HC38: Bleeding disorders

Causes

A bleeding disorder can roughly have 3 different causes:

• Decrease in procoagulant factors
  • Factor VIII
  • Factor IX
  • Factor V
• Use of anticoagulant medication
  • Vitamin K antagonists
  • Direct oral anticoagulants
• Disorders such as liver failure, leukemia or immune thrombocytopenia

Bleeding disorders can be congenital or acquired:

• Congenital disorders
  • Hemophilia
  • Von Willebrands disease
  • Platelet disorders
  • Deficiencies of other clotting factors
• Acquired disorders
  • Liver failure
  • Haematological diseases
  • Autoimmune diseases
    • Immune thrombocytopenia
    • Acquired hemophilia
  • Diffuse intravascular coagulation
  • Use of medication
    • Vitamin K antagonists
    • Direct oral anticoagulants
    • Thrombocyte aggregation inhibitors
      • Aspirin
      • Clopidogrel

Analysis

Bleeding disorders are analyzed based on:

• Patient history
  • Congenital versus acquired
  • Type of bleeding
    • Site
      • Mucosal
      • Skin
      • Gums
      • Nosebleeds
      • Menstrual bleeding
      • Joints muscles
    • When it started
      • Spontaneous
      • After trauma
      • After surgery
      • Tooth extractions
  • Other diseases
  • Use of medication
  • Family history
• Physical examination
  • Signs of bleeding
    • Haematoma
    • Petechiae
      • Red spots under the skin
    • Bleeding in joints or muscles
      • E.g. swollen knees
  • Splenomegaly or lymph node enlargement
    • These are signs of hematological malignancies
  • Skin abnormalities
    • Atypical eczema can be the cause instead of bleeding disorders
• General laboratory investigations
  • Hb and thrombocyte count
  • Prothrombin time (PT)
  • APTT
  • Fibrinogen
  • Liver and kidney function tests
• Specific laboratory investigations
  • Bleeding time
  • Platelet function analyzer (PFA)
  • Platelet aggregation tests
  • Measurement of individual coagulation factors
    • FVIII, IX, V, VII, II, X, XI, XII, XIII
  • Measurement of fibrin degradation products
    • D-dimers
  • Inhibitor assays

Von Willebrands disease

In case of von Willebrands disease (VWD), there is an abnormality in both primary and secondary hemostasis. The frequency of VWD is <1-1%. It inherits autosomal → men and women are equally affected. There are 3 types of VWD:

• Type 1: moderate lowering of vWF
• Type 2: activity of vWF is lower than the antigen level
• Type 3: severe lowering of vWF
• Normandy: less binding of factor VIIIc
  • Comparable to mild hemophilia

Clinical presentation:

VWD is characterized by the following symptoms:

• Skin and mucosal bleeding
• Nosebleeds
• Menorrhagia
• Bleeding after trauma and surgery
• Much less muscle and joint bleeds compared to hemophilia

In general, the bleeding tendency is much less severe than in case of hemophilia.

Treatment:

Treatment of VWD can consist of:

• DDAVP
  • Releases vWF and factor VIII from Weibel-Palade bodies
  • Effectiveness depends on the type of VWD
    • Ineffective in case of type 2b
    • Testing is necessary
  • Side effects
    • Headache
    • Flushing
    • Hypotension
    • Fluid retention
      • Patients need to drink less water
    • Hyponatriemia
• Clotting factor concentrates
  • Intermediate purity factor VIII concentrate
  • Contains both vWF and factor VIIIc
  • Plasma derived
  • Recombinant concentrate
• Tranexamic acid
  • Inhibits fibrinolysis
  • Often used in surgeries such as tooth extractions
  • Blocks the binding site of plasminogen to fibrin → prevents fibrinolysis
    • Normally plasminogen and plasminogen activators bind on fibrin molecules via a lysin binding site → plasmin is made → fibrinolysis

Hemophilia

There are 2 types of hemophilia:

• Hemophilia A: shortage of coagulation factor VIII
  • More common
• Hemophilia B: shortage of coagulation factor IX

There is no difference in the clinical presentation between A and B. The frequency is 1:10.000 → in the Netherlands, there are about 1500 patients. It is an X-linked hereditary disease → women are carriers and mainly men are affected.

Severity:

The severity of hemophilia can vary:

• Mild hemophilia
  • <0,01 IU/ml factor VIII/IX
  • Bleeding after trauma and surgery
• Moderate hemophilia
  • 0,01-0,05 IU/ml factor VIII/IX
  • Bleeding after trauma and surgery
  • Sometimes spontaneous bleeding
• Severe hemophilia
  • >0,05 IU/ml factor VIII/IX
  • Bleeding after trauma and surgery
  • Spontaneous bleeding

Repeated bleeding in muscles and joints leads to joint damage and severe disability.

Treatment:

Treatment of hemophilia can consist of concentrates of factor VIII or IX. These are mainly recombinant concentrates, but can also be plasma derived concentrates. Treatment is prophylactically or on demand.

Prophylactic treatment with factor concentrates starts after the first or second bleeding event. At first, treatment is given in the hospital in the outpatient clinic. Frequency increases from 1-3x per week:

• Hemophilia B: 2x per week
• Hemophilia A: 3x per week
  • Hemophilia A has a shorter half life

Placement of a port-a-catheter may be necessary. With adequate instructions, treatment can be done at home. This treatment is lifelong.

Side effects of factor concentrates may be:

• Allergic reactions
  • Fever
  • Urticaria
  • Glottic edema
  • Anaphylactic shock
  • Dizziness
  • Nausea
• Development of antibodies against the factor → inhibitors
• Viral infections → due to contamination of the used blood products
  • Hepatitis A
  • Hepatitis B
  • Hepatitis C
  • HIV

Inhibitors in hemophilia:

Antibodies against the clotting factor are inhibitors in hemophilia → consist of IgG antibodies against clotting factor VIII or IX:

• In 30% of patients with severe hemophilia A
• In 5-10% of patients with severe hemophilia B

This mostly occurs within the first 50 treatment days. Risk factors are:

• Severity of hemophilia
• Mutation
• Family history on inhibitors
• Other DNA polymorphisms
  • MHC class I and II
  • TNA-α
  • IL-10
  • CTL-4,4
• Type of the concentrate used for medication
• Intensive treatment for trauma or surgery

Due to the inhibitor, treatment with factor VIII or IX concentrates is ineffective. This leads to severe bleeding disorders which are difficult to treat. Because inhibitors neutralize the infused factor concentrate, bypassing agents have to be used:

• FEIBA: factor VIII inhibitor bypassing activity
  • Dosage: 203 dd of 50-100 U/kg
  • The half-life can slightly be prolonged via fusion to the Fc-domain of IgG
• NovoSeven: recombinant factor VIIa concentrate
  • Dosage: 90 microgram/kg
  • Short half-life of 2-3 hours → treatment has to be repeated every 2-3 hours
    • Can be increased by coupling recombinant VIIa to albumin

Emicizumab is a new concept on the market. It is a recombinant humanized bispecific antibody with affinity to both factor IXa and factor X. It takes over the function of factor VIII (factor VIII usually activates factor X with factor IX) and is insensitive to the presence of inhibitors:

• Can be used in patients with inhibitors
• Can be used in patients without inhibitors

Emicizumab has a high biologic activity after subcutaneous administration. Its half-life is about 30 days → weekly or 2-weekly subcutaneous treatment is possible. At the moment, it is available for bleeding prevention in patients with inhibitors. Side effects are limited.

Bleeding caused by treatment

Treatment such as direct oral anticoagulants can cause excessive bleeding. Direct oral anticoagulants are used for:

• Prevention of VTE after major orthopedic surgery
• Treatment of VTE
  • Deep vein thrombosis
  • Pulmonary embolism
• Prevention of embolism in atrial fibrillation

Several drugs are available:

• Factor IIa (thrombin) inhibitor
  • Dabigatran
• Factor Xa inhibitor
  • Apixaban
  • Rivaroxaban
  • Edoxaban

There are no specific antidota available for Xa-inhibitors. For dabigatran, the direct antidote idarucizumab is an option.

Antagonizing Xa-inhibitors:

High dosages of prothrombin complex concentrates are shown to antagonize the anticoagulant effect of rivaroxaban in healthy volunteers → are antagonists of Xa-inhibitors. There are some indications that FEIBA is effective in dabigatran and rivaroxaban.

Andexanet-α is a modified human recombinant factor Xa molecule without intrinsic clotting factor activity. It binds to factor Xa inhibitors such as:

• Apixaban
• Edoxaban
• Rivaroxaban
• Low molecular weight heparines

Andexanet-α neutralizes the activity of factor Xa inhibitors. Andexanet-α has a half-life of about 1 hour, with treatment consisting of a bolus infusion followed by a continuous infusion of 2 hours. However, andexanet-α has several disadvantages:

• Very limited clinical evolution
• No direct comparison with effective treatment
• Side effects
• Costly
• Not available in the Netherlands at the moment

Antagonizing IIa-inhibitors:

Dabigatran is an antagonist of factor IIa. A direct inhibitor of dabigatran is idarucizumab → it is an antagonizing-IIa inhibitor. Idarucizumab can be used in case of bleeding complications or surgery. Dosage is 5g intravenously. Only limited experience is available.

Cases

Case 1:

A 20-year-old female student visits her general practitioner. 2 weeks before, her right wisdom-tooth was removed, followed by a bleeding complication. The patient’s history is as follows:

• The bleeding started directly after the procedure
• The procedure was done without complications
• The patient suffered from previous spontaneous bleeding
  • Easy bruising
  • Severe menstrual periods
• The patient hasn’t had previous surgeries
• The patient is otherwise healthy
• The patient’s mother suffers from severe menstruation
• Symptoms
  • Fatigue
  • Fever
  • Swelling under the right armpit

The most likely diagnosis is a haematological malignancy.

Case 2:

A 13-month-old boy presents with several hematomas in the skin and a bleed in the right knee. The most likely diagnosis is severe hemophilia A (hemophilia A is more common than hemophilia B).

Case 3:

A 65-year-old male patient is treated with apixaban because of deep vein thrombosis. He is admitted to the hospital because of an intracranial bleed. On admission, his INR is 2,1. To stop the bleeding, the apixaban treatment needs to be stopped and a prothrombin complex concentrate needs to be given, if needed followed by FEIBA or NovoSeven.