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1464 SECTION 18: Hematologic and Oncologic Disorders TABLE 231-5 Polycythemia (Erythrocytosis) Relative Normal RBC numbers and mass, decreased plasma volume Dehydration, diuretics Absolute Primary Polycythemia vera (JAK2 gene mutation) Congenital mutations in erythropoietin receptor Secondary–acquired Central hypoxia: lung disease, high-altitude habitat, chronic carbon monoxide exposure Renal hypoxia: renal artery stenosis, polycystic kidney disease, post renal transplant Excess erythropoietin production: testosterone and anabolic steroids, paraneoplastic syndromes Secondary–congenital Altered oxyhemoglobin affinity Disordered oxygen sensing Idiopathic No identifiable cause TABLE 231-4 Treatment for Specific Anemias Anemia Type Treatment (Adult Doses) Iron deficiency anemia Elemental iron, 200 to 300 milligrams/d (e.g., ferrous sulfate, 325 milligrams, three to four tablets taken on an empty stomach over the course of day); reticulocyte count should increase within 4–7 d and peak at 10 d; sustained treatment after correction of anemia is usually necessary to replenish iron stores. Cyanocobalamin (vitamin B 12) deficiency anemia Cyanocobalamin, 1000 micrograms IM per week for 8 wk and every month thereafter; reticulocyte count should increase within 4 d and peak at 7 d. Oral replacement with 1000 micrograms/d is as effective (see “Treatment” section). Folate deficiency anemia Folate, 1 milligram PO per day (doses up to 5 milligrams may be needed for patients with malabsorption); reticulo cyte count should increase within 4 d with normalization of hemoglobin level in 1–2 mo. Sideroblastic anemia Evaluate for reversible causes. Discontinue any offending agents. Treatment is mainly supportive, consisting pri marily of blood transfusions to maintain the hemoglobin level. A trial of pyridoxine at pharmacologic doses (500 milligrams PO daily) may be helpful, with response most commonly seen in cases resulting from ethanol abuse or isoniazid. Some patients with hereditary X-linked sidero blastic anemia also respond to pyridoxine. Improvement with pyridoxine is rare for sideroblastic anemia of other causes. Aplastic anemia Supportive care, including transfusion if appropriate. Anemia of chronic disease Supportive care, including transfusion if appropriate. Erythropoietic agents (patients with cancer, chronic kidney disease, human immunodeficiency virus). Omega-3 polyunsaturated fatty acids (patients with rheumatoid arthritis and diabetes mellitus). Hemostasis Stephen John Cico THE BLEEDING PATIENT Most bleeding seen in the ED is a result of trauma—local wounds, lacerations, or other structural lesions—and the majority of traumatic bleeding occurs in patients with normal hemostatic mechanisms. In these patients, specific assessment of hemostasis is unnecessary. However, some ED patients have abnormal bleeding due to impaired hemostasis. Identifying CHAPTER commonly caused by dehydration from excessive fluid loss, decreased oral intake, and/or excessive diuresis. Absolute polycythemia is an increase in the RBC mass. Primary polycythemia is due to an acquired or inherited mutation in erythroid cell lines and, less commonly, erythropoietin receptor mutations. This category includes polycythemia vera. 17 Secondary polycythemia usu ally results from increased circulating levels of erythropoietin, directly stimulating RBC production (Table 231-5). CLINICAL FEATURES Symptoms of polycythemia are often vague and may include chest, abdominal, or muscle pain and generalized weakness. CNS manifesta tions may be present, from mild fatigue and headache, to focal neuro logic signs and coma.

ting levels of erythropoietin, directly stimulating RBC production (Table 231-5). CLINICAL FEATURES Symptoms of polycythemia are often vague and may include chest, abdominal, or muscle pain and generalized weakness. CNS manifesta tions may be present, from mild fatigue and headache, to focal neuro logic signs and coma. Patients with polycythemia vera will classically present with pruritus when exposed to hot water and early satiety from splenomegaly. Physical exam may reveal splenomegaly in these patients. Additional findings may include plethoric facies and ruddy skin, as well as distal cyanosis and clubbing from microemboli. 16 Hyperviscosity syndrome is a life-threatening complication of polycythemia that presents with the triad of bleeding, visual disturbances, and focal neurologic deficits caused by thrombosis and microhemorrhage. 16-18 Patients with polycythemia vera are prothrombotic and at increased risk for venous thromboembolism. DIAGNOSIS The diagnosis of polycythemia is suggested by a higher than expected hemoglobin or hematocrit for the patient’s demographics on CBC (a hemoglobin >18.5 grams/dL [>185 grams/L] or hematocrit >52% in a male and a hemoglobin >16.5 grams /dL [>165 grams/L] or a hematocrit >48% in a female). If relative polycythemia is not suspected, workup of absolute polycythemia should include urinalysis, renal and hepatic function tests, and pulse oximetry. Consider co-oximetry to assess for chronic carbon monoxide poisoning. Erythropoietin level, while not helpful in the acute setting, may guide further assessment. Chest radio graph or cardiopulmonary function testing may be indicated if second ary polycythemia is suspected. Polycythemia vera may be suggested by history, but formal diagnosis requires bone marrow biopsy or genetic testing in addition to an elevated hemoglobin level. TREATMENT AND DISPOSITION The treatment of relative polycythemia is with correction of decreased plasma volume. The mainstay of treatment for patients with polycythemia vera is low-dose aspirin and phlebotomy to a hematocrit of 45%. 16,17 Pharmacotherapy, including hydroxyurea, interferon-α, systemic anticoagulation, and the JAK1/JAK2 inhibitor ruxolitinib may be initiated after risk stratification and hematology consulta tion. 15-17,19,20 Polycythemia with hyperviscosity syndrome should be managed aggressively, with IV hydration and early hematology consultation. The patient can usually be discharged when polycythemia is discov ered as an incidental finding. Patients with clinical manifestations due to hyperviscosity syndrome require admission. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec18_p1461-1522.indd 1464 8/2/19 8:37 PM

he patient can usually be discharged when polycythemia is discov ered as an incidental finding. Patients with clinical manifestations due to hyperviscosity syndrome require admission. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec18_p1461-1522.indd 1464 8/2/19 8:37 PM CHAPTER 232: Hemostasis 1465 these patients requires attention to the history and physical findings. 1-3 Generally speaking, when patients have spontaneous bleeding from multiple sites, bleeding from untraumatized sites, delayed bleeding several hours after trauma, and bleeding into deep tissues or joints, the possibility of a bleeding disorder should be considered. Important historical data that aid in identifying a congenital bleeding disorder include the presence of unusual or abnormal bleeding in the patient and other family members and any occurrence of excessive bleeding after dental extractions, surgical procedures, or trauma. Many patients with abnormal bleeding have an acquired disorder, such as liver disease, renal disease, or drug use (particularly ethanol, aspirin, NSAIDs, antiplatelet drugs, oral anticoagulants, antibiotics, and other salicylate-containing products). Many supplements and herbal preparations, including garlic, ginseng, ginkgo biloba, ginger, and vitamin E, can also increase bleeding tendencies. The site of bleeding may provide an indication of the hemostatic abnormality. Mucocutaneous bleeding, including petechiae, ecchy moses, epistaxis, GI or GU bleeding, or heavy menstrual bleeding, is characteristic of qualitative or quantitative platelet disorders. Purpura is often associated with thrombocytopenia and commonly indicates a systemic illness. Bleeding into joints and potential spaces, such as between fascial planes and into the retroperitoneum, and delayed bleeding are most commonly associated with coagulation factor deficiencies. Patients who demonstrate both mucocutaneous bleeding and bleeding in deep spaces may have disorders such as disseminated intravascular coagulation, in which both platelet abnormalities and coagulation factor abnormalities are present (see Chapter 233, “ Acquired Bleeding Disorders, ” Chapter 234, “Clotting Disorders, ” and Chapter 235, “Hemophilias and von Willebrand’s Disease”). Common laboratory tests for hemostasis have their limitations. 4,5 They are generally useful and reliable for identifying disorders of coagulation factor function and quantitative platelet availability. However, tests of qualitative platelet function show a significant biologic variation, so that standardization has been difficult to achieve. 5 In addition, liver disease and renal failure—two conditions that increase the potential for abnormal hemorrhage—may not give consistent and measurable abnor mal results on routine tests of hemostasis. 6,7 THE PATIENT WITH A THROMBUS A patient with an intravascular thrombosis, such as a venous throm boembolism or pulmonary embolus (particularly if recurrent), sug gests the potential for an underlying hypercoagulable state (see Chapter 234). 8 Premature coronary artery disease and acute coro nary syndrome in individuals as young as teenagers have also been linked to hypercoagulable conditions. However, many, if not most, occurrences of intravascular thrombosis are not due to exaggerated hemostasis but rather are due to local conditions, with blood vessel wall injuries, local inflammation, or vascular stasis provoking the thromboembolic event. The susceptibility to hypercoagulation may be acquired or geneti cally transmitted. Common acquired hypercoagulable disorders include essential thrombocythemia, polycythemia vera, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, and cancer (often occult at the time of acute thrombosis).

mboembolic event. The susceptibility to hypercoagulation may be acquired or geneti cally transmitted. Common acquired hypercoagulable disorders include essential thrombocythemia, polycythemia vera, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, and cancer (often occult at the time of acute thrombosis). Inherited hypercoagulable disorders include factor V Leiden, prothrombin mutations, hyperhomocyste inemia, and deficiencies of protein C, protein S, and antithrombin. Patients with inherited hypercoagulable conditions tend to have venous thrombosis, whereas those with acquired disorders can have both arte rial and venous clots. Proteins C and S are vitamin K–dependent antihemostatic factors made in the liver, and deficiencies of these proteins are inherited in an autosomal manner. Protein C is activated by thrombin and functions with protein S to stop fibrin formation and to stimulate the process of fibrinolysis. Antithrombin is also an antihemostatic protein that blocks activated coagulation factors. Elevated homocysteine level is also a known risk factor for thromboembolism. Laboratory tests for a hypercoagulable diathesis show wide biologic variation, and standardization among laboratories has been difficult to achieve. The clinical utility of testing patients for suspected hypercoagulable conditions is dependent on the specific disorder.8-10 NORMAL COAGULATION The normal hemostatic system consists of a complex process that limits blood loss through the formation of a platelet plug (primary hemostasis) and the production of cross-linked fibrin (secondary hemostasis), which strengthens the platelet plug. 11 These reactions are counterregulated by the fibrinolytic system, which limits the size of the fibrin clot that is formed and thereby prevents excessive clot formation. Congenital and acquired abnormalities occur in all these systems. The affected patient may have excessive hemorrhage, excessive thrombus formation, or both.  PRIMARY HEMOSTASIS Primary hemostasis is the platelet interaction with exposed vascular subendothelial collagen that results in the formation of a platelet plug at the site of injury. Required components for this to occur are normal vascular subendothelium (collagen), functional platelets, normal von Willebrand factor (connects the platelet to the endothelium via glycoprotein Ib), and normal fibrinogen (connects the platelets to each other via glycoprotein IIb/IIIa) ( Figure 232-1). Primary hemostasis begins within 20 seconds of injury, is short lived, and requires secondary hemostasis for clot stabilization.  SECONDARY HEMOSTASIS Secondary hemostasis consists of the tightly regulated reactions of the plasma coagulation proteins. The final product is cross-linked fibrin, which is insoluble and strengthens the platelet plug formed in primary hemostasis (Figure 232-2). Secondary hemostasis is also known as the coagulation cascade. The inactivated coagulation proteins (factors) are identified by Roman numerals, and after activation, the activated factor is designated by a. There are two independent activation pathways. The contact system is known as the contact activation pathway or intrinsic pathway , and the tissue factor system is known as the tissue factor pathway or extrinsic pathway. 2,11 The pathways merge at the point of activation of factor X. Medications such as rivaroxaban, apixaban, and edoxaban inhibit the activity of factor Xa. The combination of factor Xa, factor Va, phospholipid, and calcium (“thrombinase complex”) more efficiently catalyzes the conversion of prothrombin to thrombin than free factor Xa. In turn, thrombin catalyzes the conversion of fibrinogen to fibrin monomer. Medications such as bivalirudin or dabigatran are direct thrombin inhibitors.

n of factor Xa, factor Va, phospholipid, and calcium (“thrombinase complex”) more efficiently catalyzes the conversion of prothrombin to thrombin than free factor Xa. In turn, thrombin catalyzes the conversion of fibrinogen to fibrin monomer. Medications such as bivalirudin or dabigatran are direct thrombin inhibitors. The common pathway describes the steps from factor X acti vation to cross-linked fibrin formation. THE FIBRINOLYTIC SYSTEM The fibrinolytic system regulates the hemostatic mechanism by limit ing the size of the fibrin clots that are formed ( Figure 232-3). Tissue plasminogen activator, released from endothelial cells, is the principal physiologic trigger for the fibrinolytic process, converting plasminogen, synthesized in the liver and adsorbed in the fibrin clot, to plasmin. Plasmin degrades fibrinogen and fibrin monomer into low-molecularweight fragments known as fibrin degradation products and degrades cross-linked fibrin into d-dimers. Other physiologic inhibitors of hemostasis with clinical relevance include antithrombin and the protein C–protein S system. Anti thrombin is a protein that forms complexes with all the serine protease coagulation factors (factors XIIa, XIa, Xa, and IXa and thrombin), thereby inhibiting their function. Heparin potentiates this interaction, which is the basis for its use as an anticoagulant. Proteins C and S are vitamin K–dependent factors that are produced in the liver. Activated protein C binds to the cell surface–bound protein S, and this complex is capable of inactivating the two plasma cofactors factors Va and Tintinalli_Sec18_p1461-1522.indd 1465 8/2/19 8:37 PM

basis for its use as an anticoagulant. Proteins C and S are vitamin K–dependent factors that are produced in the liver. Activated protein C binds to the cell surface–bound protein S, and this complex is capable of inactivating the two plasma cofactors factors Va and Tintinalli_Sec18_p1461-1522.indd 1465 8/2/19 8:37 PM 1466 SECTION 18: Hematologic and Oncologic Disorders XIIX IIa XI XIa VIIa VII Ca++ TF , Ca++ XIIIaX III IXa Fibrinogen (I)F ibrin (Ia) Cross-linked fibrin clot VIIIa VIII Damaged surface Prothrombin (II) Thrombin (IIa) Common PathwayXa, PL Va, Ca++ Contact activation (intrinsic) pathway Tissue factor (extrinsic) pathway FIGURE 232-2. Secondary hemostasis. Ca++ = calcium; fibrinogen is factor I; PL = phospholipid surface (often platelets); prothrombin is factor II; TF = tissue factor. Fibrinogen GP1 1b/111a Exposed subendothelial collagen Vascular endothelial cells vWF GpIb pltplt FIGURE 232-1. Primary hemostasis. GpIb = glycoprotein Ib; GpIIb/IIIa = glycoprotein IIb/IIIa; plt = platelet; vWF = von Willebrand factor. Tintinalli_Sec18_p1461-1522.indd 1466 8/2/19 8:37 PM CHAPTER 232: Hemostasis 1467 PlasminPlasminogen tPA FDP Fibrinogen and fibrin monomer Fibrin polymer (cross-linked) D-Dimer FIGURE 232-3. The fibrinolytic system. FDP = fibrin degradation product; tPA = tissue plasminogen activator. TABLE 232-1 Initial Tests of Hemostasis Screening Tests Reference Value Component Measured Clinical Correlations Primary Hemostasis Platelet count 150–400,000/mm 3 (150–400 × 10 9/L) Number of platelets per mm3 Decreased platelet count (thrombocytopenia): bleeding usually not a problem until platelet count is <50,000/mm3 (50 × 109/L); high risk of spontaneous bleeding, including CNS bleeding, seen with count of <10,000/mm3 (10 × 109/L); usually due to decreased production or increased destruction of platelets Elevated platelet count (thrombocytosis): commonly a reaction to inflammation or malignancy, and occurs in polycythemia vera; can be associated with hemorrhage or thrombosis Bleeding time (BT) Variable Typically 2.5–10.0 min using a BT template Interaction between platelets and the subendothelium

CHAPTER 232: Hemostasis 1467 PlasminPlasminogen tPA FDP Fibrinogen and fibrin monomer Fibrin polymer (cross-linked) D-Dimer FIGURE 232-3. The fibrinolytic system. FDP = fibrin degradation product; tPA = tissue plasminogen activator. TABLE 232-1 Initial Tests of Hemostasis Screening Tests Reference Value Component Measured Clinical Correlations Primary Hemostasis Platelet count 150–400,000/mm 3 (150–400 × 10 9/L) Number of platelets per mm3 Decreased platelet count (thrombocytopenia): bleeding usually not a problem until platelet count is <50,000/mm3 (50 × 109/L); high risk of spontaneous bleeding, including CNS bleeding, seen with count of <10,000/mm3 (10 × 109/L); usually due to decreased production or increased destruction of platelets Elevated platelet count (thrombocytosis): commonly a reaction to inflammation or malignancy, and occurs in polycythemia vera; can be associated with hemorrhage or thrombosis Bleeding time (BT) Variable Typically 2.5–10.0 min using a BT template Interaction between platelets and the subendothelium Prolonged BT caused by: Thrombocytopenia (platelet count <50,000/mm 3 or 50 × 109/L) Abnormal platelet function (von Willebrand’s disease, antiplatelet drugs, uremia, liver disease) Secondary Hemostasis Prothrombin time (PT) and international normalized ratio (INR) PT: 11–13 s; depends on reagent INR: 1.0 Extrinsic system and common pathway—factors VII, X, V, prothrombin, and fibrinogen INR = 1.7 corresponds to approximately 30% activity of coagulation factors as a whole Prolonged PT most commonly caused by: Warfarin (inhibits production of vitamin K–dependent factors II, VII, IX, and X) Liver disease with decreased factor synthesis Antibiotics that inhibit vitamin K–dependent factors (moxalactam, cefamandole, cefotaxime, cefoperazone) Activated partial thromboplastin time (aPTT) 22–34 s Depends on type of thromboplastin reagent used “Activated” with kaolin Intrinsic system and common pathway—factors XII, XI, IX, VIII, X, V, prothrombin, and fibrinogen

iotics that inhibit vitamin K–dependent factors (moxalactam, cefamandole, cefotaxime, cefoperazone) Activated partial thromboplastin time (aPTT) 22–34 s Depends on type of thromboplastin reagent used “Activated” with kaolin Intrinsic system and common pathway—factors XII, XI, IX, VIII, X, V, prothrombin, and fibrinogen Prolonged aPTT most commonly caused by: Heparin therapy Factor deficiencies (factor levels have to be <30% of normal to cause prolongation) Fibrinogen level Slightly variable according to specific test Typically 200–400 milligrams/dL (2–4 g/L) Protein made in liver; converted to fibrin as part of normal coagulation cascade Low levels seen in disseminated intravascular coagulation Elevated in inflammatory processes (acute-phase reactant) Thrombin clotting time (TCT) 10–12 s Conversion of fibrinogen to fibrin monomer Prolonged TCT caused by: Low fibrinogen level Abnormal fibrinogen molecule (liver disease) Presence of heparin, fibrin degradation products, or a paraprotein (multiple myeloma); these interfere with the conversion Occasionally seen in hyperfibrinogenemia “Mix” testing 15 Variable Performed when results on one or more of the above screening tests is prolonged; the patient’s plasma (“abnormal”) is mixed with “normal” plasma and the screening test is repeated If the mixing corrects the screening test result: one or more factor deficiencies are present If the mixing does not correct the screening test result: a circulating inhibitor is present VIIIa and inhibiting their participation in the coagulation cascade. A single amino acid substitution in factor V , a condition named factor V Leiden, prevents activated protein C from binding and inhibiting the activity of factor Va. Thus, patients with this inherited condition have prolonged thrombogenic factor Va activity. Factor V Leiden deficiency or defects in antithrombin, protein C, and protein S produce a poten tially hypercoagulable condition and predispose the patient to venous thromboses. TESTS OF HEMOSTASIS Before embarking on a sequence of hemostatic testing, evaluate the patient in three areas: (1) Is the bleeding abnormal? (2) Is there a current medical condition associated with increased hemorrhage? (3) Is there a structural cause that explains the bleeding? 1-3 The basic laboratory tests obtained for a patient with a suspected abnormal bleeding disorder are a CBC and platelet count, prothrombin time, and activated partial thromboplastin time ( Table 232-1). The results of these tests, coupled with clinical evaluation, should enable formulation of a differential diagnosis. 12,13 Additional studies are ordered as indicated (Table 232-2). Obtain hematologic consultation if the dif ferential diagnosis or the laboratory approach is unclear. In patients with perioperative bleeding, the basic laboratory tests for coagulation are of little help in assessment or management. Tintinalli_Sec18_p1461-1522.indd 1467 8/2/19 8:37 PM

dered as indicated (Table 232-2). Obtain hematologic consultation if the dif ferential diagnosis or the laboratory approach is unclear. In patients with perioperative bleeding, the basic laboratory tests for coagulation are of little help in assessment or management. Tintinalli_Sec18_p1461-1522.indd 1467 8/2/19 8:37 PM 1468 SECTION 18: Hematologic and Oncologic Disorders TABLE 232-2 Additional Hemostatic Tests Test Reference Value Component Measured Clinical Correlations/Comments Fibrin degradation product (FDP) and d-dimer levels FDP: variable depending on specific test, typically <2.5–10 micrograms/mL (2.5–10 milligrams/L) FDP test: measures breakdown products from fibrinogen and fibrin monomer Levels are elevated in diffuse intravascular coagulation, venous thrombosis, pulmonary embolus, and liver disease, and during pregnancy d-Dimer: variable depending on specific test, typically <250–500 nanograms/mL (250–500 micrograms/L) d-Dimer test: measures breakdown products of cross-linked fibrin Factor level assays 60%–130% of reference value (0.60–1.30 units/mL) Measures the percent activity of a specified factor compared to normal To identify specific deficiencies and direct therapeutic management Protein C level Variable Typically 60%–150% of reference value Level of protein C in the blood Vitamin K dependent Increases with age Values higher in males than females Deficiency associated with thromboembolism in people <50 y of age Protein S level Variable Typically 60%–150% of reference value Level of protein S in the blood Vitamin K dependent Increases with age Values higher in males than females Deficiency associated with thromboembolism in people <50 y of age Factor V Leiden (FVL) Variable Screening test looks for activated protein C resistance, and confirmatory test analyzes DNA sequence of factor V gene FVL not inactivated by activated protein C Heterozygotes have 7× and homozygotes have a 20× increased lifetime risk of venous thrombosis Mutation associated with thromboembolism in people <50 y of age Screening assay uses activated partial thromboplastin time with and without added activated protein C Antithrombin level Variable depending on specific test Typically 20–45 milligrams/dL (200–450 milligrams/L) Measures level of antithrombin in the blood

Screening test looks for activated protein C resistance, and confirmatory test analyzes DNA sequence of factor V gene FVL not inactivated by activated protein C Heterozygotes have 7× and homozygotes have a 20× increased lifetime risk of venous thrombosis Mutation associated with thromboembolism in people <50 y of age Screening assay uses activated partial thromboplastin time with and without added activated protein C Antithrombin level Variable depending on specific test Typically 20–45 milligrams/dL (200–450 milligrams/L) Measures level of antithrombin in the blood Not vitamin K dependent; patients with deficiency require higher dosages of heparin for anticoagulation therapy Deficiency associated with thromboembolism in people <50 y of age Antiphospholipid antibodies IgG <23 GPL units/mL and IgM <11 MPL units/mL Tests for antibodies that bind to phospholipids Lupus anticoagulant Anticardiolipin antibody Lupus anticoagulant: elevated in systemic lupus erythemato sus (SLE) and other autoimmune diseases Anticardiolipin antibody: elevated in SLE, other autoimmune diseases, syphilis, and Behçet’s syndrome Increased risk of spontaneous abortions, fetal loss, and fetal growth retardation Anti–factor Xa activity During LMWH therapeutic use: 0.5–1.1 IU/mL During LMWH prophylactic use: 0.2–0.5 IU/mL Inhibition of factor Xa activity Used to monitor LMWH therapy and determine levels of rivaroxaban, apixaban, and edoxaban using agent-specific calibration. May be elevated in renal dysfunction Platelet function assay 88–183 s Variable Tests for platelet adhesion and aggregation Affected by uremia, anemia, thrombocytopenia, antiplatelet medications, and von Willebrand’s disease Initial test done with epinephrine. A prolonged test is repeated using ADP, and if normal (<122 s), indicates probable aspirin effect Peripheral blood smear Qualitative and quantitative based on visualization Estimates quantity and appearance of platelets, WBCs, and red blood cells

Used to monitor LMWH therapy and determine levels of rivaroxaban, apixaban, and edoxaban using agent-specific calibration. May be elevated in renal dysfunction Platelet function assay 88–183 s Variable Tests for platelet adhesion and aggregation Affected by uremia, anemia, thrombocytopenia, antiplatelet medications, and von Willebrand’s disease Initial test done with epinephrine. A prolonged test is repeated using ADP, and if normal (<122 s), indicates probable aspirin effect Peripheral blood smear Qualitative and quantitative based on visualization Estimates quantity and appearance of platelets, WBCs, and red blood cells Allows identification of clumped platelets, abnormal cells interfering with coagulation (leukemia) Operator dependent Dilute Russell viper venom time 23–27 s Venom directly activates factor X and converts prothrombin to thrombin when phospholipid and factor V are present Prolonged in the presence of antiphospholipid antibodies Inhibitor screens Variable Verifies the presence or absence of antibodies directed against one or more of the coagulation factors Specific inhibitors: directed against one coagulation factor, most commonly against factor VIII Nonspecific inhibitors: directed against more than one coagulation factor; example is lupus-type anticoagulant Des-γ-carboxyprothrombin or PIVKA II (protein induced by vitamin K absence or antagonism) test Variable Measures inactive under-carboxylated form of prothrombin Increased in vitamin K–deficient states, such as hemorrhagic disease of the newborn Increased in overdoses of warfarin or cholestatic liver diseases that can respond to vitamin K therapy Abbreviations: ADP = adenosine diphosphate; GPL = 1 microgram of affinity-purified immunoglobulin G anticardiolipin antibody from an original index serum; IgM = immunoglobulin M; MPL = 1 microgram of affinity-purified immunoglobulin M anticardiolipin antibody from an original index serum; LMWH = low-molecular-weight heparin. Tintinalli_Sec18_p1461-1522.indd 1468 8/2/19 8:37 PM