Bleeding disorders and transfusion

How bleeding stops

• The first response to injury is reflex vasoconstriction; then platelet adhesion (GpIb on platelets binds von Willebrand factor on exposed collagen), activation (ADP, thromboxane A₂) and aggregation (GpIIb/IIIa linked by fibrinogen) form the primary plug; finally the coagulation cascade makes fibrin.
• Endothelial Weibel–Palade bodies store vWF and P-selectin; platelet alpha granules also contain vWF and fibrinogen.

Reading the screening tests

• A prolonged APTT that corrects with normal plasma means a missing factor; one that does not correct means an inhibitor (lupus anticoagulant, factor VIII antibody).
• Prolonged APTT with a long bleeding time and normal PT points to the intrinsic pathway plus platelet adhesion: von Willebrand disease.

Platelet disorders

• Immune thrombocytopenia (ITP): IgG-coated platelets cleared by splenic macrophages; isolated low count with large platelets; marrow shows plenty of megakaryocytes. Children: acute, post-viral, self-limiting. Adults: chronic; test HIV, hepatitis C and *H. pylori*. First line oral prednisolone; IVIG acts within days (urgent bleeding, before surgery, and in pregnancy when steroids fail); then TPO agonists, rituximab, splenectomy. Platelet transfusion helps little because the antibody destroys the new platelets.
• Platelet refractoriness: no rise one hour after random-donor platelets in a multiparous, multiply transfused woman means HLA class I alloantibodies; use HLA-matched platelets. A good one-hour rise lost by 24 hours suggests sepsis, DIC or splenomegaly.
• Antiplatelet drugs: aspirin irreversibly blocks COX-1; clopidogrel irreversibly blocks the P2Y12 ADP receptor, so stop it 7 days before elective surgery (platelets live 7–10 days). After a drug-eluting stent within the past months, postpone elective surgery rather than stop dual antiplatelet therapy, since stent thrombosis is catastrophic.
• Essential thrombocythaemia with very high counts causes bleeding: the many platelets adsorb large vWF multimers (acquired vWD).
• Vascular purpura: steroid use and old age cause bruising on the backs of hands and forearms from loss of perivascular connective tissue; normal platelets and clotting. Scurvy, Henoch–Schönlein purpura (palpable purpura, abdominal pain, nephritis with rising urea) and hereditary haemorrhagic telangiectasia also bleed with normal tests.

Inherited coagulation disorders

• Haemophilia A (factor VIII) and B (IX) are X-linked recessive: affected males, carrier females. A boy whose maternal uncle or brother bled after circumcision needs an APTT and factor VIII/IX assay. Haemarthroses, iliopsoas bleeds with femoral nerve palsy, bleeding after extraction. Severe if under 1%.
• Treatment: recombinant factor concentrates (raise to 80–100% for surgery), emicizumab prophylaxis, tranexamic acid; no IM injections or NSAIDs.
• Desmopressin releases vWF and factor VIII from endothelial Weibel–Palade bodies, raising VIII two- to threefold. It works in mild haemophilia A and type 1 vWD, but not in severe haemophilia A (nothing to release) or haemophilia B.
• Carriers in pregnancy: factor VIII rises in the third trimester and falls after delivery, so a normal level at 36 weeks does not protect against postpartum bleeding.
• von Willebrand disease is the commonest inherited bleeding disorder (mostly autosomal dominant): mucosal bleeding, menorrhagia; diagnose with vWF antigen, ristocetin cofactor activity and factor VIII; desmopressin or vWF-containing concentrate.

Vitamin K and the liver

• Factors II, VII, IX, X (and proteins C and S) need vitamin K for gamma-carboxylation. Factor VII has the shortest half-life, so the PT rises first.
• Obstructive jaundice: without bile salts, fat-soluble vitamin K is not absorbed, so the INR rises; it corrects within 24 hours of IV vitamin K. Oral vitamin K is useless in complete obstruction. Cystic fibrosis and coeliac disease cause the same through fat malabsorption.
• Cirrhosis: the INR does not correct with vitamin K because hepatocytes cannot make the factors. A high INR does not protect against thrombosis, and FFP is not given to a stable patient for a number alone.
• Vitamin K deficiency bleeding of the newborn: late form (weeks 2–12) in breastfed babies who missed vitamin K, worse with cholestasis; intracranial bleeding. Pale stools and prolonged jaundice demand urgent work-up for biliary atresia.

DIC and its mimics

• Tissue factor exposure triggers widespread clotting: microthrombi plus consumption of platelets and factors, with secondary fibrinolysis.
• Causes: Gram-negative sepsis (commonest), trauma, burns, obstetric (abruption, amniotic fluid embolism, dead fetus, HELLP, septic abortion), acute promyelocytic leukaemia, mucin-secreting adenocarcinoma, incompatible transfusion, pancreatitis.
• APL: t(15;17), PML–RARA; promyelocytes full of Auer rods (faggot cells) release procoagulants from their granules (tissue factor) and activate fibrinolysis: severe bleeding with low fibrinogen. Start all-trans retinoic acid with arsenic trioxide on suspicion. Leukaemia is confirmed by bone marrow aspirate and trephine.
• Treat DIC by treating the cause; give platelets, FFP and cryoprecipitate (fibrinogen below 1.5 g/L) only for bleeding or procedures.
• Viper envenoming (saw-scaled viper): venom enzymes consume fibrinogen directly, giving unclottable blood (venom-induced consumption coagulopathy) often with a normal platelet count; antivenom is the treatment.
• Dengue thrombocytopenia comes from marrow suppression plus immune destruction of platelets; transfuse only for significant bleeding.
• TTP (ADAMTS13 deficiency): MAHA, low platelets, fever, neurological and renal signs; urgent plasma exchange; avoid platelets. HUS: *E. coli* O157 in children, MAHA, low platelets, AKI.

Heparin, thrombophilia and anticoagulant reversal

• HIT: 5–10 days after heparin, IgG binds heparin–platelet factor 4 complexes; the immune complexes activate platelets through Fc receptors, so the count falls while thrombosis occurs. Stop all heparin, start a non-heparin anticoagulant (argatroban, fondaparinux), give no platelets, and delay warfarin until the count recovers.
• Factor V Leiden: factor Va resists inactivation by activated protein C; clotting times are normal, so it needs an APC resistance or genetic test. Thrombophilia testing during acute thrombosis or on heparin is unreliable; defer it.

Blood components

• Irradiated components prevent transfusion-associated GVHD (stem cell transplant, Hodgkin lymphoma, purine analogues, intrauterine transfusion, donations from relatives).
• Cell salvage suits operations with large expected blood loss and a clean field, such as elective open AAA repair; it returns red cells only (no platelets or factors). O-negative red cells can be given to an AB-positive patient without reaction.

Massive transfusion

• One blood volume in 24 hours, or over 4 units in 1 hour. Use a balanced ratio of red cells, FFP and platelets, tranexamic acid within 3 hours, cryoprecipitate guided by fibrinogen, and warm all products to 37 °C to prevent hypothermia, which worsens coagulopathy and causes arrhythmias.
• Complications: hypocalcaemia (citrate), hyperkalaemia from stored cells (tall T waves), dilutional coagulopathy, metabolic alkalosis later, TRALI, TACO. Lethal triad: hypothermia, acidosis, coagulopathy.

Transfusion reactions

• Transfusion-transmitted infection: units are screened for HIV, HBV, HCV, syphilis and malaria; hepatitis C was the classic post-transfusion hepatitis, and window-period infections still occur.

Remember Mucosal bleeding means platelets or vWF; joint bleeding means factors; clotting with a low platelet count means HIT, APS, TTP or DIC.

Exam trap Giant platelets that fail ristocetin even with normal plasma: Bernard–Soulier; platelets that fail everything except ristocetin: Glanzmann.

Exam trap An INR that corrects with IV vitamin K means malabsorption or obstruction; one that does not means liver failure.

How FCPS asks about this

• Commonest inherited bleeding disorder: von Willebrand disease; haemophilia A is X-linked recessive.
• Desmopressin: releases vWF and VIII from endothelium; useful only in mild haemophilia A and type 1 vWD.
• Obstructive jaundice before ERCP: no bile salts to absorb vitamin K; give it IV.
• HIT: immune complexes activate platelets; stop heparin, start argatroban, no platelets.
• DIC: low platelets and fibrinogen, high D-dimer; APL t(15;17) treated with ATRA and arsenic.
• ITP in pregnancy with bleeding: IVIG; adult ITP first line prednisolone.
• Transfusion: stop at once for ABO reaction; platelets stored at 22 °C carry bacterial risk; warm blood in massive transfusion.