtained when the platelet count drops below 50,000/mm3; if either of these becomes positive, this is a reasonable indication that serious hemorrhage may be impending.5 If the urine and stool samples are negative, prophylactic platelet concentrate therapy should not be empirically given unless the platelet count is less than 5000/mm3.5 If the urine or stool sample is positive or if the platelet count is less than 5000/mm3, the daily infusion of 6 to 8 U of platelet concentrates each day is appropriate to circumvent irreversible or life-threatening hemorrhage and should be continued until the platelet count is consistently greater than 10,000/mm3 and significant bleeding or early signs of bleeding, as manifested by quaiac studies or blood in the urine, are negative.5 If possible, directed single donor platelets are used. CML is only rarely associated with platelet counts less than 10,000/mm 3 . 3-5,50-52 However, as in acute leukemias, when the platelet count is less than 50,000/mm3

TABLE 4. Mechanisms of Thrombocytopenia in Leukemia Bone marrow infiltration (myelophthisis) Chemotherapy Radiation therapy Bacteremia Disseminated intravascular coagulation Infection-induced (immune and nonimmune) Splenomegaly and hypersplenism Immune thrombocytopenia purpura Myelofibrosis Richter's syndrome (CLL)

357 the same principles of management as earlier outlined also apply.5 More commonly, chronic myeloid leukemias are associated with hemorrhage or thrombosis secondary to a profound thrombocytosis/thrombocythemia. Like CML, CLL is rarely, at least in the early course of the disease, associated with platelet counts of less than 50,000/mm3.5 When the platelet count is less than 50,000/mm3 the approach just outlined should be followed. However, as CLL begins to enter a terminal phase, thrombocytopenia may become a very significant problem. This can result from the institution of more vigorous chemotherapy, severe marrow replacement, infections, or the development of various immune-mediated thrombocytopenic problems, including Richter's syndrome or an immune thrombocytopenic purpura (ITP)-type syndrome. Severe thrombocytopenia may also happen following the development of significant hypersplenism or the development of a frank DIC syndrome. The same management principles, as outlined earlier, should be started, specifically depending on the mechanism or combination of mechanisms involved.5 Platelet Dysfunction Significant platelet dysfunction, even in the presence of normal or elevated platelet counts, is almost uniformly noted in chronic myelogenous leukemia, essential thrombocythemia, and other myeloproliferative syndromes. 3-5,45,50,52 Generally, characteristic platelet function defects are noted in CML and these often lead to or contribute to significant hemorrhage. Although many types of defects are seen, the most common is impaired aggregation to adenosine diphosphate (ADP) and epinephrine and defective platelet factor 3 release.67"69 Also, a deficiency or absence of alpha granules occurs in patients with myeloproliferative syndromes and platelet function defects.70 It should be stressed that the platelet function defect associated with CML or essential thrombocythemia commonly leads to or contributes to significant clinical hemorrhage, especially if coupled with other defects in the hemostasis system. 3,4,62,71,72 If the platelet count is decreased or normal, the defect can be overcome using proper numbers of platelet concentrates. Platelet dysfunction associated with hemorrhage and an elevated platelet count (greater than 700,000/mm3) is rapidly corrected by platelet cytapheresis. Clinically significant platelet dysfunction happens in about 70% of patients with polycythemia vera, about 50% of patients with myelofibrosis, and about 30% of patients with CML.73 Platelet dysfunction is less commonly a problem in acute leukemias; some have reported normal platelet function to most usual aggregating agents,74 whereas others have noted impaired platelet function as assessed by platelet aggregation to thrombin, ADP, epinephrine, and colla-

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gen in patients with acute leukemias.75 Abnormal release of platelet factor 3 is noted in patients with acute leukemia. 50,52 Although platelet function defects in CML, and other of the myeloproliferative disorders, are well-known to contribute to significant hemorrhage, the role of abnormal platelet function as a dominant cause of hemorrhage in acute leukemias is less clearly defined. Platelet dysfunction is much less commonly seen in CLL and in monocytic leukemia than in the myelogenous leukemias or other myeloproliferative syndromes. 5,50,52

Coagulation Protein Abnormalities Liver infiltration with ensuing defective or decreased synthesis of the vitamin K-dependent factors is commonly a problem in acute leukemias, and impaired synthesis of other factors may also evolve. 50,52,76 Therefore, if a patient with acute leukemia develops significant liver infiltration, there may be defective or decreased synthesis of any combination of not only Factors II, VII, IX, and X, but also fibrinogen, Factors V, VIILC, XI, XII, and XIII, prekallikrein, high molecular weight kininogen, plasminogen, or antithrombin III, protein S and protein c. 3 - 5 , 3 0 , 5 0 - 5 2 Also, fibronectin levels are typically decreased in acute leukemia, probably because of decreased synthesis or possibly because of consumption from the development of a DIC syndrome; this phenomenon correlates appropriately with infectious episodes and DIC instead of defective synthesis appears to be incriminated as the mechanism for decreased levels of fibronectin in patients with acute leukemia.30 Cholestasis happens in some patients with acute leukemia and may lead to defective synthesis of the vitamin K-dependent clotting factors and sometimes cholestasis may also lead to frank DIC. 50,51,77 However, as will be discussed later, there are other more significant mechanisms for the development of DIC in patients with acute leukemia.5,52 CLL may also be associated with substantial liver infiltration, especially as the disease progresses and approaches terminal stages. 5,50,52,76,78 This may, as in the acute leukemias, lead to impaired or decreased synthesis of the vitamin K-dependent factors and any other combination of factors and proteins synthesized by the liver. Many patients with CLL exhibit prolonged prothrombin times, which may correct with more intensive appropriate chemotherapeutic agents. Factors V, VIILC, and fibrinogen may behave as acute-phase reactants and may be high, low, or normal in patients with CLL.5 Therefore the activated partial thromboplastin time may be remarkably inconsistent because of the variable levels of Factors V, VIILC, and fibrinogen. Defective hepatic synthesis of coagulation factors resulting from hepatic infiltration in CLL is an uncommon cause of life-threatening hemorrhage. CML may also be associated with significant he-

patic infiltration; however, this is much less commonly a problem than in acute leukemias or CLL. 50,62 Patients with CML who do not have DIC will usually manifest normal or near-normal global tests of hemostasis, and defective hepatic synthesis resulting from leukemic infiltrates is infrequently a singular problem accounting for hemorrhage in patients with CML.5 Acquired von Willebrand's syndrome is noted in association with many hematologic malignancies, including CLL, hairy cell leukemia, myelodysplastic syndromes, multiple myeloma, CML, polycythemia vera, essential thrombocythemia, and myelofibrosis.79-86 In most cases classified, the variant has been type II. The two mechanisms yet defined have been the development of a circulating inhibitor to von Willebrand factor or proteolysis of von Willebrand factor; sometimes treatment of the underlying malignant disorder has been accompanied by partial or complete correction of the bleeding diathesis. The use of desmopression has alleviated bleeding in some patients with malignancy-associated von Willebrand's syndrome. Malignancies associated with acquired von Willebrand's syndrome are summarized in Table 5. This important and changing topic is discussed in detail by Jakway in this issue of Seminars.

FIBRINOLYSIS Many changes in the fibrinolytic system of patients with acute leukemia have been reported; however, the findings have been inconsistent, with increased fibrinolytic activity reported by some,74 and decreased fibrinolytic activity noted by others.87 One study noted a correlation between leukocytosis, later leukostasis, and enhanced fibrinolytic activity; however, this is an isolated report that is unconfirmed.88 Generally, noteworthy changes in the fibrinolytic system components have not been noted in patients with CML or CLL. 50,62,78 High

TABLE 5. Malignancies Associated with Acquired von Willebrand's Disease Wilm's tumor Renal cell carcinoma Malignant lymphoma Waldenstrom's disease Multiple myeloma Chronic lymphocytic leukemia Hairy cell leukemia Chronic myelogenous leukemia Polycythemia vera Essential (primary) thrombocythemia Myelodysplastic syndromes

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plasminogen activator activity has been noted in association with chronic myeloid leukemias,89,90 but not lymphocytic leukemias. 5,50,52,78 One study has shown that 30% of patients with acute leukemia have excessive fibrinolytic activity; these patients also exhibited low antiplasmin levels and the presence of circulating plasminantiplasmin complexes. These findings did not correlate with findings suggestive of procoagulant activity or findings of DIC and these fibrinolytic changes appear to be independent of intravascular procoagulant activity.154

DISSEMINATED INTRAVASCULAR COAGULATION IN LEUKEMIA Myeloblasts, promyelocytes, monocytes, and lymphoblasts all contain, and can release, procoagulant materials or enzymes in patients with acute leukemia. 3-5,50-52,64,91-97 DIC may complicate the course of acute leukemia in about 50% of patients.98,99 Also, blast cells may have fibrinolytic activity or fibrinolytic system activator activity. 3-5,50,51,88,94,100-103 Granulocytes of chronic granulocytic leukemia are also capable of releasing procoagulant enzymes, procoagulant activity, and antithrombin-type materials.50,62 Also, granulocytes of CML release an antiheparin-like activity that is derived from myeloperoxidase.50,104 Mature lymphocytes of CLL also release procoagulant materials which are phospholipoprotein or "thromboplastin-like" in composition 5,50,52,60,78 Because of this ability to release procoagulant materials into the systemic circulation and potentially activate the coagulation system, essentially any leukemia may be associated with low-grade or fulminant DIC 3,4,28,29,105-107 The most common leukemia associated with DIC is acute promyelocytic leukemia (FAB M3), followed by acute myelomonocytic leukemia (FAB M4), acute myeloblastic leukemia (FAB M1&2), and acute lymphoblastic leukemia (FAB L1-3) in descending order of probability. 5,28,29,105,106 Fulminant DIC is seen much less frequently in chronic leukemias than in acute leukemias and is likelier to evolve with CML than with CLL. The development of DIC influences survival in acute leukemias and is a frequent complication in acute promyelocytic leukemia (FAB M3). The survival of patients with acute promyelocytic leukemia can be dramatically improved by suppressing development of DIC or by attenuating an existing DIC with the early application of low-dose (subcutaneous) heparin. 5,28,29,105,106,108,109

VASCULAR DEFECTS Vascular defects may evolve in patients with acute leukemia; these defects are repeatedly forgotten. Vascu-

359 lar defects in leukemia may be responsible for or contribute to significant hemorrhage.5,50,51 Although vascular defects are of clinical significance in acute leukemias, they are unlikely to be a clinical problem in chronic leukemias. Patients with acute leukemias commonly display increased vascular permeability because of: (1) infiltration of the vasculature by leukemic cells, (2) hyperviscosity or leukostasis of the vasa vasorum, or (3) foci of extramedullary hematopoiesis in the vessel wall. 5,110-112 In summary, it must be recalled that many defects of hemostasis may be associated with acute and chronic leukemias, and when significant hemorrhage happens, the defects may be multifactorial and are a combination of any one, several, or all the earlier described defects. Only by carefully evaluating the patient from both the clinical and laboratory standpoint and carefully delineating the presence or absence of each of these defects can rational and effective therapy be delivered. Coagulation syndromes associated with leukemia are summarized in Table 6.

HEMORRHAGE AND SOLID TUMORS Although thrombosis is more commonly the abnormality of hemostasis manifested with solid tumors and hemorrhage is more commonly associated with acute leukemias, hemorrhage may be a significant clinical problem in patients with solid tumors as well. 3,4 As discussed earlier, intravascular coagulation is present in many patients with malignancy and is manifested by varying clinical expressions, the most extreme form being acute fulminant DIC and catastrophic hemorrhage and thrombosis. DIC in cancer patients may be low-grade or

TABLE 6. Defective Hemostasis in Leukemia Patients* Thrombocytopenia Platelet dysfunction Disseminated intravascular coagulation Leukemia cell procoagulant activity Bacteremia Massive transfusions Shock Coagulation protein defects Liver infiltration Cholestasis Drug-induced Primary fibrinolysis Leukemia cell proteolytic activity Drug-induced Vascular defects Infiltration Hyperviscosity/leukostasis Extramedullary hematopoiesis * In descending order of probability.

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fulminant. 5,28,32,48,105-107 The low-grade form is slightly more common and is manifested clinically by mild to moderate bleeding, usually of the integument or mucous membranes. 5,29,32,105 Easy and spontaneous bruising, petechiae, and purpura, echymoses, gingival bleeding, and minor gastrointestinal bleeding, coupled with thrombosis, are usual manifestations. In contrast, fulminant DIC is characterized by an explosive catastrophic hemorrhage, with bleeding usually being from at least three unrelated sites simultaneously.29,32 The most commonly noted abnormalities are petechiae, purpura, and ecchymoses, seen with significant gastrointestinal, pulmonary, or genitourinary hemorrhage. Also, most patients with fulminant DIC will manifest oozing from intravenous sites or sites of other invasive procedures, such as intraarterial lines, subclavian catheters, and hepatic artery catheters. 3,4,28,29,32,105,107 Although these are the most common bleeding manifestations, more life-threatening bleeding, such as intracranial and intrapulmonary hemorrhage with massive hemoptysis, may also happen. This form of DIC has been noted in association with almost all types of solid tumors and is most commonly seen in carcinoma of the lung, gallbladder, stomach, colon, breast, ovary, malignant melanoma, 5,12,16,37,113-116 and is especially common in carcinoma of the prostate. 19,39,40,117 Table 7 depicts malignancies most commonly associated with DIC. In these latter disorders, initiation of chemotherapy has occasionally been associated with triggering or acceleration of DIC. 7,92,105,115,118 The initiation or enhancement of DIC in association with starting antineoplastic therapy is presumably because of release of thromboplastin-like or other clot-promoting materials or enzymes from necrotic tumor cells. In acute promyelocytic leukemia, low-dose heparin therapy, given before starting cytotoxic drugs, may protect against

TABLE 7. Malignancies Commonly Associated with Disseminated Intravascular Coagulation Acute promyelocytic leukemia Acute myelomonocytic leukemia Acute myeloblastic leukemia Lymphomas (immunoblastic) Hodgkin's disease Biliary cancer Breast cancer Colon cancer Gastric cancer Lung cancer Malignant melanoma Ovarian cancer Prostate cancer

this development, as discussed earlier. 105,108,109,119 Most patients with disseminated solid malignancy have some laboratory or clinical evidence of DIC; many patients with malignancy never develop clinical manifestations of DIC, but if one looks for laboratory findings of DIC, these are usually present. The patient with disseminated malignancy represents a special problem, since DIC may be manifested as a fulminant, subacute, or low-grade form and may therefore be manifested as local thrombosis, diffuse thrombosis, thromboembolism, minor hemorrhage, diffuse hemorrhage, or any combination thereof.3,4,105-107 There are many potential mechanisms by which malignancy provides triggers for DIC. The hemorrhagic syndrome associated with prostatic carcinoma was poorly understood for a long time and many considered this to represent DIC with secondary fibrinolysis, whereas others thought the hemorrhage associated with prostatic carcinoma to be a primary hyperfibrinolytic syndrome. 40,120 It is now recognized that both processes happen in malignant prostatic disease and may happen to a smaller extent in benign prostatic disease as well. Malignant prostatic tissue contains procoagulant-materials, which may be released into the circulation, triggering a disseminated intravascular clotting process with the usual secondary fibrinolytic response.5 Also, malignant prostatic tissue may independently either directly or indirectly activate the fibrinolytic system, leading to a primary fibrino(geno)lytic syndrome.5 Prostatic carcinoma is commonly associated with DIC and the usual secondary fibrinolytic response plus a primary fibrino(geno)lytic syndrome. This explains why, from the clinical and laboratory standpoint, patients with prostatic carcinoma more often present as an overwhelming fibrino(geno)lytic syndrome, a minimal procoagulant problem, and the clinical manifestations of this are, as expected, hemorrhage instead of diffuse thrombosis.5 One study has shown that evidence for DIC as defined by the elevated FDPs and the presence of soluble fibrin monomer is noted in many patients before surgery for malignant prostatic disease.121 Also, after transurethral resection of the prostate (TURP), blood loss appears to be correlated with preoperative evidence of DIC; these findings suggest that it is wise to look for laboratory manifestions of DIC before undertaking TURP in patients with prostatic disease because these parameters may predict postoperative bleeding, blood loss, and necessity of blood component replacement.105,121 DIC is commonly associated with pancreatic carcinoma. In this circumstance, DIC is more commonly manifested as diffuse thrombosis instead of diffuse hemorrhage because the procoagulant activity dominates and secondary fibrinolysis is minimal. DIC, manifested as acute disseminated thrombosis, is more commonly seen

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in carcinoma of the body and tail of the pancreas, since there is little ductal obstruction and large amounts of trypsin are released, the trypsin having thrombin-like activity. In carcinoma of the head of the pancreas, there is more ductal obstruction and less trypsin released into the systemic circulation, and there is less commonly an associated DIC syndrome.5,38 In patients with adenocarcinoma of many primary sites, the mechanism for DIC may be multifaceted. However, as earlier mentioned, the sialic acid moiety of secreted mucin from adenocarcinomatous tissue can invoke the nonenzymatic activation of Factor X to Factor Xa. 16,37 This can easily provide a trigger for systemic thrombin generation and a later course of fulminant or subacute DIC. 105,122 Also, this sequence may lead to thrombosis alone. 5,105-107 It is probable that other less clearly defined mechanisms exist for initiating DIC in malignancy. The systemic release of necrotic tumor tissue or enzymes with procoagulant or phospholipoprotein-like activity may activate the early phases of coagulation and platelet release. Also, many tumors undergo neovascularization; this process could potentially produce abnormal endothelial cell lining, which may either cause a platelet release or generation of Factors XIIa and XIa, with subsequent procoagulant activation and the development of a fulminant, subacute, or low-grade DIC process. 1 0 5 - 1 0 7 , 1 2 3 , 1 2 4 Table 8 lists the usual laboratory features found in most patients with disseminated malignancy and disrupted hemostasis. These findings are often associated with and are interpreted as a hypercoagulable

TABLE 8. Laboratory Abnormalities in DIC Associated with Metastatic Malignancy Elevated fibrinogen (with decreased survival) Elevated fibrin(ogen) degradation products

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state or a propensity to thrombus formation; however, these findings usually represent complicated changes of a subacute or low-grade disseminated intravascular clotting process, which may or may not become clinically manifest.5,28,29,46 Another common trigger for DIC in the patient with malignancy is the use of LeVeen or Denver shunts for malignant ascites. Patients with malignant ascites must be carefully chosen for this procedure; if ascitic fluid is positive for malignant cells, the placement of a LeVeen shunt is usually not successful,125 does not lead to significant prolongation of quality life, and is commonly associated with the development of DIC. 28,29,32,127-129 DIC may be blunted or aborted by removal of ascitic fluid at the time of shunt placement.130 Also, in this clinical setting a less common although significant complication of LeVeen shunting in the patient with malignant ascites is that of thromboembolism.125 A significant amount of discussion has concerned the association of malignancy and DIC; this is one of the most common clinical settings in which clinicians must contend with fulminant, subacute, or low-grade DIC. Also, it is especially in malignancy that DIC may display highly varied clinical manifestations. For example, the patient with malignancy may show accelerated procoagulant activity with minimal fibrinolytic response and diffuse thrombosis or may have a moderate procoagulant drive with overwhelming secondary fibrinolytic activation and subsequent purely hemorrhagic manifestations. 3,4,28,29,105-107 Also, any combination between these two extremes may be seen in patients with metastatic solid tumor.3,4 The patient with malignancy and associated DIC presents a major problem in management and a clear understanding and definition of possible triggering events is desirable and often necessary for efficacious control of the intravascular clotting process. 5,28,29,32

Circulating soluble fibrin monomer Elevated fibrinopeptide A Elevated fibrinopeptide B Cryofibrinogenemia Decreased plasminogen Elevated plasmin Elevated B-ß 15-42 related peptides Decreased fibronectin Decreased antithrombin III Decreased protein C Elevated factor VIII:C Thrombocytosis (with decreased survival) Thrombocytopenia (with decreased survival) Elevated platelet factor 4 Elevated p-thromboglobulin

DIAGNOSIS OF DISSEMINATED INTRAVASCULAR COAGULATION IN MALIGNANCY Clinical Assessment The clinical diagnosis of DIC need not be difficult; the key to a high index of suspicion is to simply note the appropriate type of bleeding and thrombosis in the patient with malignancy.3,4,105 The type of bleeding manifested by most patients with fulminant or subacute DIC suggests multiple hemostatic compartment defects. For example, most patients with fulminant DIC will bleed from at least three unrelated sites simultaneously.3,4,28,29,105 This may be expressed in a wide variety of ways and commonly is

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seen as melena and hematochezia, or epistaxis, or hemoptysis in association with oozing from intra-arterial or intravenous invasion sites, hematuria, and associated findings of petechiae and purpura. 105-107 This type of bleeding or these combinations of bleeding should immediately suggest that multiple hemostatic compartments are involved. When noting this type of bleeding presentation in cancer patients, one can be almost assured of a diagnosis of DIC. Also, most cancer patients with fulminant DIC display shock and associated end-organ hypoxia and ischemic changes. 5,105 This may be manifested in a wide variety of ways, depending on end-organ involvement and degree of occlusive changes; renal failure, resulting from fibrin thrombi deposited in the renal microvasculature is a frequent manifestation, just as is pulmonary failure or CNS symptomatology. One must also recall the interplay between coagulation proteins and other protein systems. Specifically, kinin generation and complement activation in these patients often account for many attendant signs and symptoms in these bleeding or thrombosing individuals, including pain and shock. Many patients with malignancy and subacute or low-grade DIC will not display fulminant and multiple site bleeding, as is more typically seen in those with fulminant DIC; patients with lowgrade DIC more commonly complain of minor mucosal membrane bleeding often manifested as excessive gingival bleeding with tooth brushing, minor hemoptysis, bothersome epistaxis, and sometimes hematuria. 5,29,48,105-107 Also, patients with malignancy often complain of easy and spontaneous bruising and petechiae and purpura. However, petechiae and purpura may not be noticed by the patient and may only represent minimal findings found by the clinician after attentive examination. When the patient with malignancy presents with diffuse thrombosis, this may only be a manifestation of the opposite clinical spectrum of DIC; in this setting, DIC should be strongly considered and the patient appropriately studied for confirmatory proof and proper therapy started if the diagnosis is confirmed. 48,105-107,131

Laboratory Diagnosis The laboratory diagnosis of DIC is complex. Although noting the appropriate type of bleeding in the appropriate clinical setting can essentially assure a diagnosis of DIC, laboratory confirmation is desirable, if not mandatory, before committing a cancer patient to heparin, low-dose heparin, or other anticoagulant therapy. Understanding the pathophysiology of DIC makes it clear that these patients have innumerable abnormal laboratory tests of hemostasis. Most laboratory tests abnormal in DIC are only abnormal in the fulminant form of DIC; in subacute or low-grade DIC associated with malignancy,

many laboratory parameters of hemostasis may be difficult to interpret or are within normal limits. 5,105-107,131 It must be recalled that besides malignancy itself, other common complications seen in cancer patients may act as triggers for DIC, including sepsis, initiation of radiation therapy, microangiopathic hemolytic anemia, hemolysis of any etiology, hemolytic transfusion reactions, and transfusions of large amounts of banked whole blood. 28,29,32,105,106

Therapy of Disseminated Intravascular Coagulation in Malignancy Therapy of DIC in the cancer patient represents a major clinical challenge; my approach is outlined in Table 9. Effective therapy is multiphasic and must be approached in a sequential and logical manner. 28,29,32,105,132 The first and essential modality is to treat the malignancy, since this is supplying the triggering procoagulant material for intravascular coagulation to evolve. Therapy may be surgical, radiotherapy, chemotherapy, or endocrine manipulation as the clinical situation warrants. Treatment of the trigger (tumor) is often associated with cessation or significant improvement of DIC. Until attempts at antineoplastic therapy are introduced, later therapy of bleeding or thrombosis is often unsuccessful. This is especially true if the manifestation of DIC and malignancy is that of thrombosis; unless the malignancy is well-controlled, cancer patients are notoriously resistant to anticoagulant therapy. 3-5,48,105 Ther-

TABLE 9. Sequential Treatment of DIC in Malignancy 1. Treat the malignancy Surgery as indicated Radiation as indicated Chemotherapy or hormonal therapy as indicated 2. Stop intravascular clotting process Antiplatelet drug therapy Subcutaneous heparin* Intravenous heparin* 3. Component therapy as indicated Platelet concentrates Packed red cells (washed) Fresh frozen plasma Antithrombin III concentrates 4. Inhibit residual fibrino(geno)lysis Rarely, if ever, indicated Tranexamic acid Aminocaproic acid 5. Individualize therapy Type of malignancy Site(s) of bleeding and thrombosis Age Hemodynamic and medical status * Contraindicated in central nervous system metastases.

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apy must also be highly individualized, depending on overall medical condition of the patient, sites and severity of hemorrhage and thrombosis, sites of metastases, hemodynamic status, and age of the patient. If significant bleeding continues after reasonable attempts to control the malignancy, anticoagulant therapy must be considered. For the patient with malignancy and fulminant DIC, low-dose heparin therapy at 80 to 100 U/kg is given subcutaneously three to four times per day as the site and severity of hemorrhage or thrombosis dictate. 5,29,105 Patients with low-grade DIC and bothersome but not lifethreatening hemorrhage may be started on such antiplatelet agents as aspirin and dipyridamole.5 These are usually successful at stopping a low-grade intravascular clotting process. The use of antiplatelet agents in chronic DIC will usually need 24 to 36 hours to stop the intravascular clotting process; however, the use of low-dose heparin will usually stop the process within 4 to 8 hours.5'29

OTHER DEFECTS Cancer patients may also develop bleeding from other coagulation factor abnormalities; these other defects are less common, however, and are usually associated with less serious hemorrhage than associated with DIC. Patients with malignancy, especially those with liver metastases, may acquire deficiencies of the vitamin K-dependent factors.12,117 When this results in significant or life-threatening bleeding, vitamin K is usually ineffective and the hemorrhage must be controlled with fresh frozen plasma, or prothrombin complex concentrates.133 However, before using these modalities as primary approaches to therapy, DIC must be excluded. Also, if the patient with malignancy develops extrahepatic or intrahepatic biliary obstruction and cholestasis, because of tumor at any site in the biliary tree, this is often associated with malabsorption of vitamin K and defective synthesis of the vitamin K-dependent factors.5 In this setting, DIC may also occur, although this is less commonly a complication than simple decreased synthesis of the vitamin K-dependent proteins. Factor XIII deficiency or dysfunction is common in malignancy and is most pronounced in patients with liver metastases.116,134 This may result from decreased Factor XIII activators or impaired removal of Factor XIII inhibitors by the invaded liver.5 In addition, Factor XIII is associated with albumin, and cancer patients with hypoalbuminemia may be Factor XIII deficient, although usually not to a clinically significant degree. In cancer patients, acquired Factor XIII deficiency may or may not cause hemorrhage; more commonly, impaired clot formation and poor wound healing are noted. When Factor XIII deficiency is thought to cause or contribute to hem-

363 orrhage in cancer patients, it is managed by transfusions with fresh frozen plasma given at a dose of 5 cc/kg every 7 to 10 days.135 Patients with liver metastases often have low levels of other clotting factors synthesized in the liver, including fibrinogen, Factors V, VIII.C, XI, and XII, prekallikrein, high molecular weight kininogen, plasminogen, antithrombin III, protein C, protein S, and fibronectin.5 However, the decreased synthesis of these are of unclear clinical significance. Of particular concern in malignancy is the development of a dysfibrinogenemia with either primary hepatoma or liver metastases. Abnormalities in fibrin monomer polymerization are manifestations of this dysfibrinogenemia and may lead to hemorrhage in patients with disseminated malignancy and liver metastases or patients with primary hepatoma.3-5 Acquired circulating anticoagulants may materialize in a wide variety of tumors; however, these have been isolated findings in cancer patients and often, have an unclear relationship to actual hemorrhage. Many are heparinoid in nature and are found in association with carcinoma of the lung and myeloma. 3-5,48,136-140 Some appear to inhibit the activation phase of coagulation or act as antithrombins, and these have been most commonly noted in association with carcinoma of the breast.134 The important topic of acquired anticoagulants in malignancy is discussed in detail by Kunkel in this issue of Seminars. Of significance, circulating anticoagulant in the form of FDP may assume paramount clinical importance in cancer patients with low-grade covert intravascular coagulation. 5141

Primary Fibrino(geno)lysis in Solid Tumors Primary fibrino(geno)lysis has been repeatedly noted in patients with metastatic malignancy. 5,19,33,42,116 In this disorder, hemorrhage is caused by plasmin-induced biodegradation of many clotting factors, including fibrinogen, Factors V and VIII:C, and the impairment of hemostasis by circulating FDP, which interfere with fibrin monomer polymerization, thrombin generation, and platelet function.141,142 Although primary fibrinolysis happens in malignancy, DIC is a more common cause of hemorrhage in cancer patients. Many malignant tissues are capable of spontaneous fibrinolytic activity and activation of the fibrinolytic system. This has been noted in patients with carcinoma of the breast, thyroid, colon, and stomach; however, the greatest activity is seen in patients with disseminated sarcoma.3-5,33 If patients with carcinoma of the breast, thyroid, colon, or stomach develop a systemic hemorrhagic syndrome, the cause is most probably DIC and only rarely is it because of primary activation of the fibrinolytic system and a primary fibrino(geno)lytic syndrome.5 However, the opposite is true in

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patients with disseminated sarcoma.5 If these patients develop a systemic hemorrhage syndrome, the most common cause is primary fibrino(geno)lysis and only rarely is it from DIC. 3,4,33 Kwaan et al 143 have noted a decrease in tumor fibrinolytic activity in patients with liver metastases and ascribed this phenomena to increased levels of fibrinolytic inhibitors that appear with liver involvement.143 Primary fibrino(geno)lytic hemorrhage is treated with agents that inhibit the fibrinolytic system. My approach is to give epsilon-aminocaproic acid as an initial 5 to 10 gm slow intravenous push followed by 1 to 2 gm/hour for 24 hours or until bleeding stops. 5,144 After 24 hours, the patient may be placed on oral therapy if necessary. Those using this agent should be aware of the hypotension, hypokalemia, and ventricular arrhythmias that may develop. The use of epsilon-aminocaproic acid is contraindicated in the patient with DIC. 105 A newer and more potent antifibrinolytic agent now available, and possibly associated with fewer undesirable effects, is tranexamic acid; the usual dose is 500 mg orally or intravenously every 8 to 12 hours. Tumors associated with primary fibrinolysis are summarized in Table 10.

PLATELETS AND BLEEDING Thrombocytopenia Thrombocytopenia is clearly the most common cause of hemorrhage in patients with both solid tumors and hematologic malignancies.5,17 Thrombocytopenia is also commonly the result of bone marrow suppression by radiation therapy, or chemotherapy; in this regard alkylating agents are clearly the worst offenders. 145,147 Thrombocytopenia also commonly results from bone marrow invasion by tumor and generally correlates well with marrow invasion. 5,7,12,17 Marrow metastases should be suspected and carefully searched for when unexplained thrombocytopenia develops in patients with malignancy. This is done by examination of the bone marrow aspirate or biopsy, although biopsy is more reliable than aspirate alone in detecting and evaluating bone marrow involvement by carcinoma. 5,148152

TABLE 10. Malignancies Associated with Primary Fibrino(geno)lysis Sarcomas Breast Colon Gastric Thyroid

Aside from bone marrow suppressive therapy and marrow metastases, cancer patients may develop other types of thrombocytopenia. When splenomegaly develops as a part of the malignant process, hypersplenism and later thrombocytopenia may follow. 5,147,153 Also, development of splenic metastases is more common than generally recognized, especially in carcinoma of the lung, breast, prostate, colon, and stomach;5,154,155 this may lead to reactive hypersplenism and thrombocytopenia. 5,17,147 If clinically feasible, splenectomy may be of benefit in these situations. If splenectomy is considered, in an attempt to control thrombocytopenia secondary to hypersplenism, a preoperative infusion of epinephrine may help in predicting the response to this procedure. 3 5 , 1 0 6 When thrombocytopenia from decreased bone marrow production or increased splenic sequestration becomes significant, platelet concentrates provide the mainstay of management.147 Platelet counts below 10,000/mm3 are commonly associated with spontaneous and serious hemorrhage, whereas platelet counts greater than 30,000/mm3 are usually not associated with this complication unless the patient is challenged with trauma or surgical stress. 147,156 My general approach is to infuse platelet concentrates in most situations in which a platelet count is less than 10,000/mm3 unless the patient develops signs of bleeding above this level or when surgery or other invasive procedures are planned.5,147 Platelet concentrates are now readily available and provide the most efficient modality of platelet replacement therapy. An ideal platelet concentrate contains about 1.2 × 1011 platelets and generally 1 U of platelet concentrate will elevate the platelet count by around 5000 to 7000/mm3 in an adult and about 10,000 to 12,000/mm3 in an infant.157 In practice, 6 to 8 U of platelet packs are usually administered to the severely thrombocytopenic adult every time the platelet count falls below 10,000/mm3. Appropriately reduced numbers are used for children and infants.157 If long-term platelet transfusions are foreseen and proper facilities are available, HLA compatible platelets should be used if possible, especially in leukemia patients who may be candidates for bone marrow transplantation. 35 Also, directed single-donor platelets are preferred over random donor platelets. Auto-ITP occasionally happens in patients with solid tumors but is more commonly noted in patients with lymphoid malignancies.147,158 When ITP happens in association with malignancy, the approach to management should be that generally used for this disorder, using steroids and possibly splenectomy if indicated. In cases of ITP refractory to the usual forms of therapy, the use of intravenous vincristine or intravenous gamma globulin may be potentially useful. 159,160 Another type of increased platelet destruction that may sometimes be associated with malignancy is thrombotic thrombocytopenia

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Platelet Function Defects Abnormalities of platelet function are commonly found in both solid and hematologic malignancies. Because of frequent episodes of intravascular coagulation and resulting elevated FDP's noted in cancer patients, the coating of platelet surfaces by these fragments probably is the most common cause of platelet dysfunction in patients with malignancy.3,4,141 However, other platelet function abnormalities are also noted in cancer patients. Platelet factor 3 is commonly decreased in patients with cancer.163 Other platelet function defects have also been consistently noted in cancer patients and include defective platelet aggregation to ADP and other presumptive evidence of platelet dysfunction as manifested by a prolonged thromboplastin generation test, prolonged template bleeding times, positive tourniquet test, and poor clot retraction.7,163-165 It is unclear whether these defects develop secondary to the malignancy itself, whether they happen from partial release of platelet contents after contact with malignant tissue, or whether they develop in response to circulating activated clotting factors. The malignant paraprotein disorders are frequently associated with platelet function abnormalities, which develop from coating of platelet surfaces by circulating immunoglobulins; 5,166,167 consistent platelet aggregation abnormalities are found in the myeloproliferative and myelodysplastic syndromes. 3,5,45,163 The significance of these platelet function defects in contributing to hemorrhage in patients with solid tumors is unclear. However, these defects may correlate better with the development of hemorrhage in cancer patients than does the platelet count. 3,5,163,164 At the very least, these defects must be presumed to be active in aggravating bleeding in cancer patients who have an already severely compromised hemostasis system or attendant thrombocytopenia.3,5 Clinical clues to platelet dysfunction include the noting of easy or spontaneous bruising, gingival bleeding, petechiae and purpura, and other minor forms of mucosal membrane bleeding in the presence of a normal platelet count. Also, a prolonged template bleeding time is a reasonable screening test for the possibility of platelet dysfunction in patients with malignancy and, when this test is prolonged, platelet aggregation or lumi-aggregation should be done to document the presence or absence of this defect and to delineate the type and severity of defect present.168 Unless secondary to intravascular coagulation, bleeding resulting from or aggravated by platelet dysfunction calls for platelet concentrate replace-

ment therapy. This should be approached in essentially the same manner as that outlined for thrombocytopenia. Also, the patient with malignancy and a documented associated platelet function defect should be cautioned regarding use of drugs known to interfere with platelet function. Mechanisms of hemorrhage in metastatic malignancy are summarized in Table 11. The important and evolving topic of the role of platelets in metastases is discussed in the authoratative article by Honn et al and the excellent article by Bayer and associates discusses the appropriate use of platelets and other blood products in cancer patients in this issue of Seminars.

HEMOSTASIS IN MALIGNANT PARAPROTEIN DISORDERS Defects in hemostasis associated with malignant paraprotein disorders are well-known, since these commonly lead to significant clinical hemorrhage in patients with these disorders. Alterations of hemostasis in malignant paraprotein disorders are expressed as either hemorrhage or thrombosis, or a combination of the two; however, hemorrhage is more common than thrombosis.3,166 The actual incidence of hemorrhage in malignant paraprotein disorders varies somewhat depending on the particular disease present. About 15% of patients with immunoglobulin G (IgG) myeloma experience hemorrhage, whereas those with IgA myeloma have a 40% chance of hemorrhage.3,166 Patients with Waldenstrom's macroglobulinemia or IgM myeloma have a greater than 60% chance of significant hemorrhage.6,166,169 There are many reasons for hemorrhage in patients with malignant paraprotein disorders and some of these are not simply because of changes of the hemostasis system. The most common reasons for hemorrhage are because of abnormalities in hemostasis, which are manifestations of circulating paraprotein. Also, uremia and attendant abnormal platelet function accounts for significant hemorrhage in many of these patients. Liver failure or hypersplenism may also be associated with defects in

TABLE 11. Hemorrhagic Syndromes Seen with Metastatic Malignancy* Thrombocytopenia Disseminated intravascular coagulation Decreased clotting factors Primary fibrino(geno)lysis Platelet dysfunction Vascular defects Circulating anticoagulants * In descending order of probability.

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purpura. 5,147,161,162 This rare syndrome is commonly fatal when it develops in the cancer patient but may respond to vigorous plasmapheresis, plasma exchange, or the use of intravenous prostacyclins.161

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hemostasis in patients with malignant paraprotein disorders. 3,48,166 Hypersplenism is a frequent accompaniment of malignant paraprotein disorders, and significant thrombocytopenia resulting from splenic sequestration of platelets may develop. Many patients with malignant paraprotein disorders develop liver disease with resultant decreased synthesis of the vitamin K-dependent factors, abnormal fibrinogen (dysfibrinogenemia), abnormal fibrinolytic activity, and other coagulation protein defects associated with diffuse myelomatous involvement of the liver. DIC has been reported in myeloma and may account for hemorrhage in some patients. Thrombocytopenia resulting from chemotherapy or radiation therapy may also lead to hemorrhage in patients with malignant paraprotein disorders. Also, significant thrombocytopenia obviously may result from bone marrow replacement in multiple myeloma, light chain disease, or Waldenstrom's macroglobulinemia.

Thrombocytopenia is commonly seen in malignant paraprotein disorders but is often not pronounced enough to account for clinically significant bleeding. Thrombocytopenia can happen via several mechanisms in myeloma, primarily by the development of hypersplenism and increased platelet sequestration, liver disease, radiation therapy, chemotherapy, or bone marrow replacement, as discussed earlier.

antigen-antibody reaction but simply a chemical paraprotein-protein interaction with platelet membrane receptor sites. There is poor correlation between platelet aggregation abnormalities and template bleeding times in multiple myeloma or other malignant paraprotein disorders. Up to 80% of patients with malignant paraprotein disorders have markedly abnormal aggregation and release; epinephrine-induced aggregation is abnormal in about 90% of patients, ADP-induced aggregation and release is abnormal in about 60% of patients, and collagen-induced aggregation is abnormal in about 60% of patients with malignant paraprotein disorders.170 The most sensitive indicator of abnormal platelet aggregation in multiple myeloma is epinephrine-induced platelet aggregation. 3,5,166 It is of interest that some individuals show markedly abnormal platelet lumi-aggregation but will have normal template bleeding times and the absence of clinical bleeding. Besides the conditions just mentioned, there are other causes of abnormal platelet function in multiple myeloma, including uremia, the development of liver disease, and circulating FDP. Also, malignant paraproteins may coat the vasculature, interfere with normal endothelial function, or may precipitate in the vasa vasorum, interfering with vascular function; paraprotein may interfere with in vivo collagen-induced platelet aggregation and these may account for not only prolonged template bleeding times, but also interference with the normal platelet-endothelial cell interaction.

Platelet Dysfunction

Coagulation Proteins

Platelet function defects are more common causes of hemorrhage in malignant paraprotein disorders than is thrombocytopenia.5,166 Many patients with multiple myeloma have a prolonged template bleeding time, which correlates well with clinical bleeding, however, many patients have normal or shortened bleeding times even with marked defects in platelet function. Platelet aggregation or lumi-aggregation studies are usually markedly abnormal in most patients with circulating paraprotein and these studies correlate better with predisposition to clinical hemorrhage.3,5,166 Abnormalities of platelet function in multiple myeloma have not been clearly defined, but usually result from coating of platelet membrane surfaces by paraprotein.3,5,166 Platelet aggregation abnormalities are seen in about 80% of patients with myeloma and do not correlate well with the type of paraprotein.3,166 However, there appears to be some correlation with the quantity of paraprotein circulating. Platelet factor 3 release has been normal more often than abnormal in my patient population with myeloma and associated abnormal platelet lumi-aggregation.48 It is thought that platelet membrane coating by paraprotein is not an

Malignant paraprotein may interfere with coagulation proteins. Probably the most publicized change of the coagulation system in malignant paraprotein disorders is inhibition of a single specific clotting factor, such as Factor VIILC. However, in reality, this phenomenon is rare and the least common cause of hemorrhage by paraprotein-coagulation protein interactions. When specific inhibition of blood coagulation factors by paraprotein does happen, it is usually somewhat selective, for example, IgG paraprotein is commonly directed against Factors II, VII, X, or thrombin; alternatively IgA and IgM paraproteins are more commonly directed against the larger coagulation proteins, usually Factors V and VIII:C activity. The most common coagulation protein interaction is inhibition of fibrin monomer polymerization. Paraprotein selectively attacks fibrin monomer and hampers polymerization into a stable fibrin clot. It is unclear if paraprotein coats the intact fibrinogen molecule and hinders the generation of fibrin monomer after exposure to thrombin, or, alternatively, if paraprotein attacks fibrin monomer only after its generation from fibrinogen. 166,167 It has been proposed, but not proven, that the

Thrombocytopenia

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Other Defects Low-grade DIC is present in some patients with malignant paraprotein disorders, although this is uncommon. 3,5,166 Also, enhanced fibrinolytic activity is present in many patients with malignant paraprotein disorders. This is manifested by the presence of circulating elevated FDPs, the presence of circulating plasmin, and the absence of soluble fibrin monomer complexes. The mechanism by which this happens is unclear. To complicate this situation further, rare patients develop circulating heparinoids that have, on occasion, been responsible for severe fatal hemorrhage. 136-138

Management of Hemorrhage in Paraprotein Disorders Therapy of hemorrhage in patients with malignant or benign paraprotein disorders presents difficult management problems. The exact alterations of hemostasis associated with hypersplenism, uremia, liver infiltration, and bone marrow infiltration are usually best controlled by proper management of the paraprotein disorder itself. This also applies to paraprotein inhibition of platelet function, coagulation protein defects, or inteference by paraprotein of fibrin monomer polymerization. Often, these defects will correct partly, and sometimes completely, with decreases in the myeloma cell population induced by chemotherapy or radiation therapy. When bleeding becomes severe and rapid control of hemorrhage is called for, vigorous plasmapheresis is usually effective for rapidly lowering the paraprotein concentration and restoring normal or near normal hemostasis.174 Desmopressin has been useful in aborting bleeding associated with acquired von Willebrand's syndrome in my-

eloma. The topic of coagulation defects in paraprotein disorders is discussed in greater detail by an authority on the subject, Glaspy, elsewhere in this issue of Seminars.

EFFECTS OF CHEMOTHERAPY ON HEMOSTASIS Chemotherapeutic agents may alter hemostasis by a variety of mechanisms.3'5 The most common and significant of these include the thrombocytopenia commonly associated with bone marrow suppressive cytotoxic drugs or the initiation or enhancement of DIC by cytotoxic drugs or hormones in both solid tumors and acute promyelocytic or myelomonocytic leukemia. L-asparaginase therapy is often accompanied by substantial hypofibrinogenemia, a common complication of this drug. Although earlier investigators attributed this phenomenon to decreased fibrinogen synthesis,175 others have shown this to result from the synthesis of functionally abnormal fibrinogen. This arises from reactions between L-asparaginase and asparagine residues of the fibrinogen molecule.176 Also, L-asparaginase may induce a DIC-type syndrome. Plicamycin therapy may be associated with hemorrhage in greater than 50% of patients receiving this drug and, although plicamycin causes thrombocytopenia, hemorrhage is more often because of impaired platelet function, hyperfibrino(geno)lysis, and decreased levels of Factors II, V, VIII:C, and X. 3,177 In view of these findings, the triggering of DIC by plicamycin seems probable. Actinomycin D is also associated with hemorrhage; actinomycin D is a potent vitamin K antagonist and causes defective (PIVKA) synthesis of Factors II, VII, IX, and X. 178 Mitomycin is associated with the development of a microangiopathic hemolytic anemia.179-182 Doxorubicin (Adriamycin)183 and daunorubicin (daunomycin)184 cause primary activation of the fibrinolytic system and later clinical hemorrhage. Melphalan, cytosine arabinoside, daunorubicin, vincristine, and vinblastine induce platelet dysfunction, which may contribute to bleeding in patients receiving these antineoplastic agents.3,185 Thrombosis resulting from single or multiple agent chemotherapy or hormonal therapy has been repeatedly reported. 5,186-190

HEMOSTASIS AND BONE MARROW TRANSPLANTATION The most common defect in hemostasis associated with bone marrow transplantation is hepatic veno-occlusive disease. This syndrome happens 3 to 4 weeks posttransplantation, is probably because of aggressive preconditioning radiochemotherapy, and is characterized by

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Fab segment is the primary site of attachment to fibrin monomer by paraprotein. The noting of an abnormal thrombin time or reptilase time is a good indication of inhibition of fibrin monomer polymerization in paraprotein disorders and correlates well with clinical hemorrhage resulting from this phenomenon.3,5,166 An abnormal thrombin time or reptilase time is often noted in greater than 50% of patients with malignant paraprotein disorders.3,166 The presence of an abnormal thrombin time or reptilase time is well-correlated with clinical bleeding. However, there is not good correlation between abnormal prolonged thrombin times and reptilase times and the quantity or type of paraprotein present. As mentioned earlier, acquired von Willebrand's syndrome may be noted in association with malignant paraprotein diseases; in myeloma, this has been noted to be because of an inhibition, by paraprotein, of von Willebrand factor.171"173

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sudden weight gain, hepatomegaly, ascites, hyperbilirubinemia, and hepatic encephalopathy. This syndrome is preceded by 3 to 4 days of thrombocytopenia, usually refractory to platelet transfusions. It was first thought that hepatic veno-occlusive disease, post-transplantation, may be related to graft-versus-host disease (GvHD); however, there is probably no such relationship. The early symptomatology of hepatic veno-occlusive disease can be confused with GvHD. The incidence in major transplantation centers is about 40%, with the highest incidence being noted in aggressively preconditioned patients with acute leukemia or in patients who have pretransplantation transaminasemia. The mortality may be from 30 to 4 5 % . 1 9 , 1 9 2 The pathophysiology of this devastating complication of transplantation has been thoroughly studied by Shulman et al, 193 who found an overall incidence of 21% among transplant patients, with a mortality of 33%. This study evaluated the molecular and cellular events associated with veno-occlusive disease by use of immunofluorescent staining with anti-Factor VIII, antifibrinogen, and antibody to platelet glycoprotein lb. In the 11 patients studied, eight had widespread hepatic changes and three had patchy lesions. The lesions were associated with marked widening of the subendothelial zone of terminal hepatic venules and sublobular veins by fragmented red cells within an edematous background. The central lobar area had severe congestion with hemorrhagic necrosis of hepatocytes. Five of eight patients with late veno-occlusive disease had diffuse fibrous obliteration of most central venules associated with atrophy of central lobar hepatocytes, sinusoidal widening, and fibrosis. The remaining three patients with late veno-occlusive disease had only focal fibrotic obliterative changes of the central venules. Immunohistochemical stains revealed that nine of the 11 patients with early veno-occlusive disease demonstrated intense immunostaining of the adventitial portion of the central vein walls (intima) with anti-Factor VIII and some patients had additional immunostaining for anti-Factor VIII in the subendothelial zone. It was also noted that a significant number of patients with early veno-occlusive disease had antifibrinogen staining on both the central venules and in the central lobar areas. However, none of the patients had immunostaining for antibody to platelet glycoprotein 1b. This study indicates that in the early stages of venoocclusive disease the coagulation system is activated around and within the walls of the central venules. Veno-occlusive disease and its sequellae, the deposition of interstitial collagens, can be considered a form of localized wound healing confined to the central lobar area of the liver acinus. The liver immunohistochemical studies suggest that coagulation proteins are first deposited within the adventitial zone of affected terminal hepatic venules before involving the subendothelial zone.

Shulman and associates193 could not explain the lack of antiplatelet glycoprotein lb but suggested that this may have resulted from either postmortem autolysis or from lysis of platelet thrombi following aggregation. Another complication that has, on occasion, been associated with bone marrow transplantation is that of nonbacterial thrombotic endocarditis. Jerman and Fick194 reported on two patients treated with bone marrow transplantation who later developed fatal nonbacterial thrombotic endocarditis. These particular patients developed typical findings of DIC, soft systolic cardiac murmurs, hematuria, and signs of cerebral embolic events. The overall incidence of nonbacterial thrombotic endocarditis in bone marrow transplant recipients may approximate 10%.195

SUMMARY As outlined in this review, patients with cancer may harbor many alterations of hemostasis. These are multifaceted and must be taken into account when trying to control hemorrhage or thrombosis in cancer patients. Often, hemorrhage or thrombosis is the final fatal event in many patients with metastatic solid tumor or hematologic malignancies. Patients with malignancy present a major clinical challenge in this new era of oncologic awareness and more aggressive care, which has led to prolonged survival for patients and a longer time frame during which these complications may develop. Therefore, these complications are occurring more commonly. It is important to realize that these alterations of hemostasis exist and must be approached in a sequential and logical manner with respect to diagnosis; only in this way can responsible, efficacious, and rational therapy be delivered to patients. By far the most common alteration of hemostasis in malignancy is that of hemorrhage associated with thrombocytopenia, either drug-induced, radiation-induced, or from bone marrow invasion. However, hemorrhage resulting from DIC is also quite common and may present as hemorrhage, thrombosis, thromboembolus, or any combination thereof. Many antineoplastic drugs and radiation therapy may lead to or significantly enhance hemorrhage in patients with malignancy. Thrombosis, also commonly seen in patients with malignancy, is often a manifestation of low-grade DIC, conspicuous as an intravascular thrombotic or thromboembolic event instead of an intravascular proteolytic (hemorrhagic) event. When suspecting this, confirmatory laboratory evidence must be sought and the patient treated appropriately. When approaching the patient with malignancy and either hemorrhage or thrombosis, all the potential defects in hemostasis must be taken into account, defined from the labo-

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ratory standpoint, and treated in as precise and logical manner as possible.

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Coagulation abnormalities in malignancy: a review.

As outlined in this review, patients with cancer may harbor many alterations of hemostasis. These are multifaceted and must be taken into account when...
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