Bleeding Disorders

 

• Background

  Aka bleeding diathesis, coagulopathy.

  Pathophysiology

  Dysfunction in any of the 3 elements of haemostasis:

  • Impaired vasoconstriction due to vascular defects e.g. Ehlers-Danlos.
  • Impaired platelet plug formation: thrombocytopaenia, poor platelet aggregation e.g. Von Willebrand disease (VWD).
  • Coagulopathy: haemophilia, VWD.

  Causes

  Inherited:

  • Haemophilia A and B
  • Inherited VWD.

  Acquired:

  • Iatrogenic: anticoagulants, antiplatelets.
  • Acquired VWD: aortic stenosis (Heyde's syndrome), myeloma.
  • Liver disease: ↓clotting factor synthesis, dysfibrinogenaemia, ↓platelets.
  • Kidney disease: abnormal platelet function.
  • ↓Vitamin K, including haemorrhagic disease of the newborn.
  • DIC

• Signs and symptoms

  • Easy bruising. May be spontaneous and at unusual sites.
  • Mucosal bleeding: gum, epistaxis. Common in platelet deficiency or dysfunction.
  • Menorrhagia
  • Internal bleeding: GI, intracranial.
  • Prolonged bleeding after surgery or trauma, including minor trauma such as the neonatal heel prick (if severe).
  • Haemarthrosis and haematoma are common in clotting factor deficiencies.
  • Transfusion infections. New cases are rare, but patients may have complications from previous transfusions e.g. hep C cirrhosis.

• Investigations

  Basic bloods: FBC, LFT, U&E.

  Clotting studies (aka coagulation studies):

  • Use full, citrate-containing tube.
  • (Activated) partial thromboplastin time (PTT or aPTT): tests intrinsic pathway. ↑ in haemophilia and sometimes in VWD.
  • Prothrombin time (PT): tests extrinsic pathway. ↑ in liver disease. Normal in haemophilia. Standardized form is the international normalized ratio (INR).
  • Correction study: mix sample 50:50 with normal plasma. If PTT then returns to normal, suggests a deficiency which is now corrected.
  • Normal results do not exclude a bleeding disorder.

  Further tests:

  • Factor assays: ↓F8 in haemophilia A and VWD, ↓F9 in haemophilia B, ↓VWF Ag and ↓VWF activity in VWD.
  • Genetic testing.
  • Imaging for internal bleeding.

• Management

  General approach:

  • Avoid anticoagulants, NSAIDs, and IM injections (use SC instead).
  • Replace missing factor (F8, F9, VWF) or give desmopressin for mild haemophilia A.
  • Anti-fibrinolytics: tranexamic acid (stabilises clot).

• Haemophilia

  Pathophysiology and epidemiology

  Haemophilia A:

  • Factor 8 (F8) deficiency due to X-linked mutation. 40% have intron 22 inversion; 30% de novo
  • Prevalence: 1/5000 males.
  • Mild: >5% F8 activity, only a problem in trauma. Moderate: <5% F8 activity. Severe: <1% F8 activity, causing spontaneous bleeding usually presenting by 3 years old.
  • 5% of female carriers have mild ↓F8.

  Haemophilia B:

  • Factor 9 (F9) deficiency due to X-linked mutation.
  • Prevalence: 1/30,000 males.
  • Similar symptoms and classification to haemophilia A.

  Signs and symptoms

  • Haemarthrosis, which can lead to long-term arthropathy.
  • Haematoma in muscles: severe pain, altered gait, nerve palsy, compartment syndrome.
  • Intracranial haemorrhage: affects 5% of newborns with severe haemophilia.

  Haemophilia A management

  Lifestyle:

  • Stay active, but avoid contact sport.

  IV recombinant F8 concentrate:

  • Long term prophylaxis once-weekly for severe haemophilia. Ideally self- or parent-administered.
  • In acute bleeding, give until bleeding stops. Fibrinolytics can be used as adjuncts.
  • 30% eventually develop inhibitor antibodies to F8. Overcome with daily treatment to induce immune tolerance.

  Desmopressin:

  • Given IV/SC/intranasal in acute bleeds for mild haemophilia.
  • Mechanism: increases F8 levels.
  • Need to restrict fluids and maximum 3 doses.
  • Contraindications: <2 years old, IHD.

  Haemarthrosis:

  • Acute: factor concentrate, analgesia (ice packs may help), and immobilise, elevate, and apply compression.
  • Physio post-bleed, and may need continued analgesia.
  • MRI monitoring if there is recurrent joint injury.
  • Treat synovitis from recurrent bleeds with radioactive synovectomy.

• Von Willebrand disease (VWD)

  • Commonest inherited bleeding disease. 1/1000 prevalence.
  • Deficient or ineffective VW factor (VWF) → ↓platelet binding and ↓F8 binding and protection.
  • Type 1 (75% of cases): autosomal dominant, ↓VWF levels, usually mild.
  • Type 2 (20%): normal VWF levels but structurally abnormal multimers (subunits of the VWF).
  • Type 3 (<5%): homozygous for deficient gene, and total lack of VWF. Severe disease with similar presentation to haemophilia A.

• Haemostasis physiology

  Haemostasis

  Haemostasis is the process whereby bleeding stops, via vasoconstriction, platelet plug formation, and coagulation.

  Vasoconstriction

  2 mechanisms:

  • Mechanical: reflex smooth muscle contraction.
  • Chemical: serotonin (5-HT) and thromboxane A2 (TxA2) release from platelets.

  Platelet plug formation

  1. Vessel injury exposes collagen on basement membrane.
  2. GP1a on platelets binds to collagen, and GP1b binds to Von Willebrand factor (VWF) which binds to collagen.
  3. TxA2 released by platelets, which in turn causes fibrinogen release from platelets.
  4. GP2a/b on platelets binds to fibrinogen causing platelet aggregation.
  5. Platelet surface changes to expose phospholipids, which are co-factors in the clotting cascade.

  Coagulation

  Clotting factors are synthesised in the liver, and work through a physiological cascade. There are two pathways which converge into a final common pathway.

  Extrinsic pathway (aka tissue factor pathway):

  • Tissue factor (TF) is exposed in damaged tissue (i.e. outside the blood), activating Factor 7 → activates F10.
  • Measured by prothrombin time (PT), standardized as the international normalized ratio (INR). In the lab, tissue factor is added to the sample and then clotting is timed.

  Intrinsic pathway (aka contact activation pathway):

  • Endothelial damage allows platelets to contact underlying collagen, activating Factor 12 → activates F11 → activates F9, which in presence of F8a → activates F10.
  • F8 is normally bound to vWF when inactive, otherwise it degrades rapidly. It is activated by thrombin.
  • Relatively slow process: 30-50 seconds.
  • Measured by (activated) partial thromboplastin time (aPTT, PTT).

  Final common pathway:

  • F10a cleaves prothrombin (F2) to thrombin (F2a) → thrombin cleaves fibrinogen to fibrin M (which then becomes fibrin P) and activates F13 → F13a acts on fibrin P to generate cross-linked fibrin network.
  • Drugs targets: rivaroxaban and apixaban inhibit F10a; dabigatran inhibits thrombin.

  Reversal of haemostasis

  Mechanical:

  • Vasodilation reduces haemostasis: prostacyclin (PGI2) inhibits TxA2 and nitric oxide acts on vascular smooth muscle.
  • Clotting factors are diluted by rapid blood flow at edge of injury site.

  Chemical anticoagulation:

  • Protein S activates protein C → activated protein C inhibits F10a.
  • Antithrombin 3 (AT3) inhibits thrombin and F10a. Activity enhanced by heparinoids.

  Fibrinolysis:

  1. Thrombin stimulates release of tissue plasminogen activator (tPA) from endothelium
  2. tPA converts plasminogen (present in blood) to plasmin.
  3. Plasmin is a protease that cleaves the fibrin network and breaks it down.
  4. Plasminogen and tPA also bind directly to fibrin, concentrating them at site of required action.