Author: Reed E Drews, MD

Section Editor: Lawrence LK Leung, MD

Deputy Editor: Jennifer S Tirnauer, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Jan 11, 2017.

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 with unexplained 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 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
predispose to vitamin K deficiency. The patient should also be questioned concerning the presence of thyroid,
liver, and kidney disease. Complaints such as hematuria, melena, and menorrhagia are often less helpful, since
structural causes are more commonly responsible than a bleeding diathesis.

The response to trauma is an excellent screening test. A history of surgical procedures or tooth extractions or
significant injury without abnormal bleeding is good evidence against the presence of an inherited hemorrhagic
disorder.

An inherited disorder is suggested by the onset of bleeding shortly after birth or 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
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 manifestations and diagnosis of hemophilia", section
on 'Patient and family history'.)
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, such as the induction of thrombocytopenia or platelet dysfunction, aplastic anemia, or
vascular purpura. In addition, some drugs can induce or exacerbate a coagulation disorder. Examples include
platelet dysfunction induced by aspirin and other commonly used antiinflammatory drugs, beta-lactam
antibiotics, clopidogrel, 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 immune
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

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 "Immune
thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis" and "Approach to the adult with
unexplained 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 "Management of abnormal
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.

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) and INR'.)

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 'Reptilase
time (RT)' 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 'Use of 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 37. (See "Clinical use of coagulation tests", section on 'Use of 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 antiphospholipid syndrome".)

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
'Diagnostic testing'.)

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 complications 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 "Clinical presentation and
diagnosis of the nonpregnant adult with 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 performedplatelet count, PT,
and aPTTbecause 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 For patients who have a convincing bleeding history and normal PT and aPTT testing,
it is important to evaluate the possibility of a platelet disorder; this is especially true for patients with a
mucocutaneous bleeding pattern. The first step is measurement of the platelet count, which is done as part of
the routine complete blood count (CBC) in most institutions. If a platelet count was not performed recently, this
should be obtained. Spontaneous bleeding generally does not occur with a platelet count greater than
50,000/microL, but any platelet count abnormality should be addressed, as discussed in detail separately. (See
"Approach to the adult with unexplained thrombocytopenia".)

While a finding of thrombocytopenia is helpful in evaluating unexplained bleeding, a normal platelet count does
not eliminate the possibility of a platelet abnormality, because the patient may have a condition that affects
platelet function rather than number. Examples include von Willebrand disease (VWD), in which reduced levels
of von Willebrand factor (VWF) lead to impaired binding of platelets to the endothelium; and inherited platelet
function disorders, in which platelets do not respond to usual hemostatic cues. Appropriate initial testing
includes testing for VWD and tests for platelet defects, which may include review of the peripheral blood smear,
bleeding time, and/or PFA-100 testing. The extent of testing and the order in which tests are performed depend
on the individual patient history and may vary among experts. Consulting a clinician with expertise in bleeding
disorders may be helpful in ensuring that an important diagnosis is not missed and in avoiding unnecessary
testing. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Congenital and acquired
disorders of platelet function" and "Platelet function testing".)

If thrombocytopenia, VWD, and platelet function defects are eliminated as a cause of unexplained bleeding,
additional possible causes include factor XIII deficiency, fibrinolytic defects, and disorders of vascular integrity.
These conditions and their evaluation are discussed in detail separately. (See "Rare inherited coagulation
disorders" and "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis" and "Approach to the child
with bleeding symptoms", section on 'Vascular purpuras'.)

von Willebrand disease 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 syndrome'
and "Acquired von Willebrand syndrome".)

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) [26]. 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 that increase VWF
and factor VIII levels (eg, pregnancy, oral contraceptive use, liver disease) are present.

Initial screening tests for VWD include factor VIII activity level, immunoassay of VWF antigen, and ristocetin
cofactor activity. Repeated testing may be required to establish the diagnosis of VWD, because test results may
vary over time [27]. (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, ChediakHigashi 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".)

Coagulation disorders Coagulation disorders leading to a bleeding diathesis may be associated with
normal screening coagulation tests if the factor is not involved in the steps in coagulation measured by in vitro
tests (figure 1), or if the degree of deficiency is mild.

Examples include the following:

Factor XIII deficiency Factor XIII stabilizes and crosslinks fibrin strands. Factor XIII deficiency may
present with delayed bleeding, usually 24 to 36 hours after surgery or trauma; spontaneous bleeding also
occurs. Coagulation testing shows normal values for the PT, aPTT, and TT. The diagnosis is made by
measurement of reduced plasma factor XIII activity; an immunoassay for factor XIII; or demonstration of
clot dissolution in 5 molar urea or monochloroacetic acid, although clot solubility testing may be poorly
standardized and sensitivity may be low [28]. (See "Rare inherited coagulation disorders", section on
'Factor XIII deficiency (F13D)'.)

Abnormalities of plasminogen or plasmin Plasmin is the primary enzyme responsible for fibrinolysis; it
is produced from the cleavage of plasminogen. Rare abnormalities in regulators of plasminogen activation
or plasmin degradation have been reported as causes of familial bleeding disorders (eg, alpha-2
antiplasmin deficiency, plasminogen activator inhibitor-1 deficiency). (See "Thrombotic and hemorrhagic
disorders due to abnormal fibrinolysis".)

Thrombomodulin mutation Thrombomodulin (TM) is a regulatory protein expressed by endothelial

 cells, monocytes, and megakaryocytes. Binding of cell surface thrombomodulin to thrombin converts
thrombin from a procoagulant to an anticoagulant. (See "Overview of hemostasis", section on 'Control
mechanisms and termination of clotting'.)

A family with an autosomal dominant bleeding disorder was found to have a TM gene mutation that created
a premature stop codon and eliminated the portion of the protein responsible for its cellular retention [29].
This in turn caused extremely high levels of TM in plasma (100 fold greater than normal), which was
associated with severe bleeding.

Mild hemophilia Factor activity levels above approximately 15 to 20 percent are often sufficient to
prevent spontaneous bleeding and to produce a normal PT and aPTT, although this varies by specific
factor level (table 5). However, patients with mild deficiency of a coagulation factor may have increased
bleeding with hemostatic challenges (eg, excessive surgical bleeding, menorrhagia). This may be seen in
an individual who is heterozygous for a coagulation factor defect, such as a hemophilia carrier. (See
"Clinical manifestations and diagnosis of hemophilia", section on 'Bleeding in females/carriers'.)

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 "Overview 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)"). Other inherited platelet disorders and
their mechanisms may be defined by whole genome sequencing data, genome-wide association studies,
epigenomic profiling, protein-protein interaction networks, and standardized clinical phenotype coding [30]. (See
"Congenital and acquired disorders of platelet function".)

Normal PT and prolonged aPTT

Factor deficiencies 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) [31]. 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 [32,33]. 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 [34].

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).

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 "Warfarin and other VKAs: Dosing and adverse
effects" and "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults"
and "Hemostatic abnormalities in patients with liver disease", section on 'Liver disease versus DIC'.)

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 [35-39]. The manifestations range from no
excessive bleeding to a severe hemorrhagic tendency [40,41]. (See "Rare inherited coagulation disorders",
section on 'Factor VII deficiency (F7D)'.)

Acquired inhibitors of factor VII are rare. (See "Acquired inhibitors of coagulation", section on 'Factor VII
inhibitors'.)

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 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 or hypofibrinogenemia'.)

Supratherapeutic doses of warfarin or heparin (or anticoagulant rodenticide ingestion) 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. (See "Overview of rodenticide poisoning", section on 'Anticoagulants (superwarfarins and
warfarins)' and "Anticoagulant rodenticide poisoning: Clinical manifestations and diagnosis".)

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 "Hemostatic abnormalities in patients with liver disease", section on 'Liver disease
versus DIC'.)

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.

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".)

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: Hemophilia, von
Willebrand disease, and other coagulation disorders".)

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 with unexplained thrombocytopenia", section on
'Overview of our 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 with unexplained
thrombocytopenia", section on '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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