Bleeding Disorders

Bleeding disorders may be due to a variety of causes, ranging from platelet dysfunction to coagulation factor disorders, and can be categorized as follows:

• primary hemostasis (platelet and endothelial disorders, including thrombocytopenia and von Willebrand disease)

• secondary hemostasis (coagulation factor deficiency, including hemophilia A and B)

Evaluation

Assuming a bleeding patient is clinically stable, initial evaluation is similar in most cases.

Medical history should include:

• evaluation of the duration, frequency, and timing of symptoms

• history of source of bleeding (e.g., menorrhagia, spontaneous/excessive bruising, mucocutaneous bleeding versus deep bleeding [e.g., hemarthrosis])

  • Note: Bleeding assessment tools (BATs), such as the International Society on Thrombosis and Haemostasis/Scientific and Standardization Committee (ISTH/SSC) Bleeding Assessment Tool, are helpful for taking a structured bleeding history.

• response to procedures, surgeries, or trauma (e.g., dental procedures or falls)

• family history or known genetic bleeding disorder

• thorough review of medications (e.g., anticoagulation, nonsteroidal anti-inflammatory drugs [NSAIDs], antiplatelet agents, supplements)

Physical exam should include:

• identifying signs of ongoing bleeding, including internal bleeding (e.g., peritoneal sign from intra-abdominal bleeding, hematomas, intra-articular bleeding)

• mucosal bleeding, petechiae (mucosal or skin)

• splenomegaly or hepatomegaly

Initial investigations should include:

• complete blood count (CBC) with differential, peripheral-blood smear: to evaluate platelet number and presence of clumping

• prothrombin time (PT): to measure the activity of warfarin and vitamin K antagonists; consider factor VII deficiency in patients with prolonged PT and normal activated partial-thromboplastin time

• activated partial thromboplastin time (APTT): consider factor VIII, IX, or XI deficiencies in patients with normal PT and prolonged APTT

Primary Hemostasis

Thrombocytopenia as a disorder of primary hemostasis is covered separately in this rotation guide.

Von Willebrand Disease (VWD): VWD is the most common inherited bleeding disorder and has an autosomal inheritance pattern. Von Willebrand factor (VWF) facilitates platelet binding to the vascular endothelium and serves as a carrier protein for factor VIII, preventing premature degradation of this clotting factor. Patients with low, absent, or dysfunctional VWF often describe mild-to-moderate mucocutaneous bleeding, although the severity of the phenotype varies significantly.

The three types of VWD correspond to the type of dysfunction of the VWF.

• Type 1 is characterized by decreased circulating VWF, but function is proportionally maintained.

• Type 2 is characterized by normal or low circulating levels of VWF, but platelet or factor VIII binding activity is low.

  • Type 2B is characterized by a gain of function mutation in VWF, leading to increased platelet binding.

• Type 3 is characterized by a complete absence of circulating VWF.

Other therapies (e.g., estrogen) may be helpful for treatment of heavy menstrual bleeding and will often lead to improvement in other systemic mucocutaneous bleeding. The levonorgestrel-releasing intrauterine system (an intrauterine device [IUD]) is also very effective in management of heavy menstrual bleeding. VWF levels can become elevated during pregnancy and therefore should be monitored.

Secondary Hemostasis

Hemophilia A and B

Hemophilia A and B are X-linked congenital bleeding disorders caused by deficiency of coagulation factor VIII (FVIII; hemophilia A) or factor IX (FIX; hemophilia B).

Laboratory testing: Lab results that suggest hemophilia include a normal PT with a prolonged PTT that corrects with a 50/50 mixing study. The level of disease severity depends on the amount of clotting factor as follows:

• severe: <1% of normal clotting factor level

  • clinical symptoms: spontaneous bleeding into muscles or joints in the absence of identifiable hemostatic challenge

• moderate: 1%-5% of normal clotting factor level

  • clinical symptoms: occasional spontaneous bleeding; prolonged bleeding with minor trauma or surgery

• mild: 5%-<40% of normal clotting factor level

  • clinical symptoms: spontaneous bleeding is rare; severe bleeding with trauma or surgery

Management: The initial approach to treatment of hemophilia involves factor replacement with FVIII and FIX concentrates. Unfortunately, up to 30% of patients with hemophilia A and 3% of patients with hemophilia B develop inhibitors that inactivate concentrates. In addition to determining disease severity, clotting factor levels are also used to guide management of bleeding episodes:

• Major/severe bleeding episodes: Replace factor VIII or IX to raise the factor level to 80%-100%.

• Hemarthrosis: Replace factor VIII or IX to raise the factor level to 50%.

  • Repeated episodes of bleeding in hemarthrosis can lead to chronic arthropathy. In such cases, pain control should be addressed. Avoid pain medication that can reduce the platelet count (e.g., nonsteroidal anti-inflammatory drugs). Selective cyclooxygenase-2 (COX-2) inhibitors can be used.

• Treatment options include the following:

  • Desmopressin is a synthetic analog of vasopressin and a nonfactor therapy. It has many indications (e.g., as an antidiuretic) and can also be used for treatment of mild hemophilia A, mild bleeding, or during minor invasive procedures. It acts by increasing FVIII levels in responsive patients. Sodium levels can become very low following this therapy and must be monitored closely.

  • Immunotherapy and gene therapy are novel treatment options that require further study for patients who have developed factor inhibitors.

    • Immunotherapy: Emicizumab is a monoclonal antibody that bridges activated factor IX and factor X to restore the activated factor VIII function in hemophilia A. It has been shown to reduce bleeding in patients with hemophilia A when used prophylactically. (See a NEJM QuickTake video for a summary of emicizumab prophylaxis in hemophilia A.)

    • Gene therapy has been shown to improve annual bleeding rates in patients with hemophilia A and B. Commercial products for both hemophilia A and B are now available.

Prophylaxis: The need for factor-replacement or emicizumab prophylaxis depends on the severity of hemophilia and previous episodes of bleeding.

• Primary prophylaxis is indicated in patients with high risk of bleeding due to severe factor deficiency.

• Secondary prophylaxis may be required in patients with moderate or severe hemophilia and previous bleeding episodes.

• Intermittent prophylaxis may be required in patients with mild or moderate factor deficiency and no prior bleeding and depends on the patient’s activity level or surgical procedures.

• Correction of iatrogenic defects in secondary hemostasis caused by use of anticoagulants is discussed in section on venous thromboembolism and anticoagulation in this rotation guide.

Rare Factor Deficiencies

Less common factor deficiencies, including fibrinogen, prothrombin can be associated with a range of bleeding phenotypes. Knowledge of these disorders is critical if an individual presents with a history of bleeding complications.