Bleeding Coagulopathies

Sarah Fittro

Bleeding tendency or dysfunction in clot formation can occur from either a quantitative or qualitative platelet defect, deficiency or inhibitor of coagulation factors, or compromise of vascular integrity

  • Platelet disorders will present with mucocutaneous bleeding, petechiae, mild bleeding immediately following surgery, impaired wound healing
  • Coagulation defects will present with deep tissue bleeding in joints/muscles resulting in hemarthroses, hematomas, sometimes delayed but severe bleeding after surgery, and intracranial hemorrhage

Quantitative or Qualitative Platelet Defect

Thrombocytopenia: see “Thrombocytopenia” section

von Willebrand Disease (vWD): Most common inherited bleeding disorder, affecting about 1% of the population (though many cases are mild and undiagnosed) but can also be acquired or secondary to other disease states. vWF has two big jobs:

  • Helps platelets stick: When a blood vessel is injured, vWF binds platelets to the damaged site to form a temporary plug.
  • Carries factor VIII: vWF protects factor VIII from breaking down and delivers it to where it’s needed in the coagulation cascade.

Types of vWD

  • Type 1 (60-80% of cases): Partial deficiency of vWF. Levels are low, but protein works.
  • Type 2 (15-30% of cases): vWF is present but defective. There are subtypes:
    • 2A: vWF can’t form large, effective multimers (chains) needed for platelet binding.
    • 2B: vWF binds too aggressively to platelets, causing them to clump and get cleared from circulation, reducing both vWF and platelets.
    • 2M: vWF has trouble binding to platelets due to a structural flaw.
    • 2N: vWF can’t properly carry factor VIII, mimicking mild hemophilia A.
  • Type 3 (1-5% of cases): Severe. Almost no vWF is produced, and factor VIII levels drop.
  • Acquired vWD: Rare, caused by drugs or diseases that destroy or block vWF such as:
    • Lymphoproliferative disorders: CLL, NHL, plasma cell dyscrasias
    • Myeloproliferative disorders: PV, ET, or myelofibrosis
    • Autoimmune diseases: SLE
    • Hypothyroidism
    • Sheer stress: aortic stenosis – Heyde syndrome, LVAD, ECMO
      • Heyde syndrome is a multisystem disorder characterized by a triad of aortic stenosis (causes high shear stress in blood flow), GI bleeding (from angiodysplasia in the gut) and acquired von Willebrand disease (type 2A)

Clinical presentation

  • Mild (Type 1): Easy bruising, frequent nosebleeds, menorrhagia, prolonged bleeding
  • Moderate (Type 2): Similar to Type 1 but more pronounced +/- petechiae
  • Severe (Type 3): Spontaneous hemarthrosis, symptoms resembling hemophilia.

Diagnosis: “vW Profile” = vWF Ag, Factor VIII Activity, Ristocetin Cofactor Activity Management

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

Other causes of qualitative platelet defects 

  • Uremic platelet dysfunction
  • Medications: NSAIDs, anti-platelets (ASA, Plavix), SSRIs (serotonin required for platelet activation), and melatonin (suggested by pre-clinical studies)

Deficiency of Coagulation Factors

Inherited Causes

  • Hemophilia A is a deficiency of factor VIII and Hemophilia B is a deficiency of factor IX. Both are X-linked recessive and 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, 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. Common in some populations (e.g., Ashkenazi Jews).
  • Fibrinogen Disorders: Mutations in FGA, FGB, or FGG genes can lead to afibrinogenemia (no fibrinogen) or hypofibrinogenemia (low fibrinogen).

Acquired Causes

  • Liver Disease: The liver makes most clotting factors (II, V, VII, IX, X, plus fibrinogen).
  • Vitamin K deficiency
  • Dilutional coagulopathy: Massive blood or fluid resuscitation can dilute clotting factors
  • DIC
  • Leukemia, aplastic anemia, or chemotherapy can impair factor production by affecting megakaryocytes or plasma cells.
  • Amyloidosis: can cause factor X deficiency

Inhibitors of Coagulation Factors

Acquired Inhibitors

  • Acquired Hemophilia A: Antibodies against factor VIII. Rare.
    • Onset in older age (60s)
    • Frequently presents with significant intramuscular hematomas
    • Disease associations in 50% of cases (other 50% idiopathic): autoimmune (e.g. SLE), malignancy (paraneoplastic), Pemphigus, drug-induced (e.g. interferon, penicillins), or chronic GvHD
    • Diagnosis: Elevated PTT that does not normalize with mixing study
    • Always consult hematology (rare disorder with major bleeding complications)
    • Bleeding management: Typically need a factor VIII bypassing agent (FEIBA)
    • Immunosuppression: prednisone 1mg/kg, rituximab often also used front line
  • Factor V Inhibitors: 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: Beyond reducing factor production, cirrhosis can produce abnormal proteins (e.g., dysfibrinogenemia) that interfere with clotting.
    • A FVIII level can help distinguish between liver dysfunction and DIC (elevated or normal in liver dysfunction and decreased in DIC since it is not hepatically derived)
  • Drugs: Warfarin and DOACs intentionally reduce activity of vitamin K-dependent factors (II, VII, IX, X) as therapy

Compromise of Vascular Integrity

Background

Compromise of vascular integrity can contribute to a coagulopathy by disrupting the first step of hemostasis.

  • Amyloidosis: Deposits infiltrate capillaries/arterioles and impair vasoconstriction and platelet adhesion. Can present as GI bleeding, purpura or ecchymoses (Raccoon eyes)
  • Vasculitis: purpura, alveolar hemorrhage (DAH), intracranial hemorrhage, GI bleeding
  • Vitamin C deficiency (scurvy): can present with bleeding gums, GI bleeding, 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. Often presents with epistaxis, GI bleeding
  • 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.

Management

  • Labs: Normal PT, aPTT, and platelet counts rule out factor or platelet issues.
  • Clinical Signs: Petechiae, purpura, or mucosal bleeding without deep hematomas suggest vascular fragility over hemophilia-like factor defects.
  • Tests: Bleeding time (less used now) or skin biopsy (e.g., for collagen defects) can point to vessel problems.
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