2. trauma. However, it is important to recognize when bleeding
problems are more serious or
more frequent due to an underlying hemostatic abnormality.
Abnormal bleeding represents an important health care problem.
For example, in the
United States, it has been estimated that at least 5% to 10% of
women of childbearing age
seek medical care for menorrhagia and have bleeding severe
enough to require medical
intervention. Among the many defects that can cause abnormal
bleeding, inherited and
acquired von Willebrand disease (VWD) and platelet function
disorders are much more
common than defects in coagulation and fibrinolytic proteins.
PATHOPHYSIOLOGY
REVIEW OF NORMAL HEMOSTASIS
Hemostasis consists of the following steps: (1) initiation and
formation of the platelet
plug, also known as primary hemostasis; (2) propagation and
amplification of the clotting
“cascade” or secondary hemostasis, which involves activation of
a series of coagulation
factors resulting in the generation of thrombin that cleaves
fibrinogen to fibrin; (3) cross-
linking of fibrin; (4) termination of procoagulant response by
antithrombotic control
mechanisms; (5) removal of the clot by fibrinolysis; and (6)
tissue repair and regeneration.
When a vessel is injured, platelets adhere to exposed collagen
and other components
of the subendothelium as the first defense against bleeding. This
3. initial adhesion is
dependent on von Willebrand factor (VWF) as well as specific
platelet receptors (eg,
glycoprotein IbIXV) for VWF and collagen. This adhesion leads
to platelet activation and
shape change as well as platelet aggregation, which promotes
recruitment of additional
platelets.
Coagulation is initiated in vivo when endothelial or vascular
cells are damaged. This
results in exposure of blood to tissue factor (TF), which binds
to factor VII (FVII) and its
activated form, factor VII (FVIIa). TF-FVIIa complexes
(extrinsic tenase) then activates
factors IX and X directly. Activated factor IX can also form a
complex with factor VIIIa as
well as phospholipids and calcium, called the intrinsic tenase
complex, which promotes
further conversion of factor X to factor Xa. The generated
factor Xa associates with
activated factor V, phospholipids, and calcium to form the
prothrombinase complex that
activates prothrombin to thrombin. Intrinsic and extrinsic tenase
are needed to generate
enough thrombin for normal hemostasis. Once thrombin is
generated, it cleaves fibrinogen
to fibrin, which leads to formation of a fibrin clot and promotes
platelet activation and the
generation of activated factors V and VIII. Thrombin also
results in the formation of
activated XIII, an enzyme that cross-links fibrin to make the
clot more resistant to
fibrinolysis (the cleavage of the fibrin clot).
When coagulation is activated, fibrinolysis is activated, leading
5. formation, due to the
associated factor VIII deficiency. Drugs that inhibit platelet
function (eg, aspirin,
nonsteroidal anti-inflammatory drugs, serotonin reuptake
inhibitors) and those that inhibit
coagulation (eg, heparin, warfarin) are important causes to
consider when evaluating and
managing an individual with bleeding.
TABLE 172-1 Questions to Consider when Evaluating a Patient
for a Possible Bleeding
Disorder
What are the patient’s bleeding symptoms?
• Is there a personal or family history of bleeding with trauma
or procedures?
• What are the site(s) of bleeding?
• For women: Is there a history of prolonged, heavy periods or
bleeding with childbirth?
• What is the severity of bleeding?
• What is the duration of bleeding events?
• Has the patient required any treatments for bleeding?
Does the history suggest a congenital or acquired problem?
• Note: For congenital bleeding disorders, the bleeding
symptoms may date back to
childhood and may affect other family members; acquired
bleeding disorders should be
considered when the bleeding problems are more recent, and a
drug-induced defect
should be excluded.
What is the timing of the bleeding?
• Is the bleeding immediate or delayed (onset one or more days
after challenges)?
Is the bleeding systemic or local?
7. WHEN TO SUSPECT A BLEEDING DISORDER
In general, a bleeding disorder should be suspected when
bleeding occurs with minimal or
no provocation, when it is more severe than expected for a
given challenge, and when
bleeding episodes occur repeatedly with challenges. Care should
be taken to avoid asking
very subjective questions about bleeding. For example, it is
preferable to ask women about
menstrual periods lasting longer than 7 days, with more than 2
to 3 days of heavy flow,
and/or periods that interfere with their lifestyle than to ask if
they experience “heavy”
periods. Similarly, asking about bruises as big as or larger than
oranges and/or bruises
appearing without provocation is better than asking about “easy
bruising.”
While individuals with severe bleeding problems may report
spontaneous bleeding and
serious bleeding with major and minor hemostatic challenges,
individuals with milder
defects can report abnormal bleeding with some but not all
significant hemostatic
challenges. While inherited, severe bleeding problems typically
present early in life, milder
inherited bleeding problems and acquired bleeding problems
often get diagnosed in adult
life. The clinical assessment should be directed toward
identifying the type and severity of
bleeding problems experienced by an individual, in order to
plan appropriate laboratory
testing and therapy.
KEY COMPONENTS OF THE HISTORY
8. What are the patient’s bleeding symptoms?
The patient should be questioned about his or her current
bleeding symptoms and past
bleeding symptoms and a family history of bleeding problems
(Table 172-2). The
following characteristics of the bleeding should be determined:
association with trauma or
procedures and if it occurred with some or all minor and major
procedures; site(s)
(including joint bleeds); severity (eg, bleeding resulting in
additional interventions such as
blood transfusions, intensive care unit admission, and/or
prolongation of hospitalization
stay); duration of bleeding; and any treatments that were given
to control bleeding (types
of drugs or blood products). It may be helpful to determine if
the patient received
anticoagulants or drugs that inhibit platelet function. Female
patients should be asked
questions about menstrual periods and abnormal bleeding with
childbirth and pregnancy
losses. Mucocutaneous bleeding (ie, abnormal bruising, gum
bleeding, and epistaxis) is
more suggestive of a defect in primary hemostasis. Some
bleeding symptoms, such as
deep tissue bleeding, joint hemorrhages, and spontaneous
unexplained hematuria are
uncommon but can occur in severe inherited coagulation protein
deficiencies. Some
bleeding problems, such as epistaxis, can be experienced by
individuals without bleeding
disorders. Bleeding after trauma should be considered but can
be difficult to evaluate
because it is not specific to individuals with bleeding disorders.
11. The bleeding history is often used to assess when abnormal
bleeding occurred (eg, same
day or days later) relative to invasive surgical or dental
procedures. Bleeding during,
immediately after, or on the same day as the challenge is
suggestive of a disorder of
primary hemostasis (see Disorders of Primary Hemostasis later
in this chapter), whereas
bleeding that becomes problematic one or more days after a
challenge is more typical of a
factor deficiency or a fibrinolytic defect.
Is the bleeding disorder congenital or acquired, and are there
aggravating or
contributing factors?
Inherited problems tend to present earlier in life than acquired
problems unless they are
mild. Inherited problems are often associated with a positive
family history, which may be
negative if the condition is recessive or X-linked. A thorough
bleeding history should
include questions about potential aggravating or contributing
factors such as new
medications (eg, aspirin or antidepressant therapy).
Individuals with acquired bleeding disorders often describe
bleeding that is more recent
in onset. Causes of an acquired bleeding disorder are listed in
Table 172-2 and include
liver disease, vitamin K deficiency, autoimmune-mediated
conditions (eg, immune
thrombocytopenic purpura), hypothyroidism, acquired factor
VIII deficiency or acquired
VWD, and other conditions such as Cushing syndrome.
12. It is important to emphasize that the patient’s entire bleeding
history must be assessed
in order to determine if the problem is mild or severe and if it is
likely congenital or
acquired.
Has the patient experienced any hemostatic challenges?
Patients should be questioned about how many operative and
invasive dental procedures
they have undergone, and how many of these were associated
with abnormal bleeding. It
may be helpful to ask if the patient has experienced any
unusually large ecchymosis
around incisions when evaluating the surgical bleeding history.
It is important to note that
individuals who have undergone a number of common surgical
and dental procedures (eg,
tonsillectomy, wisdom tooth extraction) without experiencing
abnormal bleeding might
still have a mild bleeding problem (particularly if other aspects
of their bleeding history are
abnormal); however, they are unlikely to have a severe bleeding
disorder. Alternately, it is
important to recognize that sometimes abnormal bleeding occurs
in healthy individuals
undergoing a major procedure due to technical complications.
What is the patient’s general medical history? Is there a
systemic disease that is causing
or contributing to the patient’s bleeding symptoms?
An evaluation of a patient’s general medical history for new or
worsening bleeding, and
other changes in health, is important for assessing undiagnosed
liver, kidney, or endocrine
14. clopidogrel, serotonin reuptake
inhibitors, or fish oil supplements); or defective coagulation
(eg, due to heparin or
warfarin).
PHYSICAL EXAMINATION
The physical examination is often not very informative in
individuals with a bleeding
disorder. An initial assessment of acute bleeding should
determine the patient’s
hemodynamic status and if there are signs of anemia. Blood
blisters in the mouth,
hemorrhages on the bite margins in the mouth, and petechiae
(tiny red-colored skin lesions
that reflect small hemorrhages into the skin, particularly on
dependent parts of the body
and at sites of trauma) may suggest significant
thrombocytopenia. Large bruises or
purpura may suggest a defect in primary hemostasis or acquired
hemophilia. Sometimes
the purpuric skin lesions of severe anticoagulant protein
deficiencies (eg, purpura
fulminans due to severe congenital protein C deficiency) are
mistaken for skin bleeding.
Abnormalities in joints, lymph nodes, spleen, and liver should
raise concern for the
possibility of a secondary bleeding disorder.
DIFFERENTIAL DIAGNOSIS BASED ON CLINICAL
ASSESSMENT
Table 172-3 outlines the differences between disorders of
primary and secondary
hemostasis.
16. Menorrhagia Common May occur
Inheritance (if congenital) Dominant or recessive Most common
cause
(hemophilia) is X-linked
Disorders of primary hemostasis
Patients with disorders of primary hemostasis will often
describe experiencing abnormal
bleeding during or within a few hours of a surgical or dental
procedure. These problems,
with or without mucocutaneous bleeding symptoms, should raise
questions about VWF
and platelet abnormalities (both qualitative and quantitative) or,
less commonly, blood
vessel abnormalities. Defects in primary hemostasis can also
present as troublesome
epistaxis and/or gingival bleeding, petechiae, superficial
bruising or ecchymosis, and
menorrhagia. Petechiae are very suggestive of a platelet or
vascular disorder.
Disorders of secondary hemostasis
Disorders of secondary hemostasis typically manifest as
delayed-onset bleeding that
becomes evident in the days following trauma or surgical
procedure. When there is a
severe factor deficiency, there can be spontaneous bleeding into
joint spaces
(hemarthroses) and into deep, soft tissues (eg, muscle
hematomas). The most common
inherited disorders of secondary hemostasis include hemophilia
A (factor VIII deficiency)
17. and hemophilia B (factor IX deficiency). Acquired hemophilia,
due to an antibody directed
against factor VIII, accounts for about 10% of all hemophilia.
Factor XIII deficiency and
fibrinolytic disorders can also present with delayed bleeding,
but these conditions are less
common. Acquired autoantibodies against coagulation proteins
are important but
infrequent causes of bleeding and most commonly affect factor
VIII, VWF, factor XIII or
factor V.
HOW SHOULD THIS PATIENT WITH A SUSPECTED
BLEEDING DISORDER BE
INVESTIGATED?
Investigations for bleeding problems need to consider the
etiologies of mild and severe
and common and rare disorders. Figure 172-1 summarizes a
stepwise approach to
investigation, some of which may be performed at the time of a
specialist evaluation.
Often, a broad range of tests is needed to assess an individual
with a suspected bleeding
disorder (see Figure 172-1). A complete blood count is helpful
to evaluate for
thrombocytopenia and to determine if there are other
hematologic abnormalities such as
anemia (which may reflect acute or chronic bleeding), or white
blood cell abnormalities
that may suggest an underlying bone marrow disorder. An
assessment for iron deficiency
(which may be present without anemia) should be considered. A
blood group and
antibody screen should be done before surgery in individuals
with a history of abnormal
19. coagulation tests.
TABLE 172-4 Differential Diagnosis of Coagulation Test
Abnormalities
PT APTT
Thrombin
Time Fibrinogen Platelet Count
Reference Intervals
~ 10-
13 s
Ranges
Vary
Ranges
Vary
150-400 mg/dL
1.5-4.0 g/L
150-400 ×
106/mL
Fibrinogen deficiency N – ↑ N – ↑ ↑ ↓ N
Factor VII deficiency ↑ N N N N
Factor VIII, IX, or XI
deficiency
N ↑ N N N
Factor II, V, X deficiency ↑ ↑ N N N
20. Factor deficiencies not
associated with bleeding
(factor XII, high-
molecular-weight
kininogen or prekallikrein
deficiency)
N ↑ N N N
Acquired hemophilia and
congenital hemophilia
with inhibitors
N ↑* N N N
Lupus anticoagulant N – ↑ N – ↑† N – ↑ N N
Heparin therapy or
sample contamination
N – ↑ ↑ ↑↑ N N
Liver disease N – ↑ N – ↑ N – ↑ ↓ – N – ↑ ↓ – N
Vitamin K deficiency ↑ N – ↑ N N N
Fibrinolytic therapy ↑ ↑ ↑ ↓ N
Consumptive
coagulopathy
N – ↑ ↑ ↑ ↓ ↓
Dilutional coagulopathy N – ↑ N – ↑ N – ↑ ↓ – N ↓
von Willebrand disease N N – ↑ N N N ↓ in type 2B
22. Additional tests can be helpful to evaluate if there is a history
of acquired bleeding,
which could reflect liver or renal disease or an endocrine
disorder such as hypothyroidism
or Cushing syndrome. As fibrinolytic defects are uncommon,
testing is rarely done except
by specialists.
PRACTICE POINT
In general, the patient’s symptoms, not the laboratory values,
should be treated. Local
factors can be significant contributors to bleeding and should be
considered in the
plans for investigation and treatment, even in patients with
documented
coagulopathies. Always consider risks and benefits (including
those of treating or not
treating) when deciding on appropriate therapies as the risks of
certain therapies
include increased prothrombotic risks. Patients with congenital
bleeding disorders are
best managed in a multidisciplinary care setting to plan
treatment and prevention of
acute bleeding episodes and to deal with complications (eg,
hemophilic arthropathy).
Information on the patient’s bleeding problem and the treatment
plans must be
communicated to both the patient and their health care
providers.
HOW SHOULD THIS PATIENT WITH A BLEEDING
DISORDER BE TREATED?
The management of each patient with a bleeding disorder
24. anticoagulants, anti-
inflammatory drugs that inhibit platelet function) should be
modified because of the
patient’s bleeding problems.
Information on the patient’s bleeding problem and the treatment
plans must be
communicated to both the patient and his health care providers.
Patients with
congenital bleeding disorders must be “taught” that prophylactic
treatment is required
prior to invasive procedures.
Patients with congenital bleeding disorders are best managed in
a multidisciplinary
care setting to plan treatment and prevention of acute bleeding
episodes and to deal
with complications (eg, hemophilic arthropathy).
OTHER ISSUES TO CONSIDER FOR TREATMENT OF
CONGENITAL BLEEDING
DISORDERS
Treatments for factor deficiencies
Individuals with moderate-to-severe clinically significant factor
deficiencies often require
factor concentrates (recombinant products generally preferred
over plasma-derived
products), although some conditions and circumstances (eg,
mild hemophilia due to
factor VIII deficiency with mild bleeding) may be managed with
desmopressin. Fibrinolytic
inhibitor drugs (aminocaproic acid and tranexamic acid) are
often used as an adjunctive
therapy for some procedures, such as dental and oral-nasal
surgeries. Fibrinolytic inhibitor
drugs are the treatment of choice for fibrinolytic disorders.
26. GENERAL MANAGEMENT OF COMMON ACQUIRED
BLEEDING DISORDERS
Liver disease
The coagulopathy related to liver disease is multifactorial, as
the liver is the major source
of all hemostatic proteins in plasma except for VWF and tissue
plasminogen activator.
Individuals with liver disease often have deficiencies of
multiple coagulation factors, and
in mild liver disease, there can be low levels of factors VII and,
at times, factors XI and XII.
Fibrinogen deficiency is typically only seen with severe liver
disease. In fact, fibrinogen
levels are often elevated in mild liver disease. Sometimes
patients with liver disease have
additional hemostatic defects such as vitamin K deficiency,
thrombocytopenia,
dysfibrinogenemia, platelet function abnormalities, and
disseminated intravascular
coagulation (DIC). If an individual with coagulopathy from
liver disease requires treatment
(ie, for active bleeding or, in some instances, before a procedure
associated with a
significantly increased risk of bleeding), one or more of the
following treatment options
should be considered: vitamin K replacement (if deficient),
plasma infusion (typically
requires four or more units to have measurable effects),
fibrinogen replacement (with
cryoprecipitate or fibrinogen concentrate), and/or platelet
transfusion. The role of
prothrombin complex concentrates in patients with liver disease
is uncertain.
27. Anticoagulant medications
Treatment of serious bleeding due to anticoagulants may require
reversal of the
anticoagulant. Patients on an oral vitamin K antagonist, who
require reversal to treat
bleeding, should receive vitamin K, and when more rapid
reversal is required (eg, to treat
life-threatening gastrointestinal bleeding), prothrombin complex
concentrate (if available)
or plasma infusion should be considered. Protamine sulfate can
be considered when there
is a need to rapidly reverse unfractionated heparin or low -
molecular-weight heparin
because of bleeding. However, this treatment reverses only
about 60% of the antifactor Xa
activity of low-molecular-weight heparin. Unfortunately, agents
are not currently available
to rapidly reverse some of the newer, novel anticoagulants that
are direct inhibitors of
thrombin or factor Xa. However, specific antidotes for direct
thrombin inhibitors and factor
Xa inhibitors have been developed and are undergoing clinical
testing. It is unclear
whether bleeding from these newer agents is improved by
treatment with desmopressin
acetate, fibrinolytic inhibitor drugs, or other treatments, such as
prothrombin complex
concentrates and factor VIIa.
Vitamin K deficiency
Acquired bleeding due to vitamin K deficiency results from
decreased gamma-
carboxylation of the vitamin K-dependent factors II, VII, IX,
and X and can be treated by
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