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28. Haley K. Congenital hemolytic anemias. Med Clin North Am. 2017;101(2):
361-374.PubMed
29. Youngster I, Arcavi L, Schechmaster R, et al. Medications and glucose-6phosphate dehydrogenase deciency: an evidence- based review. Drug Saf.
2010;33(9):713-726.PubMed
30. Ganz T. Anemia of Chronic Disease. In: Kaushansky K, Lichtman MA,
Prchal JT, Levi MM, Press OW, Burns LJ, Caligiuri M. eds. Williams
Manual of Hematology. 9th ed. New York, NY: McGraw-Hill. https://
accessmedicine- mhmedical- com.ezproxy3.library.arizona.edu/content
.aspx?bookid=1581§ionid=94303965, Accessed June 28, 2020.
31. Hayden SJ, Albert TJ, Watkins TR, etal. Anemia in critical illness:
insights into etiology, consequences, and management. Am J Respir Crit
Care Med. 2012;185(10):1049-1057.PubMed
32. Bohlius J, Bohlke K, Castelli R, et al. Management of cancer- associated
anemia with erythropoiesis- stimulating agents: ASCO/ASH clinical
practice guideline update. J Clin Oncol. 2019;37(15):1336-1351.PubMed
33. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med.
2017;376(16):1561-1573.PubMed
34. Viprakasit V, Ekwattanakit S. Clinical classication, screening and diagnosis
for thalassemia. Hematol Oncol Clin North Am. 2018;32(2):193-211.PubMed
35. Aster JC, Berliner N. Leukocyte function and nonmalignant leukocyte
disorders. In: Aster JC, Bunn H, eds. Pathophysiology of Blood Disorders,
2nd ed. New York, NY: McGraw-Hill; 2017. https://accessmedicine
mhmedical- com.ezproxy3.library.arizona.edu/content.aspx?bookid
=1900§ionid=137395503. Accessed June 28, 2020.
36. National Comprehensive Cancer Network NCCN Guidelines. Prevention
and treatment of cancer- related infections, Version 2.2020, https://www
.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed
June 28, 2020.
37. Strausbaugh LJ. Hematologic manifestations of bacterial and fungal
infections. Hematol Oncol Clin North Am. 1987;1(2):185-206.PubMed
38. McKenzie SB, Laudicina RJ. Hematologic changes associated with
infection. Clin Lab Sci. 1998;11(4):239-251.PubMed
39. Seran WE, Austen KF. Mediators of immediate hypersensitivity
reactions. N Engl J Med. 1987;317(1):30-34.PubMed
40. Smith CW. Production, distribution, and fate of monocytes and
macrophages. In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds.
Williams Manual of Hematology. 9th ed. New York, NY: McGraw-Hill;
2016. https://accessmedicine- mhmedical- com.ezproxy3.library.arizona
.edu/content.aspx?bookid=1581§ionid=101238988. Accessed
June 28, 2020.
41. Muthusamy N, Caligiuri MA. e structure of lymphocytes and plasma
cells. In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds. Williams
Manual of Hematology. 9th ed. New York, NY: McGraw-Hill; 2016. https://
accessmedicine- mhmedical- com.ezproxy3.library.arizona.edu/content
.aspx?bookid=1581§ionid=108067702. Accessed June 28, 2020.
42. Porwit A. Clinical ow cytometry. In: Greer JP, Rodgers MD, Glader B,
et al, eds. Wintrobe’s Clinical Hematology. 14th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2018:17-46.
43.
McClanahan F, Gribben J. Functions of T lymphocytes: t- cell receptors for
antigen. In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds. Williams
Manual of Hematology. 9th ed. New York, NY: McGraw-Hill; https://
accessmedicine- mhmedical- com.ezproxy3.library.arizona.edu/content
.aspx?bookid=1581§ionid=108068314. Accessed June 28, 2020.
44. Moir S, Chun TW, Fauci AS. Pathogenic mechanisms of HIV disease.
Annu Rev Pathol. 2011;6:223-248.PubMed
45. Panel on Antiretroviral Guidelines for Adults and Adolescents.
Guidelines for the use of antiretroviral agents in adults and adolescents
with HIV. Department of Health and Human Services. http://www
.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed
June 28, 2020.
46. Callus R, Buttigieg J, Anastasi AA, Halawa A. Basic concepts in kidney
transplant immunology. Br J Hosp Med (Lond). 2017;78(1):32-37.PubMed
47. Kipps TJ. Functions of B lymphocytes and plasma cells in
immunoglobulin production. In: Kaushansky K, Lichtman MA, Prchal
JT, et al, eds. Williams Manual of Hematology. 9th ed. New York, NY:
McGraw-Hill; 2016. https://accessmedicine- mhmedical- com.ezproxy3
.library.arizona.edu/content.aspx?bookid=1581§ionid=108068055.
Accessed June 28, 2020.
48. Baranski B, Young N. Hematologic consequences of viral infections.
Hematol Oncol Clin North Am. 1987;1(2):167-183.PubMed
49. Friedman AD. Hematologic manifestations of viral infections. Pediatr
Ann. 1996;25(10):555-560.
50. Dale DC, Welte K. Neutropenia and neutrophilia. In: Kaushansky K,
Lichtman MA, Prchal JT, et al, eds. Williams Manual of Hematology.
9thed. New York, NY: McGraw-Hill; 2016. https://accessmedicine
- mhmedical- com.ezproxy3.library.arizona.edu/content.aspx?bookid
=1581§ionid=101238861. Accessed June 28, 2020.
51. Curtis BR. Drug- induced immune neutropenia/agranulocytosis.
Immunohematology. 2014;30(2):95-101.PubMed
52. Arber DA, Orazi A, Hasserjian R, et al. e 2016 revision to the World
Health Organization classication of myeloid neoplasms and acute
leukemia. Blood. 2016;127(20):2391-2405.PubMed
53. Blum W, Bloomeld CD. Acute myeloid leukemia. In: Jameson J, Fauci
AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine.
20th ed. New York, NY: McGraw-Hill; 2018:677-686.
54. O’Donnell E, Cottini F, Raje N, et al. Myeloma. In: Kaushansky K,
Lichtman MA, Prchal JT, et al, eds. Williams Manual of Hematology.
9th ed. New York, NY: McGraw-Hill; 2016:1645-1681.
55. Liesveld JL, Lichtman MA. Chronic myelogenous leukemia and
related disorders. In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds.
Williams Manual of Hematology. 9th ed. New York, NY: McGraw-Hill;
2016:1331-1380.
56. Gascoyne R, Skinnider B. Pathology of lymphomas. In: Kaushansky K,
Lichtman MA, Prchal JT, et al, eds. Williams Manual of Hematology.
9th ed. New York, NY: McGraw-Hill; 2016:1511-1526.
57.
de Leval L, Jae ES. Lymphoma Classication. Cancer J. 2020;26(3):
176-185.PubMed
PubMed
Hematology: Blood
https://t.me/med1917
Coagulation Tests
17
OBJECTIVES
After completing this chapter, the
reader should be able to
•
Describe the role of platelets, the
•
assess platelets and discuss factors
•
to assess coagulation and
explain their
•
to assess clot degradation and
coagulation and discuss their
•
Interpret results and suggest
follow-up action given results of
coagulation and anticoagulant
•
of point-of-care testing devices
coagulation tests
use in evaluating
Lea E. Dela Peña
Normal hemostasis involves a complex interaction among the vascular subendothelium, platelets, coagulation factors, and proteins that promote clot formation, clot
degradation, and inhibitors of these substances. Disruption in normal hemostasis can
result in bleeding or excessive clotting. Bleeding can be caused by trauma or damage
to vessels, acquired or inherited deciencies of coagulation factors, or physiologic
disorders of platelets, whereas excessive clotting can result from abnormalities of the
vascular endothelium, alterations in blood ow, or deciencies in clotting inhibitors.
Clinicians must monitor the hemostasis process in individual patients to ensure
their safety from an imbalance in this complex system. For example, practitioners
routinely order platelet tests in patients on certain antineoplastic medications to assess
for thrombocytopenia. Likewise, clinicians may closely monitor coagulation tests for
patients receiving certain anticoagulants to prevent thromboembolic or hemorrhagic
complications; however, it should be noted that not all anticoagulants are routinely
monitored, nor are all laboratory tests available for routine clinical use. Overall, the
hemostatic process is intricate and requires a clinician knowledgeable in its dynamics for quality assessment.
is chapter reviews normal coagulation physiology, common tests used to assess
coagulation and hypercoagulable states, and factors that alter coagulation tests.
PHYSIOLOGIC PROCESS OF HEMOSTASIS
Normal hemostasis involves the complex relationship among participants that promotes clot formation (platelets and the coagulation cascade), inhibits coagulation,
and dissolves the formed clot. Each phase of the process is briey reviewed.
Clot Formation
Numerous mechanisms promote and limit coagulation. Factors that promote coagulation include malignancy, pregnancy, obesity, immobilization, damage to the blood
vessel wall, and causes of low blood ow or venous stasis. Certain medications may
also increase risk of thrombosis, including estrogen, tamoxifen, thalidomide, and
erythropoietin.1 Normal blood ow dilutes activated clotting factors and results in
their degradation in various tissues (eg, liver) and by proteases. However, when low
ow or venous stasis is present, activated clotting factors may not be readily cleared.
DOI 10.37573/9781585286423.017
Platelets
Platelets are nonnucleated, disk-shaped structures, 1 to 5 μm in diameter, that are
formed in the extravascular spaces of bone marrow from megakaryocytes. Megakaryocyte production and maturation are promoted by the hormone thrombopoietin,
which is synthesized in the bone marrow and liver. Two-thirds of the platelets are
found in the circulation and one-third is found in the spleen; however, in splenectomized patients, nearly 100% is in the circulation.
e average human adult makes approximately 100 billion platelets per day, with
the average platelet circulating for 7 to 10 days. On aging, platelets are destroyed
by the spleen, liver, and bone marrow. roughout their lifespan, platelet function
is aected by numerous factors, such as medications, vitamins, foods, spices, and
systemic conditions, including chronic renal disease and hematologic disorders
377
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FIGURE 17-1. Relationship between platelets and the
clot. 5HT = serotonin; ADP = adenosine diphosphate;
2.
TxA
2
FIGURE 17-2.2,
ASA* = low-dose, irreversible, inactivation of platelet
(eg,myeloproliferative and lymphoproliferative diseases, dysproteinemias, and the presence of antiplatelet antibodies).
e primary function of platelets is to regulate hemostasis,
but platelets also play a prominent role in the pathologic formation of arterial thrombi. ree processes (platelet adhesion,
activation, and aggregation) are essential for arterial thrombus
formation. e surface of normal blood vessels inhibits platelet
function, thereby preventing thrombosis; however, endothelial
injury to the vasculature, caused by ow abnormalities, trauma,
or the rupture of atherosclerotic plaque in the vessel wall, starts
the process of platelet plug formation. Subendothelial structures,
such as collagen, then become exposed (Figure17-1), which
can result in platelet adhesion mediated by von Willebrand factor (vWF); platelet adhesion is enhanced by substances such
as epinephrine, thrombin, adenosine diphosphate (ADP), and
serotonin.2 Circulating vWF acts as a binding ligand between
the subendothelium and glycoprotein Ib receptors on the platelet surface.
Once adhesion occurs, platelets change shape and activation occurs. Activated platelets release their contents—
including nucleotides, adhesive proteins, growth factors, and
procoagulants—which promotes platelet aggregation and completes the formation of the hemostatic plug.3 is process is
mediated by glycoprotein IIb/IIIa receptors on the platelet surface, with brinogen acting as the primary binding ligand bridging between platelets. Platelets have numerous glycoprotein
IIb/IIIa binding sites, which are an attractive option for antiplatelet drug therapy.2 However, the platelet plug is not stable
and can be dislodged. To form a more permanent hemostatic
plug, the clotting system must be stimulated. By releasing
platelet factor (PF) 3, platelets initiate the clotting cascade and
concentrate activated clotting factors at the site of vascular
(endothelial) injury.
Prostaglandins (PGs) play an important role in platelet function. Figure17-2 displays a simplied version of the complex
arachidonic acid pathways that occur in platelets and on the
vascular endothelium. romboxane A2, a potent stimulator of
platelet aggregation and vasoconstriction, is formed in platelets.
In contrast, prostacyclin (PGI2), produced by endothelial cells
lining the vessel luminal surface, is a potent inhibitor of platelet
aggregation and a potent vasodilator that limits excessive platelet aggregation.
Cyclooxygenase and PGI2 are clinically important. An aspirin dose of 50 to 81 mg/day acetylates and irreversibly inhibits
cyclooxygenase in the platelet. Platelets are rendered incapable of
converting arachidonic acid to PGs. is eect of low-dose aspirin lasts for the lifespan of the exposed platelets (8 to 12days).
Vascular endothelial cells also contain cyclooxygenase, which
converts arachidonic acid to PGI2. Aspirin in high doses (3,000
to 5,000 mg) inhibits the production of PG2.4 However, because
the vascular endothelium can regenerate PGI2, aspirin’s eect
is much shorter here than on platelets. us, aspirin’s eect at
high doses may both inhibit platelet aggregation and block the
aggregation inhibitor PGI2. is phenomenon is the rationale for
using low doses of aspirin (75 to 162 mg/day) to help prevent MI.
In summary, a complex interaction between the platelet and
blood vessel wall maintains hemostasis. Once platelet adhesion
occurs, the clotting cascade may become activated. Aer thrombin and brin are generated, the platelet plug becomes stabilized
with insoluble brin at the site of vascular injury.
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 379
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Extrinsic Pathway
Intrinsic Pathway
Thrombin
Factor Xa
Thrombin
Factor VIIa
Factor IXa
2+
Ca
Vascular injury
Tissue Factor
Factor XI
Surface
Factor IX
Factor XIa
Ca
Factor X
Prothrombin
2+
Factor IXa
Factor VIIIB
2+
Ca
PL
Ca2+ PL
Factor VIII
Factor Xa
Factor Va
2+
PL
Ca
Factor Xa
2+
PL
Ca
Factor V
Factor VIIa
Tissue Factor
Ca
Fibrinogen
2+
Factor X
Thrombin
Factor VII
Tissue Factor
Factor IX
Fibrin
Factor XIII
Ca
Fibrin
Factor VII
2+
Factor XIIIa
Fibrin (crosslinked)
FIGURE 17-3.Source: Adapted with
Biochemistry.
Coagulation Cascade
e ultimate goal of the coagulation cascade (Figure17-3) is to
generate brin from thrombin. Fibrin forms an insoluble mesh
surrounding the platelet plug. Platelets concentrate activated
clotting factors at the site of vascular injury.
In addition to the direct eects and feedback mechanisms of
thrombin shown in Figure17-3, thrombin also stimulates platelet aggregation and activates the brinolytic system.
Additional factors within the pathway. Factors such as cal-
cium and vitamin K play an intricate role within the various
pathways in the coagulation cascade. Calcium is essential for
the platelet surface binding of several factors within the pathway. Vitamin K facilitates the calcium binding function of
factors II, VII, IX, and X via carboxylation. ese processes are
critical in activating proteins within the pathway.
Inhibition of Coagulation
Mechanisms that limit coagulation include the natural inhibi
tors such as antithrombin (AT) and the vitamin K-dependent
proteins C and S, tissue factor pathway inhibitor (TFPI), and
the brinolytic system. Endothelial cells produce several substances that have antithrombotic and anticoagulant eects,
which may also activate the brinolytic system.2 Several medications also can inhibit coagulation by acting on (1) platelets,
such as aspirin and P2Y12 inhibitors or (2) one or more clotting factors, such as warfarin; low molecular weight heparins
-
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TABLE 17-1.
DRUG CLASS
Platelet
inhibitors
Oral
anticoagulants
Parenteral
anticoagulants
SPECIFIC
MEDICATIONS
Aspirin
Clopidogrel (Plavix)
Ticagrelor (Brilinta)
Jantoven)
Rivaroxaban (Xarelto)
Dabigatran (Pradaxa) DTI
UFH Inhibits factor IIa
Fondaparinux
(Arixtra)
Bivalirudin
Argatroban
MECHANISM OF
ACTION
which prevents
conversion of
arachidonic acid
to P2Y12 receptors
on platelets
dependent
clotting factors
(II,
VII, IX, X) as
well as protein C
and protein S
Inhibits factor Xa
Inhibits factors IIa
and Xa
Inhibits factor Xa
DTI
natural inhibitors can result in increased generation of thrombin,
which can lead to recurrent thromboembolic events oen starting at a young age; the prevalence of protein C or protein S deciency in the general population is estimated at <0.5%.
with either protein C or protein S deciency are at a higher risk
of warfarin-induced skin necrosis compared with individuals
without these deciencies.
sue factor (TF) to factor VII, essentially inhibiting the extrinsic
pathway (Figure17-3). UFH and LMWHs can release TFPI from
endothelial cells and from platelets.2 e complex mechanisms
that limit thrombus formation are shown in Figure17-4.
2
7-10
TFPI impedes the binding of tis-
Clot Degradation
Fibrinolysis is the mechanism by which formed thrombi are lysed
to prevent excessive clot formation and vascular occlusion. As
discussed previously, brin is formed in the nal common pathway of the clotting cascade. Tissue plasminogen activator and
urokinase plasminogen activator activate plasminogen, which
generates plasmin. Plasmin is the enzyme that eventually breaks
down brin into brin degradation products (FDPs). Medications
can either activate (eg, alteplase, reteplase, and tenecteplase) or
inhibit (eg, tranexamic acid and aminocaproic acid) brinolysis.
TESTS TO EVALUATE HEMOSTASIS
For the purpose of discussion, bleeding and clotting disorders are
organized by tests that assess platelets, coagulation, and clot degradation. Tests to assess platelets include platelet count, volume (eg,
mean platelet volume [MPV]), function (eg, bleeding time [BT]
and platelet aggregation), and others. Prothrombin time (PT)/
International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time (ACT), brinogen
assay, thrombin time (TT), and others are laboratory tests that
assess coagulation; a hypercoagulable panel can be drawn to determine whether a patient has one or more hypercoagulable disorders. Clot degradation is assessed with tests for FDPs and -dimer.
In addition, general hematologic values such as hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, and
white blood cell count, as well as urinalysis and stool guaiac
tests may be important to obtain when evaluating blood and
coagulation disorders; some of these tests are further discussed
in Chapter16. Table17-2 is a summary of common tests used to
evaluate bleeding disorders and monitor anticoagulant therapy.
5,6
Patients
(LMWHs); unfractionated heparin (UFH); direct oral anticoagulants (DOACs); fondaparinux; and direct thrombin inhibitors (DTIs). Table17-1 lists the mechanism of action of these
classes of drugs and provides specic examples.
High concentrations of thrombin, in conjunction with thrombomodulin, activate protein C, which can then inactivate cofactors Va and VIIIa. us, there is a negative feedback mechanism
that blocks further thrombin generation and subsequent steps
in the coagulation cascade. Protein S is another of the body’s
natural anticoagulants and serves as a cofactor for protein C.
AT inactivates thrombin as well as factors IX, X, and XI, and this
process can be hastened by heparin. Heparin and AT combine
one-to-one, and the complex neutralizes the activated clotting
factors and inhibits the coagulation cascade. Deciencies in these
Platelet Tests
Platelet Count
Normal range: 150,000 to 450,000/mL (150 to 450 × 109/L)
e only test to determine the number or concentration of platelets in a blood sample is the platelet count, through either manual
(rarely done) or automated methods. Interferences with platelet
counts include RBC fragments, platelet clumping, and platelet
satellitism (platelet adherence to white blood cells). Automated
platelet counts are performed on anticoagulated whole blood.
Most instrumentation that performs hematologic proles provides platelet counts. Platelets and RBCs are passed through an
aperture, generating an electric pulse with a magnitude related
to the size of the cell/particle. e pulses are counted, and the
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 381
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PLASMINOGEN
Conversion of plasminogen to plasmin can be inhibited
by the following:
(1) Endogenous proteins
2-macroglobulin
Plasminogen activator inhibitor type 1 protein
(2) Medications
Aminocaproic acid
Plasmin is directly inhibited by
macroglobulin
FIBRIN CLOT FIBRIN SPLIT PRODUCTS
2-antiplasmin and 2-
PLASMIN
Activation of plasminogen can be stimulated by the
following:
(1) Endogenous proteins
Factors XI
Kallikrein
Urokinase plasminogen activator
Tissue plasminogen activator
(2) Medications
Tissue plasminogen activators (e.g.,
alteplase, reteplase, tenecteplase)
Thrombolytics (e.g., urokinase,
streptokinase)
a
, XII
a
FIGURE 17-4.
TABLE 17-2.
Monitoring
PLATELET
DISORDER OR DRUG
COUNT PT/INR APTT TT COMMENTS
Low
Platelets appear
Factor VIII levels low
Prolonged Prolonged Prolonged Fibrinogen levels
decreased
Prolonged
Prolonged (UFH)
Prolonged
decrease
DTI Prolonged Prolonged
Direct Xa inhibitors
Vascular purpura
such as TTP or ITP
382 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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platelets are separated from the RBCs by size, providing the
platelet count and MPV as well as the RBC count and mean
corpuscular volume. An abnormal platelet count can have many
causes, which are listed in the next sections.
rombocythemia. rombocythemia, also known as throm-
bocytosis or elevated platelet count, may be considered either
primary or secondary. Primary thrombocytosis is usually
caused by myeloproliferative neoplasms and other hematologic malignancies.11 Secondary or reactive thrombocytosis
may be caused by factors such as:
3,11
• Malignancy
• Infection
• Trauma
• Iron-deciency anemia
• Inammation
• Postsurgical state
Values of 500,000 to 800,000/μL are not uncommon. rombocythemia may be seen with any of the chronic myeloproliferative neoplasms, essential thrombocythemia, polycythemia
vera, chronic myelogenous leukemia, or idiopathic myelobrosis. Clinical consequences of thrombocythemia include arterial
or venous thromboses, skin and mucous membrane hemorrhages, and microcirculatory disturbances such as headaches,
paresthesias, and erythromelalgia.11 Additionally, patients with
thrombocythemia may have abnormalities in platelet function
studies, which can manifest as bleeding problems.
rombocytopenia. e main causes of thrombocytopenia, or
decreased platelet count, are (1) increased destruction or consumption of platelets, (2) decreased production, and (3) sequestration.3 Mucosal and cutaneous bleeding is the most common
clinical consequence of thrombocytopenia; however, patients
with only modest decreases in platelet counts may be asymptomatic. When the platelet count falls below 20,000/μL, the
patient is at risk for spontaneous bleeding. Platelet transfusions
are oen initiated when counts fall below 10,000/μL, but this
number can vary based on individual patient risk factors and
clinical situation.12 Bleeding may occur at higher platelet counts
(eg, 50,000/μL) if trauma occurs. e most common cause of
death in a patient with severe thrombocytopenia is central nervous system bleeding, such as intracranial hemorrhage.
Numerous drugs have been associated with thrombocytopenia (Table17-3).
13,14
However, heparin and antineoplastics are
the most common ones implicated. rombocytopenia is also
common with radiation therapy. Many drugs associated with
thrombocytopenia alter platelet antigens, resulting in the formation of antibodies to platelets (eg, heparin, penicillin, and gold).
Several diseases, such as thrombotic thrombocytopenic purpura,
idiopathic thrombocytopenic purpura, disseminated intravascular coagulation (DIC), and hemolytic-uremic syndrome, result
in rapid destruction of platelets. Other causes of thrombocytopenia include viral infections; pernicious, aplastic, and folate
or B12-deciency anemias; complications of pregnancy; massive
blood transfusions; exposure to dichlorodiphenyltrichloroethane; and human immunodeciency virus infections.
Heparin-induced thrombocytopenia (HIT) is an antibody-
mediated adverse reaction to heparin, occurring in 1 in 5,000
TABLE 17-3. Partial List of Agents Associated with
Anti-infective
Ceftriaxone
Fluconazole
Isoniazid
Itraconazole
Linezolid
Oxacillin
Piperacillin
Quinine
Antiseizure
Phenobarbital
Valproic acid
Haloperidol
Mirtazapine
Source
hospitalized patients, that may cause venous and arterial thrombosis.15 Specically, this is due to the development of immunoglobulin G antibodies that bind to the heparin PF4 complex.
Patients receiving UFH generally have 10-fold greater risk of
developing HIT than patients receiving LMWH because it does
not bind to PF4 as well as UFH, which is thought to be due to
the smaller size of LMWH compared with UFH.16 erefore,
the heparin-PF4 complex is less likely to form with LMWH, and
there are fewer immunoglobulin G antibodies generated. e
frequency or risk of HIT is inuenced by certain factors, such as
heparin preparation, route, dose, and duration of heparin therapy, patient population, gender, previous history of heparin exposure, and the animal source of heparin (bovine versus porcine).
e 4Ts score is a clinical prediction tool to determine the
probability of HIT. is tool requires the clinician to evaluate the
degree of thrombocytopenia, timing of platelet count fall, presence of thrombosis or other clinical sequelae, and other causes
for thrombocytopenia; a score of 0 to 2 is assigned for each of the
four items based on specic patient characteristics to determine
the probability of HIT occurring in that particular patient. us,
the score range is 0 to 8. A score of 0 to 3, 4 to 5, or 6 to 8 suggests
Cardiac
Atorvastatin
Clopidogrel
Digoxin
Quinidine
UFH
Pain
Diclofenac
Ibuprofen
Other
Antineoplastics
Interferon-α
17
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 383
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TABLE 17-4.
Monitoring
RISK OF
DEVELOPING HIT >1% 0.1% TO 1% <0.1%
Platelets
Patient
platelet counts
Postoperative patients on
dose UFH ≥
Postoperative patients on
ASH
receiving UFH
or until heparin is discontinued,
or therapeutic-dose UFH or
≥
≥
Obstetrics patients
Intensive care patients
Medical and obstetrical patients
receiving UFH
Medical and obstetrical
Patients receiving
fondaparinux
ASH If patient has received heparin in
If patient has not received heparin
or until heparin is discontinued,
Source
a low, moderate, or high probability of HIT, respectively.18 HIT is
manifested both by clinical and serological features, and diagnosis
of HIT is usually made when antibody formation is detected by
an in vitro assay plus one or more of the following: unexplained
decrease in platelet count, venous or arterial thrombosis, limb
gangrene, necrotizing skin lesions at the heparin injection site,
acute anaphylactoid reactions occurring aer intravenous (IV)
heparin bolus administration, and/or bleeding.
17,19
ere are two types of tests to help diagnose HIT: (1) the
enzyme-linked immunosorbent assay (ELISA), which identies
anti-PF4/heparin antibodies, and (2) functional assays, such as
the C-serotonin release assay or the heparin-induced platelet
activation assay—both of which detect antibodies that induce
heparin-dependent platelet activation.
15,20
e ELISA test has
If patient has received heparin in
If patient has not received
or until heparin is discontinued,
high sensitivity, low specicity, and wide availability, with a relatively rapid turnaround time compared with the functional
assays, which makes it a good screening test.18 By contrast, the
functional assays have high specicity, which are useful for conrming a positive ELISA test but are technically dicult, have a
higher cost, and have longer turnaround time.
18
e typical onset for HIT is 5 to 10 days aer the start of heparin; however, onsets occurring either earlier or later than this have
been reported. Rapid-onset HIT occurs when platelet counts fall
within 24 hours of heparin initiation, which is typically the result
of repeated heparin exposure within the past 100days, and thus
patients still have circulating HIT antibodies. Delayed-onset HIT,
in which thrombocytopenia occurs several days aer discontinuation of heparin, can also occur. Table17-4 outlines the patient
384 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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TABLE 17-5. Conditions Associated with
Alterations in MPV
INCREASE IN MPV DECREASE IN MPV
Ulcerative colitis
HIV infection
FIGURE 17-5.
characteristics associated with the risk of developing HIT as well
as recommendations for monitoring platelet counts.
20,21
Mean Platelet Volume
Normal range: 7 to 11 fL (varies with laboratory)
Mean platelet volume (MPV)—the relationship between plate-
let size and count—is most likely used by clinicians in assessing
disturbances of platelet production. MPV is useful in distinguishing between hypoproductive and hyperdestructive causes
of thrombocytopenia (Figure17-5). Despite the widespread
availability of this platelet index, many clinicians do not use it
in clinical decision-making. In the past, this disuse was attributed to diculties with the laboratory measurement of indices.
Many laboratories routinely report the MPV as part of the
complete blood count, especially if a dierential is requested. In
general, lower platelet counts are common with higher platelet
volumes because an inverse relationship exists between the platelet count and the MPV. is inverse relationship correlates with
platelet production within the bone marrow. Although MPV is
most valuable in distinguishing hypoproductive from hyperdestructive causes of thrombocytopenia, a denitive diagnosis
cannot be made based on MPV alone. In thrombocytopenia,
an elevated MPV suggests no problem with platelet production,
when in fact, production is reexively increased. Conversely, a
normal or low MPV suggests impaired thrombopoiesis. Determination of MPV requires a blood collection tube containing an
anticoagulant. Usually, such tubes contain the anticoagulant ethylenediamine tetraacetic acid (EDTA), which causes an ination
of the MPV.22 Table17-5 lists conditions that aect the MPV.
23,24
Platelet Function
Simply stated, the platelet function tests look at the ability of platelets
to aggregate and form a clot. Abnormalities of platelet function may
be either inherited or acquired and can be caused by medications,
the platelet milieu, and inherent platelet defects; platelet counts are
usually normal.25 Bleeding as a result of an inherited versus acquired
disease
MI
Unstable angina
Psoriasis
Chronic obstructive
Obstructive sleep apnea
Renal failure
Sepsis
Source
abnormality may be dicult to prove. Common bleeding sites in
patients with disorders of platelet function include ecchymosis of
the skin, epistaxis, gingival bleeding, and menorrhagia; gastrointestinal (GI) hemorrhage and hematuria are less common and usually
have an associated underlying pathology.
Although the sites of bleeding may be predictable, the severity
is not predictable in patients with inherited disorders of platelet
function. Unfortunately, the risk of bleeding and bleeding patterns
in patients with acquired platelet dysfunction are less predictable and more dicult to distinguish. Because both inherited and
acquired etiologies increase the risk of bleeding, patients overtly
bleeding without a clear cause or without an invasive procedure
should be evaluated for one of these platelet function disorders.
CHAPTER 17 • HEmATology: Blood CoAgulATion TEsTs 385
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Bleeding Time
Normal range: 2 to 9 minutes
Bleeding time (BT) is a measure of platelet function and has
been used to assess bleeding risk, but this test is neither specic nor sensitive; thus, it does not help dierentiate among
the types of problems seen in disorders of primary hemostasis,
such as von Willebrand disease and platelet function defects.
Because BT is neither specic nor sensitive, its use has been
declining, and some institutional clinical laboratories no longer
perform this test. Additionally, the test is invasive and must be
performed by a trained healthcare worker. To perform the test,
small cuts are made on the forearm of the patient, and the time
it takes to stop bleeding is measured. Several factors can prolong the BT, including thrombocytopenia, certain medications,
and conditions such as uremia and macroglobulinemia. Most
acquired disorders aecting BT are related to medications that
decrease platelet numbers or reduce platelet function, including aspirin, P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor),
GPIIb/IIIa inhibitors (abciximab, eptibatide, tiroban), and
phosphodiesterase inhibitors (dipyridamole). Although BT
isinuenced by some drugs, it is not used to monitor drug
therapy. e increase in BT caused by aspirin may have benecial eects in the treatment and prevention of cardiovascular disease.
Platelet aggregation. With the many drawbacks of the BT, there
was a need for a test that could aid in the diagnosis of defects
in platelet function. e ability of platelets to aggregate is most
commonly measured by preparing a specimen of platelet-rich
plasma and warming it to 98.6°F (37°C) with constant stirring.
is test is performed with an aggregometer that measures light
transmission through a sample of platelets in suspension. Aer
a baseline reading is obtained, a platelet-aggregating agonist
(eg, epinephrine, collagen, ADP, or arachidonic acid) is added.
As platelets aggregate, more light passes through the sample.
e change in optical density can be measured photometrically
and recorded as an aggregation curve, which is then printed
on a plotter. Although light transmittance aggregometry (LTA)
testing is the gold standard in platelet function analysis, it has
requirements for specially trained personnel, large sample volume, and sample preparation, and it is costly.
22
Interpretation of platelet aggregation tests involves a comparison of the patient’s curves with the corresponding curves
of a normal control. To eliminate the optical problems of turbidity with lipemic plasma, the patient and the normal control should be fasting. Patients should not take medications that
aect platelet aggregation (eg, aspirin, nonsteroidal anti-inammatory drugs, P2Y12 inhibitors) for approximately 7 to 14 days
before the test because they may interfere with test results. Other
drugs that may aect platelet function are listed in Table17-6.
26
Novel point-of-care (POC) technologies are available and
allow for rapid and meaningful evaluation of platelet function,
although major dierences between devices do exist. ese
devices can assess the eects of medications such as aspirin,
P2Y12 inhibitors, and GP IIb/IIIa antagonists on platelet function
and help predict the incidence of major adverse cardiac events
in patients treated with medications aecting platelet function.27
Further studies of each individual device are needed to elucidate
TABLE 17-6. Medications and Drug Classes That
Inhibitors
Aspirin
β
Penicillins
Cephalosporins Phenothiazines
P2Y
SSRIs
Heparin Statins
Source
the exact place in therapy of these in monitoring antiplatelet
medications.
Other Platelet Tests
e measurement of platelet-specic substances, such as PF4
(normal values 1.7 to 20.9 ng/mL) and β-thromboglobulin
(normal levels 6.6 to 47.9 ng/mL), can now be performed by
radioimmunoassay or enzyme immunoassay.28 High concentrations of these substances may be observed with coronary artery
disease, acute MI, and thrombosis, in which platelet lifespan is
reduced. Because numerous drugs can potentially cause thrombocytopenia, detection of antibodies directed by specic drugs
against platelets may help to determine the culprit. Platelet survival can be measured by injecting radioisotopes that label the
platelets. Serial samples can then determine platelet survival,
which is normally 8 to 12 days.
Pharmacogenomics and clopidogrel metabolism. Genetic
variability in the genes coding for CYP2C19 may have an eect
on clopidogrel ecacy and safety; this concept is covered in
more detail in Chapter6. ere are commercially available
assays to test for these variants in CYP2C19.
do not recommend routine platelet function testing or genetic
testing in all patients taking clopidogrel; instead, they recognize a possible role for testing patients who undergo high-risk
percutaneous coronary intervention (PCI) procedures, such as
those involving bifurcating le main artery.
inhibitors
12
29,30
Guidelines
31-33
COAGULATION TESTS
Coagulation tests are useful in the identication of deciencies of coagulation factors responsible for bleeding as well as
thrombotic disorders. e most commonly performed tests,
including PT, INR, aPTT, and ACT, are used to monitor anticoagulant therapy. Numerous high-precision automated laboratory
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