15/5/2019

Williams Hematology, 9e

Chapter 116: Classification, Clinical Manifestations, and Evaluation of Disorders of Hemostasis

Marcel Levi; Uri Seligsohn; Kenneth Kaushansky

INTRODUCTION
SUMMARY

Evaluation of a hemostatic disorder is commonly initiated when (1) a patient or referring physician suspects a
bleeding tendency, (2) a bleeding tendency is discovered in one or more family members, (3) an abnormal
coagulation assay result is obtained from an individual as part of a routine examination, (4) an abnormal
assay result is obtained from a patient during preparation for surgery, or (5) a patient has unexplained di use
bleeding during or a er surgery or following trauma. Evaluation of a possible hemostatic disorder in each of
these scenarios is a stepwise process that requires knowledge of the various classes of hemostatic disorders
commonly found under the particular circumstances. The patient’s history, the results of physical
examination, and an initial set of hemostatic tests usually enable a tentative diagnosis. However, more
specific tests are commonly necessary to make a definitive diagnosis. This chapter reviews the necessary
steps.

Acronyms and Abbreviations

aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; ELISA, enzyme-
linked immunosorbent assay; PT, prothrombin time; RCF, ristocetin cofactor.

CLASSIFICATION OF HEMOSTATIC DISORDERS

Hemostatic disorders can conveniently be classified as either hereditary or acquired (Table 116–1).
Alternatively, hemostatic disorders can be classified according to the mechanism of the defect. Of the
acquired disorders, the thrombocytopenias are the most frequently encountered entities.
Thrombocytopenias can result from reduced production of platelets, excessive destruction caused by
antibodies or other consumptive processes, or pooling of platelets in the spleen, as in hypersplenism (Chap.
119); however, if hypersplenism is the sole cause of a hemostatic disorder, it is rarely severe enough to cause
pathologic bleeding.

1/18
15/5/2019

Table 116-1.
Classification of Disorders of Hemostasis

Major
Disorders Examples
Types

Acquired Thrombocytopenias Autoimmune and alloimmune, drug-induced, hypersplenism,

hypoplastic (primary, myelosuppressive therapy, myelophthisic marrow
infiltration), disseminated intravascular coagulation (DIC), thrombotic
thrombocytopenic purpura, hemolytic-uremic syndrome (Chaps. 117,
129, and 132)

Liver diseases Cirrhosis, acute hepatic failure, liver transplantation (Chap. 128),
thrombopoietin deficiency

Renal failure

Vitamin K deficiency Malabsorption syndrome, hemorrhagic disease of the newborn,

prolonged antibiotic therapy, malnutrition, prolonged biliary
obstruction

Hematologic Acute leukemias (particularly promyelocytic), myelodysplasias,

disorders monoclonal gammopathies, essential thrombocythemia (Chaps.
85,86,87 and 106)

Acquired antibodies Neutralizing antibodies against factors V, VIII, and XIII, accelerated
against coagulation clearance of antibody-factor complexes, e.g., acquired von Willebrand
factors disease, hypoprothrombinemia associated with antiphospholipid
antibodies (Chaps. 126, 127, and 131)

DIC Acute (sepsis, malignancies, trauma, obstetric complications) and

chronic (malignancies, giant hemangiomas, retained products of
conception) (Chap. 129)

Drugs Antiplatelet agents, anticoagulants, antithrombins, and thrombolytic,

hepatotoxic, and nephrotoxic agents (Chaps. 25 and 133–135)

2/18
15/5/2019

Major
Disorders Examples
Types

Vascular Nonpalpable purpura (“senile,” solar, and factitious purpura), use of

corticosteroids, vitamin C deficiency, child abuse, thromboembolic,
purpura fulminans; palpable-purpura (Henoch-Schönlein, vasculitis,
dysproteinemias; Chap. 122), amyloidosis

Inherited Deficiencies of Hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency),

coagulation factors deficiencies of fibrinogen factors II, V, VII, X, XI, and XIII and von
Willebrand disease (Chaps. 123–126)

Platelet disorders Glanzmann thrombasthenia, Bernard-Soulier syndrome, platelet granule

disorders (Chap. 120)

Fibrinolytic α2-Antiplasmin deficiency, plasminogen activator inhibitor-1 deficiency

disorders (Chap. 135)

Vascular Hemorrhagic telangiectasias (Chap. 122)

Connective tissue Ehlers-Danlos syndrome (Chap. 122)

disorders

BLEEDING HISTORY
The bleeding history is a crucial element in the evaluation of a patient with a hemorrhagic disorder. The
bleeding history helps define the subsequent diagnostic approach and the likelihood of future bleeding.
Eliciting and interpreting all of the relevant information requires a systematic and methodical approach. The
following points are worth considering:

1. Patients vary in their responses to hemorrhagic symptoms. Some patients ignore significant symptoms,
whereas other patients are highly sensitive to even minor symptoms. When asked in standardized
questionnaires, many normal, healthy people indicate they have excessive bleeding or bruising.1,2
Therefore, some experts believe the question “Do you bruise easily?” is virtually worthless. Women are
more likely to respond that they have excessive bleeding or bruising than are men.

2. Patients with severe hemorrhagic disorders invariably have very abnormal bleeding histories, for
example, severe hemophilia A or hemophilia B, type 3 (homozygous) von Willebrand disease, and

3/18
15/5/2019

Glanzmann thrombasthenia. Importantly, these patients may experience spontaneous bleeding

episodes.

3. The diagnostic value of any specific symptom varies in the di erent disorders. Therefore, recognizing
typical patterns of bleeding is important (Table 116–2). Unprovoked hemarthroses and muscle
hemorrhages suggest one of the hemophilias, whereas mucocutaneous bleeding (epistaxis, gingival
bleeding, menorrhagia) are more characteristic of patients with qualitative platelet disorders,
thrombocytopenia, or von Willebrand disease.

4. Assessing the extent of hemorrhage against the background of any trauma or provocation that may have
elicited the hemorrhage is important. If a patient has never had a significant hemostatic challenge, such
as tooth extraction, surgery, trauma, or childbirth, the lack of a significant bleeding history is much less
valuable in excluding a mild hemorrhagic disorder. For example, a significant percentage of patients with
mild von Willebrand disease or mild forms of hemophilia may have negative bleeding histories,1 even
though they may be at considerable risk for excessive bleeding a er surgery or other interventions. Thus,
these diagnoses must be considered even in elderly patients if their first severe hemostatic challenge
occurs at that age.

5. Obtaining objective confirmation of the subjective information conveyed in the bleeding history is
valuable. Objective data include (1) previous hospital or physician visits for bleeding symptoms, (2)
results of previous laboratory evaluations, (3) previous transfusions of blood products for bleeding
episodes, and (4) a history of anemia and/or previous treatment with iron.

6. Although self-administered questionnaires may provide useful background information, they cannot
substitute for a dialogue between the physician and the patient. Thus, history taking in general, but
especially in the o en subtle histories related to hemostatic disorders, is an intellectually active process
involving data collection, hypothesis development, new question formulation, additional data gathering,
and new hypothesis development. However, this iterative procedure has its limitations even when it is
carefully pursued.3,4

7. A medication history is a crucial component of the bleeding history, with particular attention to
nonprescription drugs, such as aspirin and nonsteroidal antiinflammatory agents, which may a ect
bleeding symptoms. A medication history is especially important in patients with thrombocytopenia,
because drug-induced thrombocytopenia is common (Chap. 120 and see Table 116–1). Medication also
may a ect hemostasis through deleterious e ects on the liver or kidney functions. The increased use of
herbal and alternative medicines poses particular problems, because patients may not readily share
information about what they are taking, and the dose they are taking of any particular active ingredient
may be di icult to determine. Ginkgo biloba and ginseng are the most commonly used herbals that can
cause platelet dysfunction and induce bleeding.5 Other dietary supplements can display similar
e ects.5,6

4/18
15/5/2019

8. A nutrition history should be obtained to assess the likelihood of (1) vitamin K deficiency, especially if the
patient also is taking broad-spectrum antibiotics, (2) vitamin C deficiency, especially if the patient has
skin bleeding consistent with scurvy (perifollicular purpura), and (3) general malnutrition and/or
malabsorption.

9. Several tissues have an increased local fibrinolytic activity. Such tissues include the urinary tract,
endometrium, and mucous membranes of the nose and oral cavity. These sites are particularly likely to
have prolonged oozing of blood a er trauma in patients with hemostatic abnormalities. Excessive
bleeding following tooth extraction is one of the most common manifestations. Bleeding resulting from
defects in fibrin crosslinking (factor XIII deficiency) or fibrinolytic defects may o en manifest as delayed
bleeding a er trauma.

10. Bleeding isolated to a single organ or system (e.g., hematuria, hematemesis, melena, hemoptysis, or
recurrent nosebleeds) is less likely to result from a hemostatic abnormality than from a local cause such
as neoplasm, ulcer, or angiodysplasia. Thus, careful anatomic evaluation of the involved organ or system
should be performed.

11. Bleeding may result from blood vessel disorders such as hereditary hemorrhagic telangiectasias, Cushing
disease, scurvy, or Ehlers-Danlos syndrome. Many primary dermatologic disorders also have a purpuric
or hemorrhagic component and must also be considered in the di erential diagnosis (Chap. 122).

12. A family history is particularly important when hereditary disorders are considered. Patients usually will
not spontaneously o er a history of consanguinity, so specific inquiry should be made about this
possibility. A diagram of the patient’s genealogic tree, extending back at least two generations, should be
included to document consideration of genetic disorders. A sex-linked pattern of inheritance is consistent
with hemophilia A or B (Chap. 123). An autosomal dominant pattern is characteristic of most forms of von
Willebrand disease (Chap. 126). An autosomal recessive pattern is typical for all other coagulation factor
deficiencies (Chap. 124), inherited platelet disorders (Chap. 120), and the rare, severe (homozygous),
type3 von Willebrand disease. Population genetic information may be helpful; for example, the higher
prevalence of factor XI deficiency in Ashkenazi Jews (Chap. 124).

13. The history should include information on diseases and organs that may a ect hemostasis, such as
cirrhosis, renal insu iciency, myeloproliferative neoplasms (e.g., essential thrombocythemia), acute
leukemia, myelodysplasia, systemic lupus erythematosus, and Gaucher disease.

5/18
15/5/2019

Table 116-2.
Clinical Manifestations Typically Associated with Specific Hemostatic Disorders

Clinical Manifestations Hemostatic Disorders

Mucocutaneous bleeding Thrombocytopenias, platelet dysfunction, von Willebrand

disease

Cephalhematomas in newborns, Severe hemophilias A and B, severe deficiencies of factor VII, X,

hemarthroses, hematuria, and or XIII, severe type3 von Willebrand disease, afibrinogenemia
intramuscular, intracerebral, and
retroperitoneal hemorrhages

Injury-related bleeding and mild Mild and moderate hemophilias A and B, severe factor XI
spontaneous bleeding deficiency, moderate deficiencies of fibrinogen and factorsII, V,
VII, or X, combined factors V and VIII deficiency, α2-antiplasmin
deficiency

Bleeding from stump of umbilical cord Afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia,

and habitual abortions factor XIII deficiency

Impaired wound healing Factor XIII deficiency

Facial purpura in newborns Glanzmann thrombasthenia, severe thrombocytopenia

Recurrent severe epistaxis and chronic Hereditary hemorrhagic telangiectasias

iron deficiency anemia

CLINICAL MANIFESTATIONS
Individual hemorrhagic symptoms o en require detailed analysis before the significance of the symptoms
and the resulting diagnosis or therapy can be determined. Some of the more common symptoms are
discussed below, and Table 116–2 summarizes clinical manifestations that are typical for specific hemostatic
disorders.

1. Epistaxis is one of the most common signs of platelet disorders and von Willebrand disease. It also is the
most common symptom of hereditary hemorrhagic telangiectasia. In the latter condition, epistaxis
almost always becomes more severe with advancing age. Epistaxis is not uncommon in normal children,
but it usually resolves before puberty. Dry air heating systems can provoke epistaxis even in otherwise

6/18
15/5/2019

normal individuals. Bleeding confined to a single nostril more likely results from a local vascular problem
than a systemic coagulopathy.

2. Gingival hemorrhage is very common in patients with both qualitative and quantitative platelet
abnormalities and von Willebrand disease. Occasional gum bleeding occurs in normal individuals,
especially if they use a hard bristle tooth brush and dental hygiene procedures. Thus, establishing
whether the bleeding is excessive may be di icult. Frequent gingival hemorrhage can occur in individuals
with normal hemostasis if they have gingivitis.

3. Oral mucous membrane bleeding in the form of blood blisters is a common manifestation of severe
thrombocytopenia. Such bleeding usually has a predilection for sites where teeth can traumatize the
inner surface of the cheek.

4. Skin hemorrhage in the form of petechiae and ecchymoses are common manifestations of hemostatic
disorders. However, skin hemorrhage also is common among individuals without hemostatic disorders.
Excessive bruising is more common in women than men. Moreover, women frequently note that the
severity of their bruising varies with the phase of their menstrual cycle, although the most severe phase
of the cycle may di er in di erent women. Features that help establish the severity of skin hemorrhage
include the size of the bruises, the frequency of bruising, whether the bruises occur spontaneously or
only with trauma, and the appearance of bruises on regions of the body that usually are not traumatized,
such as the trunk and back. The color of the bruise may yield information. Red bruises on the extensor
surfaces of the arms and hands indicate loss of supporting tissues, as occurs in Cushing syndrome,
glucocorticoid therapy, senile purpura, and damage from chronic sun exposure. Jet-black bruises may be
caused by warfarin-induced skin necrosis and similar disorders. Easy bruising can also occur in patients
with Ehlers-Danlos syndrome manifested by distensible skin or extraordinary ligament laxness, and in
patients with hyperflexibility of the thumb.8

5. Tooth extractions are common hemostatic challenges and may be helpful in defining the risk of bleeding.
Molar extractions are greater hemostatic challenges than extractions of other teeth. Objective data
regarding excessive bleeding based on the need for blood products or the need to pack or suture the
extraction site are valuable.

6. Excessive bleeding in response to razor nicks is common in patients with platelet disorders or von
Willebrand disease.

7. Hemoptysis almost never is the presenting symptom of a bleeding disorder and is rare even in patients
with serious bleeding disorders. However, blood-tinged sputum in association with upper respiratory
tract infections may be more common in patients with hemostatic disorders.

8. Hematemesis, like hemoptysis, almost never is the presenting symptom of a hemostatic disorder.
However, a hemostatic disorder may lead to hematemesis because of an anatomic abnormality in the
upper gastrointestinal tract and bleeding may be more severe than expected. Some hemostatic disorders

7/18
15/5/2019

more likely result in hematemesis because of a combination of e ects, such as liver disease with deficient
synthesis of coagulation proteins and with esophageal varices and aspirin ingestion with gastritis.

9. Hematuria is rarely the presenting symptom of a hemostatic disorder except for the hemophilias.
However, hemostatic disorders can exacerbate hematuria caused by other disorders, including simple
urinary tract infections.

10. Rectal bleeding in individuals with normal hemostasis most o en results from hemorrhoids. However,
von Willebrand disease and platelet disorders may contribute to repeated episodes of rectal bleeding
when associated with a number of di erent underlying causes, including diverticula, hemorrhoids, or
angiodysplasia. Melena is also only rarely the presenting symptom of a hemorrhagic disorder. However,
repeated episodes of melena may occur in patients with hemorrhagic disorders.

11. Menorrhagia is common in women with platelet disorders and von Willebrand disease. In general,
menstrual bleeding is considered excessive if the patient indicates she has heavy flow for more than 3
days or total flow for more than 7 days. However, an objective distinction between menorrhagia (loss of
more than 80 mL blood per period) and normal blood loss can only be made by a visual assessment
technique using pictorial charts of towels or tampons.7

12. Postpartum hemorrhage. Childbirth poses a considerable hemostatic challenge. Consequently, patients
with bleeding disorders commonly manifest excessive bleeding during or a er labor necessitating blood
transfusion. An exception may be mild and moderate von Willebrand disease due to the vast increase in
von Willebrand factor during pregnancy.

13. Habitual spontaneous abortions raise the possibility that the patient has a quantitative or qualitative
abnormality of fibrinogen (Chap. 125), factor XIII deficiency (Chap. 124), or the antiphospholipid
syndrome (Chap. 131). There is also an association between infertility and spontaneous abortion in
patients with inherited thrombophilia (Chap. 130).

14. Hemarthroses are the hallmark abnormality in the hemophiliac; they are rare in other disorders except in
severe factor VII deficiency and type 3 von Willebrand disease (Chaps. 124 and 126). Because
discoloration of the skin overlying the joint with hemarthroses does not occur, patients may not
recognize that their symptoms (pain, swelling, and limitation of motion) are caused by bleeding into their
joints.

15. Excessive hemorrhage associated with surgical procedures is common in patients with hemorrhagic
disorders. Procedures involving tissues with increased local fibrinolytic activity like urinary tract, nose,
tonsils and oral cavity are particularly prone to bleed.

16. Excessive bleeding following circumcision is common in males with severe hemostatic disorders such as
hemophilia A, hemophilia B, or Glanzmann thromboasthenia, and o en is the patient’s first symptom.

8/18
15/5/2019

17. Bleeding from the umbilical stump is characteristic of factor XIII deficiency (Chap. 124) and
afibrinogenemia (Chap. 125).

PHYSICAL EXAMINATION
Physical examination is essential for identifying signs of bleeding or their sequelae and for signs of a possible
underlying disorder that can cause the hemostatic derangement (see Table 116–1). Careful examination of
the skin is essential for detecting petechiae and ecchymoses. These signs may be prominent on the legs,
where the hydrostatic pressure is greatest, or around the hair follicles in vitamin C deficiency.

Telangiectasias may range from pinpoint erythematous dots that blanch with pressure to classic cherry
angiomata ranging in size up to several centimeters. Many normal individuals develop increasing numbers of
telangiectasias with aging. Patients with hereditary hemorrhagic telangiectasia have more florid lesions that
characteristically a ect the vermilion border of the lips and the tongue (including the underside of the
tongue), but not all patients have these classic features. Thus, a systematic search of the integument is
necessary. Spider telangiectasias found in patients with chronic liver disease have a more splotchy and
serpiginous appearance than the telangiectasias associated with hereditary hemorrhagic telangiectasia. In
addition, the telangiectasias tend to be concentrated on the shoulders, chest, and face.

Chapter 122 details the di erential diagnosis of nonpalpable purpuras and palpable purpuras. Hematomas,
ecchymoses, and protracted oozing should be sought at venipuncture sites, injection sites, and arterial and
venous catheter insertion sites. Joint deformities and limited joint mobility are suggestive of severe
hemophilia A or B, severe deficiency of factor VII, or type 3 von Willebrand disease (Chaps. 123, 124, and 126).
Hyperelasticity of the skin and hyperextensibility of joints are typical of Ehlers-Danlos syndrome, and
hyperextensibility of only the thumb probably is a variant.8

EVALUATION BASED ON BLEEDING HISTORY, PHYSICAL EXAMINATION,

AND BASIC LABORATORY TESTS
The patient’s history and results of physical examination provide important information on the likelihood of
the patient having a hemostatic defect and the possible cause of the defect, if one is present. However,
performing an initial set of widely available and inexpensive tests, including prothrombin time (PT), activated
partial thromboplastin time (aPTT), and platelet count, is important for the following reasons: (1) The
patient’s history sometimes is unreliable; (2) the patient may have a mild hemostatic abnormality that has
not manifested itself for lack of hemostatic challenge; (3) the patient may have developed an acquired
hemostatic defect that has remained asymptomatic; and (4)the tests may reveal more than one
abnormality.9

Figure 116–1 shows a series of algorithms that integrate the patient’s bleeding history and the results of the
initial hemostatic tests. A prolonged aPTT as a sole abnormality can be caused by a deficiency of factor VIII,
IX, XI, or XII; presence of heparin; or by an inhibitor, which can be either factor specific, such as an antibody
9/18
15/5/2019

against factor VIII, or factor nonspecific, such as the presence of heparin or a lupus anticoagulant (Fig. 116–
1A). A prolonged PT as the sole finding can indicate a factor VII deficiency, a mild vitamin K deficiency, or the
presence of an inhibitor (Fig. 116–1B). Abnormalities of both PT and aPTT may indicate a deficiency of
fibrinogen, prothrombin, factor V or factor X, an inhibitor to one of these factors, or a combined deficiency of
coagulation factors (Fig. 116–1C).

Figure 116–1.
Measures for establishing a tentative diagnosis of a hemostatic disorder using basic tests of hemostasis and
the patient’s history of bleeding. ↓, Decrease; ↑, increase; aPTT, activated partial thromboplastin time; BT,
bleeding time; DIC, disseminated intravascular coagulation; HMKK, high-molecular-weight kininogen; N,
normal; PK, prekallikrein; PLT, platelets; PT, prothrombin time; VWD, von Willebrand disease.

10/18
15/5/2019

To distinguish between a deficiency state and the presence of an inhibitor, repeating the abnormal test, the
PT and/or aPTT, using a 1:1 mixture of the patient’s plasma and normal plasma is useful. If the mixture
normalizes the prolonged PT or aPTT, a deficiency state is likely, as most coagulation tests are calibrated to
produce a normal result if each of the relevant factor levels are 50 percent of normal or greater. If the mixture
still yields a significantly prolonged PT or aPTT, an inhibitor probably is present. Some inhibitors, such as
antibodies to factorVIII, require time to inhibit the factor VIII activity in the assay, whereas other inhibitors,
such as lupus anticoagulant or heparin, do not. Consequently, incubating the mixture for 1 or 2 hours at 37°C
before performing the coagulation assay is desirable.

When none of the initial test results (PT, aPTT, and platelet count) is abnormal and the patient exhibits
bleeding manifestations, ristocetin cofactor (RCF) or von Willebrand factor activity and examination of the
blood film can be helpful for distinguishing among various candidate hemostatic abnormalities. The
bleeding time is not used anymore because the test is highly operator and situational (room temperature,
skin circulation, etc.) dependent and is not su iciently reliable to be useful in the diagnostic process. Instead,
many laboratories have introduced the platelet function analyzer (PFA) to detect qualitative defects in

11/18
15/5/2019

primary hemostasis. Figure 116–2 shows an algorithm that includes these secondary tests. Patients with type
1 and type 2 von Willebrand disease o en have normal findings on initial laboratory tests because factor VIII
levels are su iciently high (>30 U/dL) for a normal aPTT result (Chap. 126). Examination of the blood film is
helpful for distinguishing between Bernard-Soulier syndrome and von Willebrand disease because giant
platelets are characteristic of the former (Chap. 120). Distinguishing mild-type von Willebrand disease from
normal is di icult because levels of von Willebrand factor in the normal population is highly variable, partly
accounted for by di ering von Willebrand factor levels in individuals with di erent ABO blood types. In fact,
some investigators have questioned whether patients with von Willebrand factor levels as low as 35 percent
should be labeled as having von Willebrand disease.10 The likelihood of having von Willebrand disease is a
function of bleeding history, the von Willebrand factor level, and the number of first-degree family members
with reduced von Willebrand factor levels.11

Figure 116–2.
Tentative diagnoses in patients with bleeding manifestations and normal primary hemostatic tests using
secondary tests. ↓, Decrease; ↑, increase; Abn, abnormal; aPTT, activated partial thromboplastin time; BT,
bleeding time; CR, clot retraction; N, normal; PK, prekallikrein; PLT, platelets; PT, prothrombin time; RCF,
ristocetin cofactor activity; VWD, von Willebrand disease.

The ristocetin-induced platelet aggregation test is useful for distinguishing type 2B and platelet-type von
Willebrand disease from the other types of von Willebrand disease. In type 2B and platelet-type von
Willebrand disease, an enhanced response to low concentrations of ristocetin is observed, whereas in the
other types of von Willebrand disease, a decreased response is found. Total absence of platelet aggregates in
a blood film prepared from non–anticoagulated blood and absent clot retraction are characteristic of
Glanzmann thrombasthenia (Chap. 120).

Another simple test that may be useful for distinguishing among hemostatic disorders is the thrombin time
(i.e., time for plasma to clot a er adding thrombin). The thrombin time is prolonged in (1) afibrinogenemia,

12/18
15/5/2019

hypofibrinogenemia, and dysfibrinogenemias (Chap. 125), (2) the presence of heparin, (3) disseminated
intravascular coagulation (DIC) causing increased levels of fibrin(ogen) degradation products, which inhibit
fibrin monomer polymerization (see Fig. 116–1D and Chap. 129), and (4) patients with amyloidosis and an
immunoglobulin inhibitor of thrombin.12

PREOPERATIVE ASSESSMENT OF HEMOSTASIS

Because surgical procedures are a great challenge to the hemostatic system, careful assessment of the risk of
bleeding in every patient is important. The risk assessment is based on the bleeding history, physical
examination, the underlying disorder if any, the type and site of surgery that is planned, and the results of
basic hemostatic tests (PT, aPTT, platelet count). Several studies indicate that unselected coagulation tests
have no significant predictive value of perioperative bleeding, and that patients with a negative bleeding
history do not require routine coagulation screening.13 However, this conclusion does not consider that
patients with mild to moderate bleeding disorders who can bleed excessively following surgery may have a
negative bleeding history because they have not been challenged; obtaining a good bleeding history is an
expertise that is not shared by all physicians; and if bleeding occurs during or a er surgery for whatever
reason, the basic tests performed preoperatively are an essential reference for determining the cause of
bleeding.

Table 116–3 lists low-risk and high-risk conditions. A critical analysis of each potential cause of bleeding
should be undertaken for the high-risk conditions. In addition to the extent of the surgical trauma, the
magnitude of the fibrinolytic activity at the surgical site must be considered. For example, prostatectomy
carries considerable risk of prolonged bleeding because of the presence of high fibrinolytic activity in the
urine. Some surgical procedures can be anticipated to cause hemostatic abnormalities, such as operations in
which extracorporeal circulation is used (because the extracorporeal circuits and/or the anticoagulation
cause platelet dysfunction) and operations on patients with extensive malignancies or brain injury, which
can give rise to DIC. Finally, the ability to institute local hemostatic measures should be considered. Thus,
liver, lung, and kidney biopsies, although considered minor procedures, have a significant risk of bleeding
because local measures, such as direct pressure, cannot be used to control bleeding.

13/18
15/5/2019

Table 116–3.
Evaluation of Bleeding Risk During Surgery

Risk of Bleeding

Assessed Factor Low High

Bleeding history Negative Positive*

Underlying conditions that Absent Present

compromise hemostasis (see
Table 116–1)

Initial hemostatic tests Normal Abnormal

Type of surgery Minor Major

Not expected to induce a Expected to induce a hemostatic

hemostatic defect at a site without defect† at a site with local
local fibrinolysis
fibrinolysis‡

Local hemostatic measures Local hemostatic measures

e ective ine ective§

*Spontaneous bleeding episodes or injury-related hemorrhage.

†Open heart surgery or brain surgery.

‡Prostatectomy, tonsillectomy, oral or nasal surgery.

§Liver, lung, or kidney biopsy.

SPECIFIC ASSAYS FOR ESTABLISHING THE DIAGNOSIS

A tentative diagnosis can be made by following the stepwise process of evaluation outlined in Figs. 116–1
and 116–2. However, further testing usually is required to establish a definitive diagnosis.

THROMBOCYTOPENIAS

14/18
15/5/2019

When the laboratory reports an abnormally low platelet count, looking at the blood film to exclude
pseudothrombocytopenia as a result of anticoagulant-induced platelet clumping (e.g., induced by
ethylenediaminetetraacetic acid [EDTA]) is essential.14 Examination of the blood film also can reveal the
presence of giant platelets, as in some inherited thrombocytopenias; giant platelets and Döhle bodies in
leukocytes, as in May-Hegglin and other MYH9 platelet syndromes; moderately enlarged platelets, as in
immune thrombocytopenia or other conditions associated with shortened platelet survival; small platelets,
as in Wiskott-Aldrich syndrome; schistocytes and burr cells, as in the hemolytic uremic syndrome and
thrombotic thrombocytopenic purpura, and occasionally in DIC; rouleaux formation, as in monoclonal
gammopathies; macrocytosis and/or hypersegmentation, as in vitaminB12 or folic acid deficiency; and
abnormal white blood cells, as in leukemias and myeloproliferative disorders. Chapter 117 further discusses
the evaluation and di erential diagnosis of the thrombocytopenias.

FACTOR DEFICIENCIES

Coagulation factors usually are assayed by measuring their clotting activity. The most common assays
analyze the ability of dilutions of the patient’s plasma to correct the clotting time of a plasma known to be
deficient in the factor being measured (substrate plasma). The results are compared to the ability of dilutions
of a normal reference plasma to correct the abnormality in the substrate plasma. The activities of factors II, V,
VII, and X usually are determined in PT-based assays, whereas the activities of factors VIII, IX, XI, and XII,
prekallikrein, and high-molecular-weight kininogen are measured in aPTT-based assays. The plasma level of
fibrinogen most commonly is measured by assessing the time required for thrombin to clot the patient’s
diluted plasma (Clauss method).15 Several assays of transglutaminase activity are available for measuring
factor XIII activity,16 but a simple qualitative test based on dissolving a fibrin clot in 5 M urea usually is
su icient (Chap. 124). The RCF function of von Willebrand factor can be measured by the ability of the
patient’s plasma to support the agglutination of a suspension of formaldehyde-fixed normal platelets by
ristocetin.17 This activity is defined as RCF activity. As with the coagulation factor assays, the results using
patient plasma are compared to the results obtained with a normal reference plasma.

To determine whether a coagulation factor activity deficiency results from a quantitative decrease in protein
or a qualitative abnormality in the protein, immunologic assays can be performed using specific polyclonal
or monoclonal antibodies to assess the presence of the protein, independent of its function.
Electroimmunoassays, enzyme-linked immunosorbent assays (ELISAs), and immunoradiometric assays all
have been used successfully. Crossed immunoelectrophoresis measures both the immunologic reactivity and
the mobility of the protein in an electric field; thus, it can detect protein abnormalities that a ect
electrophoretic migration. The abnormalities include the presence of antibody–antigen complexes that
migrate di erently from the protein itself, such as antiprothrombin–prothrombin complexes in patients with
systemic lupus erythematosus or antiphospholipid syndrome. Diagnosis of the specific type of von
Willebrand disease requires additional tests of the multimeric structure of plasma and, perhaps, platelet von
Willebrand factor.

15/18
15/5/2019

INHIBITORS TO COAGULATION FACTORS

If an inhibitor is suspected as a result of a prolonged PT or aPTT performed on a 1:1 mixture of the patient’s
plasma and normal plasma, further studies can help define the nature of the inhibitor and its titer. Among
inhibitors that do not require incubation (i.e., immediate-type), perhaps the most common cause is the
presence of heparin in the sample. This cause can be verified by finding a prolonged thrombin time on a test
of the patient’s plasma that is corrected with toluidine blue or other agents that neutralize heparin. The
lupus anticoagulant also does not require incubation, and several methods for its detection are available
(Chap. 131). However, with lupus anticoagulant, the PT usually is less prolonged than is the aPTT, and aPTT
reagents have markedly di erent sensitivity to lupus-type anticoagulant depending on the amount of
phosphatidyl serine present in each reagent.

Immunoglobulin inhibitors to specific coagulation factors may develop either a er factor replacement
therapy in patients with inherited deficiencies of coagulation factors (Chaps. 123 and 124) or spontaneously
in patients without factor deficiencies (Chap. 127). Antibodies that neutralize factor activity frequently can be
detected by incubating the patient’s plasma with normal plasma, usually for 2 hours at 37°C, and then
assaying the specific factor. The Bethesda assay originally was designed to quantify factor VIII inhibitors but
can be modified to detect other inhibitors of coagulation factors (Chap. 123).18 Some inhibitors do not
directly neutralize clotting activity; instead they reduce factor levels by forming complexes with coagulation
factors, which then are rapidly cleared from the circulation. Such plasmas do not produce prolonged clotting
times when mixed 1:1 with normal plasma and thus may be confused with inherited deficiency states. More
elaborate assays are required to identify this type of inhibitor, which may, for example, produce severe
deficiency of prothrombin in some patients with the antiphospholipid syndrome (Chap. 131) and deficiency
of von Willebrand factor in some acquired forms of von Willebrand disease (Chap. 126).19

PLATELET FUNCTION DISORDERS

Some laboratories nowadays routinely use an automated PFA to detect qualitative defects in primary
hemostasis. Use of the RCF activity assay, platelet aggregation, and/or clot retraction are useful for assessing
whether the patient has von Willebrand disease or a platelet function disorder (see Fig. 116–2). Chapter 120
contains a flow diagram of the steps required to diagnose the di erent qualitative disorders of platelet
function. Additional platelet function assays and glycoprotein analysis may be required to establish the
diagnosis.

REFERENCES

1. Miller  CH, Graham  JB, Goldin  LR, Elston  RC: Genetics of classic von Willebrand’s disease: II. Optimal
assignment of the heterozygous genotype (diagnosis) by discriminant analysis. Blood 54:137, 1979. 
[PubMed: 312669]

16/18
15/5/2019

2. Wahlberg  T, Blomback  M, Hall  P, Axelsson  G: Application of indicators, predictors and diagnostic indices
in coagulation disorders: I. Evaluation of a self-administered questionnaire with binary questions. Methods
Inf Med 19:194, 1980.  [PubMed: 7432180]

3. Eikenboom  JC, Rosendaal  FR, Briet  E: Value of the patient interview: All but consensus among
haemostasis experts. Haemostasis 22:221, 1992.  [PubMed: 1468726]

4. Sramek  A, Eikenboom  JC, Briet  E  et al.: Usefulness of patient interview in bleeding disorders. Arch Intern
Med 155:1409, 1995.  [PubMed: 7794090]

5. Dinehart  SM, Henry  L: Dietary supplements: Altered coagulation and e ects on bruising. Dermatol Surg
31:819, 2005.  [PubMed: 16029673]

6. Basila  D, Yuan  C-S: E ects of dietary supplements on coagulation and platelet function. Thromb Res
117:49, 2005.  [PubMed: 15913714]

7. Janssen  CAH, Scholten  PC, Heintz  APM: A simple visual assessment technique to discriminate between
menorrhagia and normal menstrual blood loss. Obstet Gynecol 85:977, 1995.  [PubMed: 7770270]

8. Kaplinsky  C, Kenet  G, Seligsohn  U, Rechavi  G: Association between hyperflexibility of the thumb and an
unexplained bleeding tendency: Is it a rule of thumb? Br J Haematol 101:260, 1998.  [PubMed: 9609520]

9. Rapaport  SI: Preoperative hemostatic evaluation: Which tests, if any? Blood 61:229, 1983.  [PubMed:
6821695]

10. Sadler  JE: Von Willebrand disease type 1: A diagnosis in search of a disease. Blood 101:2089, 2003. 
[PubMed: 12411289]

11. Tosetto  A, Castaman  G, Rodeghiero  F: Evidence-based diagnosis of type 1 von Willebrand disease: A
Bayes theorem approach. Blood 111:3998, 2008.  [PubMed: 18187661]

12. Gastineau  DA, Gertz  MA, Daniels  TM  et al.: Inhibitor of the thrombin time in systemic amyloidosis: A
common coagulation abnormality. Blood 77:2637, 1991.  [PubMed: 1904284]

13. Chee  YL, Crawford  JC, Watson  HG, Greaves  M: Guidelines on the assessment of bleeding risk prior to
surgery or invasive procedures. Br J Haematol 140:496, 2008.  [PubMed: 18275427]

14. Payne  BA, Pierre  RV: Pseudothrombocytopenia: A laboratory artifact with potentially serious
consequences. Mayo Clin Proc 59:123, 1984.  [PubMed: 6422167]

15. Clauss  A: Gerinnungsphysiologische schnell methodes zur des fibrinogens. Acta Haematol 17:327, 1957.

17/18
15/5/2019

16. Fickenscher  K, Aab  A, Stuber  W: A photometric assay for blood coagulation factor XIII. Thromb Haemost
65:535, 1991.  [PubMed: 1871715]

17. McFarlane  DE, Stibbe  J, Kirby  EP  et al.: A method for assaying von Willebrand factor (ristocetin cofactor).
Thromb Diath Haemorrh 34:306, 1975.

18. Kasper  CK, Aledort  L, Aronson  D  et al.: Proceedings: A more uniform measurement of factor VIII
inhibitors. Thromb Diath Haemorrh 34:612, 1975.  [PubMed: 1198543]

19. Inbal  A, Bank  I, Zivelin  A  et al.: Acquired von Willebrand disease in a patient with angiodysplasia
resulting from immune-mediated clearance of von Willebrand factor. Br J Haematol 96:179, 1997.  [PubMed:
9012706]

McGraw Hill
Copyright © McGraw-Hill Education
All rights reserved.
Your IP address is 200.3.145.12
Terms of Use   •  Privacy Policy   •  Notice   •  Accessibility

Access Provided by: Universidad Pontificia Bolivariana

Silverchair

18/18