Bleeding disorders are a group of heterogeneous conditions characterized by defects in hemostasis that lead to an increased susceptibility to bleeding (also known as hemorrhagic diathesis). They are classified into disorders of primary hemostasis (when caused by a platelet abnormality), disorders of secondary hemostasis (when caused by defects in the extrinsic and/or intrinsic pathway of the coagulation cascade), and hyperfibrinolysis (when there is increased clot degradation). Although clinical features may overlap, mucocutaneous bleeding (e.g., epistaxis, petechiae, gastrointestinal bleeding) is associated with disorders of primary hemostasis, and bleeding into potential spaces (e.g., hemarthrosis, muscular bleeding) is characteristic of disorders of secondary hemostasis. The diagnostic workup of a bleeding disorder begins with a detailed clinical assessment, the CBC, and a coagulation panel. This typically allows the disorder to be classified as one of primary or secondary hemostasis. Specialized studies are then required to determine the specific etiology so that treatment can be initiated. Treatment may include transfusion of blood products, replacement of specific coagulation factors, or administration of adjuvant medications (e.g., tranexamic acid or desmopressin).
Hemostasis is the physiological process by which a bleeding stops. Its final result is a thrombus (blood clot), which consists of blood cells and fibrin strands. Hemostasis involves the following mechanisms:
- Primary hemostasis
- Secondary hemostasis: activation of the coagulation cascade, which results in the formation of a fibrin clot (red thrombus)
- Definition: : processes involved in the formation of a platelet plug (white thrombus) following endothelial injury
- Endothelial injury results in:
- Von Willebrand factor (vWF): plasma protein that is synthesized by and stored in endothelial cells (in Weibel-Palade bodies) and platelets (in α-granules)
- Platelet adhesion: platelets bind to vWF via platelet GpIb receptor at the endothelial injury site
Platelet activation: After binding to vWF, platelets change their shape and release mediators that lead to activation of more platelets (positive feedback). ; These mediators include:
- Adenosine diphosphate (ADP): promotes adhesion of platelets to endothelium
- Thromboxane A2 (TXA2): activates additional platelets and promotes vasoconstriction
- Calcium: required for secondary hemostasis
- Platelet-activating factor (PAF): a phospholipid mediator that is produced by platelets and inflammatory cells (e.g., neutrophils, monocytes, macrophages), involved in platelet aggregation and activation and
- Platelet aggregation
Definition: : processes that lead to stabilization of the platelet plug; (white thrombus; ) by creating a fibrin network
- Coagulation cascade: a sequence of events triggered by the activation of the intrinsic or extrinsic pathway of coagulation that results in the formation of a stable thrombus
- Coagulation factors
Extrinsic pathway of coagulation: triggered by endothelial injury
- Tissue factor (factor III) activates factor VII.
- Factor VIIa and tissue factor form a complex (TF-FVIIa). This step requires calcium (factor IV) found on the surface of fibrocytes and activated platelets.
- TF-FVIIa activates factor X and factor IX.
Intrinsic pathway of coagulation
- Exposed collagen, kallikrein, and kininogen (HMWK) activate factor XII.
- Thrombin activates factor XI and factor VIII.
- Factor XIa activates factor IX.
- Factors VIIIa and IXa form a complex (mediated by calcium) that activates factor X.
- This causes a positive feedback loop of factor X and thrombin activation via the intrinsic pathway.
Common pathway of coagulation: The extrinsic end intrinsic pathway both end in the common pathway.
- Factor Xa and factor Va form a complex (mediated by calcium) that cleaves prothrombin (factor II) to thrombin (factor IIa).
- Thrombin cleaves fibrinogen (factor I) into insoluble fibrin (factor Ia) monomers.
- Crosslinks of the fibrin network are stabilized by factor XIIIa; → formation of a fibrin network → fibrin closely binds to the platelet plug, forming a stable thrombus (secondary thrombus or red thrombus)
|Overview of coagulation factors|
|Factor number||Descriptive name||Activated by||Involvement in pathways||Function|
|III†|| || ||✓|
| ||✓||✓||✓|| |
|XIII*|| ||✓|| |
* = preferred term 
A helpful way of remembering the coagulation factors of the extrinsic pathway is 3 + 7 = 10: Tissue factor (factor III) and factor VII form a complex that activates factor X of the common pathway.
A helpful way of remembering the coagulation factors of the common pathway is 10/5 = 2 × 1: Factors Xa and Va form a complex that cleaves prothrombin (factor II) to thrombin (IIa). Factor IIa then cleaves fibrinogen (I) into insoluble fibrin monomers (Ia).
Inhibition of hemostasis
In order to prevent as well as excessive bleeding, activation of the coagulation cascade and the processes that inhibit it occur simultaneously in the circulatory system (procoagulant-anticoagulant balance).
- Tissue factor pathway inhibitor: inhibits tissue factor
- Protein C and protein S: Activated protein C and its cofactor protein S form the activated protein-C complex (APC complex), which inhibits factors Va and VIIIa.
- Nonspecific inhibitors: protease inhibitors in plasma (e.g., alpha-1-antitrypsin, alpha-2-macroglobulin)
- Drug-induced: anticoagulant treatment (see “ ” and “ ”)
Diseases that affect the inhibitors of the coagulation cascade may lead to .
- Definition: degradation of the fibrin network of thrombi by the enzyme plasmin
- Tissue injury leads to the release and activation of plasminogen activators, which convert plasminogen to its active form plasmin.
- Plasmin breaks down and deactivates fibrin and fibrinogen → release of fibrin degradation products (e.g, D-dimers)
Fibrinolytic therapy 
Agents: Fibrinolytics promote the degradation of thrombi by activating plasminogen to plasmin.
- Fibrin-specific agents
- Non-fibrin-specific agents
- Mechanism of action: : directly or indirectly increase the concentration of plasmin; → cleavage of thrombin and fibrin 
- Laboratory findings
- Adverse effects
- Contraindications to fibrinolytic therapy
Reversal of adverse effects
- Antifibrinolytics: group of drugs that impair fibrinolysis, typically by interfering with plasmin formation
- Fresh frozen plasma (FFP), PCC, or cryoprecipitate (Cryoprecipitate is obtained from frozen blood plasma via centrifuge and contains more factor VIII and fibrinogen than FFP.)
- Platelet transfusions (if necessary)
Disorders of fibrinolysis
- Definition: inherited genetic condition characterized by abnormally low levels of plasminogen, which results in a build-up of fibrin
- Epidemiology: rare disease; prevalence is estimated to be approx. 1:625,000
- Etiology: autosomal recessive inherited mutations in the PLG gene
- Pathophysiology: : mutations of the PLG gene → ↓ concentrations and/or functional impairment of plasminogen → ↓ plasmin → ↓ fibrinolysis → accumulation of fibrin
Clinical features: usually manifest in early infancy
- Formation of inflamed, thick, wood-like growths (ligneous pseudomembranes) on mucous membranes (especially the conjunctiva) that appear white, yellow, or red
- Other areas that can be affected: skin, CNS, gingiva, gastrointestinal tract, lungs, female genital tract (e.g., fallopian tubes)
- Not associated with thrombophilia
- Differential diagnosis: infections (most common), but also conditions such as allergies, GERD, IBD, endometriosis, depending on the area affected
Hemorrhagic diathesis is the abnormally increased susceptibility to bleeding.
Disorders of primary hemostasis
- Platelet disorders 
- Disorders affecting the vessel wall
Disorders of secondary hemostasis (disorders of the coagulation cascade)
- Intrinsic pathway
- Extrinsic pathway: : factor VII deficiency (autosomal recessive bleeding disorder caused by mutation of the F7 gene)
- Deficiency or inhibition of II, VII, IX, and X
- Inhibition of coagulation factors by autoantibodies (most commonly anti-factor VIII) 
- Impaired hepatic production of coagulation factors (e.g., )
- Fibrinogen deficiency
- Definition: pathological fibrinolysis, which leads to bleeding
- Pathophysiology: excessive plasmin activity → increased fibrin degradation → thrombus instability and dissolution shortly after formation
- Definition: : a disorder characterized by low plasma fibrinogen levels
- Symptoms and findings: epistaxis, gastrointestinal hemorrhage, gingival bleeding
Clinical features of bleeding disorders 
|Disorder||Onset of bleeding||Manifestations|
- A thorough physical examination is essential for diagnosing bleeding disorders and should include the inspection of the entire skin, mucosa (esp. oral cavity), and joints.
- Watch out for signs of physical abuse, which may produce patterns of bruising that resemble those of bleeding disorders. Signs of physical abuse include:
Clinical assessment and basic laboratory testing are used to differentiate between primary and secondary disorders of hemostasis. Advanced testing is used to identify the specific disorder.
Clinical assessment 
- Features associated with bleeding disorders
Use of medications
- Antithrombotic agents: anticoagulants, antiplatelet agents
- Other drugs that can affect platelet function and/or count, including:
Most bleeding disorders are acquired; i.e., secondary to medications or associated with acute or chronic illness. 
Bleeding assessment tools (BATs) 
BATs are questionnaires that standardize the assessment of bleeding symptoms and identify patients who may benefit from advanced testing. Multiple tools are available.
- The International Society of Thrombosis and Hemostasis BAT includes the following symptoms: 
- Mucocutaneous symptoms: cutaneous signs of bleeding, bleeding from minor wounds, epistaxis, bleeding in the oral cavity
- Bleeding after procedures: after a surgery or dental extraction
- Musculoskeletal bleeding: hemarthroses, or muscular hematomas
- CNS bleeding
- GI bleeding
- Gynecological bleeding: menorrhagia or postpartum hemorrhage
- Each symptom receives a score based on its severity.
- An elevated total score should prompt evaluation for bleeding disorders.  
- A low score does not exclude bleeding disorder.
Initial laboratory studies 
- History or physical examination suggestive of a bleeding disorder
- Elevated BAT score
- CBC, BMP, liver chemistries
- Peripheral blood smear
- Coagulation panel; including fibrinogen level: Elevated PT/INR and/or aPTT are suggestive of disorders of secondary hemostasis.
- Platelet function analysis (PFA): Abnormal platelet function (or, if not available, a prolonged bleeding time; ) suggests a disorder of primary hemostasis. 
- vWF antigen and vWF activity (vWF ristocetin activity): for diagnosis of vWD
Von Willebrand disease is the most common inherited bleeding disorder, affecting up to 1% of the population. Von Willebrand factor concentration and vWF activity are now commonly part of initial diagnostic studies. 
Interpretation of laboratory findings in bleeding disorders 
|Defective pathway||Disorders|| |
PFA or bleeding time
| || || || |
(e.g., aspirin therapy)
| || || || |
Extrinsic pathway (e.g., )
| || || || |
Intrinsic pathway (e.g., , heparin therapy)
| || || || |
Intrinsic and extrinsic pathways (e.g., deficiency of )
| || || || |
|Disorders of primary AND secondary hemostasis|| |
| || || || |
| || || || |
A detailed clinical assessment and initial laboratory studies are sufficient to diagnose the most common disorders of hemostasis (e.g., platelet dysfunction secondary to medications or bleeding disorders associated with acute or chronic disease).
Advanced laboratory studies 
Advanced laboratory studies help identify specific disorders. The choice of studies depends on the suspected underlying pathology and usually requires specialist consult.
- Disorders of primary hemostasis: low platelet count or abnormal platelet function test with normal INR and PTT
- Disorders of secondary hemostasis: abnormal INR or PTT with normal platelet counts and platelet function
- Unclear after initial studies: normal platelet count and function and normal coagulation panel but high clinical suspicion for a bleeding disorder
Suspected disorders of primary hemostasis
Low platelet count
- Base further testing on clinical suspicion. For example:
- Thrombocytopenia in a pregnant patient: Start investigations for HELLP syndrome.
- Anemia and thrombocytopenia in a patient with suggestive symptoms: Start investigations for TTP.
- Presence of B symptoms or other abnormalities on CBC and/or blood smear: Start investigations for a hematologic malignancy.
- See “Diagnostics” in “Thrombocytopenia” for details.
- Base further testing on clinical suspicion. For example:
Abnormal platelet function 
- Acquired (most common): etiology (e.g., medications or chronic illness) usually clear after initial evaluation
- Inherited (rare): advanced testing to further assess platelet function and identify the etiology
- See also “Differential diagnoses of platelet disorders.”
Suspected disorders of secondary hemostasis 
- Congenital factor deficiencies: confirmed with factor assays (low factor concentrations)
- Presence of factor inhibitors: can be diagnosed using mixing studies
|Possible mechanisms and coagulation factors affected in disorders of secondary hemostasis |
|Elevated PT/INR||Normal PT/INR|
|Elevated aPTT|| || |
|Normal aPTT|| || |
Disorder unclear after initial testing 
Additional testing is required if suspicion of a bleeding disorder is high but coagulation testing is normal. Possible etiologies include:
- Hyperfibrinolysis: Testing includes alpha 2-antiplasmin level and plasminogen activation inhibitor-1 level. 
- Vascular disorders (e.g., Ehler Danlos syndrome, hereditary hemorrhagic telangiectasia): Genetic testing is required.
- Factor XIII deficiency
- Combined coagulation factor deficiency
If the diagnosis remains unclear, repeat testing for vWD is recommended. 
Treatment should be guided by a specialist and target the specific cause of the bleeding. Occasionally, the transfusion of blood products may be indicated. For patients with acute or major bleeding, see “Management of acute bleeding” below.
General principles 
- Avoid medications that may impair hemostasis.
- Ensure optimal preventive medical and dental health care.
- Consult a specialist to determine any preventive measures that are necessary before invasive procedures.
- Provide patient education on lifestyle modification in the setting of bleeding disorders.
- Consider screening for HIV and hepatitis if the patient has a history of multiple transfusions.
Disorders of primary hemostasis 
- Platelet transfusion
- Uremic platelet dysfunction 
- Drug-related platelet dysfunction 
- Discontinue medications causing dysfunction.
- Consider desmopressin
- corticosteroids and IVIG. Platelet transfusion is typically ineffectual. : Treatment may include
- heparin and initiate an alternative form of anticoagulation. : Stop all
- obstetrician immediately for specific management. : Consult
One random donor platelet unit typically increases platelet count by 5,000–10,000/mm3 in a 70-kg patient. One apheresis unit (the equivalent of 6–8 single units) increases platelet count by 30,000–40,000/mm3. 
Inherited coagulation factor deficiency 
- Depending on the etiology, treatment can include one or more of the following:
- Blood product transfusions
- Replacement of specific coagulation factors, e.g.:
- Pharmacological therapy (e.g., desmopressin, antifibrinolytics)
- Intravenous immunoglobulin therapy
- Monoclonal antibody therapy
- See “Treatment” in “Hemophilia” and in “Von Willebrand Disease” for specific recommendations.
Acquired coagulation factor deficiency
- Vitamin K deficiency 
- Liver disease: complex management 
The effect of liver disease on hemostasis is complex: The clinical effects of thrombocytopenia and reduced coagulation factor synthesis are often negated by a simultaneous decrease in the production of profibrinolytic factors. Bleeding often does not occur, even if the laboratory values of hemostasis are markedly abnormal. 
Impaired coagulation factor function
- Therapeutic or accidental anticoagulant use: See “Anticoagulant reversal.”
- Coagulation factor inhibitors: Treatment includes immunosuppression (e.g., glucocorticoids) and occasional use of bypassing agents. 
Patients with an inhibitor to a coagulation factor are at high risk of severe or fatal bleeding. 
- Start ABCDE approach and stabilize the patient as needed.
- Establish appropriate IV access.
- Consult hematology service.
- Assess the need for anticoagulant reversal, discontinue ongoing anticoagulants and platelet inhibitors, unless contraindicated.
- Consider consultation for a procedural intervention to control bleeding (e.g., upper endoscopy, colonoscopy, surgery).
- Start transfusion of blood products if needed (see also “Massive transfusion”).
- pRBCs: Target Hb using a liberal or restrictive transfusion strategy.
- Platelet transfusion: for thrombocytopenia or as part of a massive transfusion protocol
- Fresh frozen plasma (FFP), cryoprecipitate : as part of massive transfusion protocol or to replace coagulation factors and/or fibrinogen
- : Use only with expert guidance; potentially fatal thrombotic complications may occur. 
- Consider replacement of specific coagulation factors
- Consider adjuvant drug therapy depending on suspected etiology
Diagnostics should not delay factor replacement therapy in patients with known bleeding disorders presenting with major bleeding. 
- Routine testing
- Viscoelastic hemostatic assays (VHAs): a point-of-care test with rapid results that provides a comprehensive assessment of hemostatic function