Bleeding disorders are characterized by defects in hemostasis that lead to an increased susceptibility to bleeding (also known as hemorrhagic diathesis). Bleeding disorders can be caused by platelet disorders (primary hemostasis defects), coagulation defects (secondary hemostasis defects), or increased clot degradation (hyperfibrinolysis). Coagulation defects may be general or further divided into either intrinsic or extrinsic defects according to the specific pathway of the coagulation cascade that is affected. Bleeding disorders may be inherited or acquired. Although clinical features may overlap, mucocutaneous bleeding (e.g., epistaxis, petechiae, gastrointestinal bleeding) is associated more with platelet disorders, while bleeding into potential spaces (e.g., hemarthrosis, muscular bleeding) is more characteristic of coagulation defects. A basic understanding of physiological processes during hemostasis and fibrinolysis is necessary for properly interpreting laboratory studies and accurately diagnosing bleeding disorders. Treatment depends on the underlying cause and may involve blood transfusion and replacement of coagulation factors.
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†|| || ||✓|
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|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)
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., )
- Definition: : pathological fibrinolysis, which leads to bleeding
- Pathophysiology: excessive plasmin activity → increased fibrin degradation → thrombus instability and dissolution shortly after formation
- History of present illness: : details regarding bleeding symptoms
- Past medical history
- Family history: : evidence or signs suggestive of hereditary bleeding disorders
- Medication: ,
- Nutrition: : A poor diet can cause signs of vitamin C deficiency () or .
- : can detect
- irregular-shaped platelets in thrombocytopathy : may show
- (prothrombin time); : prolonged in disorders that affect the extrinsic pathway and/or the common pathway of hemostasis
- (international normalized ratio); : ratio of a patient's prothrombin time relative to a normal (control) sample
- (activated partial thromboplastin time): prolonged in disorders that affect the intrinsic pathway and/or the common pathway of hemostasis
- prolonged in disorders of primary hemostasis :
- Consider and .
- autoantibodies are suspected) (if
- See “ ” for additional test.
Laboratory findings of bleeding disorders 
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|Disorders that affect primary and secondary hemostasis|| || || || || || |
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|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:
- Transfusion of blood products, e.g.:
- Replacement of specific coagulation factors, e.g.:
- Drug therapy, e.g.:
See also the articles on the conditions listed in “Etiology” above for more specific treatment details.