Bleeding disorder of unknown cause (BDUC)

INTRODUCTION — 

Despite extensive evaluations, a large proportion of individuals with abnormal or excessive bleeding do not have a clear diagnosis of a specific bleeding disorder. These individuals are referred to as having bleeding disorder of unknown cause (BDUC), which is a diagnosis of exclusion with specific evaluations and management implications.

This topic discusses the evaluation of such individuals and presents an approach to their management at times of bleeding challenges such as surgery and delivery.

The initial approach to evaluating a suspected bleeding disorder is presented separately:

●Children – (See "Approach to the child with bleeding symptoms".)

●Adults – (See "Approach to the adult with a suspected bleeding disorder".)

DEFINITION AND CAUSE — 

BDUC refers to a bleeding disorder in an individual with negative laboratory testing for known bleeding disorders [1]. Previous names included "bleeding of unknown cause" or "unclassified bleeding disorder." Use of the term BDUC facilitates case definition, research, and management.

BDUC is a diagnosis of exclusion made after specific testing for known bleeding disorders, including normal results for the following [1]:

●CBC including platelet count showing normal platelet count and morphology (microcytic anemia due to iron deficiency or an unrelated cause of anemia may be present)

●Prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, and fibrinogen

●von Willebrand disease testing (von Willebrand factor antigen and activity)

●Factor VIII, IX, and XI activity

●Platelet aggregation testing (functional testing)

This evaluation is discussed below. (See 'Laboratory evaluation to exclude specific bleeding disorders' below and 'Diagnosis' below.)

BDUC does not include individuals without a bleeding history, even if they have a positive family history or abnormal coagulation or hemostasis testing [1].

The cause of BDUC is unknown; this entity likely is a collection of disorders that are yet to be identified or a condition caused by pathogenic variants in several low penetrance genes [1]. (See "Principles of complex trait genetics".)

Patients are encouraged to enroll in clinical trials to identify the underlying pathophysiology of unexplained bleeding disorders.

EPIDEMIOLOGY

●Prevalence – Since awareness of this entity is increasing, the diagnosis of BDUC is being made more frequently [2]. However, lack of standardized diagnostic criteria for BDUC makes it challenging to identify affected individuals, and the true prevalence remains unknown [1].

●Proportion of bleeding disorders – In studies of BDUC frequency among patients referred for a bleeding tendency, BDUC accounted for 46 to 66 percent of cases [2].

CLINICAL FEATURES

Patient characteristics and inheritance pattern — In studies of BDUC, 66 to 87 percent of individuals were female, and the average age at diagnosis was 33 to 42 years [2].

Approximately 50 percent of individuals with BDUC have a positive family history with an autosomal dominant pattern of inheritance (transmission from affected parent to 50 percent of affected offspring). (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Autosomal dominant'.)

Bleeding — BDUC by definition is associated with abnormal bleeding; however, determining what is abnormal can be subjective. Heavy menstrual bleeding can be especially challenging to quantify. (See 'Medical history' below.)

A bleeding assessment tool quantifies bleeding and provides a standardized framework for evaluation. (See 'Bleeding assessment (BAT)' below.)

The extent of bleeding with BDUC is comparable to other types of moderate bleeding disorders such as von Willebrand disease [1].

Common bleeding manifestations include:

●Heavy menstrual bleeding (HMB, likely the most common manifestation)

●Mucocutaneous bleeding

●Excessive surgical bleeding

●Postpartum hemorrhage (PPH)

In a cohort of 124 patients with BDUC, the mean condensed MCMDM-1 (molecular and clinical markers for the diagnosis and management of type 1) VWD bleeding score was 9.7 in females and 6.6 in males (normal range for the scoring tool in this study, ≤3) [3]. The higher scores in females were attributable to heavy menstrual bleeding and postpartum hemorrhage. Bleeding severe enough to warrant transfusion occurred in 23 percent.

Iron deficiency — BDUC often causes iron deficiency or iron deficiency anemia [1].

Surveillance for iron deficiency and iron supplementation when needed are important components of management. (See 'Surveillance and treatment for iron deficiency' below.)

Associated findings in other organ systems — Associated findings that may indicate a specific bleeding disorder are summarized in the table (table 1) and discussed separately. (See "Approach to the adult with a suspected bleeding disorder", section on 'Targeted physical examination'.)

EVALUATION

Medical history — A full medical history is required to assess the extent of bleeding and evaluate for uncommon causes of bleeding. This includes:

●Family history of excessive bleeding and iron deficiency anemia

●Personal medication history

●Personal history of bleeding (including menstrual bleeding) and bleeding challenges

●Personal history of other medical problems that could contribute to (or be caused by) bleeding episodes

The medication history includes both prescribed as well as over-the-counter medications, herbs, and supplements. If a drug-induced cause is suspected based on the history, it may be appropriate to substitute another agent that does not affect platelet function or to discontinue the drug and observe for resolution of the bleeding manifestations. (See "Platelet biology and mechanism of anti-platelet drugs", section on 'Anti-platelet drugs' and "Clinical use of ginkgo biloba", section on 'Adverse effects'.)

As heavy menstrual bleeding is one of the most common types of bleeding, it should be specifically queried using objective measures [4,5].

Despite heavy menstrual bleeding being one of the most common features of many bleeding disorders, including BDUC, in our experience, many individuals with heavy menstrual bleeding get serially discounted, for various reasons including [6-8]:

●Lack of well-validated questions to ask, criteria to use, or specific measurements to quantify bleeding

●Lack of awareness of what is abnormal by members of the medical team

●Inaccurate assessment of what is normal by the patient, especially if their mother also had a bleeding disorder (often undiagnosed)

The National Institution for Clinical Excellence (NICE) defines heavy menstrual bleeding as excessive menstrual blood loss that interferes with physical, social, emotional, and/or material quality of life [9,10]. Up to 90 percent of females with BDUC report heavy menstrual bleeding at some point [1,11].

An example of a patient's delayed diagnosis of a bleeding disorder despite multiple documented serious bleeding events is presented separately. (See "Patient perspective: von Willebrand disease".)

Certain chronic medical conditions can increase bleeding risk. If chronic kidney disease, liver disease, a myeloproliferative neoplasm, or other acquired condition is suspected of causing platelet dysfunction, it may be appropriate to re-evaluate after treating the underlying disorder rather than embarking on an extensive evaluation. (See "Uremic platelet dysfunction" and "Hemostatic abnormalities in patients with liver disease" and "Overview of the myeloproliferative neoplasms".)

Bleeding assessment (BAT) — Bleeding can be quantified using a bleeding assessment tool (BAT) such as the International Society on Thrombosis and Haemostasis BAT (ISTH-BAT), which asks about the severity of several types of bleeding and can be completed in a short period of time by a member of the medical team [12].

The ISTH-BAT provides a numerical bleeding score from 0 to 56 depending on the number of bleeding sites and the severity of bleeding (with the most severe requiring transfusion or surgical intervention).

Each type of bleeding (epistaxis, heavy menstrual bleeding, severe dental bleeding) can add from 0 to 4 points to the score; as a result, most females with isolated bleeding in one site will not have a positive score.

Very young individuals may not have had sufficient bleeding challenges to elicit their bleeding phenotype and positive BAT.

This speaks to the need for clinical judgment in determining the extent of evaluation needed. (See 'Laboratory evaluation to exclude specific bleeding disorders' below.)

The ISTH-BAT normal range is considered to be 0 to 2 in children, 0 to 5 in adult females, and 0 to 3 in adult males. A positive score suggestive of a bleeding disorder is as follows [13]:

●Child – ≥3

●Adult female – ≥6

●Adult male – ≥4

However, a 2023 study provided additional resolution in females and provided the following values for a positive BAT [14]:

●Child <18 years – ≥3

●Male 18 years or older – ≥4

●Female 18 to 30 years – ≥5

●Female 31 to 51 years – ≥6

●Female 52 to 88 years – ≥7

Additional aspects of the interpretation are discussed separately. (See "Approach to the adult with a suspected bleeding disorder", section on 'Bleeding score'.)

Laboratory evaluation to exclude specific bleeding disorders

Initial laboratory testing (all patients) — Initial testing for patients with abnormal or excessive bleeding includes CBC with platelet count and platelet morphology, coagulation testing, von Willebrand disease (VWD) testing, factor VIII, IX, and XI activity, and, if that testing is all unrevealing, platelet aggregation studies.

This approach is summarized in the flowchart (algorithm 1) and discussed separately. (See "Approach to the child with bleeding symptoms", section on 'Initial laboratory evaluation' and "Approach to the adult with a suspected bleeding disorder", section on 'Laboratory evaluation'.)

Testing for vitamin C deficiency — Vitamin C deficiency can cause bleeding symptoms that are thought to be due to impaired collagen synthesis and disordered connective tissue; these generally occur when the vitamin C level is <0.2 mg/dL (<11 micromol/L).

The role of vitamin C testing in BDUC has not been systematically evaluated; testing may be reasonable in all individuals or selected individuals, such as those with increased bruising and hematomas.

Arguments in favor of testing are that it is straightforward and may eliminate the need for more extensive testing, and treatment is easy and of low risk if deficiency is found.

Testing is with serum or white blood cell (WBC) vitamin C level. Recent vitamin C intake can falsely normalize the result. (See "Overview of water-soluble vitamins", section on 'Measurement'.)

In a series of 60 patients with BDUC and mean ISTH-BAT score 13, vitamin C levels were lower than in controls (mean 55.9 micromol/L, versus 70.4 micromol/L in controls) [15]. Of the BDUC patients, 18 (30 percent) had suboptimal vitamin C levels and one had severe deficiency.

Other physiologic roles of vitamin C and a discussion of scurvy are presented separately. (See "Overview of water-soluble vitamins", section on 'Vitamin C (ascorbic acid)'.)

Additional testing (selected individuals)

Tests for abnormal fibrin crosslinking or fibrinolysis — This testing is not routinely recommended but may be appropriate in patients with severe bleeding from birth [16].

●Fibrin crosslinking (factor XIII) – Thrombin-activated factor XIII (factor XIIIa) crosslinks fibrin to stabilize clots. (See "Overview of hemostasis", section on 'Continuation of the coagulation cascade'.)

Factor XIII deficiency is a rare autosomal disorder that presents with severe bleeding (eg, umbilical stump, intracranial hemorrhage). Rare cases of acquired factor XIII inhibitors have also been reported. Diagnostic testing is with qualitative or quantitative factor XIII levels. Testing can be considered in patients with delayed bleeding, severe unexplained bleeding, or positive family history of factor XIII deficiency. (See "Rare inherited coagulation disorders", section on 'Factor XIII deficiency (F13D)' and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Factor XIII inhibitors'.)

●Fibrinolysis – Fibrinolysis (clot breakdown) is a normal hemostatic process.

Disorders of fibrinolysis often show delayed bleeding. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".)

•Inherited disorders – These include congenital deficiencies of fibrinolytic inhibitors such as alpha-2-antiplasmin or plasminogen activator inhibitor-1.

•Acquired causes include:

-Hyperfibrinolysis associated with envenomations

-Acute promyelocytic leukemia

-Overdoses of fibrinolytic agents

-Prostate cancer

-Disseminated intravascular coagulation (DIC)

Laboratory testing involves measurement of fibrinogen levels and D-dimer (a fibrin degradation product), euglobulin clot lysis test (ECLT), or related tests (table 2). Testing can be considered in patients with delayed bleeding, severe unexplained bleeding, positive family history, or findings that suggest one of the acquired disorders listed above. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Individuals with bleeding phenotypes'.)

Chromogenic factor VIII assays — Most testing for factor VIII activity in the United States is done using a one-stage aPTT-based assay, but 40 percent of individuals with mild hemophilia A have a factor VIII molecule that shows discrepant values in the one-stage factor VIII assay versus the factor VIII activity measured using a chromogenic assay [17]. Patients with mild hemophilia A and some female lyonized carriers of these types of factor VIII variants might show a normal aPTT and a normal one-stage factor VIII assay but a low factor VIII activity in a chromogenic factor VIII assay. An example of the use of this testing is described separately. (See "Approach to the adult with a suspected bleeding disorder", section on 'Clinical vignettes'.)

Testing for extremely rare disorders — Additional extremely rare coagulation disorders may be worth evaluating in selected individuals.

As an example, variants in the F5 gene can cause factor V deficiency or gain-of-function. Gain-of-function variants include factor V Amsterdam and factor V East Texas, giving rise to a truncated factor V ("factor V short") that binds to and prolongs the half-life of tissue factor pathway inhibitor (TFPI). (See "Rare inherited coagulation disorders", section on 'Factor V deficiency (F5D)' and "Rare inherited coagulation disorders", section on 'Genetics'.)

Whole genome sequencing is not indicated in routine care, but patients should be encouraged to enroll in clinical trials to determine whether there is a genetic contribution [1].

Clinical and genetic testing for vascular and other disorders — Testing for bleeding disorders due to vascular abnormalities is appropriate if there is a positive family history or any clinical features of the disorder. Examples include:

●HHT – Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder associated with telangiectasias and arteriovenous malformations (AVMs) of the small vessels in skin, oropharynx, lungs, gastrointestinal tract, and other tissues. Common findings include epistaxis, gastrointestinal bleeding, telangiectasias on the lips and fingertips, and iron deficiency anemia. Bleeding may begin in childhood; by age 16, most patients will experience hemorrhagic symptoms. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

●Ehlers-Danlos syndromes – Ehlers-Danlos syndromes (EDS) refer to a group of collagen disorders characterized by easy bruising and hemorrhage from ruptured blood vessels; there are several genes involved [18].

The classical hypermobile EDS causing joint hypermotility and hyperextensibility of the skin may cause bruising but is not likely to result in massive bleeding. Genetic testing is not available because the responsible gene(s) have not been identified.

In a series of 60 patients with BDUC (mean ISTH-BAT score 13), 10 patients met clinical diagnostic criteria for hypermobile EDS [15]. One additional patient had Noonan syndrome, confirmed by genetic testing. Nearly 50 percent of the 60 patients had a positive Beighton score, and one-third had hypermobile skin. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Hypermobile Ehlers Danlos syndrome'.)

The vascular type IV EDS is due to pathogenic variants in the COL3A1 gene; bruising can be very extensive, and vascular rupture can be fatal. The skin may be thin and wrinkled, but joint hyperextensibility is rare. Tests of platelet and clotting function are normal. The diagnosis is made clinically in some of the EDS disorders (classical, hypermobile); for other EDS disorders (vascular, dermatosparaxis), diagnosis requires demonstration of the genetic abnormality. (See "Ehlers-Danlos syndromes: Clinical manifestations and diagnosis" and "Gene test interpretation: COL3A1 (vascular Ehlers-Danlos syndrome gene)".)

●Osteogenesis imperfecta – Osteogenesis imperfecta (OI) is a connective tissue disorder that primarily affects bone but can also be associated with bleeding due to capillary fragility [19]. (See "Osteogenesis imperfecta: An overview".)

Other tests for platelet disorders — Platelet function testing can detect hereditary and acquired disorders. Testing is challenging because some tests are highly operator-dependent, many tests are poorly standardized and poorly reproducible, and no test is able to assay all aspects of platelet function [20]. Details are discussed separately and summarized briefly below. (See "Platelet function testing", section on 'Overview'.)

●Platelet aggregation studies – This measures platelet-platelet cohesion as induced by various known physiologic platelet agonists (eg, thrombin, collagen, epinephrine, ADP). Aggregation causes platelets to come out of solution, which increases light transmission in a spectrophotometer-based assay. (See "Overview of hemostasis", section on 'Platelet aggregation'.)

Aggregometry is considered the gold standard for platelet function testing. Platelet aggregation abnormalities in different disorders are summarized in the table (table 3) and discussed separately. (See "Platelet function testing", section on 'Platelet aggregometry'.)

●PFA-100 – The platelet function analyzer (PFA-100) measures the time it takes for blood flow to stop under shear stress in a capillary tube containing a membrane impregnated with collagen and epinephrine (Col/Epi) or collagen and ADP (Col/ADP). Sensitivity for bleeding disorders is low, and different centers have different conventions for use. (See "Platelet function testing", section on 'PFA-100'.)

●Genetic testing – Genetic testing for known disorders (eg, using a gene panel) is becoming more widely available and may be reasonable in certain individuals with a suspected platelet disorder of genetic origin [16]. (See "Inherited platelet function disorders (IPFDs)", section on 'Specific disorders'.)

●Electron microscopy – Electron microscopy (EM) to examine the ultrastructure of platelets is typically ordered by specialized referral centers. Transmission EM may be used to image the ultrastructure of platelet granules in individuals with suspected platelet storage pool diseases (SPDs; eg, Chediak-Higashi syndrome, Hermansky-Pudlak syndrome) who have a normal platelet aggregometry and PFA-100. EM can also be used to diagnose the nonmuscle myosin heavy chain 9 (MYH9)-related disorders (previously referred to a May-Hegglin anomaly, Fechtner syndrome, Epstein syndrome, and Sebastian syndrome). (See "Causes of thrombocytopenia in children", section on 'Large or giant platelets' and "Inherited platelet function disorders (IPFDs)", section on 'Specific disorders'.)

Diagnosis — BDUC is a diagnosis of exclusion. The diagnosis is made when an individual with a documented bleeding disorder (based on a bleeding assessment tool such as the ISTH-BAT (see 'Bleeding assessment (BAT)' above)) has normal evaluations of hemostasis, including:

●CBC including platelet count showing normal platelet count and morphology (microcytic anemia due to iron deficiency or an unrelated cause of anemia may be present)

●Prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, and fibrinogen

●von Willebrand disease testing (von Willebrand factor antigen and activity)

●Factor VIII, IX, and XI activity

●Platelet aggregation testing (functional testing)

It is understood that some individuals have an underlying condition that remains undiagnosed (see 'Additional testing (selected individuals)' above), and for others, further evaluation and diagnosis may be possible in the future when new bleeding disorders are defined.

Differential diagnosis — The differential diagnosis of BDUC includes various bleeding disorders for which the cause is known:

●VWD – von Willebrand disease (VWD) is the most common hereditary bleeding disorder. (See "Clinical presentation and diagnosis of von Willebrand disease".)

•Like BDUC, it can affect males and females, mucosal bleeding is common, and the aPTT and platelet count may be normal, depending on the factor VIII activity level and type of VWD.

•Unlike BDUC, specific VWD testing will show reduced von Willebrand factor (VWF) activity. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Laboratory testing' and "Approach to the adult with a suspected bleeding disorder", section on 'VWD testing'.)

●Platelet function disorders – Hereditary platelet function disorders can be associated with thrombocytopenia or normal platelet number. (See "Inherited platelet function disorders (IPFDs)".)

•Like BDUC, these can affect males and females, and the PT and aPTT (and possibly the platelet count) will be normal.

•Unlike BDUC, most platelet function disorders will have specific testing that identifies an abnormality of platelet aggregation or other function. (See "Platelet function testing", section on 'Platelet aggregometry'.)

●Mild hemophilia – Mild hemophilia (factor VIII or factor IX activity level 5 to 40 percent) can cause a bleeding phenotype with infrequent bleeding in response to bleeding challenges, in contrast to severe hemophilia, which is associated with spontaneous joint bleeding. (See "Clinical manifestations and diagnosis of hemophilia A and B", section on 'Disease severity' and "Clinical manifestations and diagnosis of hemophilia A and B", section on 'Bleeding in females/carriers'.)

•Like BDUC, there may be a positive family history, it can affect males and females, the platelet count is normal, and the aPTT may be normal, depending on the factor activity level.

•Unlike BDUC, the factor activity level will be low when measured by a factor activity assay. (See 'Chromogenic factor VIII assays' above and "Clinical manifestations and diagnosis of hemophilia A and B", section on 'Diagnostic evaluation'.)

●Connective tissue and vascular disorders – Connective tissue disorders such as Ehlers-Danlos syndromes and vascular disorders such as hereditary hemorrhagic telangiectasia (HHT). (See 'Clinical and genetic testing for vascular and other disorders' above and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

•Like BDUC, these disorders can affect males and females, and the platelet count, PT, and aPTT will be normal.

•Unlike BDUC, most connective tissue and vascular disorders, including HHT, have specific clinical diagnostic criteria and/or genetic testing that identifies pathogenic variant(s) in causative genes. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetic testing' and "Ehlers-Danlos syndromes: Clinical manifestations and diagnosis".)

●Scurvy – Vitamin C deficiency with scurvy causes bleeding and other symptoms due to impaired collagen synthesis and disordered connective tissue. It is most common in severely malnourished individuals, after bariatric surgery, and in individuals who do not consume fruits and vegetables. (See 'Testing for vitamin C deficiency' above and "Overview of water-soluble vitamins", section on 'Vitamin C (ascorbic acid)'.)

•Like BDUC, testing for coagulation and platelet abnormalities will be normal.

•Unlike BDUC, vitamin C levels are low and the symptoms respond to vitamin C supplementation.

●Rare clotting factor deficiencies or abnormal fibrinolysis – Rare coagulation disorders may not be appreciated on initial hemostasis screening; these include autosomal dominant and autosomal recessive conditions. (See "Rare inherited coagulation disorders" and "Disorders of fibrinogen" and "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".)

•Like BDUC, these disorders may have normal initial testing, especially with factor XIII deficiency.

•Unlike BDUC, specific tests of clotting factor activity may be abnormal.

MANAGEMENT

Decreasing the risk of bleeding — The table summarizes advice for reducing the risk of bleeding (table 4).

This includes avoiding risk factors for trauma, avoiding excess alcohol and medications that could impair hemostasis, and maintaining good communication with medical personnel, especially around invasive procedures and new medications.

Surveillance and treatment for iron deficiency — Individuals with bleeding disorders are at risk for iron deficiency, especially if they are menstruating or have been pregnant. Iron deficiency can progress to iron deficiency anemia if not addressed. (See "Iron requirements and iron deficiency in adolescents" and "Anemia in pregnancy" and "Determining the cause of iron deficiency in adolescents and adults", section on 'Causes (organized by mechanism)'.)

In a person who menstruates, we check a complete blood count (CBC) and ferritin at least annually (more frequently if bleeding is severe). (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Screening (asymptomatic individuals)'.)

Individuals with symptoms of anemia (fatigue, mood changes, dyspnea) or iron deficiency (pica, restless legs syndrome, hair loss, fatigue, mood changes) should be evaluated. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Clinical manifestations' and "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

Management of iron deficiency is discussed separately. Some individuals with significant blood loss may require intravenous iron. (See "Iron requirements and iron deficiency in adolescents", section on 'Management' and "Treatment of iron deficiency anemia in adults".)

Treatment/prevention of bleeding in specific scenarios — Involvement of the consulting hematologist or hemostasis expert is advised to ensure that the appropriate diagnostic evaluations have been pursued, since a specific diagnosis would likely lead to enhanced therapeutic options.

Surgery and invasive procedures — Prevention of surgical bleeding can be challenging since there is no specific hemostatic parameter or laboratory test to monitor [21]. Surgery and invasive procedures require close communication with the surgeon and anesthesiologist.

General principles include [1]:

●Regional anesthesia is avoided when possible.

●An antifibrinolytic agent (tranexamic acid or epsilon aminocaproic acid) is suggested for most procedures, especially those with mucosal bleeding.

●Desmopressin (DDAVP) has also been used and may be added to tranexamic acid for higher-risk cases.

●Platelet transfusions may be used for severe bleeding, or if the patient's bleeding responded to these interventions previously. However, platelet transfusions should be used judiciously to prevent alloimmunization.

These therapies (antifibrinolytic agent, DDAVP, transfusions) can be combined if desired.

Data on the benefits of these interventions perioperatively in people with BDUC are very limited [21]. Involvement of a hemostasis expert to assist with planning and management is advised.

Heavy menstrual bleeding — Heavy menstrual bleeding is the most common manifestation of BDUC. (See 'Bleeding' above.)

Management depends on the cause, and an evaluation for anatomic/structural causes (eg, uterine or cervical polyp, benign tumor, cancer) is appropriate before attributing bleeding solely to a bleeding disorder. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis", section on 'Initial evaluation of all patients'.)

If the anatomic/structural evaluation is normal, possible medical therapies may include the following, with shared decision-making regarding the expected benefits, risks, and burdens of each therapy [1,22]:

●Tranexamic acid, which can be used intermittently (during menses)

●Desmopressin (DDAVP), which can be used during menses

●Hormonal therapies

Choice among hormonal treatments in individuals without an anatomic/structural cause of bleeding (unknown etiology from a gynecologic perspective) depends on whether the individual is trying to conceive. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management", section on 'Patients without a structural, infectious, or endocrine etiology'.)

These therapies can be combined if needed. We generally start with one therapy, and if it is not fully effective, we consider adding another. If side effects of one of the therapies are intolerable, it can be discontinued and replaced with another.

Data on the benefits of these interventions for heavy menstrual bleeding in people with BDUC are very limited; individuals treated with tranexamic acid and/or DDAVP have reported improvements, without thrombotic complications [21].

Endometrial ablation and hysterectomy are options if future childbearing is not desired. Hysterectomy is generally done for gynecologic indications, but if severe menstrual bleeding does not respond to other interventions and childbearing is not desired, then endometrial ablation or hysterectomy may be considered. (See "Overview of endometrial ablation" and "Hysterectomy (benign indications): Patient-important issues and surgical complications".)

Pregnancy — Management of pregnancy can be challenging. Individuals with BDUC are at increased risk of postpartum hemorrhage (PPH). The following may be helpful, based on limited retrospective data [1]:

●Avoid neuraxial anesthesia.

●Use cesarean delivery for obstetric indications but do not prefer it over vaginal delivery for patients with BDUC.

●Use fetal precautions (eg, avoid forceps delivery).

●Use tranexamic acid during childbirth (example dose, 1 gram orally or intravenously when labor is established and continued three times per day orally until bleeding stops). The duration of therapy may be for a few weeks, and it can be continued during breastfeeding. Extrapolating from the WOMAN trial, it does not appear to increase the risk of thrombosis [23]. (See "Overview of postpartum hemorrhage", section on 'Short-term morbidity'.)

●Monitor closely for PPH and intervene rapidly if PPH occurs. This may involve:

•Platelet transfusions

•Correction of hypofibrinogenemia if present

•Intrauterine tamponade or laparotomy in severe cases

Additional details are presented separately. (See "Overview of postpartum hemorrhage" and "Postpartum hemorrhage: Medical and minimally invasive management" and "Postpartum hemorrhage: Use of an intrauterine hemorrhage-control device" and "Postpartum hemorrhage: Management approaches requiring laparotomy" and "Secondary (late) postpartum hemorrhage".)

When to refer — Patients with unexplained or excessive bleeding should be seen by a specialist in hemostasis or managed in consultation with such a specialist. This is useful for:

●Clarification of the diagnosis

●Advice on management bleeding symptoms

●Confirmation of the management plan

●Management of labor and delivery

●Perioperative management

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: von Willebrand disease" and "Society guideline links: Rare inherited bleeding disorders" and "Society guideline links: Acquired bleeding disorders".)

SUMMARY AND RECOMMENDATIONS

●Definition – BDUC is a bleeding disorder in which the following are normal (see 'Definition and cause' above):

•Complete blood count (CBC) showing normal platelet count and morphology

•Prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, and fibrinogen

•von Willebrand factor antigen and activity

•Factor VIII, IX, and XI activity

•Platelet aggregation testing

It does not include individuals with a negative bleeding history, even if they have a positive family history or abnormal testing.

●Prevalence – Prevalence is challenging to evaluate. BDUC accounts for 44 to 66 percent of mild bleeding disorders. (See 'Epidemiology' above.)

●Evaluation

•History and bleeding assessment – Includes family history, medication history, bleeding history, and medical problems that could contribute to bleeding (table 1). Heavy menstrual bleeding should be specifically queried using objective measures. The ISTH-BAT provides a bleeding score based on answers to simple questions. (See 'Medical history' above and 'Bleeding assessment (BAT)' above.)

•Laboratory – Initial testing for a patient with a suspected bleeding disorder includes CBC with platelet count and platelet morphology, coagulation testing, von Willebrand disease (VWD) testing, and factor VIII, IX, and XI activity (algorithm 1). Testing for vitamin C deficiency is also reasonable, although supportive data are limited. (See "Approach to the child with bleeding symptoms", section on 'Initial laboratory evaluation' and "Approach to the adult with a suspected bleeding disorder", section on 'Laboratory evaluation'.)

If this is unrevealing, a bleeding disorders specialist will obtain platelet aggregation studies. Specialized testing for other disorders may be indicated but is not always required. (See "Platelet function testing", section on 'Platelet aggregometry' and 'Additional testing (selected individuals)' above.)

•Diagnosis and differential diagnosis – Individuals with an abnormal bleeding score and normal results of the above are diagnosed with BDUC. The differential diagnosis includes mild hemophilia, VWD, platelet function disorders, connective tissue and vascular disorders, scurvy, and rare disorders of clotting and fibrinolysis. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Management – High quality data to guide management are limited. Involvement of a consulting hematologist or hemostasis expert is advised. (See 'Treatment/prevention of bleeding in specific scenarios' above and 'When to refer' above.)

•General advice – Patients should be educated about practices to reduce bleeding risk (table 4). Surveillance for iron deficiency is important. (See 'Decreasing the risk of bleeding' above and 'Surveillance and treatment for iron deficiency' above.)

•Surgery – Options to prevent and treat bleeding include antifibrinolytic agents (tranexamic acid [TXA] or epsilon aminocaproic acid), desmopressin (DDAVP), and in some cases platelet transfusions. (See 'Surgery and invasive procedures' above.)

For people with BDUC undergoing surgery:

-We suggest TXA (Grade 2C), especially for surgeries involving the mucosa.

-If TXA is ineffective or if prior surgeries were associated with bleeding despite TXA, we suggest adding DDAVP (Grade 2C).

-If this is ineffective and there is serious bleeding, we transfuse platelets.

•Heavy menstrual bleeding – Anatomic causes should be evaluated before attributing heavy menstrual bleeding to BDUC. (See 'Heavy menstrual bleeding' above.)

Options for reducing bleeding include hemostatic and hormonal therapies. The choice is individualized based on bleeding severity, patient preference, and desire for childbearing. Endometrial ablation and hysterectomy are additional options if future childbearing is not desired. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management", section on 'Most patients (no contraindications to medical therapy)'.)

For people who choose a hemostatic therapy, we suggest TXA rather than DDAVP (Grade 2C); tranexamic acid has a lower side effect profile.

•Pregnancy – The greatest concern is postpartum hemorrhage (PPH). (See 'Pregnancy' above.)

For people with BDUC who are pregnant:

-We suggest TXA starting when labor is established and until bleeding stops (Grade 2C).

-We avoid neuraxial anesthesia.

-We use fetal precautions.

We maintain a low threshold for evaluating PPH and intervene rapidly if PPH occurs.