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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e

Chapter 232: Chapter 232: Tests of HemostasisTests of Hemostasis Stephen John Cico; Robin R. Hemphill

THE BLEEDING PATIENTTHE 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.1 In these patients, specificassessment of hemostasis is unnecessary. However, some ED patients have abnormal bleeding due to impaired

hemostasis. Identifying these patients requires attention to the history and physical findings.2,3,4 Generally speaking,when patients have spontaneous bleeding from multiple sites, bleeding from untraumatized sites, delayed bleedingseveral hours a�er trauma, and bleeding into deep tissues or joints, the possibility of a bleeding disorder should beconsidered.

Important historical data that aid in identifying a congenital bleeding disorder include the presence of unusual orabnormal bleeding in the patient and other family members and any occurrence of excessive bleeding a�er dental

extractions, surgical procedures, or trauma.5 Many patients with abnormal bleeding have an acquired disorder, suchas liver disease, renal disease, or drug use (particularly ethanol, aspirin, nonsteroidal anti-inflammatory drugs,

antiplatelet drugs, oral anticoagulants, antibiotics, and other salicylate-containing products).2,3,4 Many supplementsand herbal preparations, including garlic, ginseng, ginkgo biloba, ginger, and vitamin E, can also increase bleedingtendencies.

The site of bleeding may provide an indication of the hemostatic abnormality. Mucocutaneous bleeding, includingpetechiae, ecchymoses, epistaxis, GI or GU bleeding, or heavy menstrual bleeding, is characteristic of qualitative orquantitative platelet disorders. Purpura is o�en associated with thrombocytopenia and commonly indicates asystemic illness. Bleeding into joints and potential spaces, such as between fascial planes and into theretroperitoneum, and delayed bleeding are most commonly associated with coagulation factor deficiencies. Patientswho demonstrate both mucocutaneous bleeding and bleeding in deep spaces may have disorders such asdisseminated intravascular coagulation, in which both platelet abnormalities and coagulation factor abnormalitiesare present (see chapters 233, "Acquired Bleeding Disorders," 234, "Clotting Disorders," and 235, "Hemophilias andvon Willebrand's Disease").

Common laboratory tests for hemostasis have their limitations.6,7 They are generally useful and reliable foridentifying 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 di�icult to achieve.8,9 Inaddition, liver disease and renal failure—two conditions that increase the potential for abnormal hemorrhage—may

not give rise to consistent and measurable abnormal results on routine tests of hemostasis.10,11,12

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THE PATIENT WITH A THROMBUSTHE PATIENT WITH A THROMBUS

Presentation of a patient to the ED with a disorder due to an intravascular thrombosis, such as a deep venousthrombosis or pulmonary embolus, suggests the potential for an underlying hypercoagulable state (see chapter 234).Premature coronary artery disease and acute coronary syndrome in individuals as young as teenagers have also beenlinked to hypercoagulable conditions. However, many, if not most, occurrences of intravascular thrombosis are notdue to exaggerated hemostasis, but rather are due to local conditions, with blood vessel wall injuries, local

inflammation, or vascular stasis provoking the thromboembolic event.13,14

The susceptibility to hypercoagulation may be acquired or genetically transmitted. Common acquiredhypercoagulable disorders include essential thrombocythemia, polycythemia vera, paroxysmal nocturnalhemoglobinuria, antiphospholipid syndrome, and cancer (o�en occult at the time of acute thrombosis). Inheritedhypercoagulable disorders include factor V Leiden, prothrombin mutations, hyperhomocysteinemia, and deficienciesof protein C, protein S, and antithrombin. Patients with inherited hypercoagulable conditions tend to have venousthrombosis, whereas those with acquired disorders can have both arterial and venous clots.

Proteins C and S are vitamin K–dependent antihemostatic factors made in the liver, associated with disorders leadingto deficiencies of these proteins inherited in an autosomal manner. Protein C is activated by thrombin and functionswith protein S to stop fibrin formation and to stimulate the process of fibrinolysis. Antithrombin is also anantihemostatic protein that blocks activated coagulation factors. Elevated homocysteine level is also a known riskfactor for thromboembolism.

Laboratory tests for a hypercoagulable diathesis show wide biologic variation, and standardization amonglaboratories has been di�icult to achieve. The clinical utility of testing patients for suspected hypercoagulable

conditions is dependent on the specific disorder.13,14,15

NORMAL COAGULATIONNORMAL COAGULATION

The normal hemostatic system consists of a complex process that limits blood loss through the formation of aplatelet plug (primary hemostasis) and the production of cross-linked fibrin (secondary hemostasis), whichstrengthens the platelet plug. These reactions are counterregulated by the fibrinolytic system, which limits the size ofthe fibrin clot that is formed and thereby prevents excessive clot formation. Congenital and acquired abnormalitiesoccur in all these systems. The a�ected patient may have excessive hemorrhage, excessive thrombus formation, orboth.

PRIMARY HEMOSTASISPRIMARY HEMOSTASIS

Primary hemostasis is the platelet interaction with the vascular subendothelium that results in the formation of aplatelet 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 viaglycoprotein Ib), and normal fibrinogen (connects the platelets to each other via glycoprotein IIb and IIIa) (Figure 232-Figure 232-11). Primary hemostasis begins within 20 seconds of injury, is short-lived, and requires secondary hemostasis for clotstabilization.

FIGURE 232-1.FIGURE 232-1.

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Primary hemostasis. plt = platelet; vWF = von Willebrand factor.

SECONDARY HEMOSTASISSECONDARY HEMOSTASIS

Secondary hemostasis consists of the tightly regulated reactions of the plasma coagulation proteins. The finalproduct is cross-linked fibrin, which is insoluble and strengthens the platelet plug formed in primary hemostasis(Figure 232-2Figure 232-2).

FIGURE 232-2.FIGURE 232-2.

Secondary hemostasis. Ca2+ = calcium; fibrinogen is factor I; PL = phospholipid surface (o�en platelets); prothrombinis factor II.

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Secondary hemostasis is also known as the coagulation cascade. The inactivated coagulation proteins (factors) areidentified by Roman numerals, and a�er activation, the activated factor is designated by a. There are twoindependent activation pathways. The contact system is known as the contact activation pathway or intrinsicpathway, and the tissue factor system is known as the tissue factor pathway or extrinsic pathway. The pathways

merge at the point of activation of factor X. Medications such as rivaroxaban (Xarelto®) and apixaban (Eliquis®) inhibitthe activity of factor Xa. The combination of factor Xa, factor Va, phospholipid, and calcium ("thrombinase complex")more e�iciently 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 (Angiomax®) or dabigatran (Pradaxa®)are direct thrombin inhibitors. The common pathway describes the steps from factor X activation to cross-linkedfibrin formation.

THE FIBRINOLYTIC SYSTEMTHE FIBRINOLYTIC SYSTEM

The fibrinolytic system regulates the hemostatic mechanism by limiting the size of the fibrin clots that are formed(Figure 232-3Figure 232-3). Tissue plasminogen activator (tPA), released from endothelial cells, is the principal physiologic triggerfor the fibrinolytic process, converting plasminogen, synthesized in the liver and adsorbed in the fibrin clot, to

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plasmin. Plasmin degrades fibrinogen and fibrin monomer into low-molecular-weight fragments known as fibrindegradation products and degrades cross-linked fibrin into d-dimers.

FIGURE 232-3.FIGURE 232-3.

The fibrinolytic system. FDP = fibrin degradation product; tPA = tissue plasminogen activator.

Other physiologic inhibitors of hemostasis with clinical relevance include antithrombin and the protein C–protein Ssystem. Antithrombin is a protein that forms complexes with all the serine protease coagulation factors (factors XIIa,XIa, Xa, IXa, and thrombin), thereby inhibiting their function. Heparin potentiates this interaction, and this is the basisfor 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 twoplasma cofactors factors Va and VIIIa and inhibiting their participation in the coagulation cascade. A single amino acidsubstitution in factor V, a condition named factor V Leiden, prevents activated protein C from binding and inhibitingthe 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 potentially hypercoagulablecondition and predispose the patient to venous thromboses.

DIAGNOSISDIAGNOSIS

Before embarking on a sequence of hemostatic testing, evaluate the patient in three areas: (1) Is the bleedingabnormal? (2) Is there a current medical condition associated with increased hemorrhage? (3) Is there a structural

cause that explains the bleeding?13,14,15,16,17

The basic laboratory tests obtained for a patient with a suspected abnormal bleeding disorder are a CBC and plateletcount, prothrombin time, and activated partial thromboplastin time (Table 232-1Table 232-1). The results of these tests, coupled

with clinical evaluation, should enable formulation of a di�erential diagnosis.18 Additional studies are ordered asindicated (Table 232-2Table 232-2). Obtain hematologic consultation if the di�erential diagnosis or the laboratory approach isunclear. In patients with postoperative bleeding, the basic laboratory tests for coagulation are of little help in

assessment or management.19

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TABLE 232-1

Initial Tests of HemostasisInitial Tests of Hemostasis

Screening TestsScreening TestsReferenceReference

ValueValueComponent MeasuredComponent Measured Clinical CorrelationsClinical Correlations

Primary HemostasisPrimary Hemostasis

Platelet count 150–400/mm3

(150–400 ×

109/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 Interaction between

platelets and the

subendothelium

Prolonged BT caused by:

Typically 2.5–

10.0 min using

a BT template

Thrombocytopenia (platelet count <50,000/mm3

or 50 × 109/L)

Abnormal platelet function (von Willebrand's

disease, antiplatelet drugs, uremia, liver disease)

Secondary HemostasisSecondary Hemostasis

Prothrombin

time (PT) and

international

normalized

ratio (INR)

PT: 11–13 s;

depends on

reagent

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:

INR: 1.0 Warfarin (inhibits production of vitamin K–

dependent factors II, VII, IX, and X)

Liver disease with decreased factor synthesis

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Screening TestsScreening TestsReferenceReference

ValueValueComponent MeasuredComponent Measured Clinical CorrelationsClinical Correlations

Antibiotics that inhibit vitamin K–dependent

factors (moxalactam, cefamandole, cefotaxime,

cefoperazone)

Activated

partial

thromboplastin

time (aPTT)

22–34 s Intrinsic system and

common pathway—factors

XII, XI, IX, VIII, X, V,

prothrombin, and

fibrinogen

Prolonged aPTT most commonly caused by:

Depends on

type of

thromboplastin

reagent used

Heparin therapy

"Activated"

with kaolin

Factor deficiencies (factor levels have to be <30%

of normal to cause prolongation)

Fibrinogen

level

Slightly

variable

according to

specific test

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)

Typically 200–

400

milligrams/dL

(2–4 g/L)

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 Variable Performed when results on

one or more of the above

screening tests is

prolonged; the patient's

plasma ("abnormal") is

If the mixing corrects the screening test result:

one or more factor deficiencies are present

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Screening TestsScreening TestsReferenceReference

ValueValueComponent MeasuredComponent Measured Clinical CorrelationsClinical Correlations

mixed with "normal"

plasma and the screening

test is repeated

If the mixing does not correct the screening test

result: a circulating inhibitor is present

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TABLE 232-2

Additional Hemostatic TestsAdditional Hemostatic Tests

TestTest Reference ValueReference Value Component MeasuredComponent Measured Clinical Correlations/CommentsClinical 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 di�use

intravascular coagulation,

venous thrombosis, pulmonary

embolus, and liver disease, and

during pregnancyd-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 Level of protein C in the

blood

Vitamin K dependent

Typically 60%–150% of

reference value

Increases with age

Values higher in males than

females

Deficiency associated with

thromboembolism in people <50

y of age

Protein S level Variable Level of protein S in the

blood

Vitamin K dependent

Typically 60%–150% of

reference value

Increases with age

Values higher in males than

females

Deficiency associated with

thromboembolism in people <50

y of age

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TestTest Reference ValueReference Value Component MeasuredComponent Measured Clinical Correlations/CommentsClinical Correlations/Comments

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

Screening assay uses

activated partial

thromboplastin time with

and without added

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

Antithrombin level Variable depending on

specific test

Measures level of

antithrombin in the blood

Not vitamin K dependent;

patients with deficiency require

higher dosages of heparin for

anticoagulation therapy

Typically 20–45

milligrams/dL (200–450

milligrams/L)

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: elevated in

systemic lupus erythematosus

(SLE) and other autoimmune

diseases

Lupus anticoagulant Anticardiolipin antibody:

elevated in SLE, other

autoimmune diseases, syphilis,

and Behçet's syndrome

Anticardiolipin antibody Increased risk of spontaneous

abortions, fetal loss, and fetal

growth retardation

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TestTest Reference ValueReference Value Component MeasuredComponent Measured Clinical Correlations/CommentsClinical Correlations/Comments

Anti–factor Xa activity During therapeutic

anticoagulant use: 0.7–

1.1 units/mL

Inhibition of factor Xa

activity

Used to monitor low-molecular-

weight heparin therapy, and

newer anticoagulants such as

apixaban and rivaroxaban

During prophylactic

anticoagulant use: 0.2–

0.3 units/mL

May be elevated in renal

dysfunction

Platelet function assay 88–183 s Tests for platelet adhesion

and aggregation

A�ected by uremia, anemia,

thrombocytopenia, antiplatelet

medications, and von

Willebrand's disease

Variable Initial test done with

epinephrine. A prolonged test is

repeated using ADP, and if

normal <122 s, indicates

probable aspirin e�ect

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

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Abbreviations: ADP = adenosine diphosphate; GPL = 1 microgram of a�inity-purified immunoglobulin G anticardiolipin antibody

from an original index serum; IgM, immunoglobulin M; MPL = 1 microgram of a�inity-purified immunoglobulin M anticardiolipin

antibody from an original index serum.

1. 

2. 

3. 

4. 

5. 

6. 

7. 

TestTest Reference ValueReference Value Component MeasuredComponent Measured Clinical Correlations/CommentsClinical Correlations/Comments

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

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