Approach Bleeding Diathesis

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Approach to the adult patient with a bleeding diathesis
Author Section Editor Deputy Editor

Reed E Drews, MD Lawrence LK Leung, MD Jennifer S Tirnauer, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Nov 2013. | This topic last updated: Oct 11,
2013.
INTRODUCTION — Bleeding that is spontaneous, excessive, or delayed in onset

following tissue injury results from a localized pathologic process or a disorder of the
hemostatic process, involving a complex interplay among vascular integrity, platelet
number and function, coagulation factors, and fibrinolysis. This topic review will
discuss the diagnostic approach to the patient with abnormal bleeding.
Congenital and acquired disorders of platelet function, as well as the hemostatic

process and associated disorders, are discussed separately.
(See "Overview of hemostasis".)

(See "Approach to the adult patient with thrombocytopenia".)
(See "Congenital and acquired disorders of platelet function".)
(See "Disorders of fibrinogen".)
PATIENT HISTORY — The clinical evaluation of a patient with a bleeding disorder

begins with a careful history. Patients with inherited hemostatic disorders may
report little bleeding, while others without inherited or acquired hemostatic
abnormalities may report exaggerated tendencies to bleed [1,2]. Given the variability
in patients' perceptions of bleeding, as well as the lack of a uniform clinical measure
of bleeding severity [3], a dialogue between the patient and physician is essential for
the consideration of a bleeding diathesis. A careful assessment of the presenting
complaint can provide important clues as to where a defect might reside in the
hemostatic process and whether the defect is inherited or acquired, providing a
rational approach to laboratory investigation (table 1). Use of a standardized
bleeding assessment tool may help in the prospective evaluation of patients referred
Related Searches: for hemostatic evaluation [4,5].
Bleeding history — Patients with a suspected bleeding disorder should be

questioned about past bleeding problems, a history of iron-responsive anemia,
bleeding outcomes following surgical procedures and tooth extractions, history of
transfusion, character of menses, and dietary habits or antibiotic use which might
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predispose to vitamin K deficiency. The patient should also be questioned
Map Of Indonesia concerning the presence of thyroid, liver, and kidney disease. Complaints such as
hematuria, melena, and menorrhagia are often less helpful, since structural causes
Malaysian Ringgit are more commonly responsible than a bleeding diathesis.
The response to trauma is an excellent screening test. A history of surgical

Indonesia Online procedures or tooth extractions or significant injury without abnormal bleeding is
good evidence against the presence of an inherited hemorrhagic disorder.
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Bandung An inherited disorder is suggested by the onset of bleeding shortly after birth or
Conference during childhood and a positive family history with a consistent genetic pattern.
Thus, hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are
characterized by X-linked recessive inheritance. However, a negative family history
Malaysian Music
does not exclude an inherited coagulation disorder. As an example, up to 30 to 40
percent of patients with hemophilia A have a negative family history. (See "Clinical
Bandung Hotels manifestations and diagnosis of hemophilia", section on 'Family history'.)
Jakarta Hotels Medication use — A careful history of medication use is important, including
prescribed medications, over-the-counter medications, and herbal products. Drug
ingestion may be associated with a bleeding diathesis via a variety of mechanisms,
Abdul Halim
such as the induction of thrombocytopenia or platelet dysfunction, aplastic anemia,
or vascular purpura. In addition, some drugs can induce or exacerbate a coagulation
Travel Indonesia disorder. Examples include platelet dysfunction induced by aspirin and other
commonly used antiinflammatory drugs, beta-lactam antibiotics, clopidogrel,
Hotel Bandung ticlopidine, and the co-ingestion of drugs that may potentiate the anticoagulant
effects of warfarin. (See "Nonselective NSAIDs: Overview of adverse effects" and
"Drug-induced thrombocytopenia".)
An example of the co-ingestion of drugs potentiating the incidence of bleeding was

provided in a study of over 21,000 elderly patients recovering from an acute
myocardial infarction [6]. In this study, the rates of hospitalization for bleeding
(incidence rate per 100 patients per year) for various combinations of antiplatelet
agents and anticoagulants were [6]:
Aspirin alone — 3.2

Warfarin alone — 5.9
Aspirin plus either ticlopidine or clopidogrel — 6.8
Aspirin plus warfarin — 8.3
A similar study in 27,058 older adult patients discharged following acute myocardial
infarction found the following rates of hospitalization for bleeding associated with a
different combination of drugs (aspirin, clopidogrel, SSRI) [7]. (See "Selective
serotonin reuptake inhibitors: Pharmacology, administration, and side effects",
section on 'Bleeding'.)
Aspirin alone — 0.65

Clopidogrel alone — 1.55
Aspirin plus a selective serotonin reuptake inhibitor (SSRI) — 1.61
Aspirin plus clopidogrel — 2.08
Clopidogrel plus SSRI — 2.43
Aspirin plus clopidogrel plus SSRI — 3.63
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CLINICAL MANIFESTATIONS — Clinical manifestations of disordered hemostasis
can be divided into two major categories: those associated with disorders of blood
vessels or qualitative or quantitative platelet abnormalities; and those associated
with disorders of coagulation (table 1).
Disorders of platelets or blood vessels — These conditions are often referred to

as disorders of primary hemostasis or the purpuric disorders since they are
characteristically associated with mucosal and cutaneous bleeding (picture 1).
Mucosal bleeding may be manifest as epistaxis and/or gingival bleeding, and large
bullous hemorrhages may appear on the buccal mucosa due to the lack of vessel
protection afforded by the submucosal tissue. Bleeding into the skin is manifested
as petechiae or superficial ecchymoses. (See "Clinical manifestations and
diagnosis of immune thrombocytopenia (ITP) in adults" and "Approach to the adult
patient with thrombocytopenia".)
Patients with platelet abnormalities tend to bleed immediately after vascular trauma
and rarely experience delayed bleeding, which is more common in the coagulation
disorders. The following are the types of bleeding most often associated with these
disorders:
Petechiae — Petechiae are small capillary hemorrhages. They

characteristically develop in crops in areas of increased venous pressure, such as
the dependent parts of the body. As a result, they are most dense on the feet and
ankles, fewer are present on the legs (picture 1). Petechiae are not found on the
sole of the foot where the vessels are protected by the strong subcutaneous tissue.
They are asymptomatic and not palpable, and should be distinguished from small
telangiectasias, angiomas, and vasculitic purpura.
Ecchymoses — Ecchymotic lesions characteristically are purple in color and

are small, multiple, and superficial in location. They usually develop without
noticeable trauma and do not spread into deeper tissues.
Menorrhagia — Menorrhagia (menstrual flow that does not taper after more
than three days) and metrorrhagia (bleeding in between periods) are common in
women with bleeding disorders; up to 15 to 20 percent of women presenting with
menorrhagia may have some type of bleeding diathesis, such as von Willebrand
disease, immune thrombocytopenia (ITP), platelet function defect [8,9]. (See
"Clinical presentation and diagnosis of von Willebrand disease", section on 'Clinical
presentation' and "Chronic menorrhagia or anovulatory uterine bleeding".)
Coagulation disorders — The typical manifestations of bleeding in the coagulation

disorders are large palpable ecchymoses and large, spreading, deep soft tissue
hematomas.
Hemorrhage into synovial joints (hemarthrosis) most often indicates a severe

inherited coagulation disorder, such as hemophilia (table 1). Postsurgical bleeding
can be extensive. (See "Clinical manifestations and diagnosis of hemophilia".)
In some patients with a coagulation disorder, the onset of bleeding after trauma may
be delayed. As an example, bleeding after a tooth extraction may stop, only to recur
in a matter of hours. The reason for this phenomenon and for the absence of
petechiae or bleeding from small cuts or scratches is the preservation of normal
platelet function.
The cardiac surgery patient — Evaluation of the patient undergoing cardiac

surgery can be difficult due to competing bleeding and thrombotic tendencies.
Abnormalities which may occur in such patients include some or all of the following
[10].
Endothelial damage/activation with disseminated intravascular coagulation

Presence of prosthetic valves, stents, vascular grafts, assist devices
Use of antiplatelet and/or anticoagulant agents
Intraoperative metabolic abnormalities (eg, hypothermia, acidosis, anemia,
hypocalcemia)
Presence of associated hepatic or renal failure
LABORATORY TESTING — Laboratory tests of primary and secondary hemostatic

mechanisms are used for two purposes:
General screening tests

Tests to define specific platelet or clotting factor abnormalities
General screening tests include the platelet count, bleeding time (BT), prothrombin
time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT).
Specific tests include examination of the peripheral blood smear, platelet

aggregation in response to ADP, epinephrine, collagen, and ristocetin; platelet
release assays, coagulation factor assays, and assessment of factor XIII activity via
clot solubility testing. Tests of fibrinolysis include the measurement of fibrin split
products and D-dimer levels. Assays for the less commonly seen bleeding disorders
include alpha-2-antiplasmin activity, euglobulin clot lysis time, as well as tissue
plasminogen activator and plasminogen activator inhibitor-1 antigens.
Appropriate emergency laboratory testing for those with active bleeding is discussed
separately. (See "Shock in adults: Types, presentation, and diagnostic approach",
section on 'Laboratory evaluation'.)
Platelet counting and the peripheral smear — Platelets may be counted

directly or with the use of fully automated electronic methods. (See "Automated
hematology instrumentation".) While some automated methods may flag for the
presence of unusually small or extremely large platelets, there is no substitute for
direct examination of the peripheral blood smear for detection of quantitative as well
as qualitative (ie, abnormalities of platelet size) platelet abnormalities. (See
"Congenital and acquired disorders of platelet function", section on 'CBC and
peripheral smear examination'.)
Examination of the peripheral blood smear is essential in patients with low platelet
counts to exclude the presence of pseudothrombocytopenia due to in vitro platelet
agglutination in the presence of EDTA (picture 2). This phenomenon is thought to
result from a "naturally occurring" platelet autoantibody directed against a normally
concealed epitope on the platelet membrane, which becomes exposed by EDTA.
Use of alternative anticoagulants (eg, citrate or heparin), may circumvent this
technical problem.
Bleeding time — The bleeding time (BT) is a measure of the interaction of platelets
with the blood vessel wall. A prolonged bleeding time may occur in
thrombocytopenia (platelet count usually below 50,000/microL), qualitative platelet
abnormalities (eg, uremia), von Willebrand disease (VWD), some cases of vascular
purpura, and severe fibrinogen deficiency, in which it is probably the result of platelet
dysfunction. Among patients with a normal platelet count who are not taking aspirin,
the bleeding time is used primarily to screen patients for inherited disorders of
platelet function [11,12]. An abnormal test in a patient with mucocutaneous bleeding
would justify further testing for platelet dysfunction or specific tests for von
Willebrand disease (VWD). However, a normal value for the BT should not preclude
testing for VWD [13,14]. As will be discussed below, the Platelet Function Analyzer
is more sensitive for detection of VWD than is the BT (see below) [15,16].
A normal BT does not predict the safety of surgical procedures, nor does an
abnormal BT predict for excessive bleeding. Since assessment of the BT is subject
to considerable variation due to technical factors in executing the test, a normal
range for the test varies from laboratory to laboratory, and cannot be generalized
here. Of importance, the BT is not recommended as a preoperative screening test.
Because of considerable variation due to technical factors in executing the test, the
BT plays a limited role, if any, in evaluating hemostatic defects. (See "Preoperative
assessment of hemostasis", section on 'Bleeding time'.)
The Platelet Function Analyzer — The commercially-available Platelet Function

Analyzer (PFA-100) is an alternative technology that assesses platelet function with
greater sensitivity and reproducibility than the bleeding time (BT) [15]. Because the
BT is insensitive, invasive, time consuming, and subject to variation due to technical
factors, many centers have adopted the PFA-100 in place of the BT as their
screening test of platelet function [17]. (See "Platelet function testing", section on
'The platelet function analyzer'.)
This test may be performed on citrated samples of whole blood that have been
stored at room temperature, and is considerably faster to perform than platelet
aggregation studies. Normal PFA-100 test results may obviate the need for further
expensive platelet function testing. Unlike the in vivo BT, the PFA-100 test does not
provide a measure of vascular function.
Prothrombin time — The production of fibrin via the extrinsic pathway and the final
common pathway (common to both extrinsic and intrinsic cascades) requires tissue
thromboplastin (tissue factor), factor VII (extrinsic pathway), and factors X, V,
prothrombin (factor II), and fibrinogen. The functioning of these pathways is
measured by the plasma prothrombin time (figure 1). The test bypasses the intrinsic
pathway and uses thromboplastins to substitute for platelets. Within this combined
pathway, factors VII, X, and prothrombin are vitamin-K dependent and are altered by
warfarin. For this reason, the PT is used as a measure of the anticoagulant activity
of warfarin and other vitamin K antagonists. (See "Clinical use of coagulation tests",
section on 'Prothrombin time (PT)'.)
Activated partial thromboplastin time — The activated partial thromboplastin

time (aPTT) measures the intrinsic and common pathways of coagulation (figure 1).
It is called partial since platelet substitutes are used which are only partial
thromboplastins; they are incapable of activating the extrinsic pathway, which
requires complete tissue thromboplastin (tissue factor). In the original method, a
glass test tube provided contact activation. However, the addition of activators such
as ellagic acid or particulate silicates provided better and more standardized contact
activation. This activated version of the PTT (aPTT) is now the routine assay used to
evaluate intrinsic coagulation and the degree of heparin anticoagulation. (See
"Clinical use of coagulation tests", section on 'Activated partial thromboplastin time
(aPTT)'.)
The aPTT is sensitive to inhibitors such as heparin and to deficiencies of all

coagulation factors except factors VII and XIII. It is less sensitive than the PT to
deficiencies of the common pathway (factors X and V, prothrombin, and fibrinogen)
[18]. High levels of a single factor (eg, factor VIII) can shorten the aPTT. However, an
association between a short aPTT and a hypercoagulable state remains
controversial.
Thrombin time and reptilase time — The thrombin time (TT) and reptilase time
(RT) measure conversion of fibrinogen to fibrin monomers and the formation of initial
clot by thrombin and reptilase, respectively. Reptilase, a thrombin-like snake
enzyme, differs from thrombin by generating fibrinopeptide A but not fibrinopeptide B
from fibrinogen and by resisting inhibition by heparin via antithrombin. Fibrin strand
cross-linking, which is mediated by factor XIII, is not measured by these assays.
Prolonged thrombin times and reptilase times may be due to hypofibrinogenemia,

structurally abnormal fibrinogens (dysfibrinogens), or increased fibrin split products
[19]. Since heparin prolongs the TT but not the RT, the RT is useful for determining if
heparin is the cause of a prolonged TT. Alternatively, one can test for heparin activity
via its anti-factor Xa activity, or with the use of a commercial heparinase. (See
"Clinical use of coagulation tests", section on 'Thrombin time (TT)' and "Clinical use
of coagulation tests", section on 'Heparin in the sample' and "Disorders of
fibrinogen".)
Factor deficiencies and inhibitors — A prolonged aPTT can be due to a

deficiency (or absence) of a coagulation factor or the presence of a coagulation
factor inhibitor. A factor deficiency should be correctable by addition of normal
plasma to the test reaction tube. This is normally done by performing a PT or aPTT
on a 1:1 mixture of patient and normal plasma [18]. (See "Clinical use of coagulation
tests", section on 'Mixing studies'.)
Specific factor deficiencies are then determined by assessing the PT or aPTT in

mixes of test plasma with commercially available plasmas deficient in known
factors. Factor levels can be functionally assessed by comparing test results to
standard curves generated by mixtures of serially diluted normal plasma and factor-
deficient plasma. Immunologic assays can also be used to measure factor levels.
Immunologic and functional assays should give equivalent results when a factor
deficiency is present. On the other hand, a low functional assay but normal
immunologic assay indicates the presence of a functionally abnormal factor.
The presence of a factor inhibitor is suspected when the abnormal test does not
correct, or only partially corrects, following an immediate assay of a 1:1 mixture of
patient and normal plasma. In some cases, such as acquired factor VIII antibodies,
the aPTT may correct immediately after mixing, but becomes prolonged after 60 to
120 minutes of incubation at 37º. (See "Clinical use of coagulation tests", section
on 'Mixing studies'.)
In addition to factor inhibitors, lupus anticoagulants can result in a prolonged aPTT

that is not correctable by the addition of normal plasma. The effect of these
antibodies on the aPTT can be overcome by adding excess platelet phospholipid
(particularly a hexagonal phase phospholipid) or by assessing the diluted Russell's
viper venom time [20]. Paradoxically, the antiphospholipid syndrome is usually
associated with a tendency to thrombosis rather than bleeding; the prolonged aPTT
is an artifact of the antiphospholipid phenomenon. (See "Clinical manifestations of
the antiphospholipid syndrome" and "Pathogenesis of the antiphospholipid
syndrome", section on 'Anticardiolipin antibodies'.)
Fibrinogen — Fibrinogen's functional activity is measured as thrombin-coagulable

protein, while levels of structural fibrinogen are measured by immunologic assays.
Immunologic and functional assays of fibrinogen may be discordant in patients with
an inherited dysfibrinogenemia. (See "Disorders of fibrinogen", section on
'Diagnosis'.)
Urea clot solubility — The initial fibrin clot, held together by noncovalent bonds, is
soluble in urea. Subsequent transglutamination by factor XIII covalently crosslinks
overlapping fibrin strands, which then become resistant to solubilization. The ability
of 5M urea or monochloroacetic acid to solubilize the clot reflects deficiency of
factor XIII (figure 1).
Tests for fibrinolysis — Fibrin and fibrinogen degradation products (FDP) are
protein fragments resulting from the action of plasmin on fibrin or fibrinogen,
respectively. Elevated levels are seen in states of fibrinolysis such as disseminated
intravascular coagulation (DIC). FDP assays do not differentiate between fibrin
degradation products and fibrinogen degradation products. It is possible to
accurately measure the concentration of fibrin D-dimers, which are degradation
products of cross-linked fibrin [21]. The method of choice is the enzyme-linked
immunosorbent assay (ELISA).
When fibrinolysis exceeds thrombin generation, thereby increasing the risk of

hemorrhage rather than thrombosis (eg, disseminated intravascular coagulation
associated with acute promyelocytic leukemia), quantitative FDP levels may be
more sensitive than D-dimer levels as an indication of the degree of fibrinolytic
activity. (See "Hematologic consequences of malignancy: Anemia and bleeding",
section on 'Microangiopathic hemolysis'.)
Because D-dimers specifically reflect fibrinolysis of cross-linked fibrin (ie, the fibrin
clot), assessment of D-dimer levels suggests thrombosis more reliably. As an
example, in patients who have a low pretest probability of deep vein thrombosis, the
negative predictive value of D-dimers is high [22]. (See "Diagnosis of suspected
deep vein thrombosis of the lower extremity", section on 'D-dimer'.)
The euglobulin lysis time, which assesses overall fibrinolysis is less useful, since
results from this test may vary significantly in relation to calcium ion concentrations
as well as plasma levels of tissue plasminogen activator and plasminogen activator
inhibitor-1 [23-25]. Alpha-2 antiplasmin, an inhibitor of fibrinolysis, is not measured
in this test.
More specific tests of the fibrinolytic system include assays for plasminogen, tissue
plasminogen activator (t-PA), alpha-2 antiplasmin, plasminogen activator inhibitor-1
(PAI-1), and thrombin-activatable fibrinolysis inhibitor (TAFI). Assays for alpha-2
antiplasmin are used clinically to identify patients with alpha-2 antiplasmin
deficiency, an inherited disorder associated with delayed bleeding. However, specific
assays for t-PA, PAI-1 and TAFI are of uncertain use clinically. (See "Thrombotic
and hemorrhagic disorders due to abnormal fibrinolysis".)
DIAGNOSTIC APPROACH — In many patients with a bleeding diathesis, the likely

diagnosis will be apparent from the history and physical examination; the diagnosis
can then be confirmed with the appropriate specific tests (table 2). Individual tests
(eg, either PT or aPTT alone) can also be used for monitoring the effect of an
anticoagulant or assessing patients with a known condition that has a predictable
effect on coagulation.
When the diagnosis is not immediately apparent, three initial tests should be
performed—platelet count, PT, and aPTT—because defects in primary or secondary
hemostasis, including intrinsic, extrinsic, and common pathway defects, can all be
responsible for bleeding (table 2). The pattern of results provides a presumptive
diagnosis which can then be confirmed with specific testing (table 3 and table 4).
Normal PT and aPTT — Thrombocytopenia with a normal PT and aPTT is the

most common of the acquired bleeding disorders. In the presence of significant
thrombocytopenia, the bleeding time is prolonged and clot retraction is deficient.
Measurement of the bleeding time or PFA-100 (see 'Bleeding time' above) is not
necessary in patients who have platelet counts below 50,000/microL. (See
"Approach to the adult patient with thrombocytopenia".)
The bleeding time or PFA-100 test (see 'The Platelet Function Analyzer' above)
should be measured in patients with a history of mucocutaneous bleeding who have
a normal platelet count, PT, and aPTT. A prolonged bleeding time or PFA-100
justifies further platelet function testing, including assays to evaluate von Willebrand
disease (VWD) and platelet aggregation studies [26]. (See "Platelet function
testing".) However, a normal bleeding time should not preclude evaluation for VWD,
especially since the PFA-100 test has substantially higher sensitivity for detecting
VWD than the bleeding time [15,16]. (See "Clinical presentation and diagnosis of
von Willebrand disease", section on 'Bleeding time'.)
A rare cause of bleeding associated with normal PT, aPTT, and TT is factor XIII
deficiency. (See "Rare (recessively inherited) coagulation disorders", section on
'Factor XIII deficiency'.)
vWD — von Willebrand disease (VWD) is the most common inherited bleeding
disorder, with an estimated prevalence of up to 1 percent. A small number of
patients have been described with acquired VWD due to antibodies, usually
associated with autoimmune or clonal proliferative disorders. (See "Classification
and pathophysiology of von Willebrand disease", section on 'Acquired von

Willebrand disease'.)
Most patients with VWD present with moderate to severe mucocutaneous bleeding
due to reduced levels of von Willebrand factor (VWF). They may have a prolonged
aPTT due to a mild to moderate concordant deficiency of factor VIII (table 4) [27]. In
some patients, however, the clinical manifestations are mild, the aPTT is normal,
and further studies are necessary to make the diagnosis. This is particularly true
when factors which increase VWF and factor VIII levels (eg, pregnancy, oral
contraceptive use, liver disease) are present. In such cases, the test should be
repeated when these conditions are no longer present.
Useful tests include bioassay of factor VIII, immunoassay of VWF antigen, and
measurement of ristocetin cofactor activity. Repeated testing is required to establish
the diagnosis of VWD because test results may vary over time [28]. (See "Clinical
presentation and diagnosis of von Willebrand disease".)
Platelet dysfunction — Studies to confirm the presence of qualitative disorders

of platelet function include evaluation of platelet morphology, and tests of platelet
aggregation and function. (See "Platelet function testing".)
Inherited disorders of platelet function are relatively rare and include:
Bernard-Soulier syndrome — characterized by a defect in any of the

components of the glycoprotein (GP) Ib/IX/V complex, giant platelets, and
greater than expected bleeding for the degree of thrombocytopenia
Glanzmann thrombasthenia — characterized by a defect in the GP IIb/IIIa

complex, normal platelet counts, normal platelet morphology, and abnormal
in vitro platelet aggregation.
Storage pool diseases — these include Wiskott-Aldrich syndrome,

thrombocytopenia with absent radii syndrome, Chediak–Higashi syndrome,
and Hermansky-Pudlak syndrome. The much more common acquired
causes include use of aspirin and nonsteroidal antiinflammatory drugs, beta-
lactam antibiotics, uremia, and myeloproliferative and myelodysplastic
syndromes. (See "Nonselective NSAIDs: Overview of adverse effects" and
"Platelet dysfunction in uremia" and "Congenital and acquired disorders of
platelet function".)
Other disorders — Other disorders leading to a bleeding diathesis which are

associated with normal screening coagulation tests include factor XIII deficiency and
rare abnormalities in regulators of plasminogen activation or plasmin degradation
(eg, alpha-2 antiplasmin deficiency, plasminogen activator inhibitor-1 deficiency).
(See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".)
Factor XIII deficiency presents with delayed bleeding, usually 24 to 36 hours after
surgery or trauma. The diagnosis is made by demonstration of clot dissolution in 5
molar urea or monochloroacetic acid (figure 1) [29]. As noted above, patients with
VWD may have normal screening test results (eg, normal PT, aPTT, and BT).
The clinical relevance of the factors involved in the initial phase of the intrinsic (also
called contact activation) pathway (eg, prekallikrein, HMWK, and factor XII) is
discussed separately. (See "Overview of hemostasis", section on 'Intrinsic
pathway'.)
Vascular purpuras — With the possible exception of a prolonged bleeding

time, screening tests are usually normal in patients with bleeding disorders related
to vascular abnormalities (table 4). These include structural abnormalities (eg,

hereditary hemorrhagic telangiectasia), hereditary disorders of connective tissue (eg,
Ehlers-Danlos disease, osteogenesis imperfecta), acquired connective tissue
disorders (eg, scurvy, steroid-induced purpura), small vessel vasculitis, and purpura
associated with the presence of paraproteins. (See "Classification of and approach
to the vasculitides in adults", section on 'Small vessel vasculitis'.)
Unknown cause — Some patients are encountered with a significant bleeding

history for which there is no explanation. Abuse, occasionally self-inflicted, should
be considered, but it is likely that some disorders of hemostasis escape detection
with currently available methods. Psychogenic purpura may be among these
disorders. (See "Psychogenic purpura (Gardner-Diamond syndrome)".)
Normal PT and prolonged aPTT — A normal PT and a prolonged aPTT is

characteristic of disorders of the intrinsic pathway of coagulation (figure 1 and table
3). Inherited disorders include deficiencies of factors VIII (hemophilia A, von
Willebrand disease), IX (hemophilia B), and XI. Hemophilia A and B are the most
common. In one study in six states, the age-adjusted prevalence of hemophilia in
1994 was 13.4 cases/100,000 males (10.5 for hemophilia A and 2.9 for B) [30].
Patients with these disorders present with life-long recurrent soft tissue and joint
bleeding, generally requiring frequent factor replacement therapy (table 1).
Factor XI deficiency, which is relatively common in Ashkenazi Jews, but can be

seen in a variety of ethnic groups, presents with a variable and unpredictable
bleeding history [31,32]. Bleeding in these patients, when present, is most
commonly seen following surgical procedures. (See "Factor XI deficiency".)
There are also a variety of disorders that prolong the aPTT but are not associated
with excessive bleeding. These include inherited or acquired factor XII deficiency, as
well as deficiencies of prekallikrein or high molecular weight kininogen [33].
Acquired inhibitors — Acquired inhibitors include antiphospholipid antibodies

which, as noted above, may be associated with thrombosis rather than bleeding,
and antibodies to factor VIII (acquired hemophilia), IX, and XI, which may be
associated with catastrophic bleeding (table 3). Factor VIII inhibitors have been
described in association with malignancy, clonal lymphoproliferative disorders,
pregnancy, rheumatologic disorders, as well as in the absence of underlying
disease. Acquired antibodies to factor IX and XI are rare. (See "Acquired inhibitors of
coagulation".) Acquired inhibitors of factor V may have variable effects on the PT,
aPTT, and BT (see below).
Prolonged PT and normal aPTT — A prolonged PT with a normal aPTT is

indicative of an abnormality in the extrinsic pathway and suggests factor VII
deficiency, which can be inherited or acquired (table 3). Inherited factor VII
deficiency displays considerable phenotypic and molecular heterogeneity, and there
are inconsistencies between the clinical picture, the underlying clotting and
molecular defects, and the response to prophylactic treatment with recombinant
human factor VIIa [34-38]. The manifestations range from no excessive bleeding to a
severe hemorrhagic tendency [39,40]. (See "Rare (recessively inherited) coagulation
disorders", section on 'Factor VII deficiency'.)
Acquired inhibitors of factor VII are rare. (See "Acquired inhibitors of coagulation",
section on 'Factor VII inhibitors'.)
This pattern is most commonly seen following warfarin therapy, early liver disease,
and vitamin K deficiency, and, less commonly, in certain (early) cases of DIC. (See
"Therapeutic use of warfarin and other vitamin K antagonists" and "Clinical features,
diagnosis, and treatment of disseminated intravascular coagulation in adults" and
"Coagulation abnormalities in patients with liver disease", section on 'Prothrombin

time (PT) and the International Normalized Ratio (INR)'.)
Prolonged PT and aPTT — Prolongation of both the PT and the aPTT indicates an
inherited disorder of the common pathway or a more complex acquired disorder
involving multiple pathways (table 3).
Inherited disorders include deficiency of factor X, factor V, prothrombin (factor

II), or fibrinogen (factor 1). These deficiencies are extremely rare. (See "Rare
(recessively inherited) coagulation disorders".)
Inherited disorders with a low fibrinogen level include afibrinogenemia, a rare

autosomal recessive disorder with mucocutaneous bleeding episodes that
may abate in severity with age and that are treatable with fibrinogen
replacement, and the dysfibrinogenemias, a heterogeneous group of
autosomal dominant disorders occasionally associated with either a bleeding
or thrombotic diathesis. (See "Disorders of fibrinogen", section on 'Congenital
afibrinogenemia/hypofibrinogenemia'.)
Supratherapeutic doses of warfarin or heparin can cause prolongation of both

the PT and aPTT. It is common to see prolongation of both the PT and aPTT
when heparin and warfarin are employed simultaneously, as in the initial
treatment of venous thromboembolic disease.
Acquired disorders with multiple abnormalities which produce this pattern

include vitamin K deficiency, liver disease, disseminated intravascular
coagulation, and fibrinolysis. Differentiating among these possibilities may be
difficult. The following may help in distinguishing among these conditions:
In both liver disease and vitamin K deficiency, there is deficient synthesis of

factors II, VII, IX and X. Since factor V production is independent of vitamin K
status, low factor V levels can be used as evidence for either reduced hepatic
synthetic function or increased consumption, as in DIC. Since factor VIII
production is independent of vitamin K status and this factor is not
manufactured by hepatocytes; factor VIII levels are usually normal or
increased in liver disease. Thus, low levels of factor VIII would favor a
diagnosis of DIC in this setting. (See "Coagulation abnormalities in patients
with liver disease", section on 'Tests of coagulation in liver disease'.)
Acquired inhibitors of factor V have been described, at times in association

with topical bovine thrombin therapy. Acquired antibodies to bovine thrombin
and/or factor V contaminating bovine thrombin preparations may cross-react
with endogenous human factor V as well as with human thrombin. Effects of
these antibodies on PT, aPTT, and TT testing can vary, and associated risks
of bleeding, which can be severe, are unpredictable. (See "Acquired inhibitors
of coagulation", section on 'Factor V inhibitors'.)
The first step in the evaluation of patients with a prolonged PT and aPTT should be
to exclude or identify an abnormality of fibrinogen. This can be achieved by
measurement of the plasma fibrinogen concentration and the thrombin time, and
testing for increased amounts of D-dimer or fibrin/fibrinogen degradation products
(FDP). In patients with an inherited coagulation disorder and normal amounts of
fibrinogen, deficiencies of factor V, factor X, and prothrombin can be diagnosed by
specific factor assays. In patients with an acquired disorder, the likely diagnosis, in
the absence of heparin, warfarin, and fibrinogen abnormalities, is vitamin K
deficiency or liver disease.
rshs.or.id/uptodate/p/browse.php?u=http%3A%2F%2Fwww.uptodate.com%2Fuptodate%2Fp%2Fbrowse.php%3Fu%3Dhttp%253A%252F%252Fwww.upt… 10/13
Acquired inhibitors to prothrombin and factor X are extremely rare. Acquired factor X
deficiency may be seen in patients with primary amyloidosis, and results from the
binding of factor X to amyloid fibrils. (See "Pathogenesis of immunoglobulin light
chain (AL) amyloidosis and light and heavy chain deposition diseases".)
SUMMARY AND RECOMMENDATIONS
Bleeding that is spontaneous, excessive, or delayed in onset following tissue

injury results from one or more of the following:
A localized pathologic process

Disorders involving vascular integrity
Disorders of platelet number and/or function
Disorders of the various coagulation factors
Increased fibrinolysis
A careful assessment of the presenting complaint and the patient's bleeding

history can provide important clues as to where a defect might reside in the
hemostatic process and whether the defect is inherited or acquired (table 1).
(See 'Patient history' above and "Preoperative assessment of hemostasis",
section on 'The classic approach' and "Approach to the adult patient with
thrombocytopenia", section on 'Initial approach'.)
The physical examination is helpful in determining the type of bleeding

present, as well as for detecting other conditions that might be present. (See
'Clinical manifestations' above and "Preoperative assessment of hemostasis",
section on 'The physical examination' and "Approach to the adult patient with
thrombocytopenia", section on 'The physical examination'.)
In many patients the likely diagnosis will be apparent from the history and
physical examination alone; the diagnosis can then be confirmed with the
appropriate specific tests.
When the diagnosis is not immediately apparent, three initial tests should be
performed: platelet count, prothrombin time (PT), and activated partial
thromboplastin time (aPTT) (table 2). (See 'Laboratory testing' above and
"Clinical use of coagulation tests".)
The pattern of results provides a presumptive diagnosis which can then be

confirmed with specific testing (table 3 and table 4). (See 'Diagnostic
approach' above.)
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Topic 1367 Version 13.0

Approach Bleeding Diathesis

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12/7/13 rshs.or.id/uptodate/p/browse.php?u=http%3A%2F%2Fwww.uptodate.com%2Fuptodate%2Fp%2Fbrowse.php%3Fu%3Dhttp%253A%252F%252Fwww.

Official reprint from UpToDate®

Approach to the adult patient with a bleeding diathesis

Author Section Editor Deputy Editor

INTRODUCTION — Bleeding that is spontaneous, excessive, or delayed in onset

Congenital and acquired disorders of platelet function, as well as the hemostatic

(See "Overview of hemostasis".)

PATIENT HISTORY — The clinical evaluation of a patient with a bleeding disorder

Bleeding history — Patients with a suspected bleeding disorder should be

The response to trauma is an excellent screening test. A history of surgical

An example of the co-ingestion of drugs potentiating the incidence of bleeding was

Aspirin alone — 3.2

Aspirin alone — 0.65

Disorders of platelets or blood vessels — These conditions are often referred to

Petechiae — Petechiae are small capillary hemorrhages. They

Ecchymoses — Ecchymotic lesions characteristically are purple in color and

Coagulation disorders — The typical manifestations of bleeding in the coagulation

Hemorrhage into synovial joints (hemarthrosis) most often indicates a severe

The cardiac surgery patient — Evaluation of the patient undergoing cardiac

Endothelial damage/activation with disseminated intravascular coagulation

LABORATORY TESTING — Laboratory tests of primary and secondary hemostatic

General screening tests

Specific tests include examination of the peripheral blood smear, platelet

Platelet counting and the peripheral smear — Platelets may be counted

The Platelet Function Analyzer — The commercially-available Platelet Function

'The platelet function analyzer'.)

Activated partial thromboplastin time — The activated partial thromboplastin

The aPTT is sensitive to inhibitors such as heparin and to deficiencies of all

Prolonged thrombin times and reptilase times may be due to hypofibrinogenemia,

Factor deficiencies and inhibitors — A prolonged aPTT can be due to a

Specific factor deficiencies are then determined by assessing the PT or aPTT in

In addition to factor inhibitors, lupus anticoagulants can result in a prolonged aPTT

Fibrinogen — Fibrinogen's functional activity is measured as thrombin-coagulable

When fibrinolysis exceeds thrombin generation, thereby increasing the risk of

DIAGNOSTIC APPROACH — In many patients with a bleeding diathesis, the likely

Normal PT and aPTT — Thrombocytopenia with a normal PT and aPTT is the

and pathophysiology of von Willebrand disease", section on 'Acquired von

Platelet dysfunction — Studies to confirm the presence of qualitative disorders

Inherited disorders of platelet function are relatively rare and include:

Bernard-Soulier syndrome — characterized by a defect in any of the

Glanzmann thrombasthenia — characterized by a defect in the GP IIb/IIIa

Storage pool diseases — these include Wiskott-Aldrich syndrome,

Other disorders — Other disorders leading to a bleeding diathesis which are

Vascular purpuras — With the possible exception of a prolonged bleeding

to vascular abnormalities (table 4). These include structural abnormalities (eg,

Unknown cause — Some patients are encountered with a significant bleeding

Normal PT and prolonged aPTT — A normal PT and a prolonged aPTT is

Factor XI deficiency, which is relatively common in Ashkenazi Jews, but can be

Acquired inhibitors — Acquired inhibitors include antiphospholipid antibodies

Prolonged PT and normal aPTT — A prolonged PT with a normal aPTT is

"Coagulation abnormalities in patients with liver disease", section on 'Prothrombin

Inherited disorders include deficiency of factor X, factor V, prothrombin (factor

Inherited disorders with a low fibrinogen level include afibrinogenemia, a rare

Supratherapeutic doses of warfarin or heparin can cause prolongation of both

Acquired disorders with multiple abnormalities which produce this pattern

In both liver disease and vitamin K deficiency, there is deficient synthesis of

Acquired inhibitors of factor V have been described, at times in association

SUMMARY AND RECOMMENDATIONS

Bleeding that is spontaneous, excessive, or delayed in onset following tissue

A localized pathologic process

A careful assessment of the presenting complaint and the patient's bleeding

The physical examination is helpful in determining the type of bleeding

The pattern of results provides a presumptive diagnosis which can then be

Use of UpToDate is subject to the Subscription and License Agreement.