Bleeding Disdrdelrs

L. Roy Eversole, DDS, MSD, MA

Pathophysiology, 61
Clinical features and diagnosis, 64
Clinical considerations for dental care, 65
Suggested reading, 66
A hemorrhagic diathesis can be a serious life-threaten-
ing event to patients undergoing an oral or periodontai
surgical procedure. In general, bleeding tendencies
occur when there are pathologic conditions that affect
(1) platelet adhesion to damaged vascular walls and
aggregation of platelets to one another, (2) the coagula-
tion factor cascade and its fibrinolytic counterpart path-
ways, and {3} fragility of small vessel walls. The latter is
rare and is not discussed here.
The clinical findings that herald an underlying
bleeding disorder include purpura; spontaneous gingi-
val, nasal, or genital tract bleeds; and hemarthrosis.
When a disorder of hemostasis is present, these signs
typically occur in the absence of any provocative trau-
matic event. Two major types of purpura are encoun-
tered: petechiae, which are punctate 1- to 2-mm red
spots of skin or mucosa and are more common in
platelet disorders (Figure 7-1); and ecchymoses, which
appear as diffuse macular blue, red, or brown bruises
and are more often encountered among patients with
clotting factor deficiencies (Figure 7-2}.
Ipathophysiology
Damage to the cndothcliuni exposes underlying con-
nective tissues, extracellular matrix (ECM) proteins,
and glycosaminoglycans of the vascular wall, to the
circulation. A serum protein, von Willebrand factor
VIII complex, adheres to ECM and then serves as a hnk
for platelets, which have a binding receptor for this
adhesion molecule (Figure 7-3). In the von Willebrand
group of diseases, this factor is inherited in a mutated
hypofunctional form or may not be synthesized in
physiologically functional amounts. Platelet adhesion is
delayed or does not occur. Assuming an intact von
Willebrand factor, the next phase of hemostasis
involves aggregation of platelets to those that are
adherent to the damaged vascular wall. This is medi-
ated by a group of platelet membrane adhesion mole-
cules that bind to a receptor on the adherent thrombo-
cytes bound to von Willebrand factor. Fibrinogen, a
serum clotting factor, is an important platelet-platelet
link. The cyclooxygenase pathway is involved in
Figure 7-1 Petechial hemorrhages in the palate. Figure 7-2 Diffuse mucosal hemorrhage or ecchymosis of the palate.
61
62 C H A P T H R 7
Adhesion
von Willebrand
Figure 7-3 Hemostasis. Platelet adhesion.
platelet aggregation by synthesis of thromboxane A2
from arachidonic acid within the platelet. Acetylsati-
cylic acid is an inhibitor of this metabolic pathway, and
administration of aspirin inhibits aggregation for the
entire 160-day life span of the platelet. Clinically rele-
vant bleeding problems are not usually encountered
until a patient ingests more than eight 325-mg tablets
per day. Many other nonsteroidal anti-inflammatory
drugs (NSAIDs) also affect this pathway adversely.
In addition to thromboxane and fibrinogen, there are
other platelet adhesion molecules necessary for platelet
aggregation. There are rare disorders in which these
molecules are inherited in mutated hypofunctional form.
Thrombocytopenia is a condition comprising a wide
variety of etiologies. Table 7-1, although not compre-
hensive, lists the more common diseases that can culmi-
nate in thrombocytopenia. The idiopathic forms fre-
quently manifest antibodies that bind to autologous
antigens on platelet membranes, resulting in IgG com-
plement-mediated clearance by phagocytes. This form
Table 7-1 Platelet Disorders
Adhesion defect
von Willebrand factor group of diseases
Aggregation defects
Aspirin, various NSAIDS
Inherited platelet adhesion molecule diseases
Thrombocytopenia
Idiopathic or autoimmune
Drug-induced
Leukemia-associated
Total body irradiation
may be encountered in untreated human immunodefi-
ciency virus (HlV)-infected subjects. The thrombocy-
topenia seen in leukemia is a consequence of bone mar-
row depletion of megakaryocyte precursors by
malignant leukocyte proliferation and infiltration.
Chemotherapeutic agents used to treat cancer, inhibit
dividing cells and induce tbrombocytopenia, anemia,
and leukopenia.
Coagulopathies are the consequence of either inher-
ited or acquired defects in the proteins that constitute
the coagulation cascade, a complex stepwise sequence
of enzymatic reactions that leads to the formation of a
fibrin clot (Figure 7-4) (Table 7-2). Fibrin is formed by
activation of an enzyme known as thromboplastin. This
enzyme acts upon a precursor protein, prothrombin,
which is cleaved to the enzyme thrombin. In turn,
thrombin cleaves fibrinogen to form the sticky thread-
like protein fibrin. Fibrin intercalates between aggre-
gated platelets to form a stabilized clot within a dam-
aged vessel. In damaged tissues, fibrin forms a diffuse
gel-like matrix that serves as a scaffold for organization
by granulation tissue in the process of wound healing.
These enzymatic steps are collectively referred to as the
common pathway.
Clots forming outside of vessels, as in wounds, are ini-
tiated by factors of the extrinsic pathway. Tissue tbrom-
boplastin is released by fibroblasts during injury and is
activated by serum factor VII (Figure 7-5). This activated
thromboplastin then propagates through the common
pathway. Factor VII deficiency is extremely rare.
Clots that form inside vessels are initiated by factors
released from adherent, aggregated platelets that then
act upon serum proteins, collectively known as clotting
Figure 7-4 Hemostatis. Clotting mechanism.
B L E E D I N G D I S O R D E R S 63
Table 7-2 Coagulopathies
Heritable extrinsic pathway
Factor Vil deficiency
Heritable intrinsic pathway
Factor VIII (hemophilia A)
Factor IX (Christmas disease)
Heritable common pathway
Factor 1 afibrinogenemia
Acquired common pathway
Chronic and acute liver disease
Malabsorption of lipids and fat-soiuble vitamin K
Drug-Induced (Coumadin)
Consumptive coaguiopathy
Heparinized patients
factors. The factors, derived from aggregated platelets,
activate serum factor XII (Hageman factor), which in
the presence of calcium, activates a stepwise series of
reactions that includes factor IX, factor XI, and factor
VIIl, to yield the plasma form of thromboplastin (fac-
tor X}. This constitutes the intrinsic pathway. Subse-
quently, the common pathway is entered, progressing to
form a fibrin network that wraps around and through
aggregated platelets, thereby forming a stable thrombus
over the vessel wound. Endothelial cells can then resur-
face the wound. The hemophilias are hereditary dis-
eases: in hemophilia A defective factor VIII is derived
the material allele, being an X-linked recessive disorder.
In Christmas disease or hemophilia B, factor IX is
mutated and defective. In von Willebrand disease, there
is a defect in the von Willebrand factor Vlil adhesion
molecule, with impaired platelet adhesion coupled with
a mild intrinsic pathway coagulopathy. There are three
major subtypes of von Willebrand disease, the more
common of which is mild. A less frequent form presents
with severe bleeding.
Since the liver synthesizes many clotting factors of
the intrinsic and common pathways, it is axiomatic that
hepatocyte destruction will result in coagulopathy that is
reflected by prolonged intrinsic and extrinsic pathway
clotting (see Chapter 6). Fat malabsorption, such as seen
in nontropical sprue, is characterized by steatorrhea that
also contributes to coagulopathy through the common
Intrinsic pathway
1
Extrinsic pathway:
Platelet factors
Hageman factor
Factor IX
Factor XI
Factor VIIl
Extravascular clot
(skin wound)
Intravascular clot
Figure 7-5 Extrinsic and intrinsic pathways of coagulation.
64 C H A P T E R 7
pathway. When the fat-soluble vitamin K, a coenzyme
required for prothrombin synthesis, cannot be absorbed
because oi bowel disease, coagulation is delayed. Simi-
larly, in biliary obstruction, bile salts fail to reach the
gut, chylomicrons are not cleared, and vitamin K is not
absorbed in adequate quantities. Hypoprothrombinemia
then contributes to a bleeding tendency. Coumadin is a
vitamin K antagonist and is, therefore, used for control
of thiomboembolic vascular disease. Patients treated
with Coumadin may show prolonged clotting and man-
ifest significant bleeding during oral surgery.
The antithesis to hemostasis is clot dissolution. This
is accomplished by the plasminogen-fibrinolysin
enzyme pathways that initiate clot lysis. These path-
ways can be inhibited by pharmacologic agents.
Both platelets and clotting factors can be consumed
when disseminated intravascular coagulation occurs as
a consequence of serum factors that favor clot forma-
tion. Disseminated intravascular coagulation (DIC) is a
complication of certain widespread metastatic cancers.
:Mnical features and diagnosis
Platelet disease encompasses two major defects. A
decrease in absolute numbers is termed thrombocytope-
nia. A deficiency in the functional properties of adhe-
sion or aggregation is termed thrombocytopathia (or
rhrombasthenia). Thrombocytes, or platelets, are nor-
mally found in a concentration of 250,000 to
500,000/cm' of blood. Significant bleeding with pur-
pura is seen when the thrombocyte count falls below
50,000. Defects in adhesion are detected by assessing in
vitro aggregation from venipuncture samples. Certain
specific adhesion molecules that normally mediate
adhesion and aggregation can be measured in special
reference clinical laboratories that specialize in analysis
of hematologic diseases.
The chief clinical test for assessment of thrombocyte
disease is the bleeding time. This simple test can be
ordered from the laboratory or can be performed in the
office. A blood pressure cuff is placed on the upper arm
and is then inflated to 40 mm Hg. A blood lancet is used
to make a small puncture through the skin of the fore-
arm. The oozing blood is then blotted with filter paper
(a coffee filter will suffice) every 15 seconds untii no
blood appears on the filter (Figure 7-6). This normally
takes 4 to 6 minutes, the time required for platelets to
adhere, aggregate, and affect closure of the punctured
vascular walls. Prolonged bleeding times are seen in
both thrombocytopenia and thombocytopathia.
Defects in clotting factors lead to ecchymosis, spon-
taneous bleeding and intra-articular bleeding after even
minor trauma to a ioint. Clotting factors are activated
when platelets plug a severance in the endothelium and
their activation culminates in the formation of a fibrin
clot. Intravascular hemostasis uses clotting factors ofthe
intrinsic pathway, and blood samples can be subjected to
a test that assesses the integrity of this pathway, the par-
tial thromboplastin time (PTT). In a normal patient, the
PTT is about 25 to 30 seconds and is an in vitro measure
of the actual time required for the intrinsic pathway fac-
tors to form a fibrin clot (see Figure 7-5).
The PTT is performed in an instrument that electron-
ically detects the presence of a fibrin thread. The PTT is
performed on a blood sample that has been placed in a
tube containing anticoagulant. A portion of plasma is
obtained, and to this sample, an activator of the intrinsic
pathway is added, alleviating the anticoagulant effect and
stimulating the Hageman factor activation. This leads to
generation of plasma thromboplastin, hence the term
partial thromboplastin time, which then progresses
through the common pathway to form a fibrin clot, a
multistep process that normally occurs in 30 seconds.
The extrinsic pathway is responsible for extravascu-
lar coagulation (ie, forming clots in wounded tissues,
such as tooth extraction sites). Some of the clotting fac-
tors of the extrinsic pathway differ from those of the
intrinsic cascade. The test for the extrinsic pathway is
the prothrombin time (PT), which is typically 11 to
13 seconds. The PT also uses anticoagulated plasma, to
which an activator of the extrinsic pathway is added,
thereby stimulating prothrombin (prothrombin time).
The PTT and PT are delayed when one or more proteins
in their respective pathways are absent or nonfunc-
tional. Both pathways are prolonged when there is a
defect in one of the factors from the common pathway,
since both converge here.
The most reliable assessment of coagulation status is
the international normalized ratio (INR). The INR is
based upon the prothrombin time and is controlled over
Figure 7-6 The bleeding time is assessed with a cuff inflated to 40
mm Hg. A lancet initiates bleeding on the forearm, and after 4 minutes
have transpired, a fitter paper is dabbed over the bleeding spot every 15
seconds until bleeding has ceased.
B L E E D I N G D I S O R D E R S 65
many laboratories, whereby a ratio is generated to indi-
cate coagulation status. An I N R of 1.0 is normal, and
any ratio from 1.0 to 2.0 is considered to be only mildly
decreased, approaching normal coagulability. When the
I N R is 2.0, this would correspond to a PT of 24, if the
control sample across laboratories was 12 seconds,
thereby indicating that coagulation is one-half the effi-
ciency of the norm. An I N R of 2.0 to 3.0 indicates a
moderate-level bleeder, whereas 3.0 to 5.0 is considered
to be at high risk for uncontrolled bleeding.
The clinical test for coagulation disorders is the clot-
ting time. To conduct this test, a blood lancet is used to
puncture the finger pad. I mmediately, eight capillary
microhematocrit tubes are placed over the puncture site,
one at a time, filling them by capillary action. After
waiting 4 minutes, a tube is fractured in the center and
gently pulled apart. This procedure is repeated every 15
seconds until a thin threadlike band connects the frac-
tured ends of the tube (Figure 7-7). This thread repre-
sents the formation of fibrin, which was activated once
blood contacted the glass surface of the tube. N ormally,
the fibrin thread forms within 4 to 5 minutes. Prolon-
gation of the clotting time equates to a defect of the
intrinsic or common pathways of coagulation. The vast
majority of coagulopathies can be screened using the
clotting time test.
indicative of a bleeding disorder warrants the procure-
ment of appropriate blood tests, such as platelet count,
platelet aggregation, PT, and PTT. If leukemia is sus-
pected, a complete blood count should be ordered as well.
If a surgical procedure is undertaken and bleeding
becomes problematic, 911 should be called and the
patient should be admitted to the emergency depart-
ment. Thrombin packs with direct pressure should be
placed over the wound until the patient can be admitted.
For patients with thrombocyte deficiency who need
tooth extraction or other oral surgical interventions, the
patient should be treated in the hospital or surgical cen-
ter with hematologic consultation. A platelet transfu-
sion can then be administered prior to oral surgery.
Aspirin or indomethacin toxicity may be encountered in
patients with arthritis or chronic headache. The drug
should be withdrawn, using a substitute analgesic with-
out aspirin (acetometaphine with codeine or
hydrocodone), and surgery postponed for 5 to 7 days.
Patients with factor deficiencies should be hospital-
ized in consultation with a hematologist. Missing factor
can be administered intravenously just prior to dental
surgery. Cryoprecipitate and recombinant factors
should be obtained in advance. For patients on
Coumadin requiring immediate surgery for severe
odontalgia, vitamin K can be given intravenously under
Clinical considerations for dental care
Uncontrolled bleeding from tooth extraction, periodontal
surgery, or other oral and maxillofacial surgery proce-
dures can occur in patients with either platelet disorders
or coagulopathies. As alluded to earlier, the oral manifes-
tations include petechia, ecchymosis, and spontaneous
oronasal bleeds that occur in the absence of any signifi-
cant trauma. Purpura found in conjunction with gingival
enlargement and malaise may underlie leukemia. If facial
spider telangiectasias are evident and the skin or con-
junctivae are jaundiced, cirrhosis of the liver must be con-
sidered. Purpura can occur in patients with HFV infec-
tion, indicating thrombocytopenic purpura. E cchymosis
of the mucosa or skin in a patient with a history of vas-
cular occlusive disease may be indicative of Coumadin
therapy. The medical history should be thoroughly
reviewed to explore whether there are any past or present
episodes indicative of a hemorrhagic diathesis.
Two dilemmas can occur in dental patients: (1)
unknowingly performing a surgical procedure on a hem-
orrhagic subject, and (2) performing necessary extractions
or surgeries in a patient with a known coagulation disor-
der. The first scenario can often be avoided by taking a
thorough medical history, asking the appropriate ques-
tions regarding bruisability, spontaneous or poorly con-
trolled bleeding, and drug history (Table 7-3). Any sign
Figures 7-7 The clotting time. Microcapillary tubes { A ) are filled with
blood taken from a finger lancet puncture (S) and after 3.5 minutes one
Is broken every 15 seconds until a fibrin thread is observed across the
broken ends.
66
CHAPTER 7
Table 7-3 Commonly Prescribed Drugs That Can Produce a
Hemorrhagic Diathesis
(fitamin K antagonist
Coumadin
Platelet aggregation inhibition
Acetylsalicylic acid
Indomethacin
Ibuprofen
Ketorolac
Persantine*
Acetaminophen*
Corticosteroids*
Heparin sulfate
Platelet synthesis inhibition
Cytotoxic antineoplastic agents
Cyclophosphamide
5-fluorouracil
Methotrexate
Mitomysin
Bleomycin
Doxorubicin
Vinbiastine or vincristine
Antihypertensive myelosuppression
ACE inhibitors
Beta blockers
*Mild effect.
ACE = angiotensin-converting enzyrriG.
direction of the patient's physician, and coagulation sta-
tus can be monitored by obtaining a prothrombin time.
For elective surgery, the dentist should consult with the
physician about withdrawing the Coumadin for 3 to 4
days prior to surgery. It should be noted that most
physicians managing patients with thromboembolic dis-
eases are reluctant to have them discontinue their anti-
coagulant for any extended period.
In general, anyone with a platelet count beiow 50,000
should not have dental or periodontai surgery in the gen-
eral office setting. Similarly, if platelet aggregation is less
than 50% of normal control values, the same holds true.
With regard to coagulation disorders or patients receiv-
ing anticoagulant therapy, the PT or PTT should be
above 50% of nortnal or prolonged no more than double
normal values for in-office procedures, or the INR should
be under 3.0. Recent studies have shown that teeth can be
safely extracted without altering Coumadin levels, even
with ratios up to 5.0, provided extraction sites are
sutured and occluded with fibrin sealant. Antifibrinolytic
preparations, such as tranexamic acid, may also be used
in patients with coagulopathic disorders.
Patients who are heparinized while undergoing
hemodialysis for end-stage renal disease should be
treated the day prior or 1 day subsequent to dialysis.
Heparin is rapidly metabolized, and its anticoagulant
effects last only 4 to 6 hours.
Capillary fragility is generally not a problem in den-
tal practice. Although hereditary hemorrhagic telangiec-
tasia involves the oral mucosa, fragile vessels are not
present in the periodontal tissues. A case of ascorbic
acid deficiency would be so rare as to be a candidate for
a grand rounds session!
Basi DL, Schmiechen NJ. Bleeding and coagulation problems
in the dental patient. Hereditary disease and medication-
induced risks. Dent Clin North Am 1999;43:457-70.
Bodner L, Weinstein JM, Baumgarten AK. Efficacy of fibrin
sealant in patients on various levels of oral anticoagulant
undergoing oral surgery. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 1998;86:421^.
Garfunkel AA, Galili D, Findler M, et al. Bleeding tendency: a
practical approach in dentistry. Compend Cont Educ Dent
1999;20:836-8, 840-2, 844. (Passim)
Troulis MJ, Head TW, Lecierc JR. Dental extractions in
patients on an oral anticoagulant: a survey of practices in
North America. J Oral Maxillofac Surg 1998;56:914-7.