29 - Transfusion Therapy, Bleeding, and Clotting | Handbook of Cancer Chemotherapy

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section IV - Selected Aspects of Supportive Care of Patients with Cancer > Chapter 29 - Transfusion Therapy, Bleeding, and Clotting

Chapter 29

Transfusion Therapy, Bleeding, and Clotting

Mary R. Smith

NurJehan Quraishy

Disorders of the hemostatic mechanisms are common in patients with malignancy. Abnormalities associated with thromboembolic events cause significantly more morbidity and mortality than disorders leading to hemorrhage.

I. Thromboembolism in cancer

A. Pathophysiology

The thromboembolic risk associated with neoplasia reflects an imbalance between platelet number, platelet function, levels of coagulation factors, and generation of thromboplastins as compared with the levels of inhibitors of hemostasis and fibrinolytic activity. Thrombosis may be minor and localized or widespread and associated with multipleorgan damage. There may also be hemorrhage of varying degrees of severity in association with the thromboembolic events.

Factors that may affect the risk of thromboembolism vary widely from patient to patient and include the following:
- Specific type of tumor
- Nutritional status of the patient
- Type of chemotherapy
- Response to chemotherapy (e.g., tumor lysis syndrome)
- Liver and renal function
- Patient immobility and venous stasis
Factors that can initiate thrombus formation are common to many cancers:
- Circulating tumor cells adhere to the vascular endothelium and form a nidus for clot formation.
- Tumors may penetrate the vessel, destroying the endothelium and promoting clot formation.
- Neovascularization associated with many tumors may stimulate clotting.
- Arterial thrombosis associated with tumors may result from vasospasm.
- A systemic hypercoagulable state develops (e.g., decreased protein C).
- External compression of vessels by tumor masses impedes blood flow and leads to stasis and clot development.
Platelet abnormalities associated with an increased risk of thromboembolism include thrombocytosis and increased platelet adhesion and aggregation. Tumors may produce substances that cause increased platelet aggregation with subsequent release of platelet factor III and ensuing acceleration of coagulation.

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B. Clinical syndromes

A variety of noteworthy clinical syndromes are associated with the hypercoagulable state of malignancy and its treatment.

Disseminated intravascular coagulation (DIC). DIC is a syndrome with many signs, symptoms, and abnormal laboratory results (Table 29.1). As many as 90% of patients with metastatic neoplasms have some laboratory manifestation of DIC, but only a small fraction of these patients suffer morbidity from the coagulation process or subsequent depletion of coagulation factors and consequent bleeding due to DIC. The initiating factor for DIC is apparent in some situations but unknown in others.

Among the common initiators of DIC are the following:

Thromboplastic substances in granules from promyelocytes of acute promyelocytic leukemia (DIC may worsen with therapy). There is a significant concomitant fibrinolysis in many patients.
Sialic acid from mucin produced by adenocarcinomas of the lung or gastrointestinal tract.
Trypsin released from pancreatic cancer.
Impaired fibrinolysis associated with hepatocellular carcinoma.
DIC in any patient may be fostered by sepsis or other causes of the systemic inflammatory response syndrome (SIRS).

Table 29.1. Laboratory diagnosis of disseminated intravascular coagulation (DIC)

Laboratory Tests	Acute DIC	Chronic DIC
Screening
PT, aPTT	Usually prolonged	Normal
Platelets	Usually decreased	Normal or slightly decreased
Fibrinogen	Usually decreased but may be normal^a	Usually normal^a
Confirmatory^b
Fibrin monomer	Positive	Positive
FDP	Strongly positive	Positive
D-Dimer	Positive	Positive
Thrombin time	Normal or abnormal	Usually normal
Factor assays	Decreased factors V and VIII	Normal factors V and VIII
Antithrombin III	May be reduced	Usually normal
PT, prothrombin time; aPTT, activated partial thromboplastin time; FDP, fibrinogen degradation products. ^aFibrinogen is usually elevated in advanced malignancy or acute leukemia that is not complicated by DIC. Therefore, a normal fibrinogen level may actually be decreased for the physiologic state of the patient. ^bChanges indicated are confirmatory if present; the absence of the indicated findings in some of the confirmatory tests does not exclude the diagnosis.

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Lupus anticoagulant in neoplastic disease. The lupus anticoagulant is an antiphospholipid antibody (immunoglobulin G or M). Antiphospholipid antibodies are reported to be associated with a number of malignant disorders including hairy cell leukemia, lymphoma, Waldenstr m's macroglobulinemia, and epithelial neoplasms. The lupus anticoagulant leads to a prolonged activated partial thromboplastin time (aPTT) but is paradoxically associated with an increased risk of thrombosis.
Trousseau's syndrome (tumor-associated thrombophlebitis). The possibility of neoplasia should be suspected in the following circumstances:
- An unexplained thromboembolic event occurs after the age of 40 years.
- Thromboses occur in unusual sites.
- The thromboses affect superficial as well as deep veins.
- The thromboses are migratory.
- The thromboses tend not to respond to the usual anticoagulant therapies.
- An unexplained thrombosis occurs more than once.
Thrombotic events that occur after surgery for tumors of the lung, ovary, pancreas, or stomach.
Nonbacterial thrombotic endocarditis may be found in association with carcinoma of the lung. These thrombi are formed from accumulations of platelets and fibrin. The mitral valve is the most frequent site of origin of these thrombi, which frequently embolize.
Thrombotic thrombocytopenic purpura (TTP) is a poorly understood syndrome characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, fluctuating neurologic signs and symptoms, and acute renal failure. TTP and the hemolytic uremic syndrome (thrombocytopenia, hemolysis, and acute renal failure) have been associated with untreated malignancies as well as with a number of drugs used for treating malignant disease. The agent most often reported is mitomycin, but other drugs including bleomycin, cisplatin, cyclophosphamide, gemcitabine, and vinca alkaloids may also be associated with these syndromes. TTP may be difficult to diagnose in this setting because the chemotherapy suppresses platelet production, some agents may impair renal function, and many of the features of TTP are similar to those of DIC. Careful review of the peripheral blood smear is required to identify the changes in red blood cells (RBCs) that are associated with a microangiopathic hemolytic process.

There is growing evidence that damage to the endothelium is seen in association with TTP. For many patients with TTP, von Willebrand cleaving protease levels are very low or absent, leading to the presence of unusual ultralarge multimers of von Willebrand factor (vWF). The von Willebrand cleaving proteolytic activity is thought to be inhibited by an anti vWF-cleaving protease immunoglobulin G.

The prognosis of patients with TTP is poor, and its therapy has been varied. Plasmapheresis and transfusion with fresh frozen plasma (FFP) appear to be the best modalities
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of therapy. Plasmapheresis and FFP infusion replace the von Willebrand cleaving protease that is missing in patients with TTP. In patients who are nonresponders to plasmapheresis or plasma transfusion, immunoadsorption of the patient's plasma by staphylococcal protein A columns has been used.

Complications from platelet transfusions are not as common in TTP associated with malignancy and bone marrow transplantation as in other cases of TTP; therefore, platelet transfusion can be used especially if there is a threat of bleeding.
Thromboembolism associated with chemotherapy
- The use of central arterial or venous catheters has markedly facilitated the delivery of chemotherapy, but all such catheters are associated with a significant risk of vascular thrombosis. The empiric use of low doses of warfarin (1 mg/day) decreases the risk of thrombosis without inducing a hemorrhagic state. It is not necessary to monitor the prothrombin time (PT) with low-dose warfarin.
- Many chemotherapy agents cause significant chemical phlebitis. The most common offending agents are mechlorethamine (nitrogen mustard), anthracyclines, nitrosoureas, mitomycin, fluorouracil, dacarbazine, and epipodophyllotoxins.
- L-Asparaginase inhibits the synthesis of proteins, including coagulation factors. This inhibition may cause either hemorrhage or thrombosis. Patients with preexisting hemostatic disorders are at particular risk for complications when using L-asparaginase. L-Asparaginase also decreases antithrombin III (AT-III) activity.
- Tamoxifen has been associated with thromboembolic events. This effect may be magnified when tamoxifen is combined with chemotherapeutic agents.
- Thalidomide and lenolidomid are associated with a high frequency of thromboembolism, particularly when used in combination with high dose steroids in the treatment of multiple myeloma.
- Estrogens may increase the risk of thromboembolism. This is likely due, at least in part, to a decrease in protein S and an increase in coagulation factors.
- Superior vena cava syndrome is nearly always associated with thrombosis in the thoracic venous system cephalad to the site of obstruction and may lead to upper-extremity thrombosis.

C. Principles of therapy for thrombosis associated with neoplasia

Discrete vascular thrombosis

General guidelines. Therapy should be directed at controlling the neoplasm. As an anticoagulant, heparin is superior to warfarin in these patients. Warfarin and antiplatelet drugs have been used with varying degrees of success in some patients with thromboembolism associated with tumors. The use of heparin, warfarin, and antiplatelet agents alone or in combination may be associated with normalization of hemostatic parameters.
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Despite this, patients with malignant disease are often resistant to anticoagulant therapy and may continue to have thrombotic events even while receiving what appears to be adequate anticoagulant therapy. Great care must be exercised in the use of both heparin and warfarin in patients with malignant disease because hemorrhage into areas of necrotic tumor can be hazardous. The use of anticoagulant therapy is generally contraindicated in patients with central nervous system metastases. Bulky disease is a relative contraindication, especially if central necrosis of the tumor is suspected and particularly if the lesion is in the mediastinum or pleural spaces.

The decision to treat thromboembolism occurring in a patient with malignancy may be difficult. One must carefully weigh the risks of therapy against expected benefits. The patient's life expectancy, concurrent therapy, and type of malignancy also influence the decision.
Heparin. Low doses of heparin (5,000 U given SC every 12 hours) can be used to protect patients with malignant disease from thromboembolism during perioperative periods. Heparin may be used as the initial or long-term therapy for thromboembolic events in patients with malignant disease. Heparin may be administered either IV or by the SC route. Generally, the IV route is preferred for initial therapy so that the anticoagulant effect begins at once and adjustment of doses can be easily achieved. An initial dose of 5,000 U (70 U/kg) of heparin is given as an IV bolus followed by 1,000 to 1,200 U (15 U/kg)/hour as a continuous infusion. One should check the aPTT 1 hour after the heparin bolus to ensure that the patient is heparinizable (i.e., not AT-III deficient), 6 hours after beginning therapy, and 6 hours after any change in the dose of heparin. Some patients with malignant disease may appear to be refractory to heparin; in all likelihood, this reflects low levels of AT-III, owing to poor production or increased consumption, both of which may occur in patients with malignant disease. (Note: infusion therapy with L-asparaginase has been associated with reduced levels of AT-III.) As long as the AT-III activity is above 50% of normal, it is usually possible to achieve the desired anticoagulant effect if adequate doses of heparin are given. If AT-III activity is less than 50% of normal, AT-III may be replaced using AT-III concentrates or FFP.

Heparin may be administered by the SC route for both acute and chronic management of thromboembolism associated with malignancy. Using the SC route may be less desirable when treating acute events because the onset of anticoagulant effect is somewhat slower (2 3 hours), and adjusting the therapeutic effect may be more difficult. SC heparin can be considered for chronic therapy, provided that the patient can manage the twice-daily injection and weekly monitoring of the aPTT. In a patient who has been receiving IV heparin, half the total dose of IV heparin received in the previous 24 hours should be given SC twice a day (e.g., 1,000 U/hour by IV
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infusion equals an SC dose of 12,000 U b.i.d.). For the patient being started on SC heparin, the initial dose is 7,500 to 10,000 U SC, b.i.d. The aPTT should be checked 6 hours after the third dose of heparin. Otherwise, the aPTT should be checked 6 hours after an SC dose of heparin. The goal for the aPTT should be similar to that of IV heparin, namely, 1.5 to 2 times the patient's baseline aPTT.

Low molecular weight (LMW) heparin(s) can be used for thromboembolism and for primary prevention. The selection of drug and its dosing schedule should be made by the treating physician. If monitoring of the drug is indicated owing to liver or kidney dysfunction in the patient, one must use anti-Xa levels as the aPTT is not indicative of the anticoagulant effect of LMW heparins.

Warfarin is often selected as the therapy of choice for the chronic management of thromboembolic events associated with malignant disease. The use of warfarin in this setting is of concern because patients with malignant disease are frequently taking multiple medications that can alter the patient's response to warfarin. An additional concern about the use of warfarin in patients with malignancy is the development of purpura fulminans. This complication may be due to lower-thannormal protein C levels in patients who had DIC before initiation of warfarin therapy. Warfarin should not be used if there is laboratory evidence of DIC.

Despite these caveats, warfarin is often used for the prevention and treatment of clotting problems in patients with cancer. For most patients, an international normalized ratio (INR) of 2 to 3 is required; for patients with mechanical prosthetic valves, recurrent systemic embolism, or lupus anticoagulant with thrombosis, an INR of 2.5 to 3.5 is necessary (Table 29.2). Table 29.3

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also gives the recommended vitamin K dose necessary to reduce the INR to therapeutic levels in patients who are taking warfarin and have INR values higher than 5. Care must be taken to balance the risks of bleeding in patients with elevated INRs with or without thrombocytopenia against the risks of clotting and thrombosis if the reversal of anticoagulation is too vigorous.

Table 29.2. Clinical indications and international normalized ratio (INR) goals: using the INR for anticoagulation monitoring

A. Clinical indications requiring an INR of 2.0 3.0
Prophylaxis of venous thrombosis (high-risk surgery)
Treatment of venous thrombosis
Treatment of pulmonary embolism
Prevention of systemic embolism
Tissue heart valves
Valvular heart disease
Atrial fibrillation
Recurrent systemic embolism
Cardiomyopathy
B. Clinical indications requiring an INR of 2.5 3.5
Mechanical prosthetic valves (high risk)
Acute myocardial infarction

Table 29.3. Vitamin K1 administration for patients on warfarin doses of vitamin K1 to reduce INR in patients on warfarin

INR	Vitamin K1 Dosage (slow IVP)^a	Time Expected for Response to Vitamin K or to Repeat INR
>3.5 but <5	None, hold warfarin	24 h
5 but <9.0 (no significant bleeding)	Omit one or two doses, monitor closely and resume at a lower dose or Give 0.5 1.0 mg; may repeat dosage if INR is still high at 24 h	Reduction of INR expected at 8 h; therapeutic INR expected at 24 48 h
9.0 (no significant bleeding)	3 5 mg; may repeat dosage if INR is still high at 6 12 h	Reductions of INR expected at 6 h; repeat INR every 6 12 h
(significant bleeding)	Vitamin K 10 mg IV slowly and fresh frozen plasma or prothrombin complex if situation is urgent Hold warfarin
(life-threatening bleeding)	Give prothrombin complex or recombinant factor VIIa
^aIf patient is bleeding, a procedure is planned, or patient has just had a procedure, consider the use of fresh frozen plasma or prothrombin complex. Modified from Ansell J, Hrish J, Poller L, et al. The pharmacology and management of oral vitamin K antagonists. Chest 2004;126:204S 233S

The use of platelet-inhibiting drugs such as aspirin, other nonsteroidal anti-inflammatory agents, and dipyridamole has met with varying degrees of success in the prevention of repeated thromboembolic events in patients with malignant disease. Care must be taken with the use of such drugs, especially in thrombocytopenic patients, because the risk of bleeding associated with thrombocytopenia is increased.
Fibrinolytic therapy. Systemic malignancy is a relative contraindication to fibrinolytic therapy.
Vascular interruption devices such as inferior vena caval filters may be used in patients who cannot tolerate anticoagulant therapy or who develop emboli while on adequate anticoagulant therapy.

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Disseminated intravascular coagulation. Therapy for DIC includes the following:
- Correct shock urgently (if present).
- Treat the underlying disease process; when it is not possible to treat the underlying disease process it is unlikely that the complicating DIC can be successfully managed.
- Replace depleted blood components (e.g., platelets, cryoprecipitated antihemophilic factor [AHF] for fibrinogen and factor VIII, FFP for other factors) if clinically significant bleeding is present.
- Consider the use of heparin only in the following situations:
  - In patients with acute promyelocytic leukemia (see Chapter 19)
  - When there is clear evidence of ongoing end-organ damage due to microvascular thrombosis
  - If venous thrombosis occurs
The latter two complications of DIC are most likely to occur as a component of the SIRS, and the treatment of the underlying cause of the SIRS is necessary in addition to treatment with heparin. There is no evidence that chronic warfarin therapy is of value for treating the chronic DIC seen in some patients with neoplasia if thromboses are absent. Warfarin may predispose to the development of purpura fulminans in the presence of chronic DIC due to acquired protein C deficiency.

II. Bleeding in patients with cancer

A. Tumor invasion

It is well recognized that bleeding may be a warning sign of cancer. Bloody sputum may indicate carcinoma of the lung, blood in the urine may be a sign of carcinoma of the bladder or kidney, blood in the stool may be due to carcinoma of the alimentary tract, and postmenopausal vaginal bleeding may be caused by endometrial carcinoma. In each of these instances, bleeding can be directly related to the invasive properties of cancer and disruption of normal tissue integrity.

B. Hemostatic abnormalities

Often bleeding in patients with cancer is not due to the direct effects of the neoplasm but rather due to indirect effects of the cancer or its therapy on one of the components of the hemostatic system. Because of the special management problems caused by abnormalities in the hemostatic system in patients with cancer and the frequency with which these problems occur, it is important to consider the possible causes and corrective measures in detail.

Increased vascular fragility may be due to chronic corticosteroid therapy, chronic malnutrition, or senile purpura. Bleeding is usually not severe, but bruising, particularly around IV sites, is common. Hemostatic therapy is not necessary.
Thrombocytopenia may occur for a variety of reasons. Some of the more common causes are as follows:
- Chemotherapy and radiotherapy regularly cause depression of platelet production. Serial blood cell counts must be monitored while patients are being treated.
- Bone marrow invasion or replacement causing thrombocytopenia is commonly seen only with leukemias or lymphomas but may occur in other cancers that invade the bone marrow.
- Splenomegaly with splenic sequestration is most common with leukemia or lymphoma.
- Folate deficiency with decreased platelet production is common in patients with cancer because of poor nutrition. Dietary history should provide the clues to the diagnosis.
- Neoplasm-induced immune thrombocytopenic purpura. Patients with lymphoproliferative malignancies (e.g., chronic lymphocytic leukemia, Hodgkin's disease) often develop immune thrombocytopenic purpura (ITP). ITP may also be the presenting symptom of a nonhematologic malignancy. Usually, the ITP improves with prednisone 1 mg/kg/day followed by treatment of the malignancy.
- Drug-induced immune thrombocytopenia. Many nonchemotherapy medications used to treat patients with malignancy can cause immune thrombocytopenia. Offending agents to consider are heparin, vancomycin, H2-receptor antagonists, penicillins, cephalosporins, interferon, and sulfa-containing antibiotics, diuretics, and hypoglycemic agents.
- Graft-versus-host disease developed after bone marrow transplantation may produce a chronic (often isolated) immune-mediated thrombocytopenia. The platelet count may respond to increased immunosuppression.
Abnormalities of platelet function must be suspected in patients who have a normal or near-normal platelet count but signs or symptoms of bleeding and a documented prolonged bleeding time. Most cases are secondary to drug effects including aspirin and other nonsteroidal anti-inflammatory agents, antibiotics (e.g., ticarcillin), antidepressants (e.g., tricyclic drugs), tranquilizers, and alcohol. Consider any drug that the patient is taking as a possible offender until proved otherwise. The presence of fibrin degradation products is a common cause of platelet dysfunction in patients with malignancy who also have DIC. Platelet dysfunction may occur in patients with malignant paraproteinemias as a result of the coating of platelet surfaces by the immunoglobulin. When renal failure develops or is present in such patients, the platelet dysfunction is magnified.
Coagulation factor deficiencies may develop in patients with malignancy for several reasons:
- Acute (decompensated) DIC depletes most clotting factors but to variable degrees.
- Liver failure causes deficiency of all clotting factors except factor VIII.
- Malnutrition leads to deficiency of factors II, VII, IX, and X (the vitamin K dependent factors).
- Fibrinolysis may be due to the release of urokinase in prostate cancer or secondary to DIC. This may produce
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  hypofibrinogenemia as well as fibrin split products, which act as circulating anticoagulants.
- Functionally abnormal clotting factors are occasionally seen. The most commonly diagnosed abnormality is dysfibrinogenemia.
Acquired circulating anticoagulants may develop in patients with a number of different tumors. Many of these anticoagulants are heparinoid in nature. The most common associations are with carcinoma of the lung and myeloma. Other anticoagulants act as antithrombins; in this case, the most common association is with carcinoma of the breast.
Chemotherapy and other drug-induced bleeding
- Mithramycin, although rarely used now, may lead to platelet dysfunction and a reduction in multiple coagulation factors. Hemorrhage due to these effects may occur in up to half the number of patients treated with mithramycin.
- Anthracyclines may be associated with primary fibrinolysis or fibrinogenolysis and hemorrhage.
- Dactinomycin is a powerful vitamin K antagonist that causes defective synthesis of all vitamin K dependent proteins (factors II, VII, IX, and X, protein C, and protein S).
- Melphalan, cytarabine, doxorubicin, vincristine, and vinblastine are all associated with platelet dysfunction.
- Mitomycin, daunorubicin, cytarabine, bleomycin, CDDP, methyl-CCNU, tamoxifen, deoxycoformycin, gemcitabine, atorvastatin, clopidogrel, ticlopidine, cyclosporine, sulfonamides, tacrolimus, sirolimus, crack cocaine, penicillin, rifampin, penicillamine, oral contraceptives, arsenic, quinine, and iodine are all associated with TTP.

III. Laboratory evaluation of hemostasis in patients with malignancy

About half of all patients with cancer and approximately 90% of those with metastases manifest abnormalities of one or more routine coagulation parameters (Table 29.4). These abnormalities may be minor early in the patient's disease, but as the disease progresses, the hemostatic abnormalities become more pronounced. Serial coagulation tests may offer the clinician a clue to response to therapy or recurrence of malignant disease. Serial evaluations of coagulation tests are of more value in patients with no symptoms of hemostatic disruption than is a single determination.

A. Screening tests for bleeding

The following tests provide an adequate screening battery: platelet count, bleeding time or whole blood platelet function screening testing, aPTT, PT, thrombin time, and fibrinogen level.

B. Interpretation of screening laboratory studies

Abnormal results of the screening tests reflect hematologic problems caused by blood vessels, platelets, or coagulation factors. The following list provides clues to the interpretation of the screening test results that help determine the most likely cause or causes of the patient's bleeding.

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Table 29.4. Coagulation tests that may show an abnormality in patients with cancer without clinical bleeding or thrombosis

Test	Common Results in Patients with Malignancy
Antithrombin III	Decreased
-Thromboglobulin	Increased
Cryofibrinogen	Present
D-Dimer	Increased
Factor VIII	Increased
Fibronectin	Decreased
Fibrin monomer (soluble)	Present
Fibrinogen	Increased
Fibrin(ogen) degradation products	Present
Fibrinopeptide A	Increased
Fibrinopeptide B	Increased
Plasmin	Increased
Plasminogen	Decreased
Platelet count	Increased or decreased
Platelet factor 4	Increased
Protein C	Decreased

Platelet count

Normal: 150,000 to 450,000/ L.

If thrombocytopenia is less than 100,000/ L, consider the following:
- Bone marrow failure
- Increased consumption of platelets
- Splenic pooling of platelets
Thrombocytosis with a platelet count of more than 500,000/ L has the following characteristics:
- It is common in patients with neoplasms.
- It may be seen in association with iron deficiency (e.g., secondary to gut neoplasm).
- It usually poses no risk of arterial thrombosis unless the patient has a myeloproliferative disorder.
Bleeding time.

This is a useful screening test if the platelet count is normal and platelet dysfunction is suspected.
- A normal bleeding time requires normal platelet number, normal platelet function, and normal function of the blood vessels and connective tissues.
- A prolonged bleeding time may be due to thrombocytopenia, abnormal platelet function, and, rarely, inadequate vessel function. The bleeding time may be spuriously prolonged in elderly people with tissue-paper skin.
- The following formula is a rough rule of thumb to be used to estimate what the bleeding time should be in
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  patients who have platelet counts between 10,000 and 100,000/ L. Although it was derived using the Mielke template, the principle should still hold for contemporary bleeding time devices: bleeding time (minutes) =30 ([platelet count/ L]/4,000).
Whole blood platelet function screening is replacing bleeding time tests in many laboratories. This method of screening for platelet function abnormalities appears to be a better predictor for the risk of bleeding due to platelet function abnormalities than the bleeding time.
Prolonged prothrombin time. This is seen in the presence of the following:
- Deficiency of one or more of the following clotting factors: VII, X, V, II (prothrombin), or I (fibrinogen); oral anticoagulant therapy leads to a deficiency of factors II, VII, IX, and X
- Circulating anticoagulants against factor VII, X, V, or II
- Dysfibrinogenemia
Prolonged activated partial thromboplastin time
- Deficiency of any of the following clotting factors: XII, XI, IX, VIII, X, V, II, or I. Factor XII deficiency is not associated with bleeding. Fletcher and Fitzgerald factor deficiencies (both rare) may also prolong the aPTT.
- Circulating anticoagulants directed against the factors mentioned earlier or the lupus inhibitor.
- Anticoagulant therapy with heparin or oral anticoagulants.
Prolonged thrombin time. Prolongation of the thrombin time may be due to the following:
- Hypofibrinogenemia (fibrinogen <100 mg/dL)
- Some forms of dysfibrinogenemia
- Fibrin fibrinogen split products
- Heparin therapy
- Paraproteins
If the thrombin time is prolonged, further studies to clarify the cause may be required.
Low fibrinogen level. When evaluating the results of a fibrinogen assay, one must be familiar with the assay method used. Many laboratories use immunologic assays, which measure both functionally normal and abnormal fibrinogens. If such an assay is in use, the thrombin time can be used to evaluate the functional integrity of the fibrinogen. A low functional fibrinogen level means that production is decreased, consumption is increased, or a dysfibrinogen is present. Fibrinogen is an acute-phase reactant and is often elevated with advanced malignancy. A fibrinogen level in the normal range may actually be relatively low for the patient's physiologic state and therefore may be a sign of DIC (see Table 29.1).

C. Laboratory findings in patients with disseminated intravascular coagulation

Acute DIC is often associated with significant hemorrhage, whereas chronic DIC may be asymptomatic or associated with thromboses. Screening and confirmatory laboratory tests are shown in Table 29.1.

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Review of peripheral smear for schistocytes and decrease numbers of platelets if TTP suspected.

IV. Treatment of hemorrhagic syndromes in patients with malignant disease

A. Transfusion therapy

General guidelines
- Regard elective transfusion with allogeneic blood as an outcome to be avoided. Consider the factors that will influence the use of blood products, including the following:
  - Alternative forms of therapy that could control bleeding (e.g., topical measures or desmopressin).
  - How symptomatic is the patient? Do not treat for an abnormal laboratory test in a symptom-free patient. For example, patients with chronic DIC may demonstrate prolongation of both the PT and the aPTT and mild to moderate thrombocytopenia. If there is no demonstrable bleeding, transfusion therapy is not necessary.
- Use the specific blood component needed by the patient.
- Minimize complications of transfusion by using the following:
  - Only the amount and type of blood product indicated for the patient in the specific clinical setting
  - Leukoreduced blood products, irradiated blood, or both, when indicated

Blood component therapy

Platelet transfusions

Available forms of platelets for transfusion. Platelets may be ordered and transfused in various ways. Because most patients with an underlying malignancy have the potential for needing long-term platelet support, platelet products should be leukocyte reduced from the initiation of transfusion (see Section IV.A.3. in the subsequent text). In general, patients who need platelet support can be started with whole blood derived platelets. Given the added expense and the limited number of platelet apheresis donors in many centers, single donor and human leukocyte antigen (HLA) matched platelets should be reserved for patients who have become refractory to whole blood derived platelets (see Section IV.A.2.a. (4) in the subsequent text). There are no solid data to suggest that starting with platelet apheresis products decreases the incidence of alloimmunization. In fact, the Trial to Reduce Alloimmunization to Platelets Study Group study (1997) did not show any benefit in the use of platelet apheresis products over whole blood derived platelets. Conversely, patients who are candidates for bone marrow transplantation should receive single-donor platelets (if available) from the initiation of platelet therapy. Many blood centers have geared up production of platelet apheresis, and this product may be more
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readily available in some places than in others. Patients who are candidates for transplantation with bone marrow from an HLA-matched sibling should not receive apheresis products from the potential donor before the transplantation.
- Whole blood derived platelets (Random-donor platelets or platelet concentrates). Four to 6 U (usually pooled in one bag) are considered an adequate dose for a 70-kg adult.
- Platelets obtained by apheresis (single-donor platelets) and HLA-matched platelets obtained by apheresis. These come as a single pack and represent the platelets obtained by apheresis from a single donor. One unit of platelets obtained by apheresis is equivalent to 4 to 6 U of platelet concentrate.
Check platelet count 10 minutes to 1 hour, and then 24 hours after platelet transfusion to estimate survival of platelets in the patient. Each unit of platelet concentrate should increase the platelet count by approximately 7,000/ L. The expected 1-hour posttransfusion rise in platelets is 15,000 platelets/ L divided by the patient's body surface area in square meters for each unit of platelet concentrate (Therefore, for a person of 2 m², 6 U should produce a rise of 45,000/ L [6 x 15,000/2]).
Criteria for transfusing platelets
- (a) For patients with reduced platelet production, criteria for transfusion are shown in Table 29.5.
- Increased platelet destruction. Platelet transfusions are of limited benefit in patients with thrombocytopenia due to increased destruction as a result of either antibodies or consumption. If potentially life-threatening bleeding complicates thrombocytopenia due to increased destruction, platelet transfusions may be given; however, only small increments in the platelet count usually occur. -Globulin 1 g/kg IV daily x 2 days given before the platelet transfusions might improve the response.
- Dysfunctional platelets. One must stop any drugs known to cause platelet dysfunction. Although the use of platelet transfusions should be considered, pharmacologic methods of enhancing platelet function, such as desmopressin, should be used if possible (see Section IV.B.1.).

Refractoriness to platelet transfusions rise of <5,000/ L after 5 to 6 U of platelet concentrates or 1 U of platelets obtained by apheresis on two separate occasions) is a common problem in multiply transfused patients. Alloimmunization is the most difficult form to treat and is therefore best prevented (see Section IV.A.3). Apparent refractoriness to platelets may be due to shortened platelet lifespan

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from fever, septicemia, DIC, splenomegaly, drugs, infections, or bleeding.

Table 29.5. Guidelines for platelet transfusion in patients with reduced platelet production

Platelet Count	Recommendation
0 5,000/ L	Transfuse with platelets even if there is no evidence of bleeding
6,000 10,000/ L	Transfuse with platelets in the presence of the following: Fresh minor hemorrhage Temperature of 38C or active infection Rapid decline in platelet count (>50%/day) Headache Significant gastrointestinal blood loss Recent chemotherapy that may be expected to cause severe stomatitis or gastrointestinal ulceration Presence of confluent petechiae (as opposed to scattered petechiae) Continuous bleeding from a wound or other sites Planned minor procedure such as a bone marrow biopsy
11,000 20,000/ L	Transfuse with platelets if there is more rapid bleeding or if more complicated procedures are anticipated
20,000/ L	If major surgery is planned or when life-threatening bleeding occurs, the platelet count should be increased to at least 50,000/ L For intracranial surgery or opthalmic surgery, transfuse to a platelet count of at least 100,000/ L (bleeding time must be checked before surgery and must be normal) In fully anticoagulated patients, it is advisable to keep the platelet count at least at 50,000/ mL.

Evaluation. Patients who become refractory to platelet transfusions should have a laboratory evaluation for alloimmunization. They should also be evaluated for infection and DIC. Further, all potentially offending medications should be stopped.
Therapy. The therapeutic modalities for ITP (corticosteroids, IV globulin, danazol) are generally ineffective for platelet refractoriness due to alloimmunization. Two therapeutic options exist:
- (i) Human leukocyte antigen (HLA) matched platelets
- (ii) Cross-matched platelets. Because platelets are available at most blood centers, if a blood center performs cross-matching, it is often easier to obtain cross-matched platelets since no specific donor qualification is required. This product is as effective as HLA-matched platelets in producing a platelet response in the alloimmunized patient. Either platelet concentrates or apheresed platelets can be cross-matched with the recipient. Nonreactive or, in extenuating circumstances, the least reactive platelets can then be selected for transfusion.

Coagulation factor support
- Fresh frozen plasma (FFP) contains all clotting factors (but not platelets) and should be used for multiple coagulation factor deficiencies. FFP requires 20 to 30 minutes to thaw and must be thawed at 37C. Once thawed, FFP must be transfused within 5 days of thawing as long as it is maintained at 1C to 6C.
- Plasma frozen within 24 hours of phlebotomy is often used interchangeably with FFP.
- Cryoprecipitated antihemophilic factor is a source of factor VIII vWF complex, fibrinogen, and factor XIII. Each bag of cryoprecipitated AHF contains approximately 50% of the factor VIII vWF complex (minimum of 80 U) and 20% to 40% of the fibrinogen (minimum of 150 mg) harvested from 1 U of blood. Cryoprecipitated AHF is stored in a frozen state and has the advantage of concentrating the clotting factors in a small volume (10 to 15 mL/bag). It is used primarily in deficiencies of fibrinogen. The goal is to keep the fibrinogen level higher than 100 mg/dL. The usual dosage of cryoprecipitated AHF to correct hypofibrinogenemia is one bag of cryoprecipitated AHF for every 5 kg body weight. Because 50% is recovered after transfusion, this may raise the fibrinogen level only by approximately 50 mg/dL. Larger doses may be needed for severe hypofibrinogenemia or flaming DIC. The patient is evaluated to determine if the laboratory values have been corrected.
- Factor IX concentrates are available as factor IX complex concentrates, which contain factors II, VII, IX, and X, or as coagulation factor IX concentrates. The latter are highly purified factor IX concentrates with few or no other coagulation factors. Several precautions are worth noting regarding the factor IX concentrates:
  - (a) This concentrate is made from pooled plasma but is treated with viral attenuation processes such (i) dry or vapor heat in the case of factor IX complex concentrates (therefore the risk is significant) or (ii) solvent-detergent or monoclonal antibody in the case of coagulation
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    factor IX concentrates. The dose depends on the preparation to be used. The goal is to bring the factor concentration to no more than 50% of normal.
  - (b) There is a small risk of DIC resulting from the use of factor IX complex concentrates. Patients with liver dysfunction and newborns are at increased risk. The coagulation factor concentrates are far less thrombogenic and should be used in cases at increased risk for venous thrombosis or DIC.
  - (c) Factor IX concentrates are stored in the lyophilized state. Do not shake when reconstituting.

Leukocyte reduction. Patients who have not previously received transfusions and who will need long-term blood product support should receive leukocyte-reduced (<5 x 10⁶ leukocytes/bag) blood products. Leukocyte reduction may prevent febrile transfusion reactions, prevent cytomegalovirus (CMV) infections, and delay alloimmunization. Controversy still exists as to whether tumor recurrence and infections are a result of immunomodulatory effects of blood transfusion and if they can be reduced by leukoreduction. Two methods of leukocyte reduction by filtration are currently available: bedside and prestorage.
- Bedside filtration involves leukocyte reduction at the time of transfusion. Disadvantages include plugging of the filter, the presence of leukocyte breakdown products, bag breakage, and lack of consistency of products. Filters are available for RBCs and platelets.
- AS-1 or AS-3 prestorage filtered red blood cells are RBCs that have been leukocyte reduced generally within 8 to 24 hours of collection. Advantages are fewer leukocyte breakdown products, ease of administration, and consistent quality (guaranteed less than 5 x 10⁶ leukocytes/bag). Cost may be perceived as a disadvantage. However, this is offset by the expense of stocking filters, training of staff in the use of filters, and breakage. There is ongoing controversy as to whether leukocyte-reduced blood products should be provided to all patients, not just patients at risk.
Cytomegalovirus-negative blood. Only patients known to be anti-CMV negative with impaired immunity should be considered for the use of CMV-negative blood. This group includes children, for the most part. The use of CMV-negative blood seriously restricts the potential donor pool for these patients. Leukocyte-reduced blood products (less than 5.0 x 10⁶/bag) are, in general, equivalent to CMV-negative screened products and both are considered CMV-reduced risk products.

White blood cell (WBC) depletion filters also remove CMV since it resides in the WBCs. Irradiation of blood products does not render them CMV-free. Frozen deglycerolized blood is considered free of CMV contamination.
Irradiated blood products. These prevent the development of graft-versus-host disease. Irradiated blood
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products, in the case of patients with cancer or hematologic malignancies, are indicated in the following situations:
- Congenital immunodeficiency
- Bone marrow, peripheral blood stem cell, or umbilical cord stem cell transplantation
- Directed blood donations to blood relatives
- HLA-matched or cross-matched platelets
- Granulocyte transfusions
- High-dose chemotherapy with growth factor or stem cell rescue
- Hodgkin's lymphoma
- Leukemia and non Hodgkin's lymphoma (relative indication)
- Fludarabine treatment

B. Other forms of therapy

Desmopressin. Desmopressin 0.3 g/kg IV over 30 minutes every 12 to 24 hours for 2 to 4 days may be used to elevate factor VIII and vWF levels as well as to improve platelet function. Tachyphylaxis may occur if therapy is continued for longer periods. Intranasal desmopressin 0.25 mL b.i.d. using a solution containing 1.3 mg/mL has been given for minor bleeding episodes.
Fibrin glue. This is a topical biologic adhesive. Its effects imitate the final stages of coagulation. The glue consists of a solution of concentrated human fibrinogen, which is activated by the addition of bovine thrombin and calcium chloride. The resulting clot promotes hemostasis and tissue sealing. The clot is completely absorbed during the healing process. The best adhesive and hemostatic effect is obtained by applying the two solutions simultaneously to the open wound surface. Fibrin glue has been used primarily in surgical settings. It has been most effective when used for surface, low-pressure bleeding. There is a small risk of anaphylactic reaction because of the bovine origin of the thrombin.
Antifibrinolytic agents. -Aminocaproic acid (EACA) and tranexamic acid have been used to control bleeding associated with primary fibrinolysis as seen in patients with prostatic carcinoma and in a small number of patients with refractory thrombocytopenia. Great care must be taken in the use of these agents because of a possible increased risk of thrombosis. EACA may be used topically to control small-area, small-volume bleeding.
Oprelvekin (interleukin-11). Oprelvekin has recently been approved by the U.S. Food and Drug Administration for the treatment and prevention of chemotherapy-related thrombocytopenia. Oprelvekin is a thrombopoietic growth factor that directly stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells as well as megakaryocyte maturation, resulting in increased platelet production. It may cause substantial fluid retention and should be used with caution in patients who have congestive heart failure (CHF), those with a history of CHF, and those being treated for CHF. One must also
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be cautious in using this agent in patients who are receiving diuretic therapy or ifosfamide because sudden deaths have been reported as a result of severe hypokalemia. Oprelvekin should be used to prevent thrombocytopenia, which would be severe enough to require platelet transfusions. Therapy usually begins 6 to 24 hours after the completion of chemotherapy, and patients should be monitored for any signs or symptoms of allergic reactions or cardiac dysfunction.