Bleeding Coagulopathies

Michael Zargari

Bleeding disorders result from abnormalities in one of the following:

  • Platelet disorders (quantitative or qualitative): Mucocutaneous bleeding, petechiae, mild bleeding immediately following surgery, impaired wound healing.
  • Coagulation factors (deficiency or inhibitor): Deep tissue bleeding in joints/muscles (hemarthroses, hematomas), bleeding after surgery, intracranial hemorrhage.
  • Vascular integrity.

Quantitative or Qualitative Platelet Defects

Thrombocytopenia: see “Thrombocytopenia” section

von Willebrand Disease (vWD)

  • Most common inherited bleeding disorder (~1%).
  • vWF has two key functions:
    • Platelet adhesion.
    • Stabilizing factor VIII.

Types of vWD

  • Type 1 (70-80%):
    • Partial quantitative deficiency.
    • Mild bleeding.
  • Type 2 (~20%):
    • Qualitative defect
    • Similar mild bleeding to type 1 ± petechiae
    • Subtypes: 
      • 2A: Decreased platelet binding.
      • 2B: Increased platelet binding → thrombocytopenia.
      • 2M: Impaired platelet binding.
      • 2N: Impaired factor VIII binding (mimics hemophilia a).
  • Type 3 (5%):
    • Severe deficiency.
    • Hemarthrosis.
  • Acquired vWD (rare): Increased destruction or dysfunction associated with the following:
    • Lymphoproliferative disorders (CLL, NHL, plasma cell dyscrasias).
    • Myeloproliferative disorders (PV, ET, myelofibrosis).
    • Autoimmune diseases (SLE).
    • Hypothyroidism.
    • Shear stress (aortic stenosis/Heyde syndrome, LVAD, ECMO).
    • Diagnosis:
      • vWF antigen.
      • vWF activity (ristocetin cofactor).
      • Factor VIII level.

Management

  • Desmopressin (DDAVP): Type 1 and most Type 2.
  • vWF/Factor VIII Concentrates: For Type 3, severe Type 2, or when DDAVP fails.
  • Antifibrinolytics (e.g., Tranexamic Acid) for mucosal bleeding.
  • Platelet transfusions: Rarely, for Type 2B with severe thrombocytopenia.
  • Avoid NSAIDs.

Other causes of qualitative platelet defects 

  • Uremia (most common).
  • Medications: NSAIDs, antiplatelet agents (ASA, clopidogrel), SSRIs.

Deficiency of Coagulation Factors

Inherited Causes

Hemophilia A = factor VIII deficiency.

Hemophilia B = factor IX deficiency.

  • X-linked recessive.
  • Most commonly affect males.
  • Frequently presents with hemarthroses and hematomas.
  • Diagnosis:
    • Isolated prolonged PTT with normalization upon mixing study.
  • Management:
    • Purified/recombinant Factor VIII or IX replacement.
    • Mild disease can be managed with desmopressin.
    • Consult Benign Hematology on admission.
  • Factor XI Deficiency (Hemophilia C):
    • Rare, autosomal recessive.
    • Caused by F11 gene mutations.
    • Commonly seen in Ashkenazi Jews.
  • Fibrinogen Disorders:
    • Mutations in FGA, FGB, or FGG genes can lead to:
      • Afibrinogenemia (no fibrinogen).
      • Hypofibrinogenemia (low fibrinogen).

Acquired Causes

  • Liver Disease (most common acquired coagulopathy):
  • Liver produces factors II, V, VII, IX, X, and fibrinogen.
  • FVIII level can help distinguish liver dysfunction (elevated/normal) from DIC (decreased).
  • Vitamin K deficiency (malnutrition, antibiotics, cholestasis) – affects II, VII, IX, X.
  • Dilutional coagulopathy (Massive blood or fluid resuscitation).
  • DIC (sepsis, malignancy, trauma)
  • Leukemia
  • Aplastic anemia
  • Chemotherapy
  • Amyloidosis (factor X deficiency).

Inhibitors of Coagulation Factors

Acquired Inhibitors

Acquired Hemophilia A: Antibodies against factor VIII.

  • Onset: Older adults (60s)
  • Presentation: New severe bleeding, intramuscular hematomas
  • Associations (50% of cases; other 50% idiopathic):
  • Autoimmune (e.g. SLE)
  • Malignancy (paraneoplastic)
  • Bullous pemphigoid > pemphigus vulgaris
  • Drug-induced (e.g. interferon, penicillins)
  • Chronic GvHD.

Diagnosis:

  • Elevated PTT that does not normalize with mixing study.
  • Always consult hematology (rare disorder with major bleeding complications).

Management:

  • Typically need a factor VIII bypassing agent (FEIBA).
  • Immunosuppression: prednisone 1mg/kg, rituximab often also used front line.

Factor V Inhibitor:

  • Even rarer, linked to surgery, antibiotics, or autoimmune triggers.
  • Alloantibodies in hemophilia: patients with congenital hemophilia A or B receiving factor VIII or IX infusions can develop antibodies.

Other Inhibitory Mechanisms 

  • Liver disease: In addition to decreased clotting factor production, cirrhosis can lead to the production of abnormal proteins (e.g., dysfibrinogenemia) that interfere with clotting.
  • Drugs: Warfarin and DOACs intentionally reduce activity of vitamin K-dependent factors (II, VII, IX, X) as therapy.

Vascular Integrity Compromise

Background

Can contribute to a coagulopathy by interfering with vasoconstriction and platelet plug
formation.

  • Amyloidosis: Deposits infiltrate capillaries/arterioles and impair vasoconstriction and platelet adhesion. GI bleeds, purpura, and/or ecchymoses (Raccoon eyes)
  • Vasculitis: purpura, alveolar hemorrhage (DAH), intracranial hemorrhage, GI bleeds.
  • Vitamin C deficiency (scurvy): bleeding gums, GI bleeds, ecchymoses, hematomas, anemia.
  • Ehlers-Danlos Syndrome: Defective collagen = vessels tear easily, resulting in bruising or even arterial rupture.
  • Marfan Syndrome: Abnormal fibrillin in vessel walls alters subendothelial structure, potentially affecting platelet binding.
  • Hereditary hemorrhagic Telangiectasia: 2nd most common inherited bleeding disorder.
    Recurrent epistaxis and GI bleeds.
  • DIC or thrombotic microangiopathies (e.g., HUS, TTP) can lead to endothelial injury and microclots, consuming platelets and factors, resulting in secondary bleeding.
  • Allergic reactions: Histamine increases permeability = petechiae or ecchymosis.
  • Cushing’s Syndrome: Excess cortisol thins vessel walls = easy bruising.
  • Infections (e.g., Ebola, Dengue): Viral damage to endothelium = hemorrhagic fever.
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