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Hemostasis and bleeding disorders

Last updated: August 27, 2021

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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 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).

Overview [1][2]

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

Overview of coagulation factors
Factor number Descriptive name Activated by Involvement in pathways Function
Common Intrinsic Extrinsic
I
II
III

IV

V*
  • Proaccelerin
VII*
  • Proconvertin
VIII*
IX*
  • Factor XIa
X*
  • Complexes TF-VIIa and VIIIa-IXa
XI*
XII*
XIII*
  • Stabilizes the fibrin network by introducing crosslinks

* = preferred term [3]
= rarely used term

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: 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 hypercoagulability 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).

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

Overview [2]

Fibrinolytic therapy [4]

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

Hemorrhagic diathesis is the abnormally increased susceptibility to bleeding.

Disorders of primary hemostasis

Disorders of secondary hemostasis (disorders of the coagulation cascade)

In disorders of primary hemostasis, platelet aggregation is impaired, whereas in disorders of secondary hemostasis it is the coagulation cascade that is impaired.

Hyperfibrinolysis [10]

Clinical features of bleeding disorders [11][12]

Disorder Onset of bleeding Manifestations

Primary hemostasis disorders [7]

  • Immediately after trauma
Secondary hemostasis disorders
  • Delayed (minutes to hours after trauma)
Disseminated intravascular coagulation
  • Variable (depends on underlying cause)
  • Bleeding symptoms may include:
  • Symptoms of hypercoagulation (see “Clinical features” in “DIC”)
  • 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:

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

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 [13][14][15]

Most bleeding disorders are acquired; i.e., secondary to medications or associated with acute or chronic illness. [13]

Women presenting with menorrhagia should also be evaluated by a gynecologist.

Bleeding assessment tools (BATs) [16][17][18]

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: [17][18][19]
  • Each symptom receives a score based on its severity.
  • An elevated total score should prompt evaluation for bleeding disorders. [18][20] [21][22]
  • A low score does not exclude bleeding disorder.

Initial laboratory studies [14][15][16][23]

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. [16][23]

Interpretation of laboratory findings in bleeding disorders [14][16][24]

Defective pathway Disorders

Platelet count

PFA or bleeding time

PT/INR aPTT
Disorders of primary hemostasis

Thrombocytopenia

  • Normal
  • Normal

Platelet dysfunction (e.g., aspirin therapy)

  • Normal
  • Normal
  • Normal
Disorders of secondary hemostasis

Extrinsic pathway (e.g., factor VII deficiency)

  • Normal
  • Normal
  • Normal

Intrinsic pathway (e.g., hemophilia, heparin therapy)

  • Normal
  • Normal
  • Normal

Intrinsic and extrinsic pathways (e.g., deficiency of vitamin K-dependent coagulation factors)

  • Normal
  • Normal
Disorders of primary AND secondary hemostasis

Von Willebrand disease

  • Normal
  • Normal
  • Normal/↑ [23]

Disseminated intravascular coagulation (DIC)

DIC is characterized by thrombosis, hemorrhage, and organ dysfunction and can be a medical emergency that requires immediate treatment.

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 [14][15]

Advanced laboratory studies help identify specific disorders. The choice of studies depends on the suspected underlying pathology and usually requires specialist consult.

Suspected disorders of primary hemostasis

Suspected disorders of secondary hemostasis [15][26]

  • 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 [15][26]
Elevated PT/INR Normal PT/INR
Elevated aPTT
Normal aPTT
  • See “Disorder unclear after initial testing” below

Disorder unclear after initial testing [15]

Additional testing is required if suspicion of a bleeding disorder is high but coagulation testing is normal. Possible etiologies include:

If the diagnosis remains unclear, repeat testing for vWD is recommended. [15]

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 [26][28]

  • 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 [29][30]

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. [33]

Disorders of secondary hemostasis

Inherited coagulation factor deficiency [23]

Acquired coagulation factor deficiency

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. [35]

Impaired coagulation factor function

Patients with an inhibitor to a coagulation factor are at high risk of severe or fatal bleeding. [39]

Management [13]

Diagnostics should not delay factor replacement therapy in patients with known bleeding disorders presenting with major bleeding. [43][44][45]

Patients with a suspected disorder of secondary hemostasis presenting with major bleeding can benefit from the transfusion of fresh frozen plasma while diagnostic studies are performed. [13]

Diagnostics [13]

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