Bleeding Disorders — Screening Tests, ITP, von Willebrand Disease, Haemophilia, DIC and Vitamin K Deficiency

Normal haemostasis has two steps. In primary haemostasis platelets stick to injured vessel wall (helped by von Willebrand factor) and clump together through the glycoprotein IIb/IIIa receptor. In secondary haemostasis the clotting cascade turns fibrinogen into a stable fibrin mesh. A defect in either step causes bleeding, but the pattern is different, and that difference is the first clue in any vignette.

Four simple tests localise most bleeding problems. The platelet count measures number; the bleeding time measures platelet function; the prothrombin time (PT) tests the extrinsic and common pathways; the activated partial thromboplastin time (aPTT) tests the intrinsic and common pathways.

Immune thrombocytopenia (ITP) is autoimmune destruction of platelets. The American Society of Hematology (ASH) defines it as a purpuric rash with a platelet count below 100,000/μL and a normal white cell count and haemoglobin. Secondary causes must be excluded: drug reactions, SLE, chronic lymphocytic leukaemia and infections such as HIV and hepatitis C.

• Children: usually follows a viral illness, is self-limiting and most recover within 3 months; ASH recommends observation (rather than IVIG or anti-D) for children with no or only mild bleeding.
• Adults: spontaneous remission is uncommon, so a chronic course is more likely.
• Bone marrow examination is usually not needed for typical ITP and is often inconclusive.

Complications of ITP. Most patients with symptoms have mucocutaneous bleeding — petechiae and epistaxis, but also gastrointestinal or urinary tract bleeding. The dangerous complication is intracranial haemorrhage, which presents with neurological deficits and causes most ITP-related deaths in both children and adults. Critical bleeding (intracranial, intraocular, retroperitoneal or any bleed with haemodynamic instability) needs urgent combined treatment. In chronic paediatric ITP, much of the morbidity comes from the infections that follow long-term immunosuppression.

Von Willebrand factor (vWF) has two jobs: it glues platelets to damaged endothelium and it carries factor VIII, protecting it from breakdown. Von Willebrand disease (vWD) is estimated to affect about 1% of the population, although clinically significant disease is much rarer. The gene is on chromosome 12, so — unlike haemophilia — it affects males and females equally.

• Labs: platelet count usually normal; bleeding time increased; aPTT may be prolonged because factor VIII is broken down faster without its carrier.
• Specific tests: vWF antigen, ristocetin cofactor activity (vWF:RCo; normal above 50 IU/dL) and collagen-binding activity; a low activity-to-antigen ratio suggests type 2.
• Treatment: a desmopressin (DDAVP) trial in type 1, some type 2 (not 2B) and acquired vWD; tranexamic acid as an antifibrinolytic (not in gross haematuria); cryoprecipitate or FFP only in life-threatening situations because of infection risk.

Haemophilia is the most common severe inherited bleeding disorder. Both forms are X-linked recessive, so affected males are typical; all daughters of an affected father are carriers and none of his sons are affected.

• Presentation: bruising when the infant starts to crawl or walk, bleeding after circumcision or intramuscular vaccination, and haemarthrosis — most often knees, then elbows, ankles, shoulders, wrists and hips.
• Avoid intramuscular injections; paracetamol and some COX-2 inhibitors are safe analgesics.
• Treatment: factor concentrates; adjuncts include desmopressin, tranexamic acid and epsilon-aminocaproic acid.
• Inhibitors: some patients form antibodies against infused factor VIII; they are measured with the Bethesda (or Nijmegen) assay.
• Emicizumab is a monoclonal antibody that mimics activated factor VIII; it does not resemble factor VIII structurally, so inhibitors do not block it.

In DIC the clotting system is switched on throughout the circulation, usually by tissue factor released in sepsis, trauma, cancer or obstetric emergencies. Widespread micro-clots use up platelets and clotting factors, so the patient clots and bleeds at the same time. Severe sepsis is the most common cause — DIC occurs in an estimated 30–50% of cases — classically with gram-negative organisms. Other triggers include severe trauma, haematological malignancy and placental abruption.

• ISTH scoring system: combines platelet count, a fibrin marker such as D-dimer, PT and fibrinogen; a high score indicates overt DIC.
• Treat the cause — this is the key step (antibiotics and source control in sepsis, delivery in abruption).
• Platelets if count < 50 × 10⁹/L with active bleeding, or 10–20 × 10⁹/L in those at high risk of bleeding.
• Fresh frozen plasma 15–30 mL/kg and cryoprecipitate to replace factors and fibrinogen.
• Heparin if thrombosis dominates; non-bleeding patients should get prophylactic heparin or LMWH.

Vitamin K is the cofactor for γ-glutamyl carboxylase, which adds Gla residues to factors II, VII, IX and X and to the natural anticoagulants proteins C, S and Z. Without it these proteins are made but stay inactive; they circulate as PIVKA (proteins induced by vitamin K absence). Warfarin produces the same state by blocking VKOR, the enzyme that recycles vitamin K — see anticoagulants.

• Labs: PT prolonged is the hallmark, with normal platelets and fibrinogen; aPTT is prolonged only in more severe deficiency.
• Adult causes: poor intake, fat malabsorption, liver disease and drugs that interfere with vitamin K.
• Newborns: almost all are relatively deficient (poor placental transfer, low liver stores, low levels in breast milk); exclusively breastfed babies without prophylaxis are most at risk.

For postpartum causes of bleeding see postpartum haemorrhage; for the opposite problem, excessive clotting, see Virchow's triad.