Bleeding Disorders

[TomHsiung]

Bleeding disorders can be subdivided into three categories, including:

• Primary hemostasis disorders
• Secondary hemostasis disorders
• Fibrinolysis disorders

Primary hemostasis disorders are caused by platelet function disorders or vWF disorders. Secondary hemostasis disorders are caused by coagulation factor disorders, including hemophilia A and B, acquired hemophilia, and rare factor deficiencies.

The first thing to deal with patients with bleeding is the medical history collection which includes eight questions:

• Bleeding location/anatomic site
• Bleeding frequency
• Bleeding pattern
• Age of onset
• Time required for cessation
• Medication history
• Family history
• Bleeding challenge

In these questions, the bleeding location might help to distinguish primary hemostasis disorders with secondary hemostasis disorders.

After medical history collection, screen tests are available including

• Platelet count
• RBC count
• PT
• aPTT
• PFA-100

Platelet count of <100,000/uL and the hemoglobin of <10 g/dL would cause the closure time (PFA-100) to be abnormal.
PT reflects the function of FII, FV, FVII, and FX, of which the issue could be qualitative or quantitative.
aPTT reflects the function of FVIII, FIX, FXI, FXII, FII, FV, and FX, of which the issue could be qualitative or quantitative.

[TomHsiung]

Medical History
Obtaining a detailed patient and family history is crucial regardless of prior laboratory testing. The history includes a detail discussion of specific bleeding and clinical symptoms. Information regarding bleeding symptoms should include location, frequency, and pattern as well as duration both in terms of age of onset and time required for cessation.

The location may suggest the part of the hemostatic system affected; patients with disorders of primary hemostasis often experience mucocutaneous bleeding, including easy bruising, epistaxis, heavy menstrual bleeding, and postpartum hemorrhage in women of child-bearing age; whereas patients with disorders of secondary hemostasis may experience deep-tissue bleeding, including the joints, muscles, and central nervous system.

The bleeding pattern and duration of each episode, particularly for mucus membrane bleeding, assist in the determination of the likelihood of the presence of an underlying bleeding disorders.

The onset of symptoms can suggest the presence of a congenital versus acquired disorder. Although congenital conditions can present at any age, it is more likely that patients with a long history of symptoms or symptoms that begin in childhood have a congenital condition, whereas patients whose onset occurs at an older age are more likely to have an acquired condition. Congenital clotting factor deficiencies that do not present until later in life do occur and include mild factor deficiencies and coagulation factor deficiencies associated with variable bleeding patterns, most notably FXI deficiency.

Additional important information to be collected includes the current use of medications and herbal supplements, as these may affect the hemostatic system; the presence or absence of a family history of bleeding; a history of hemostatic challenges, including surgery, dental procedures, and trauma; and a menstrual history in females.

The goal at the end of the history is to establish the likelihood of a bleeding disorder, as this will guide the direction of the laboratory investigation. Quantification of clinical bleeding is a challenge, particularly in the outpatient setting. In recent years, several bleeding assessment tools (BAT) have been developed to more accurately differentiate bleeding phenotypes in healthy individuals and in patients with bleeding disorders. These tools, which are originally designed for assessing bleeding in von Willebrand disease (vWD) do not appear to be diagnostic and are in the process of being validated from the ability to screen other bleeding disorders. However it is increasingly clear that a normal bleeding score rules out the presence of a bleeding disorder.

From thread "[HEMOSTASIS] GENERAL – DIAGNOSTIC APPROACH TO THE BLEEDING DISORDERS" at http://www.tomhsiung.com/wordpress/2...ing-disorders/

[TomHsiung]

Screening Tests
The laboratory evaluation for bleeding includes performance of initial screening tests. The most common screening tests utilized include the platelet count, prothrombin time, and activated partial thromboplastin time. When the PT or aPTT is prolonged, mixing studies are required via a one-to-one mix of patient plasma with known normal standard plasma. Test correction in the mixing study indicates a deficiency state, whereas lack of correction indicates an inhibitor, either one directed against a specific factor or a global inhibitor as best exemplified by a lupus anticoagulant. Specific factor analyses are performed after mixing studies reveal a correction of prolonged coagulation screening test(s) indicative of a deficiency state or in the face of normal screening tests with a positive history.

Screening tests are not sensitive and do not evaluate all abnormalities associated with bleeding including vWF, FXIII, PAI-1, and alpha₂AP deficiencies; therefore, a patient history strongly suggestive of a bleeding disorder may warrant testing for such deficiencies, including rare abnormalities regardless of screening test results.

The most common screening tests utilized include the platelet count, prothrombin time, and activated partial thromboplastin time. When the PT or aPTT is prolonged >10 seconds, mixing studies are required via a one-to-one mix of patient plasma with known normal standard plasma.

Screening tests also are utilized to identify individuals with a high likelihood of vWD or platelet disorders. The bleeding time, once widely used, has become obsolete because of the lack of sensitivity and specificity. The PFA-100 (platelet function analyzer) has been proposed to have a role in screening individuals with suspected platelet dysfunction or vWD. Initial studies demonstrated the efficacy of the PFA-100 in the evaluation of patients with known severe platelet disorders or vWD. The PFA-100 induces high shear stress and simulates primary hemostasis by flowing whole blood through an aperture with a membrane coated with collagen and either adenosine diphosphate (ADP) or epinephrine. Platelets adhere to the collagen-coated surface and aggregate forming a platelet plug that enlarges until it occludes the aperture, causing cessation of blood flow. The time to cessation of flow is recorded as closure time (CT). The sensitivity and specificity of the CT of the PFA-100 were reported as 90% for severe platelet dysfunction or vWD, with vWF plasma levels below 25%. The utility of the PFA-100 as a screening tool, however, has been challenged based on the reported low sensitivity of the device in individuals with mild platelet secretion defect, mild vWD or storage pool disorders. Additionally, a significant limitation of the PFA-100 is the fact that the platelet count and hemoglobin levels affect the CT. The CT will be abnormal if the platelet count is less than 100,000/uL and the hemoglobin is <10 g/dL.

It is likely that by the time patients are referred to a hematologist that some, if not all of the previously mentioned tests may have been performed. Screening tests are sensitive to specimen handling, may vary in reliability based on laboratory, and may be influenced by medications. Repeating these laboratory tests often is required; if possible, it is best to discontinue medications known to affect their results. Therefore, although screening tests are used widely to identify hemostatic abnormalities associated with bleeding, they are not perfect. Therefore, the clinical suspicion for a bleeding disorder is critical to determine extent of the laboratory investigation.

Platelet Count
Normal range: 150,000 - 450,000 /uL
The only test to determine the number or concentration of platelets in a blood sample is the platelet count, through either manual (rarely done) or automated methods. Interferences with platelet counts include RBC fragments, platelet clumping, and platelet stellitism (platelet adherence to WBCs). Automated platelet counts are performed on anti coagulated whole blood.

Thrombocytemia
An abnormal platelet count can have many causes. Thrombocythemia, also known as thrombocytosis or elevated platelet count, may be caused by several factors including

• Stress
• Infection
• Splenectomy
• Trauma
• Asphyxiation
• Rheumatoid arhritis
• Iron-deficiency anemia
• Posthemorrhagic anemia
• Cirrhosis
• Chronic pancreatitis
• Tuberculosis
• Occult malignancy
• Recovery from the bone marrow suppression

Values of 500,000 - 800,000 /uL are not uncommon. Thrombocythemia may be seen with any of the chronic myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, chronic myelogenous leukemia, or idiopathic myelofibrosis.

Clinical consequences of thrombocythemia include thrombosis, hemorrhage, and microcirculatory disturbances. Thrombotic events may be either arterial or venous and include cerebrovascular accidents, myocardial infarction, deep venous thrombosis, pulmonary embolism, and intra-abdominal (portal and hepatic) vein thrombosis. Hemorrhagic complications usually involve the skin and/or mucous membranes, which include ecchymosis, epistaxis, and menorrhagia. Microcirculatory disturbances, such as headache, paresthesias, and erythromelalgia, may be due to microthrombi, which results in occlusion and ischemia. Additionally, patients with thrombocythemia may have abnormalities in platelet function studies, which can manifest as bleeding problems.

[TomHsiung]

Constructing A Differential Diagnosis

• Structural causes
  
  • Tissue injury from trauma
  • Abnormality of the tissue such that minor trauma causes bleeding, such as a toothbrush causing gum bleeding from inflammatory gingival disease
  
  
• Bleeding due to platelet disorders
  
  • Disorders of platelet number
    
    • Decreased production of platelets
      
      • Medications
      • Bone marrow replacement by malignancy, fibrosis, granulomas
      • Bone marrow aplasia
      • Alcohol
      • B₁₂ deficiency
      
      
    • Increased loss or consumption of platelets
      
      • Splenic sequestration
      • Autoimmune thrombocytopenia
        
        • Idiopathic
        • HIV
        • Systemic lupus erythematosus
        • Lymphoproliferative disorders
        • Medications
        
        
      • Disseminated intravascular coagulation
      • Thrombotic thrombocytopenic purpura
      • Sepsis
    
    
  • Disorders of platelet function
    
    • Congenital
      
      • von Willebrand disease
      • Other rare genetic abnormalities
      
      
    • Acquired
      
      • Medications
      • Myeloproliferative disorders
      • Coating of platelets by abnormal proteins
      • Uremia
  
  
• Bleeding due to clotting factor abnormalities
  
  • Congenital
    
    • Hemophilia A
    • Other clotting factor deficiencies
    
    
  • Acquired
    
    • Deficiency of a factor or factors
      
      • Liver disease
      • Vitamin K deficiency
      • Abnormal adsorption of a factor
      • Consumption of factors
      • Dilution of factors
      
      
    • Acquired inhibitor to clotting factor or factors

[TomHsiung]

Pivotal points

• Bleeding location
• Time course of bleeding
• Bleeding volume
• Bleeding challenge
• Acquired or congenital

[TomHsiung]

The approach to GI bleeding is similar to the approach to other potentially life-threatening illnesses. Patient stabilization, specifically, hemodynamic stabilization is the first step in management. In a patient with GI bleeding, management precedes diagnosis, usually made by colonoscopy or esophagogastroduodenoscopy (EGD).

Initial management follows a regimented course. The patient must be hemodynamically stabilized, preparation must be made in case of further bleeding, and initial diagnostic tests must be completed.

• Hemodynamic stabilization
  
  • ​Clinically assess volume status.
    
    • Signs of shock may be seen with 30-40% volume depletion
    • Orthostasis can be seen with 20-25% volume depletion
    • Tachycardia may be present with 15% volume depletion
    
    
  • Calculate necessary replacement (weight in kg x 0.6 (lean body weight made up of water) x % volume depletion)
  • Replace fluid losses initially with normal saline or Ringer solution
  • Consider the need for blood transfusion
    
    • In patients who are not bleeding, withholding transfusions until the hemoglobin reaches 7-8 g/dL is a conservative approach supported by recent data
    • There has, until recently been general agreement on the following recommendations for transfusion in actively bleeding patients
      
      • Patients should receive a blood transfusion when there has been 30% loss of blood volume (manifested by tachycardia, hypotension, tachypnea, decreased urinary output, or CNS symptoms [e.g., anxiety/confusion])
      • Alternatively, if 2 L of crystalloid have been given without successful resuscitation, blood should be transfused
      • If a hemoglobin level is available, actively bleeding patients should receive a transfusion when the level falls below 10 g/dL
      • If large amounts of blood are needed (>4 units of packed red blood cells), fresh frozen plasma and platelets should also be given
      
      
    • A recent randomized trial of patients with upper GI bleeding compared a restrictive strategy of transfusion (threshold for transfusion of hemoglobin <7 g/dL) with a liberal strategy (threshold of hemoglobin <9 g/dL)
      
      • This study demonstrated a mortality benefit with the restrictive strategy
      • Exclusion criteria in this study were massive exsanguinating bleeding, an acute coronary syndrome, symptomatic peripheral vasculopathy, stroke, or transient ischemic attack
      • All patients had endoscopy within 6 hours of presentation
      • Patients in this study also received blood if symptoms of anemia or massive bleeding developed or if they required surgery
      
      
    • It is important to remember the patients may initially have a normal hemoglobin level when they present with an acute hemorrhage. It will only fall after fluid resuscitation.

[TomHsiung]

For the differential diagnosis of hematuria please refer to the post at Hematuria