• Clinical science

Hemostasis and bleeding disorders

Abstract

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.

Classification

Hemostasis is the processes involved in stopping hemorrhages, while hemorrhagic diathesis implies an abnormal and increased susceptibility to bleeding.

Disorders of primary hemostasis

Disorders of secondary hemostasis

Fibrinolytic disorders

Other important types

Von Willebrand disease

  • Definition: : a disorder of primary hemostasis characterized by either a deficiency or disorder of vWF
  • Epidemiology: most common congenital hemostatic disorder
  • Clinical findings
    • Mostly asymptomatic
    • Symptomatic patients:
      • Ecchymosis (esp. mucosal hemorrhages) → from reduced half-life of factor VIII
      • Petechial hemorrhages in severe cases → caused by impaired platelet aggregation
      • Other symptoms include epistaxis, gingival bleeding, menorrhagia; (∼ 50% of women with vWD), GI bleeding, and excessive bleeding during surgical procedures.
  • Diagnosis
    • Prolonged bleeding time and sometimes prolonged activated partial thromboplastin time (aPTT)
    • Factor VIII levels
    • vWF-specific measurements
      • Quantitative assesment by vWF antigen assay: ↓ factor levels
      • Qualitative assesment by a collagen or glycoprotein Ib binding assay, or a ristocetin cofactor activity assay
        • Ristocetin normally activates vWF to bind to glycoprotein Ib
        • Failure of aggregation with a ristocetin assay or a ristocetin cofactor level < 30 IU/dL is considered definitive for vWD
  • 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 because of the increased risk of bleeding!

Variants of von Willebrand Disease
Type Inheritance/Etiology Pathophysiology
Congenital Type 1 (80%)
  • Quantitative deficiency of vWF and factor VIII
Type 2 (15-20%)
  • Qualitative defect in vWF
Type 3 (∼ 1%)
  • Complete absence of vWF and factor VIII
Acquired
  • Typically associated with malignancies
  • Unknown
  • Autoimmune diseases

Disseminated intravascular coagulation

  • 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 disseminated intravascular coagulation in the learning card on shock.

In disorders of primary hemostasis, platelet aggregation is impaired, whereas disorders of secondary hemostasis are caused by impairment of the coagulation cascade!!References:[1][2][3][4][5][6][7][8]

Pathophysiology

Activation of hemostasis

  1. Injury to endothelium → activation of the extrinsic pathway (hemostasis)
    • Tissue factor ; (factor III), which is present under the endothelium on fibroblasts, binds to and thus activates factor VII.
    • Factor VIIa; and tissue factor ; form a complex (TF-FVIIa)* that activates factor X
    • Factor Xa and factor Va; form a complex* that activates thrombin.
  2. Additionally, activation of the intrinsic pathway (hemostasis), especially through thrombin
    • Thrombin activates factors XI and VIII.
      • Factor XIa activates factor IX.
      • Factors IXa and VIIIa form a complex* that activates factor X.
    • This causes a positive feedback loop of factor X and thrombin activation via the intrinsic pathway
  3. The common pathway (hemostasis) of the extrinsic and intrinsic pathways then follows:

(*) The formation of complexes marked with an asterisk is mediated by Ca2+ on the (negative) surface of the fibrocytes/active platelets.

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 soluble fibrin monomers (Ia).

Inhibition of hemostasis

Diseases that affect the inhibitors of the coagulation cascade may lead to hypercoagulability!

Fibrinolysis

Since the fibrinolytic system continuously cleaves and degrades fibrin, hemostasis and fibrinolysis are processes that occur simultaneously in the circulatory system.

Alteplase is a synthetic tissue plasminogen activator that converts plasminogen to plasmin and is used in the treatment of STEMI, massive pulmonary embolism, and ischemic stroke.

References:[9][10][11]

Clinical features

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
  • Deep tissue bleeding (e.g., hemarthrosis, hematomas)
  • Large, palpable ecchymoses
Disseminated intravascular coagulation Variable (depends on underlying cause)

Petechial bleeding and ecchymosis; bleeding from intravenous (IV) lines and catheters

Petechial bleeding indicates defects of primary hemostasis, whereas large, palpable ecchymoses and deep tissue bleeding suggest defects of secondary hemostasis!

References:[1][3][4]

Diagnostics

Coagulation studies

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
    • Time it takes for hemostasis to occur after lancet puncture
    • Can be used to assess both quantitative and qualitative platelet pathologies
    • Reference value: depending on the testing protocol, about 2–7 minutes

Diagnosing defects of secondary hemostasis

Blood parameters and their importance
Unit Description Interpretation Clinical relevance
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.
  • Vitamin K deficiency
  • Impaired coagulation factor production (e.g., liver cirrhosis)
  • Monitoring of warfarin therapy
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

Measures the time it takes for fibrin polymers to form after adding thrombin

Reptilase time seconds Measures the time it takes for fibrin to form after adding reptilase
Laboratory results of coagulation pathway disorders
Defective pathway Disorders

Platelets

Bleeding time

INR PT aPTT
Disorders of primary hemostasis = = =
= = = =
Disorders of secondary hemostasis = = =
= = = =
= =
Combined defects = = = n/↑

Additional diagnostic measures

References:[3][12]

Treatment

Disorders of primary hemostasis

Disorders of secondary hemostasis

Other

References:[1][13]