- Clinical science
Bleeding disorders are characterized by defects in hemostasis that lead to an increased susceptibility to bleeding (also known as hemorrhagic diathesis). They are caused either by platelet disorders (primary hemostasis defect), coagulation defects (secondary hemostasis defect), or, in some cases, a combination of both. 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 of inherited and acquired disorders 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 hemostasis is necessary for properly interpreting laboratory studies in order to accurately diagnose the disorder and ensure appropriate treatment.
- Platelet disorders
- Platelet deficiency
- Disorders affecting the vessel wall
Disorders of secondary hemostasis (disorders of the coagulation cascade)
- Intrinsic pathway: hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency)
- Extrinsic pathway: factor VII deficiency
- Deficiency or inhibition of vitamin K-dependent coagulation factors II, VII, IX, and X
- Inhibition of coagulation factors by antibodies (e.g., )
- Impaired hepatic production of coagulation factors: e.g., liver cirrhosis
- Description: pathological fibrinolysis, which leads to bleeding (caused by, e.g., congenital or metabolic causes, trauma, decreased hepatic clearance caused by liver dysfunction, sepsis, etc)
- Mechanism: Excessive plasmin activity causes increased fibrin degradation → Blood clots become unstable or dissolve shortly after forming.
- Can occur in:
Other important types
- Definition: : a disorder of primary hemostasis characterized by either a deficiency or disorder of vWF
- Epidemiology: most common congenital hemostatic disorder
- Mostly asymptomatic
- Symptomatic patients:
- Prolonged bleeding time and sometimes prolonged activated partial thromboplastin time (aPTT)
- ↓ Factor VIII levels
- Quantitative assessment by vWF antigen assay: ↓ factor levels
- Qualitative assessment by a collagen or glycoprotein Ib binding assay, or a ristocetin cofactor activity assay
Therapy: only if symptoms occur
- Recombinant von Willebrand factor (rVWF) concentrate
- Desmopressin; : Stimulates vWF release from endothelial cells.
- Other treatment options: factor VIII concentrates ; oral contraceptives in cases with menorrhagia; antifibrinolytic drugs (i.e., aminocaproic acid, tranexamic acid)
- Avoid aspirin, NSAIDS, and intramuscular injections
Platelet aggregation inhibitors are contraindicated in von Willebrand disease because of the increased risk of bleeding!
|Variants of von Willebrand disease|
|Congenital||Type 1 (80%)|| |
|Type 2 (15-20%)|| |
|Type 3 (∼ 1%)|| |
|Acquired|| || |
- Also known as consumption coagulopathy, it is a condition in which the procoagulant pathways are abnormally active, resulting in the formation of blood clots in the small blood vessels throughout the body.
- For further information, see in the learning card on .
In disorders of primary hemostasis, platelet aggregation is impaired, whereas disorders of secondary hemostasis are caused by impairment of the coagulation cascade!!References:
Activation of hemostasis
Primary hemostasis: hemostasis achieved via platelet adhesion and aggregation at the site of endothelial injury
- Initiation: endothelial injury results in transient vasoconstriction; . → exposure of subendothelial collagen → vWF, which is stored in Weibel-Palade bodies of endothelial cells and α-granules of platelets, binds the exposed collagen
- Adhesion: vWF and platelet GpIb receptors mediate the adhesion of platelets to the injured endothelium by forming pseudopodia; phospholipid is expressed on cellular membranes.
- Activation: release of adenine diphosphate (ADP), thromboxane, calcium, and platelet activating factor (PAF), which assist in platelet aggregation, vasoconstriction and degranulation
- Aggregation: mediated by GpIIb/IIIa-receptor and fibrinogen → formation of a white thrombus composed of platelets and fibrin
- Secondary hemostasis: hemostasis achieved via the interaction of plasma coagulation factors (coagulation cascade)
- Injury to endothelium → activation of the extrinsic pathway (hemostasis)
- Additionally, activation of the intrinsic pathway (hemostasis), especially through thrombin
- The common pathway (hemostasis) of the extrinsic and intrinsic pathways then follows:
- Factor Xa and factor Va form a complex* that cleaves prothrombin to thrombin (= factor II).
- Thrombin cleaves fibrinogen (factor I) into insoluble fibrin (factor 1a) monomers.
- Cross links of the fibrin network are stabilized by factor XIIIa → formation of a fibrin network → fibrin closely binds to the platelet plug, forming a stable fibrin clot (secondary or red thrombus)
The coagulation cascade requires the presence of calcium ions (factor IV)!
A helpful way of remembering the coagulation factors of the extrinsic pathway is 3 + 7 = 10. Factor III and factor VII form a complex to activate factor X of the common pathway.
Prothrombin time, which measures the activity of the extrinsic pathway, is increased by warfarin therapy (Ex-PresidenT went to War!)
A helpful way of remembering the coagulation factors of the common pathway is 1 x 2 x 5 = 10. Factors Xa and Va form a complex that cleaves prothrombin (II) to thrombin (IIa). Factor IIa then cleaves fibrinogen (I) into insoluble fibrin monomers (Ia).
Inhibition of hemostasis
- Extrinsic pathway: tissue factor pathway inhibitor, which inhibits tissue factor
- Protein S; : cofactor of protein C
- Protein C: forms the activated protein C complex together with its cofactor protein S (APC complex) → inhibition of factors Va and VIIIa → inhibition of coagulation cascade
- Nonspecific inhibitors of hemostasis: protease inhibitors found in plasma (e.g., alpha-1-antitrypsin, alpha-2-macroglobulin)
Diseases that affect the inhibitors of the coagulation cascade may lead to hypercoagulability!
- For further information, see .
Tissue injury → release of factor XII , urokinase and tissue plasminogen activator (tPA)
- → Breakdown of plasminogen, leading to the formation of active plasmin → breakdown of fibrin by activated plasmin
- → Release of degradation products, including D-dimers
- Regulation of fibrinolysis: tPA activity is reduced if tPA binds to plasminogen activator inhibitor (PAI).
- Fibrin-specific agents
- Mechanism of action: directly or indirectly increase the conversion of plasminogen to plasmin
- Active bleeding
- Prior intracranial hemorrhage
- Recent surgery
- Severe hypertension
- Adverse effect: bleeding
- Reversal of adverse effects
|Onset of bleeding||Type of bleeding|
|Features of primary hemostasis disorders (i.e., platelet defects)||Immediately after trauma|
|Features of secondary hemostasis disorders (i.e., clotting defects)||Minutes to hours after trauma|
|Disseminated intravascular coagulation||Variable (depends on underlying cause)|
Clinicians can use several tests to assess the functional adequacy of the different steps of hemostasis.
Diagnosing defects of primary hemostasis
- Abnormal platelet count
- Abnormal bleeding time
Diagnosing defects of secondary hemostasis
|Blood parameters and their importance|
|Prothrombin time (PT)||Seconds||Measures the time it takes for the extrinsic system to produce fibrin polymers following activation by thromboplastin and calcium. Normal value range: 11–15 seconds.|
|International normalized ratio (INR)||None|| |
Derived from prothrombin time, but calculated by comparing the laboratory-specific prothrombin time to a standardized prothrombin time, measured using a standardized tissue factor reagent. Normal value: 1.0.
|(Activated) partial thromboplastin time (aPTT, PTT)||Seconds|| |
Measures the time it takes for the intrinsic system to produce fibrin polymers following activation by the addition of phospholipids
|(Plasma‑)thrombin time (TT)||Seconds|
|Reptilase time||Seconds||Measures the time it takes for fibrin to form after adding reptilase|| |
|Laboratory results of coagulation pathway disorders|
Additional diagnostic measures
- Anti-factor Xa: Measuring anti-factor Xa activity may be helpful in the following circumstances:
- D-dimers: correlate with activity of coagulation and fibrinolysis
- Platelet deficiency, platelet disorders, platelet coagulation: Treat the underlying condition and control symptoms (see ).
- Disorders affecting the vessel walls
- supportive care:
- prompt : plasma exchange therapy (see for details)
Disorders of the intrinsic pathway
- (factor VIII deficiency) and (factor IX deficiency): substitution of clotting factors
- For autoantibodies directed against individual coagulation factors :
- Disorders of the extrinsic pathway
- Tranexamic acid: a synthetic lysine analog and inhibitor of plasminogen with antifibrinolytic action
- : Treat the underlying condition (see ).
- See .