Bleeding due to Secondary Hemostatic Dysfunction

Explain how disorders of secondary hemostasis can cause hemorrhagic and thrombotic disorders

Hemorrhagic

• deficiency in the quantity or quality of coagulation factors which leads to unstable fibrin clot formation

Thrombotic

• Alterations in the regulatory system leading to inappropriate or excessive thrombus (clot) formation

List the two etiological classifications of hemorrhagic secondary hemostatic disorders and conditions that belong to each group

Congenital Disorders

• Hemophilia A

• Hemophilia B

• Hemophilia C

• von Willebrand Disease

• Fibrinogen Deficiencies

  • Afibrinogenemia

  • hypofibrinogenemia

  • dysfibrinogenemia

• Factor 8 Deficiency

• Contact Factor Deficiencies

• Single Factors: 2, 5, 7, and 10

Acquired Disorders

• LIver disease

• Vitamin K deficiency

• Renal Disease

  • Hemolytic Uremic Syndrome (HUS)

  • Nephrotic Syndrome

• Consumptive Coagulpathies

• Factor inhibitors

  • Alloantibodies

  • Autoantibodies

Describe the etiology, pathogenesis, genetics (if an inherited disease), clinical features, and laboratory findings of the following

Liver Disease

• Etiology & Pathogenesis: The liver is responsible for synthesizing thrombopoietin, the Prothrombin group (Factors II, VII, IX, and X), and the Fibrinogen group (Factors I, V, VIII, and XIII). Liver disease leads to a lack of activity in these factors and moderate thrombocytopenia.

• Clinical Features: Bleeding is a major cause of death in these patients, often exacerbated by pre-existing varices. It typically presents as mucocutaneous (MC) and general/anatomic (G/A) bleeding.

• Laboratory Findings: Common findings include a prolonged PT and aPTT, low platelet count, and abnormal results in Fibrinogen assays and Thrombin Time (rarely). Factor V levels are the most sensitive indicator of the degree of liver damage because Factor V is not vitamin K-dependent and is not an acute-phase reactant.

Vitamin K Deficiency

• Etiology & Pathogenesis: A lack of Vitamin K results in reduced activity of the Prothrombin group factors (II, VII, IX, and X). Causes include dietary insufficiency, biliary duct obstruction (since Vitamin K is fat-soluble), antibiotic usage impacting gut flora, sterile guts in newborns, or Vitamin K agonist medications like Coumadin.

• Laboratory Findings: This is primarily detected via a prolonged PT, which may or may not be accompanied by an increased aPTT. The deficiency is confirmed if the PT corrects during a mixing study with normal fresh plasma.

Renal Dysfunction

• Etiology & Pathogenesis: Two primary forms of renal disease impact secondary hemostasis:

  • Hemolytic Uremic Syndrome (HUS): This condition consumes platelets and coagulation factors.

  • Nephrotic Syndrome: In this condition, coagulation factors are lost as they are filtered into the urine.

• Clinical Features: Both forms lead to hemorrhagic bleeding disorders.

Hemophilia A, B, and C

• Hemophilia A (Factor VIII Deficiency):

  • Genetics: It follows an X-linked recessive inheritance pattern; however, 30% of cases arise from spontaneous mutations.

  • Pathogenesis: A quantitative deficiency in Factor VIII, which is normally carried by vWF and activated by thrombin.

  • Clinical Features: Characterized by anatomic bleeding (deep muscle and joint involvement) and hemarthroses (acute joint bleeding). Severity is linked to factor levels: Severe (<1 Unit/dL) causes frequent spontaneous bleeds, while Mild (6–30 Unit/dL) may only be discovered after trauma.

  • Laboratory Findings: Prolonged aPTT with a normal PT, platelet count, and Thrombin Time. Diagnosis is confirmed via a Factor VIII assay.

• Hemophilia B (Factor IX Deficiency / Christmas Disease):

  • Genetics: Sex-linked (X-linked) recessive.

  • Clinical Features: Clinical symptoms are essentially identical to Hemophilia A.

  • Laboratory Findings: Similar screening results to Hemophilia A (prolonged aPTT, normal PT), but specifically shows a deficiency in Factor IX.

• Hemophilia C (Factor XI Deficiency):

  • Pathogenesis: Deficiency in Factor XI.

  • Clinical Features: This is the only contact factor deficiency associated with a bleeding tendency. Symptoms range from bruising and epistaxis to severe hemorrhage, though hemarthroses are rare.

  • Laboratory Findings: Characterized by a prolonged aPTT with a normal PT.

Deficiencies of Fibrinogen, Prothrombin, and Factors V, VII, X, and XIII

These are generally inherited as autosomal recessive mutations.

• Fibrinogen (Factor I):

  • Etiology: Can manifest as afibrinogenemia (absent), hypofibrinogenemia (low), or dysfibrinogenemia (malfunctioning).

  • Laboratory Findings: Abnormal PT, aPTT, and Thrombin Time (TT).

• Prothrombin (Factor II), Factor V, and Factor X:

  • Laboratory Findings: All three result in abnormal PT and abnormal aPTT. Factor X deficiency may also show an abnormal Russell’s viper venom test.

• Factor VII:

  • Laboratory Findings: This results in an abnormal PT but a normal aPTT.

• Factor XIII:

  • Clinical Features: Uniquely associated with poor wound healing and "oozing" from wounds.

  • Laboratory Findings: All standard screening tests (PT, aPTT, TT, and platelet count) are normal. Diagnosis requires follow-up testing based on clinical suspicion or family history

Determine the best follow-up test when provided PT and aPTT results

General:

MIxing study

Normal PT and abnormal aPTT

• Specific Factor Assays

• Differentiating Hemophilia A from vWD

• Inhibitor Testing

Abnormal PT and Normal aPTT

• Factor VII Assay

Abnormal PT and aPTT

• Thrombin Time

• Factor 5 Level

• Russell’s Viper Venom Test

Normal PT and aPTT

• FActor 13

• vWD assay

Define the term factor specific inhibitor

Antibody that specifically targets and neutralizes a particular coagulation factor

Define and differentiate afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia

Afibrinogenemia

• Total quantitative absence of fibrinogen

Hypofibrinogenemia

• Quantitative deficiency where the levels of fibrogen are lower than normal

Dysfibrinogenemia

• Qualitative defect where the quantity of fibrinogen may be sufficient, but protein is malfunctioning

Explain the method and clinical utility of a mixing study

The method involves combining the patient's plasma with normal fresh plasma

The primary clinical utility of a mixing study is to differentiate between a factor deficiency and the presence of a circulating anticoagulant (inhibitor)

• If correction occurs: paitent missing one or more coagulation factors - HA, B, or C, or Vitamin K deficiency

• If not corrected:indicates presence of a circulating anticoagulation or factor-specific inhibitor

Determine if a factory deficiency or inhibitor is present when provided mixing study results

Factory Deficiency

• A correction

Inhibitor

• Prolonged after incubation

Determine the hemorrhagic secondary hemostatic disorder when provided a case study

PT	aPTT	TT	Platelet Count	Suspected Disorder
Abnormal	Normal	Normal	Normal	Factor VII Deficiency or early Vitamin K Deficiency
Normal	Abnormal	Normal	Normal	Hemophilia A (VIII), B (IX), or C (XI); or Factors XII, PK, HK
Abnormal	Abnormal	Normal	Normal	Factors X, V, or II (Prothrombin)
Abnormal	Abnormal	Abnormal	Normal	Fibrinogen Deficiency (Afibrinogenemia)
Normal	Normal	Normal	Normal	Factor XIII Deficiency
Normal	Abnormal or Normal	Normal	Normal	von Willebrand Disease (vWD) (Check PFA-100)
Abnormal	Abnormal	Variable	Low	Liver Disease (Factor V is the most sensitive marker)