The pathophysiology of bleeding disorders presenting as

abnormal uterine bleeding

Bruce M. Ewenstein, MD, PhD
Boston, Massachusetts

Abnormal uterine bleeding is often the presenting complaint in women with underlying coagulopathies. A
clear understanding of the pathophysiology of common bleeding disorders will help the practicing
obstetrician/gynecologist in the diagnosis and treatment of these conditions. The normal hemostatic
process can be divided into three phases. The first phase, primary hemostasis, consists of platelet
adhesion and aggregation. After vascular injury, proteins in the subendothelium are exposed that promote
platelet adhesion. Platelet adhesion is uniquely dependent on von Willebrand factor, a plasma protein
that serves as a molecular bridge between components of the vessel wall and the platelet glycoprotein
Ib/IX receptor. Activation of the adherent platelets promotes additional platelet recruitment, culminating in
the formation of the platelet plug. Quantitative or qualitative defects in either the platelet or von
Willebrand factor (von Willebrand disease) lead to defective primary hemostasis. Patients present with a
prolonged bleeding time and mucocutaneous bleeding manifestations. In the next phase, secondary
hemostasis, the plasma coagulation factors are sequentially activated, which leads to fibrin formation and
cross-linking. These reactions take place primarily on the surface of activated platelets and are essential
in maintaining the stability of the initial platelet plug. Defective secondary hemostasis arises from
congenital or acquired deficiencies in coagulation factors. Although these defects are most often
associated with bleeding into joints and soft tissues, other manifestations, including abnormal uterine
bleeding, may be present. The prothrombin time and the activated partial thromboplastin time serve as
initial screening tests for these coagulation disorders, although more specific tests, including factor levels,
thrombin time, clot solubility, and mixing studies, are needed to fully define the defect. In the final phase
of normal hemostasis, fibrinolysis, the fibrin clot undergoes an orderly process of degradation.
Deficiencies in the normal inhibitors of fibrinolysis, such as c~2-antiplasminor plasminogen activator
inhibitor-I, may be underdiagnosed causes of delayed bleeding because they are not identified by the
usual coagulation screening tests. Disorders of primary hemostasis, including thrombocytopenia and von
Willebrand disease, are particularly important to consider when evaluating women with abnormal uterine
bleeding. Patients with acquired or congenital deficiencies of either coagulation factors or the regulators
of the fibrinolytic system may also present with menorrhagia. Accurate diagnosis of a bleeding disorder is
essential to the design of an appropriate therapeutic regimen and is likely to have important clinical
implications beyond that of the presenting gynecologic complaint. (Am J Obstet Gynecol
1996; 175:770-7.)

Key words: Uterine bleeding, von Willebrand disease, menorrhagia

Abnormal uterine bleeding (AUB) represents one of proach to the diagnosis and treatment of these condi-
the most common problems encountered by the practic- tions. Mild bleeding disorders may become clinically ap-
ing obstetrician/gynecologist/ Once the physician has parent only at times of hemostatic stress, such as with
established that the hypothalamic-pituitary-ovarian axis surgery or other trauma. Because the cessation of men-
is functioning normally and has ruled out uterine and struation is partially dependent on normal coagulation,
other pelvic organic disease, the possibility of a systemic AUB may be the cardinal manifestation of such disorders.
coagulopathy should be considered. A working under-
standing of the pathophysiology of common bleeding The medical history
disorders provides the framework for a systematic ap- As is true in evaluation of abnormal bleeding in any
patient, 2 a careful clinical history frequently provides es-
sential diagnostic information in patients with AUB and
From the Boston Hemophilia Cent~ Children's Hospital~Brigham &
Women's Hospital. serves as a guide to effective laboratory evaluation. In
Reprint requests: Bruce M. Ewenstein, MD, PhD, Hematology-Oncology taking a medical history of a patient with a suspected
Division, Brigham & Women's Hospital, 75 Francis St., Boston, MA bleeding abnormality, the severity of the hemorrhage and
02115.
Copyright @ 1996 by Mosby-Year Book, Inc. its temporal relationship to surgery or other trauma
0002-9378/96 $5. O0 + 0 6/0/70679 should be elicited as precisely as possible. The presence

770
Volume 175, Number 3, Part 2 Ewenstein 771
~4anJ Obstet GynecoI

of a systemic coagulopathy is most strongly suggested by a Blood Flow

history of abnormal bleeding either occurring on mul-
tiple occasions or involving diverse anatomic sites. The vWF Fibrinogen
F

development of iron deficiency or the need for red blood V V

cell transfusion provides objective evidence of significant
blood loss; it has been estimated that one fourth of
women with hemoglobin levels of less than 10 g m / d l and
one third of those who require transfusion have an un-
~_.._..
derlying coagulation defect. 3
For didactic purposes, the hemostatic process can be Vessel before injury
divided into three phases: formation of the platelet plug
(primary hemostasis), stabilization of the platelet plug
through .fibrin deposition (secondary hemostasis), and
orderly dissolution of the blood clot (fibrinolysis).4 The
clinical history is fi-equently useful in localizing the pa-
tient's abnormality (Table I). For example, defects in the
primary hemostatic process most often present as muco-
cutaneous bleeding such as epistaxis, gingival bleeding, Injured vessel
or menorrhagia. The bleeding time is characteristically
prolonged in these patients. In contrast, abnormalities in
secondary hemostasis often result in bleeding into soft
tissues such as muscles and joints. In the context of sur-
gery, defective primary hemostasis produces excessive
bleeding that is often evident intraoperatively to the sur-
geon. This contrasts with defects in the coagulation cas- 1 o Hemostatic plug
cade, which most commonly result in abnormal bleeding
starting several hours or longer after surgery. Similarly,
disorders of the fibrinolytic system result in delayed-onset
bleeding lhat may first become evident 1 or more days
after surgery.
The duration of the patient's symptoms and the pres-
ence of a familial history of bleeding can help distinguish
congenital from acquired disorders. Moreover, when a 2 ° Hemostatic plug
family history of bleeding is obtained, an analysis of the
pedigree can provide important insights regarding the Fig. I. Primary and secondary hemostasis in flowing blood after
genetics of the disorder, which are in turn helpful in vessel injury. (From HawigerJ. Hum Pathol 1987;18:111-22.)
establishing a diagnosis. For example, a family history in
which males are primarily affected suggests an X-linked fortunately, no practicable methods exist m accurately
disorder, such as hemophilia A (factor VIII deficiency), measure blood loss in this setting, and the physician is
whereas the autosomal dominant transmission of a bleed- often left to rely on surrogate indicators such as pro-
ing tendency is suggestive of most types ofvon Willebraxld longed menstruation (greater than 7 days), signs or symp-
disease (vWD). Particular attention also should be paid to toms of volume depletion during menstruation, the pas-
any medication that appears to be temporally associated sage of frank blood clots, or the development of iron
with an increase in bleeding symptoms. For example, deficiency anemia when diagnosing AUB.
many nonprescription medications contain aspirin and
may be overlooked by both the patient and physician at Disorders of primary hemostasis
the time a medical history is elicited. h n p a i r m e n t of primary hemostasis may result from
In normal women, average menstrual blood loss varies quantitative platelet abnormalities, from defects in yon
over awide range (25 to 69 ml) and loss in excess of 80 ml Willebrand factor (vWF), or from abnormal blood vessel
is often cited as an objective criteria for abnormal bleed- wall components. The first phase of hemostasis consists of
ing. s Most commonly, however, only when a woman per- platelet adhesion and aggregation. As a result of vascular
ceives a deviation from her n o r m will she seek medical injury, protein components of the subendothelium, prin-
attention.* Thus, the presence of a lifelong bleeding dis- cipally collagen fibrils, are exposed to the cellular and
order, such as vWD, may go undiagnosed because the plasma components of blood (Fig. 1). Platelets initially
patient does not perceive her menses as abnormal. Un- adhere in a monolayer to the exposed collagen, thus
772 Ewenstein September 1996
AmJ Obstet Gynecol

Table I. Clinical features of bleeding due to platelet or plasma protein deficiencies

Plateletdeficiency/vWD I Clottingfactor deficiency
Site of bleeding Skin Deep in soft tissues (joints, muscles)
Mucous membranes (epistaxis, gum,
vaginal, and gastrointestinal bleeding)
Bleeding after cuts and scratches Yes No
Petechiae Yes No
Ecchymoses Small, superficial Large, deep (palpable)
Hemarthroses/muscle bleeding Extremely rare Common
Bleeding after surgery Immediate, usually mild Delayed (usually 1-2 days): often severe

Modified from Schafer A. Approach to bleeding. In: Loscalzo J, Schafu A, eds. Thrombosis and hemorrhage. Cambridge,
Massachusetts: Blackwell Scientific Publications, 1994:407-30,

initiating hemostasis. U n d e r conditions of high sheer count, 6 are of particular interest to the obstetrician/gyne-
stress, as encountered in small veins and venules, platelet cologist because of the association of these diseases with
adhesion is primarily d e p e n d e n t on vWF, a plasma pro- pregnancy and the postpartum period. Disseminated in-
tein that serves as a molecular bridge between compo- travascular coagulation may arise in a wide variety of
nents of the vessel wall and a specific receptor on the clinical circumstances and include several peculiar to the
platelet, the platelet G p l b / I X complex. Adherent plate- obstetric setting such as abruptio placentae, intrauterine
lets then undergo activation leading to the release of fetal demise syndrome, and amniotic fluid embolism, r
potent agonists of platelet aggregation, principally aden- Each of these conditions, however, is associated with a
osine diphosphate (ADP) and thromboxane A 2 (TXA2). rapidly progressive clinical course and only rarely is a
These agents stimulate the aggregation of additional diagnostic challenge. Moreover, these disorders are usu-
platelets Onto the monolayer of the initially adherent ally accompanied by microangiopathic red blood cell
platelets. Fibrinogen cross-links the aggregating platelets changes and, in the case of acute disseminated intravas-
in a process that requires activation of a second platelet cular coagulation, other abnormalities of coagulation
receptor, the glycoprotein I I b / I I I a complex. Thrombox- such as increased prothrombin time (PT) and activated
ane A 2, which is generated from platelet membrane phos- partial thromboplastin time (aPTT), decreased flbrino-
pholipids, f u r t h e r enhances hemostasis by stimulating gen, and the presence of circulating fibrin split products.
vasoconstriction. The most common causes of platelet hyperdestruc-
Thrombocytopenia. A reduced number of circulating tion are immunologic, most often of an autoimmune
platelets (thrombocytopenia) can arise f r o m d e f e c t i v e nature. In adults, autoimmnne thrombocytopenia pur-
bone marrow production, increased sequestration in the pura (AITP) usually has an insidious onset of easy bruis-
spleen, or accelerated destruction in the circulation. ing or mucosal bleeding of several months' duration.
Thrombocytopenia caused by bone marrow failure is of- Patients are predominantly female and menorrhagia may
ten accompanied by abnormalities in other cellular com- be a prominent presenting complaint. Examination of
ponents of blood. Anemia, when present, is frequently the bone marrow reveals an increased number of mega-
associated with an increased red blood cell volume (mac- karyocytes. Autoantibodies may be demonstrated on the
rocytosis). In these conditions a bone marrow biopsy is circulating platelets or in the serum, but the tests avail-
frequently diagnostic. Severe thrombocytopenia (platelet able in most clinical laboratories lack the sensitivity and
count <20,000/pl), such as that encountered in patients specificity necessary for accurate diagnosis, s Thus the
receiving antineoplastic agents, is often associated with diagnosis of AITP is one of exclusion and often depends
uterine bleeding. Splenic sequestration, which may arise in part on the clinical response to therapeutic agents such
in any clinical situation associated with splenomegaly in- as corticosteroids and intravenous immunoglobulin.
cluding portal hypertension, lymphoma, or metabolic In the evaluation of patients with recent onset of
disease, typically produces mild thrombocytopenia. thrombocytopenia, the physician should elicit a careful
Increased peripheral destruction accounts for most of history of recent exposure to drugs such as the sulfon-
quantitative platelet disorders and may be subdivided amides, quinine, and phenytoin, which can cause throm-
into immune and n o n i m m u n e etiologies. Nonimmune bocytopenia through the formation of antigen-antibody
platelet destruction is associated with a number of sys- complexes that bind to platelets. Immune thrombocyto-
temic disorders including vasculitis and thrombotic penia may also be the cardinal manifestation of a variety
thrombocytopenic purpura. Thrombotic thrombocyto- of other autoimmune diseases such as systemic lupus
penic purpura and related conditions, including the erythematosus, lymphoma, or viral infections including
hemolytic-uremic syndrome and the syndrome of h u m a n immunodeficiency virus. Thus initial evaluation
hemolysis, elevated liver enzymes, and low platelet of any patient with unexplained thrombocytopenia
Volume 175, Number 3, Part 2 Ewensteirl 773
AmJ Obstet Gynecol

should include a careful history, physical examination, static system. Bleeding time is often prolonged but may
and laboratory testing appropriate for the diagnosis of be in the normal range, especially in patients with type 1
each of these conditions. vWD. Clinical symptoms tend to parallel the level of
Qualitative platelet abnormalities. Some patients have plasma v~T, which is affected by several factors, including
clinical manifestations suggestive of a defect in primary ABO blood type, age, and endocrine status. These "ex-
hemostasis despite a normal platelet count. 9 Often these tragenic" factors may explain in part the variable pen-
patients have either qualitative platelet abnormalities or etrance of the type 1 vWD gene. Physiologic fluctuation
defects in vWF. Qualitative platelet abnormalities are di- in vWF levels may also obscure the diagnosis ofvWD, and
agnosed in the laboratory by stimulating the patient's repeat laboratory testing over time is recommended for
platelet-rich plasma with agonists known to cause platelet evaluation of patients with strong personal and family
aggregation and release. This methodology can be used histories suggestive of vWD. 14' 15 vVvT factor levels rise
to define specific congenital or acquired defects in plate- during pregnancy in normal individuals and in patients
let function such as absence of the platelet glycoprotein with type 1 vWD. 16' ~vThis physiologic correction usually
IIb/IIIa receptor (Glanzmann's disease), absence of the obviates the need for specific treatment during delivery,
platelet glycoprotein I b / I X receptor (Bernard-Soulier although abnormal uterine bleeding may develop in the
disease), or a deficiency in intracellular pools of platelet early postpartum period when vWF values return to basal
ADP (storage pool disease). levels. In general, patients with any of the several variants
By far the most common cause of qualitative platelet of type 2 vWD have more severe clinical symptoms with
dysfunction is secondary to medication. Of the causative less episodic variation. Obstetric bleeding is more cmn-
agents, the most important group is the nonsteroidal mort among these patients. ~8
antiinflammatory drugs (NSAIDs), including ibuprofen Primary hemostasis and AUB. It is believed that uterine
and naproxen, which block platelet TXA2 formation. hemostasis during menstruation shares many of the basic
Each acts by inhibiting platelet cyclooxygenase, the rate- features outlined above and that formation of a platelet
limiting step in platelet TXA9 biosynthesis. The inhibi- plug is a critical first step in the regulation of blood flow.~9
tory effects of aspirin are particularly long-lived because Thus it is not surprising that thrombocytopenia and vWD
they are irreversible and render the platelet incapable of each have been associated with menorrhagia, sometimes
regenerating new enzyme. Thus ingestion of a single of a severe nature, ts' 20-.*aand further that menorrhagia is
aspirin can increase bleeding symptoms for as long as 5 to a common presenting symptom among female patients
7 days, the time required for generation of new platelets with vWD. 24 Hemorrhage may be particularly severe at
from the bone marrow megakaryocyte. menarche, 25 when estrogen-dominated stimulation of
von Willebrand disease, von Willebrand disease com- the endometrium produces an especially vascular en-
prises a broad spectrum of disorders that arise from de- dometrial lining.2~ From an historical perspective, it is
fects in vWF biosynthesis or structure. 1°-12 Taken as a interesting to note that the first patient identified with
whole, vWD is the most common inherited bleeding dis- this disorder (originally termed "hereditary pseudohe-
order found in women and may be as prevalent as 0.1% to mophilia") by Dr. Erik von Willebrand in 1926 eventually
0.8% in the general population) 3 There are three types died of uncontrollable menstrual bleeding at age 13
and four subtypes ofvWD that can be defined on the basis years. 27
of sophisticated laboratory testing (see Lusher, this issue), The normal balance between hemostasis and thrombo-
but type 1 vWD is the most common by far. Patients with sis is maintained, in part, by production within the vascu-
type 1 vWD have a moderate reduction (30% to 50% of lar wall of prostaglandins, particularly prostaglandin E2
normal) in immunologic and functional measurements (PGE2) and prostacyclin (PGI2), which inhibit platelet
of vWF, as well as a concomitant reduction in factor VIII. formation and promote vasodilation. The local genera-
Although the inheritance of type 1 vWD is autosomal tion of these compounds may be of particular importance
dominant, there is variable penetrance, so that patients to uterine hemostasis, which appears to be more depen-
may carry the abnormal vWD gene and yet have little or dent than other tissues on vasoconstriction, beyond the
no clinical or biochemical evidence of disease. Type 2 first day of menstrual bleeding. 28 This feature likely
vWD is characterized by structural abnormalities in the explains the otherwise paradoxic clinical successes
vWF protein, most commonly reflected in a dispropor- achieved with NSA1Ds such as ibuprofen and naproxen in
tion between immunologic and functional v ~ T studies. the treatment of many patients with AUB. 2931 In normal
Type 3 vWD refers to a virtually complete absence ofvWF, individuals inhibition of prostaglandin production in the
which secondarily produces very low (<10%) plasma lev- uterine vasculature outweighs the antiaggregatory effects
els of factor VIII. Fortunately, the incidence of this variant of these drugs on platelet function. However, when used
is extremely low. in patients with underlying coagulopathies, NASIDs are
Clinically, patients with vWD have mucocutaneons ineffective in controlling AUB and may promote in-
bleeding characteristic of defects in the primary hemo- creased bleeding,a° Such a response should therefore
774 Ewenstein September 1996
AmJ ObstetGynecol

Intrinsic Pathway Table II. Systemic bleeding disorders associated

PK PK Prekallikrein with AUB
HK HK High molecular weight Abnormalities in primary hemostasis
kininogen Thrombocytopenia
Xll Xlla PL Phospholipids Bone marrow failure
/
• .... -, [HK Immune: AITR drug related, HIV
..v, Nonimmune: TTP, HUS, HELLP
Qualitative platelet abnormalities
Extrinsic Pathway
vWD
Xl Abnormalities in secondary hemostasis
Congenital factor deficiencies
Oral anticoagulants
Acquired factor VIII inhibitors
IX IXa Vlla/tissue factor Hyperfibrinolytic states
VIII v,a ,Ic: 0t2-antiplasmindeficiency
?PAId deficiency
Complex coagulopathies
DIC
Liver disease
X Xa X
J HUS, Hemolytic uremic syndrome; HELLP, hemolysis, el-
evated liver enzymes, and low platelet count; DIC, disseminated
v ,1 2 2- intravascular coagulation.

Disorders of secondary hemostasis

Prothmmbin Thrombin
Activation of the coagulation cascade (secondary he-
mostasis) results in the stabilization of the primary plate-
let plug. The sine qua n o n of secondary hemostasis is the
Classic formation of fibrin from its soluble plasma precursor,
> coagulation Fibrin monomer Xllla fibrinogen, by the action of thrombin. Like thrombin,
cascade
most of the coagulation factors are proteolytic enzymes
Positive
Fibrinpolymer similar in structure to trypsin and chymotrypsin (serine
.... -) feedback
(hypothesized)

Extrinsic-to-
I' proteases). The enzymes circulate in precursor forms
(zymogens), which are activated in a sequential fashion
) intrinsic Cross-linked to produce a dramatic amplification of the initiating
activation fibrin polymer
events. Further amplification is achieved through asso-
Fig. 2. Modifications to blood coagulation cascade including ciation of the activated clotting factors with factors V and
activation of factor IX by issue factor/factor VII complex and VIII into macromolecular complexes on plasma mem-
positive feedback activation of clotting factors V, VIII, and possi- branes. These associations result in the generation of
bly XI by thrombin. (Reproduced with permission. Roberts H, extremely high concentrations of coagulation factors a t
LozierJ. Hospital Practice, 1992;27(1):97. © 1992. The McGraw-
Hill Companies.) the site of clot formation and dramatic e n h a n c e m e n t of
enzymatic activity. 35
Historically, the coagulation cascade was separated into
distinct pathways, "intrinsic" and "extrinsic" to the
blood, each separately capable of activating factor X and
alert the physician to the possibility of a systemic bleeding ultimately leading to the conversion of soluble fibrinogen
disorder. (Table II). Similarly, a history of postpartum to fibrin (Fig. 2s~). In this model, the intrinsic pathway is
hemorrhage associated with the use of low-dose aspirin to first activated through factor XII and other contact fac-
treat preeclampsia32 may be indicative of an underlying tors (prekallikrein, high molecular weight kininogen).
bleeding diathesis. Activated factor XII then activates factor XI, which in
Occasionally, one may encounter patients with an ac- turn activates factor IX. A macromolecular complex con-
quired form of vWD, which is associated with certain sisting of factor IX a, factor VIIIa, phospholipid, and cal-
malignancies, angiodysplasia, and hypothyroidism. Men- cium (the intrinsic tenase complex) then activates factor
orrhagia is a common presenting symptom of hypothy- X. Alternatively, the extrinsic pathway is initiated by the
roidism, S~ and the reduced levels of vWF associated with activation of factor VII by tissue factor and trace amounts
this endocrine disorder may be contributory. Replace- of factor X a. A macromolecular complex consisting of
ment with thyroid h o r m o n e corrects both the coagulop- factor VIII~, tissue factor, phospholipid, and calcium (the
athy and the symptom of AUB? 4 extrinsic tenase complex) then activates factor X. A third
Volume 175, Number 3, Part 2 Ewenstein 775
AmJ Obstet Gynecol

aPT]-
Normal Prolonged

Deficienciesof: prekallikrein- I
HK ..J- NO bleeding
factor Xll
factor XI }
factor IX Bleeding
yon Willebranddisease factor VIII
I
Dysfibrinogenemias ~ ' - ' [ L u p u s ~ - -
anticoagulant

Deficiencyof factor VII

Deficiencies of: FactorX
factor V
Liverdisease, prothrombin
vitamin K deficiency, fibrinogen
warfarin therapy

Fig. 3. Schematic representation of detected abnormalities of PT and aPTF in congenital and acquired
coagulation disorders. PT, Prothrombin time; aPTT, activated partial thromboplastin time. (From Scha-
fer A. Approach to bleeding. In: LoscalzoJ, Schafer A, eds. Thrombosis and hemorrhage. Cambridge,
Massachusetts: Blackwell Scientific Publications, 1994:407-30. Reprinted by permission of Blackwell
Science, Inc.)
(inactive)

PAl-1 / tPA Plasminogen Fibrin

PAl-1 tPA
(x2-antiplasmin
Plasmin ] "-
ira,--

Fibrin
degradation
products
Fig. 4. Fibrinolytic system depicting plasmin degradation of fibrin and its principal sites of regulation.
(Modified from Kottke-Marchant k. Hematol Oncol Clin North Am 1994;8:809-53.)

macromolecular complex consisting of factor X~, factor Xa, and thus thrombin. In addition to its action on 13.-
Va phospholipid, and calcium (the prothrombinase com- brinogen, thrombin may also activate factor XI u n d e r
plex) converts prothrombin to its active form, thrombin. certain circumstances.
Finally, limited proteolysis by thrombin converts fibrino- Despite these physiologic interrelationships, it is pos-
gen to fibrin, which polymerizes and is then crosslinked sible to separately evaluate individual pathways in the
by factor XlIL laboratory. Analysis of the PT and activated PTT assays
More recently, the coagulation cascade model has been can be used to accurately pinpoint deficiencies (Fig. 3)? 9
modified to take into account newly recognized regula- The revised model of coagulation provides a rationale
tory steps and pathways? 6' 37It is now believed that activa- for the lack of clinical bleeding associated with factor XII
tion of factor IX by the factor VIIa/tissue factor complex deficiency, the heterogeneity of factor XI deficiency, and
plays a major role in the initiation of normal hemostasis. the importance of factors VIII and IX deficiencies (he-
The factor VIIa/tissue factor complex also activates factor mophilia A and B) despite the presence of an intact
IX, thus providing important crosstalk between the ex- extrinsic pathway. Disorders affecting the coagulation
trinsic and intrinsic pathways. Once the coagulation pro- factors are recessive. Congenital deficiencies of most co-
cess is begun, tissue factor pathway inhibitor effectively agulation factors are relatively u n c o m m o n in women and
blocks this pathway ~s and the intrinsic pathway factors occur in approximately 1 to 20 per million individua]s.
VIII and IX become the dominant generators of factor However, several deficiencies warrant special mention.
776 Ewenstein September1996
AmJ Obstet Gynecol

Because the genes for both factors VIII and IX are on the individual components must be assayed in patients for
X-chromosome, a single copy of an abnormal gene in a whom there is a high suspicion of an undiagnosed bleed-
male always results in a clinical disorder. Although ing disorder. 45 Deficiency of either PAI-1 or ct2-antiplas-
women are usually viewed as carriers of these disorders, rain results in a hyperfibrinolytic state characterized by
unfavorable "Lyonization" may lead to deficiencies sig- the premature lysis of hemostatic plugs and clinical
nificant enough to produce symptoms. Factor XI defi- bleeding with a delayed onset. Platelet and coagulation
ciency, although rare in the general population, is quite activities are normal, as are results of standard screening
c o m m o n among patients of European Jewish descent, tests of hemostasis: PT, aPTT, platelet count, and bleed-
among whom the incidence approaches 1 per 1000. ing time. In addition to the rare congenital deficiencies,
The physician is also likely to encounter women with levels of o~2-antiplasmin are significantly reduced in the
acquired coagulation defects. Such patients include those presence of liver disease, and this reduction is thought to
taking oral anticoagulant therapy, those with severe liver be a major determinant of the increased fibrinolytic ac-
disease, or, rarely, those with acquired inhibitors to coagu- tivity associated with hepatic cirrhosis.
lation factors, chiefly factor VIII. Oral anticoagulants, The fibrinolytic system and AUB. There is now experi-
such as warfarin, interfere with the regeneration of vita- mental evidence that essential menorrhagia is related to
min K in the liver. Vitamin K is a fat-soluble c o m p o u n d locally enhanced fibrinolysis46' 47 and antiflbrinolytic
required for carboxylation of glutamic acid residues, an agents such as tranexamic acid and e-aminocaproic acid
essential step in the biosynthesis of factors II (prothrom- frequently are effective in reducing menstrual blood
bin), VII, IX, and X. Severe liver disease results in a loss.28. 48, 4~ Clinical data relating to the incidence of AUB
complex coagulopathy that includes defective clotting in patients with systemic hyperfibrinolytic states are
factor synthesis (both quantitative and qualitative) and highly limited, but at least one patient with congenital
impaired clearance of activated factors and fibrin degra- c~2-antiplasmin deficiency and menorrhagia has been re-
dation products (chronic disseminated intravascular co- ported? °
agulation). Acquired inhibitors to factor VIII may arise in
a variety of clinical circumstances, including pregnancy Summary
and the puerperium, producing a bleeding diathesis that The possibility of a systemic coagulation disorder
is typically severe. 4°' 41 should be considered in all patients with AUB. A history
Defects in secondary hemostasis and AUB. In general, of abnormal bleeding or bruising at other anatomic sites,
coagulation factor deficiencies predispose the patient to an increase in menstrual bleeding associated with the use
bleeding in soft tissues and joints as opposed to mucocu- of NSAIDs, or a family history of bleeding are particularly
taneous sites. However, menorrhagia and postpartum suggestive of a systemic coagulopathy. Disorders of pri-
hemorrhage associated with congenital factor deficien- mary hemostasis, including thrombocytopenia and vWD,
cies, including those of factor VIII, fibrinogen, and those are important considerations when evaluating women
of factor XIII, have been reported. TM 42, 43 Menorrhagia with AUB. Less commonly, patients with acquired or con-
has also been well documented in patients receiving oral genital deficiencies of either coagulation factors or regu-
anticoagulant therapy. 42 The rare congenital deficiencies lators of the fibrinolytic system may also have menor-
of fibrinogen and factor XIII are particularly important rhagia. Accurate diagnosis of a bleeding disorder is essen-
in women because they are associated with spontaneous tial to the design of an appropriate therapeutic regimen.
abortions and postpartum hemorrhage. 43 Moreover, early recognition of a systemic bleeding disor-
der is likely to have important clinical implications be-
Disorders of the fibrinolytic system yond those of the presenting gynecologic complaint, for
the patient, and frequently for other members of her
The fibrinolytic system is responsible for the orderly
family.
dissolution of hemostatic plugs. 44 The system consists of
plasminogen, an inactive proenzyme ultimately con-
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hibitor-1 (PAI-1) and at the level of plasmin by c~-anti- ed. Orlando, Florida: WB Saunders Co, 1994;599-609.
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AmJ Obstet Gynecol

4. HawigerJ. Formation and regulation of platelet and fibrin 28. van Eijkeren MA, Christiaens GC, Scholten PC, Sixma j[J.
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