Transfusion and Coagulopathy

Summary

• Surgical bleeding is far more often a mechanical problem than a haematological one: incomplete haemostasis is the most common cause of bleeding after an operation [1].
• The value of understanding the clotting cascade is therefore not that it explains most bleeding, but that it tells you which of the small number of patients who really do have a coagulopathy needs which product.
• This page covers normal haemostasis, the congenital and acquired bleeding disorders a surgeon meets, the tests used to characterise them, blood components and their indications, and the complications of transfusion, from the febrile reaction that is common and benign to the acute haemolytic reaction that can kill.
• The best single predictor of bleeding risk is not a coagulation screen but the history and examination [1].

Definition

Coagulopathy here means an impairment of clot formation or clot stability sufficient to cause or perpetuate bleeding. It may be inherited, acquired through drugs, organ failure or consumption, or produced by the resuscitation itself.

Massive transfusion is defined by the Oxford Handbook as replacement of the patient's whole circulating volume within 24 hours [2]. Bailey & Love separates the complications of blood transfusion into those arising from a single transfusion and those related to massive transfusion, which is a useful way to hold them in mind [3].

A type and crossmatch determines ABO compatibility; a type and screen determines ABO compatibility and additionally looks for preformed antibodies to minor antigens [4].

Pathophysiology

Three things happen at once when a vessel is injured: vasoconstriction, platelet adhesion, and thrombin generation [5].

• Platelet adhesion depends on von Willebrand factor, which links the GpIb receptor on the platelet to exposed collagen [1].
• Platelets then bind to each other through GpIIb/IIIa, which fibrin links together to form the platelet plug [5].
• Thromboxane A2, released from platelets, drives this: it increases platelet aggregation, promotes vasoconstriction, and triggers calcium release within the platelet, which exposes the GpIIb/IIIa receptor [5].
• Prostacyclin from endothelium does the opposite, it decreases platelet aggregation and promotes vasodilatation, raising platelet cAMP [5].

• The two pathways converge on factor X.
• The intrinsic pathway begins with exposed collagen, prekallikrein, high molecular weight kininogen and factor XII, which activates XI, then IX with VIII, then X with V [5].
• The extrinsic pathway is shorter: tissue factor from injured cells with factor VII activates X directly [5].
• From that convergence both routes convert prothrombin to thrombin and thrombin converts fibrinogen to fibrin; factor XIII then crosslinks the fibrin [5].

Thrombin is the key to coagulation, it converts fibrinogen to fibrin and fibrin split products, activates factors V and VIII, and activates platelets [5].

• Several facts about individual factors matter clinically.
• Factor VII has the shortest half-life [5].
• Factors V and VIII are the labile factors: their activity is lost in stored blood but retained in fresh frozen plasma [5].
• Factor VIII is the only factor not synthesised in the liver, it is made in endothelium along with von Willebrand factor [5].
• The vitamin K–dependent factors are II, VII, IX and X, together with proteins C and S [5].

Natural anticoagulation is dominated by antithrombin III, which binds and inhibits thrombin and inhibits factors IX, X and XI; heparin works by activating it, up to a thousandfold [6]. Protein C, vitamin K–dependent, degrades factors V and VIII and fibrinogen; protein S is its vitamin K–dependent cofactor [6].

Fibrinolysis runs on tissue plasminogen activator released from endothelium, which converts plasminogen to plasmin; plasmin degrades factors V and VIII, fibrinogen and fibrin, so the platelet plug is lost [6]. Alpha-2 antiplasmin is the natural inhibitor of plasmin, also released from endothelium [6].

• Dilutional coagulopathy is the mechanism that matters most in a bleeding surgical patient.
• Dilutional thrombocytopenia and dilution of coagulation factors occur with massive transfusion, and preventing this is central to damage control resuscitation [3][7].
• Two other resuscitation-induced problems compound it: cold products or a cold patient slow the enzyme reactions, so the patient must be warm to clot properly, and the citrate in stored blood binds calcium after transfusion and causes hypocalcaemia, which impairs clotting and can itself cause hypotension [7].

The cell-based model and its brakes in Schwartz's account

• Platelet α-granules release thrombospondin (stabilising fibrinogen binding), platelet factor 4 (a potent heparin antagonist) and β-thromboglobulin during the irreversible release reaction, which aspirin, NSAIDs, cAMP and nitric oxide inhibit at the second wave of aggregation, and the altered phospholipid surface ("platelet factor 3") catalyses Xa-Va-calcium conversion of prothrombin and IXa-VIII-calcium activation of X [9].
• The cascade's two arms map onto the tests, aPTT for the intrinsic factors (XII, XI, IX, VIII plus common II, X), PT for the extrinsic VII plus common factors, vitamin K and warfarin affecting II, VII, IX and X, but the cell-based model is truer: initiation as tissue factor–VIIa activates X and IX and Va assembles a prothrombinase making a little thrombin; amplification as thrombin activates adherent platelets; propagation as "tenase" (VIIIa/IXa) and prothrombinase (Va/Xa) complexes on the platelet surface produce the thrombin burst, VIIIa-IXa being 50 times more effective than TF-VIIa and five to six orders of magnitude more than IXa alone; thrombin then cleaves fibrinopeptide A for end-to-end and B for side-to-side polymerisation, stabilised by factor XIII and thrombin-activatable fibrinolysis inhibitor [9].
• Clot is confined by thrombomodulin acting as a thrombin sink and activating protein C, which with protein S cleaves Va and VIIIa (the most potent thrombin brake, factor V Leiden resists it and predisposes to venous thromboembolism) and consumes PAI-1 so tPA activity rises; tissue factor pathway inhibitor blocks TF-VIIa; antithrombin III neutralises all procoagulant serine proteases; and fibrinolysis by plasmin, from fibrin-selective endothelial tPA (released by thrombin and by kallikrein-cleaved bradykinin) or non-selective urokinase, yields fibrin degradation products, E-nodules and D-dimers that impair platelet aggregation and weaken clot in hyperfibrinolytic trauma coagulopathy and DIC, restrained by α2-antiplasmin cross-linked into fibrin by factor XIII and by TAFI's removal of lysine residues [9].
• Platelets live 7–10 days and account for 80% of overall clot strength, so aspirin (irreversible acetylation of prostaglandin synthase), clopidogrel and prasugrel (irreversible ADP-receptor blockade), dipyridamole and GP IIb/IIIa inhibitors are stopped about 5–7 days before elective surgery, without randomised evidence and with no guide for urgent cases beyond emerging TEG platelet mapping [9].

Clinical features

• The pattern of bleeding points to the compartment at fault. Platelet disorders cause bruising, epistaxis, petechiae and purpura [1].
• Epistaxis is common with von Willebrand factor deficiency and platelet disorders, and menorrhagia is common with bleeding disorders generally [1].
• The most common symptom of von Willebrand's disease is epistaxis; of haemophilia A, haemarthrosis [1].

Two points from the history are worth asking for by name. Abnormal bleeding with tooth extraction or tonsillectomy picks up 99% of patients with a bleeding disorder [1]. A normal circumcision does not exclude one, because the newborn may still have clotting factors from the mother, factor VIII crosses the placenta, so babies with haemophilia A may not bleed at circumcision [1].

In the anaesthetised patient the usual symptoms are unavailable, and a transfusion reaction may present as diffuse bleeding in the field [10].

Etiology

Congenital bleeding disorders

• Von Willebrand's disease is the most common congenital bleeding disorder [1].
• Types I and II are autosomal dominant, type III autosomal recessive [1].
• Type I, a reduced quantity of von Willebrand factor, accounts for 70% of cases and is often only mildly symptomatic; type II is a defect in the molecule itself; type III is complete deficiency, rare, and causes the most severe bleeding [1].
• The prothrombin time is normal and the PTT may be normal or abnormal, with a long bleeding time and an abnormal ristocetin test [1].

Haemophilia A is factor VIII deficiency, sex-linked recessive, with a prolonged PTT and normal PT [1]. Haemophilia B, Christmas disease, is factor IX deficiency, also sex-linked recessive, with the same laboratory pattern [1]. Factor VII deficiency is the mirror image: prolonged PT with a normal PTT, and a bleeding tendency [1].

Two named platelet receptor defects are worth separating, because their names are easily transposed. Glanzmann's is deficiency of the GpIIb/IIIa receptor, so platelets cannot bind to each other; Bernard-Soulier is deficiency of GpIb, so platelets cannot bind to collagen [1].

Acquired bleeding disorders

Uraemia inhibits platelet function, mainly by inhibiting the release of von Willebrand factor, and becomes relevant as the blood urea rises above roughly 60 to 80 [1].

Heparin-induced thrombocytopenia is caused by an IgG antibody to the heparin-platelet factor 4 complex, which destroys platelets but can also aggregate them and cause thrombosis, in which case it is HITT [1]. The clinical signs are a platelet count under 100, a fall of more than 50% from admission levels, or thrombosis while on heparin; it can occur with low doses, and it forms a white clot [1].

Disseminated intravascular coagulation shows decreased platelets, low fibrinogen, high fibrin split products with a high D-dimer, and prolongation of both PT and PTT; it is often initiated by tissue factor [1].

Drugs account for much of the rest. Aspirin inhibits cyclo-oxygenase in platelets and reduces thromboxane A2, and because platelets have no DNA they cannot resynthesise the enzyme, the effect lasts the life of the platelet [1]. Clopidogrel is an ADP receptor antagonist [1]. Acquired thrombocytopenia can also follow H2 blockers and heparin [1].

Hypercoagulable states

These present as venous or arterial thrombosis or embolism [11]. Factor V Leiden is the most common congenital hypercoagulability disorder, accounting for 30% of spontaneous venous thromboses; the defect is on factor V and causes resistance to activated protein C [11].

Antithrombin III deficiency deserves separate mention because heparin does not work in these patients, and the deficiency can develop after previous heparin exposure [11]. Treatment is recombinant AT-III concentrate or fresh frozen plasma, which has the highest concentration of AT-III, followed by heparin and then warfarin [11].

Antiphospholipid antibody syndrome is procoagulant despite a prolonged PTT, which is the trap [11]. It is caused by antibodies to phospholipids including cardiolipin and lupus anticoagulant; not all patients have lupus [11]. Diagnosis rests on a prolonged PTT not corrected with FFP, a positive Russell viper venom time, and a false-positive RPR test for syphilis [11].

Tobacco is the most common factor causing acquired hypercoagulability; the other acquired causes are malignancy, inflammatory states including inflammatory bowel disease, infection, oral contraceptives, pregnancy, rheumatoid arthritis, the postoperative state and myeloproliferative disorders [11].

Two iatrogenic states complete the list. Cardiopulmonary bypass activates factor XII and produces a consumptive coagulopathy, prevented with heparin [11]. Warfarin-induced skin necrosis occurs when a patient is started on warfarin without being heparinised first: proteins C and S have short half-lives and fall before the procoagulant factors, producing a transient hyperthrombotic state, and patients with relative protein C deficiency are especially susceptible [11].

Virchow's triad (stasis, endothelial injury and hypercoagulability) remains the framework for venous thrombosis; for arterial thrombosis the key element is endothelial injury alone [11].

Schwartz's detail on congenital and acquired defects

• Haemophilia A and B are X-linked recessive: under 1% activity is severe (spontaneous joint, intracranial, intramuscular, retroperitoneal, GI, GU and retropharyngeal bleeds), 1–5% moderate, 5–30% mild; normal platelets mean bleeding may be delayed and the diagnosis made only after a first extraction or tonsillectomy; targets are 30–40% for mild, 50% for severe and 80–100% for life-threatening bleeding, recombinant products are preferred for the untreated and HIV/HCV-negative, and up to 20% develop factor VIII inhibitors managed by higher doses when low-titre or by porcine VIII, prothrombin complex (plain or activated) or recombinant VIIa when high-titre [9].
• Von Willebrand's disease, the commonest congenital disorder, type I partial quantitative (desmopressin-responsive), II qualitative (variable), III total (vWF concentrate), bleeds like a platelet disorder with bruising, mucosal bleeding and menorrhagia; factor XI deficiency ("haemophilia C", recessive, Ashkenazi-enriched) rarely bleeds spontaneously and is treated with FFP (1 unit/mL) plus antifibrinolytics for menorrhagia and VIIa for inhibitors, its carriers being protected from thrombosis; deficiencies of II, V and X are recessive and treated with FFP (prothrombin half-life 72 hours, 25% sufficing; factor V labile, target 20–25%, sometimes with platelets for the platelet-V deficiency, and co-inherited VIII deficiency needing concentrate too); factor VII deficiency bleeds below 3% with epistaxis, mucosal and postoperative bleeding in 30% of operations, treated by FFP (VII half-life up to 4 hours) or recombinant VIIa (2 hours); factor XIII deficiency (Duckert, 1960) gives delayed bleeding because clots form but lyse, umbilical stump bleeding, intracranial haemorrhage and habitual abortion, replaced to 1–2% with FFP, cryoprecipitate or concentrate [9].
• Glanzmann thrombasthenia (1918; absent or dysfunctional GP IIb/IIIa) and Bernard-Soulier (GP Ib/IX/V vWF receptor) need platelet transfusion; storage pool disease, dense granule loss, isolated or with albinism in Hermansky-Pudlak, rarely both granule types, responds to DDAVP when mild and platelets when severe [9].
• Acquired thrombocytopenia arises from marrow failure (leukaemia, myelodysplasia, B12 or folate deficiency, chemotherapy, radiation, acute alcohol, viruses; reduced megakaryocytes), shortened survival (immune, DIC, TTP, HUS) or splenic sequestration (portal hypertension, sarcoid, lymphoma, Gaucher's, total platelet mass normal, bleeding less than the count suggests, transfused platelets also sequestered, splenectomy not indicated for portal hypertension); qualitative defects follow massive transfusion, antiplatelet drugs, myeloproliferative disease (intrinsic; delay surgery until the count is lowered), monoclonal gammopathy (protein–platelet interaction; chemotherapy or plasmapheresis), uraemia (dialysis or DDAVP; platelets merely raise antibodies) and liver disease [9].
• Immune thrombocytopenia, acute and post-viral in children, gradual and chronic in adults, with young functional platelets bleeding less per count, impaired production plus T-cell destruction, takes first-line corticosteroids (longer courses) or IVIG or anti-D 1 g/kg (Rh-positive), second-line splenectomy, rituximab, thrombopoietin agonists or immunosuppression, third-line combinations; drug-induced cases may need only withdrawal [9].
• Heparin-induced thrombocytopenia, anti-PF4–heparin antibodies at 5–7 days (1–2 days on re-exposure), suspected when platelets fall below 100,000 or by 50%, in 1–3% on full-dose unfractionated heparin but also with prophylactic or low molecular weight heparin (17% and 8% form antibodies, far fewer become thrombocytopenic), arterial or venous thrombosis without necessarily any thrombocytopenia, is scored by the 4Ts (low score excludes it), confirmed by ELISA (high negative, low positive predictive value; IgG-restricted or paired with serotonin release or platelet activation assays second line) and treated by stopping heparin and starting lepirudin, argatroban or danaparoid (argatroban in renal failure), with warfarin only after full alternative anticoagulation and platelet recovery because of its early hypercoagulability [9].
• TTP (ADAMTS13 inhibition leaving large vWF multimers; thrombocytopenia, microangiopathic haemolysis with schistocytes, fever, renal and neurological signs) is treated by plasma exchange with FFP and rituximab when relapsing; HUS (E. coli O157:H7 or other Shiga toxin producers, normal metalloproteinase, renal failure often needing replacement, fewer neurological signs) and overlap forms with lupus, HIV, ticlopidine, mitomycin C, gemcitabine, ciclosporin or tacrolimus are managed by drug withdrawal and plasmapheresis [9].
• DIC requires an inciting condition, embolised brain, marrow or amniotic fluid, malignancy, pancreatitis, liver failure, large aneurysms, snake bite, drugs, transfusion reaction, transplant rejection and above all sepsis, with thrombocytopenia, prolonged PT, low fibrinogen and raised FDPs, D-dimer or soluble fibrin monomers, the ISTH score tracking mortality; treatment is the cause and perfusion, FFP for bleeding (cryoprecipitate, fibrinogen or platelets as needed) and heparin when thrombosis or purpura fulminans predominates, activated protein C having been disproven; primary fibrinolysis follows urokinase release at prostatectomy or extracorporeal bypass and answers to ε-aminocaproic acid or tranexamic acid; polycythaemia vera thromboses and paradoxically bleeds, controlled by low-dose aspirin, phlebotomy and hydroxyurea [9].
• The liver makes II, VII, IX, X, fibrinogen, V, VIII, XI–XIII, antithrombin, plasminogen and proteins C and S, so cirrhosis is both hypo- and hypercoagulable: thrombocytopenia from hypersplenism, low thrombopoietin and immune destruction (hepatitis C, primary biliary cirrhosis) plus platelet–endothelial dysfunction, against low protein C, S, antithrombin and plasminogen with high vWF and VIII; TEG or ROTEM reads this better than PT/INR, correction is reserved for bleeding or procedures (platelets last hours and breed antibodies; splenectomy or embolisation risk portal vein thrombosis; TIPS is not indicated for platelets), FFP cannot fully correct because factor V is not the problem, cryoprecipitate helps below 200 mg/dL fibrinogen, vitamin K helps only cholestatic deficiency not hepatocellular failure, and raised D-dimers predict variceal bleeding [9].
• Trauma-induced coagulopathy is present in over a third of the severely injured at admission, independent of dilution, acidosis and hypothermia, driven by activated protein C, endothelial glycocalyx shedding with "auto-heparinisation" by heparan and chondroitin sulphate, platelet dysfunction and hyperfibrinolysis, occurring even without shock in isolated brain injury (tissue factor release) and pulmonary contusion; in 2540 patients physiological lysis (0.8–2.9%) carried 14% mortality, fibrinolytic shutdown (under 0.8%) 22% mostly from late organ failure and hyperfibrinolysis (3% or more) 34% mostly from haemorrhage, and clinical coagulopathic bleeding has fallen with damage control resuscitation [9].
• Antiphospholipid syndrome (lupus anticoagulant, anticardiolipin; lupus, rheumatoid arthritis, Sjögren's, infection, drugs) prolongs the aPTT in vitro yet thromboses in vivo and should be sought in recurrent thrombosis [9].

Diagnosis

PT and INR test the extrinsic pathway, measuring factors II, V, VII and X and fibrinogen; the PT is also the best single measure of liver synthetic function, and it is the test used to monitor warfarin, with a target INR of 2 to 3 for routine anticoagulation [12].

PTT tests the intrinsic pathway, measuring most factors except VII and XIII (so it does not pick up factor VII deficiency) as well as fibrinogen, and it is the test used to monitor heparin, with a target of 60 to 90 seconds for routine anticoagulation [12].

Activated clotting time is used intraoperatively: 150 to 200 seconds for routine anticoagulation, and above 400 seconds for cardiopulmonary bypass [12]. Bleeding time tests platelet function [12].

Thromboelastography reads as a set of abnormalities each with its own product. A raised R, the reaction time, calls for FFP; a raised K time or a low angle calls for cryoprecipitate; a low maximum amplitude calls for platelets or DDAVP; and a high LY30, the lysis at 30 minutes, calls for an antifibrinolytic, aminocaproic or tranexamic acid [12].

• Blood grouping and crossmatching have different timings, and knowing them determines what you can ask for in an emergency.
• Grouping (adding A, B and RhD agglutinins to donated blood) takes under 5 minutes; crossmatching, mixing donated blood with recipient serum, takes about 20 minutes [2].
• Bailey & Love gives longer laboratory figures: full crossmatching may take up to 45 minutes, type-specific blood matched only for ABO and rhesus can be issued within 10 to 15 minutes, and where blood must be given immediately group O is used [3].

For an acute haemolytic reaction the confirmatory findings are a haptoglobin below 50 mg/dL, free haemoglobin above 5 g/dL, and a rise in unconjugated bilirubin [10].

Tests, thresholds and viscoelastic assays in Schwartz's account

• Platelets run 150,000–400,000/µL; counts over 1,000,000 bleed or thrombose, major surgery bleeds below 50,000, minor surgery below 30,000, spontaneous haemorrhage occurs below 20,000, and ophthalmic and neurosurgical procedures still transfuse below 100,000 without supporting evidence [9].
• PT (thromboplastin and calcium) tests I, II, V, VII and X and suits vitamin K deficiency and warfarin because VII has the shortest half-life; the INR = (PT/normal PT)^ISI corrects for thromboplastin batches (human brain ISI 1, optimal reagent 1.3–1.5); aPTT (phospholipid, activator, calcium) tests I, II, V, VIII, IX, X and XII with heparin targeted to 1.5–2.5 times control (about 50–80 seconds), low molecular weight heparin mildly prolonging it without routine monitoring, anti-Xa assays when renal failure or severe obesity demand it; hirudin, chondroitin and dermatan sulphate, streptokinase and tPA also derange results; but plasma-based tests miss in vivo complexity and poorly reflect the actively bleeding patient [9].
• TEG (celite- or kaolin-activated whole blood, kaolin plus tissue factor for rapid TEG, oscillating cuvette and stationary pin) and ROTEM (stationary cuvette, oscillating pin read by light deflection) measure clot kinetics, strength and stability: r-value (reaction time to first fibrin; prolonged by factor deficiency or dilution (plasma), k-time (to a set strength; prolonged by hypofibrinogenaemia and factor deficiency) plasma), α-angle (clot acceleration; reduced by hypofibrinogenaemia and platelet dysfunction, cryoprecipitate or fibrinogen), maximal amplitude (clot strength; reduced by platelet or fibrinogen deficits, platelets, plus cryoprecipitate when the angle is also low), G-value (overall firmness; high in hypercoagulability) and LY30 (percentage amplitude loss 30 minutes after MA; fibrinolysis); TEG predicts thromboembolism, early transfusion needs, life-saving intervention and 24-hour and 30-day mortality, guides tranexamic acid for hyperfibrinolysis, returns faster and may cost less, and some centres use it instead of conventional tests in the emergency department [9].
• Excessive operative bleeding confined to the field means mechanical failure; diffuse bleeding may be the first sign of a haemolytic transfusion reaction (ADP from lysed cells aggregating platelets); post-transfusion purpura from HPA-1-positive donor platelets sensitises the recipient whose antibody then destroys their own antigen-coated platelets 5–6 days later for weeks, platelets being useless and steroids helpful; and Gram-negative, meningococcal, clostridial and staphylococcal sepsis defibrinate partly through haemolysis [9].

Thresholds and severity

Platelets: aim for a count above 50,000 before surgery and above 20,000 afterwards [1].

INR: above 1.5 is a relative contraindication to performing a surgical procedure; above 1.3 is a relative contraindication to central line placement, percutaneous needle biopsy and eye surgery [12].

Expected response to a unit: one unit of packed red cells should raise the haemoglobin by 1 g/dL, and the haematocrit by 3 to 5 points; one six-pack of platelets should raise the platelet count by 50,000 [4].

Timing of reversal agents: intravenous vitamin K takes 12 hours to start working and 24 hours for full effect; FFP acts immediately on infusion, though it takes 2 hours to thaw and complete the infusion; prothrombin complex concentrate also acts immediately, and the infusion itself takes 30 minutes [5].

Half-lives worth remembering: red cells 120 days, platelets 7 days, polymorphs 1 to 2 days [5].

Triggers and component facts in Schwartz's account

• The 1988 NIH consensus overturned the 10 g/dL or 30% haematocrit rule; a randomised ICU trial found haemoglobin 7–9 g/dL no worse than liberal transfusion, with lower mortality under 55 or with APACHE II 20 or less; data in ischaemic heart disease are mixed but mostly favour restriction in non-ST-elevation coronary syndromes; AABB recommends 7 g/dL for stable patients and 8 g/dL for cardiac or orthopaedic surgery and cardiovascular disease, with clinical context, one unit at a time for symptoms and no transfusion for isolated asymptomatic anaemia, since stored cells with low 2,3-DPG and P50 and deformed membranes offload oxygen and perfuse capillaries poorly [9].
• Landsteiner defined ABO in 1900 and Levine and Stetson Rh in 1939; component therapy displaced whole blood in the late 1970s on economics without outcome studies; Rh-negatives are 15% of the population, Rh-positive cells are acceptable to them except women of childbearing age, O-negative cells and AB plasma are universal, low anti-B-titre type A plasma now substitutes for scarce AB (85% of Americans are A or O; AB plasma carries more TRALI), platelets need no crossmatch, cold agglutinins mandate a warmer and forbid hypothermia when high-titre, alloimmunised or autoimmune patients need time to accumulate blood, and crossmatch precedes dextran, which interferes with typing [9].
• Red cells keep 42 days but age with falling ADP and 2,3-DPG, acidosis, lactate, potassium and ammonia and worse inflammation and organ failure; cryopreserved cells at −80°C keep 10 years with preserved ATP and 2,3-DPG and proved as safe as standard cells in a trauma trial, though 90 minutes of thawing limits emergency use; leukocyte reduction (99.9% of white cells removed by filtration, washed if needed) prevents most febrile reactions, HLA alloimmunisation, platelet refractoriness and CMV transmission and is standard in the West, its effect on infection and organ failure unproven though a large Canadian series suggested fewer deaths [9].
• Platelets are stored agitated at room temperature for 5 days (bacterial risk), one unit is about 50 mL and 5.5 × 10¹⁰ platelets raising the count by about 10,000/µL in a 70 kg adult, 50,000–100,000 is therapeutic, fever, infection, hepatosplenomegaly and alloantibodies blunt the rise, and HLA-matched platelets serve the refractory; FFP (the only source of factor V, frozen within hours, kept 2 years at −18°C, 20–30 minutes to thaw) becomes thawed plasma usable for 5 days at 2–4°C, liquid plasma never frozen keeps 26 days with a better haemostatic profile, and freeze-dried plasma, a World War II fluid abandoned for disease transmission, now made in France, Germany and South Africa, shelf-stable 2 years, reconstituted in minutes, used at the point of injury by the Israeli Defense Force and under IND by US Special Forces, is pathogen-reduced but unapproved in the United States [9].
• Schwartz's factor table: fibrinogen 200–400 mg/dL, half-life 72 hours, 60–100 mg/dL needed; prothrombin 72 hours, 15–20%; factor V 36 hours, 5–20%, labile (40% at a week); VII 5 hours, 5–30%; VIII 6–12 hours, 30%, labile; IX 24 hours, 20–30%; X 40 hours, 15–20%; XI 40–80 hours, 10%; XIII 4–7 days, under 1%; platelets 8–11 days, 60,000–100,000 needed, 40% at 20 hours and none at 48 hours in bank blood [9].

Treatment and Management

Choosing the component

Cryoprecipitate contains the highest concentrations of von Willebrand factor and factor VIII, along with high levels of fibrinogen, and is used in von Willebrand's disease and haemophilia A [14]. Fresh frozen plasma has high levels of all coagulation factors, protein C, protein S and antithrombin III [14]. DDAVP and conjugated oestrogens cause release of factor VIII and von Willebrand factor from endothelium [14].

Congenital disorders

Von Willebrand's disease is treated with recombinant VIII:vWF, DDAVP or cryoprecipitate, with one important exception: DDAVP will not work for type III, in which there is no von Willebrand factor to release [1].

Haemophilia A requires factor levels of 100% preoperatively, maintained at 80 to 100% for 10 to 14 days after surgery, with the PTT followed 8-hourly [1]. Haemophilia B requires 100% preoperatively but only 30 to 40% for 2 to 3 days afterwards, treated with recombinant factor IX or FFP [1]. A haemophiliac joint bleed should not be aspirated; treatment is ice, keeping the joint mobile with range of movement exercises, and factor VIII concentrate or cryoprecipitate [1].

Glanzmann's and Bernard-Soulier are both treated with platelets [1].

Acquired disorders

Uraemic bleeding is treated first with haemodialysis; DDAVP is used for acute reversal, and cryoprecipitate for moderate to severe bleeding [1].

Heparin-induced thrombocytopenia is managed by stopping heparin and anticoagulating with argatroban, a direct thrombin inhibitor; platelets should be avoided because of the risk of thrombosis [1]. Diagnosis is by ELISA for heparin antibodies as the initial screen, with the serotonin release assay for confirmation [1].

Disseminated intravascular coagulation is treated by treating the underlying cause, for example sepsis [1].

Antiplatelet and anticoagulant drugs before surgery

Aspirin, clopidogrel and warfarin are each stopped 7 days before surgery [1]. For warfarin, heparin can be started while it wears off [1]. A patient with a coronary stent who must stop clopidogrel for elective surgery is bridged with eptifibatide, a GpIIb/IIIa inhibitor [1].

For bleeding on these drugs the treatments differ: platelets for clopidogrel, and for warfarin prothrombin complex concentrate, which is fastest, or FFP, with vitamin K if there is time [1].

Major haemorrhage

Prevention of dilutional coagulopathy is the point of a balanced transfusion regimen. In most practice this means matched units of red blood cells, plasma and platelets in a 1:1:1 ratio, approximating whole blood, with crystalloids and colloids avoided if at all possible [3].

• A balanced regimen will not correct an established coagulopathy.
• Most bleeding patients are hyperfibrinolytic and should be given tranexamic acid empirically, as quickly as possible [3].
• Low fibrinogen levels are very common, and cryoprecipitate can be given empirically or guided by laboratory or point-of-care clotting tests such as thromboelastometry; platelet concentrates are given for low counts or observed platelet dysfunction [3].
• Clotting function should be assayed repeatedly during haemorrhage and acted on until bleeding is controlled [3].

The Oxford Handbook lists the practical measures that limit the damage of massive transfusion: infusion warmers and a warming blanket, close monitoring of the central circulation and respiratory function, calcium supplementation given with care, checking platelets, APTT and fibrinogen and replacing what is low, and checking potassium regularly [2].

Emergency blood

• Type O is the universal donor, containing no A or B antigens; men may receive Rh-positive blood, whereas prepubescent girls and women of childbearing age should receive Rh-negative blood [15].
• Type-specific blood, neither screened nor crossmatched, can be given relatively safely, though effects from antibodies to minor HLA antigens in the donated blood remain possible [15].
• Bailey & Love states the same convention in practical terms: O-negative to females, O-positive to males [3].

Anticoagulant reversal and perioperative management in Schwartz's detail

• Continuous heparin infusion bleeds less than intermittent dosing; low molecular weight heparin anticoagulates more reliably and cheaply but escapes conventional tests.
• Warfarin's effect is reduced (dose raised) by barbiturates, low-vitamin-K diets, oral contraceptives and oestrogens, corticosteroids and ACTH, and increased by phenylbutazone, clofibrate, anabolic steroids, L-thyroxine, glucagon, amiodarone, quinidine and cephalosporins; for major or life-threatening bleeding the 2012 CHEST guidance gives vitamin K 10 mg by slow IV infusion (to outlast the short half-life of the reversal agent) plus plasma or prothrombin complex concentrate, PCC reverses faster with less fluid overload at equal thrombotic risk and higher cost, and four-factor PCC (II, VII, IX, X) corrects INR more reliably than three-factor, Schwartz's protocol dosing Kcentra at 25 units/kg (max 2500) for INR 1.5–3.9, 35 units/kg (max 3500) for 4–6 and 50 units/kg (max 5000) above 6, withholding it for thrombosis within 3 months, overt DIC, HIT, high-risk thrombophilia or antiphospholipid syndrome, and rechecking INR at 1, 6 and 24 hours with repeat phytonadione if over 1.5 [9].
• Direct oral anticoagulants have no routine monitoring: idarucizumab, a humanised antibody fragment, reverses dabigatran; rivaroxaban, apixaban and edoxaban lack an approved antidote, andexanet alfa (recombinant Xa variant) and ciraparantag (cationic small molecule) are in trials, so four-factor PCC is used, and electively the drugs are held 36–48 hours before surgery with normal renal function, with activated or ecarin clotting time for dabigatran and anti-Xa levels for rivaroxaban when needed [9].
• Surgery can often proceed without full reversal when the aPTT is under 1.3 times control on heparin or the INR under 1.5 on warfarin, given meticulous technique and close observation, but not for the CNS or eye; emergency heparin reversal uses protamine, which causes hypotension, flushing, bradycardia and vomiting (worst in fish allergy) and itself prolongs the aPTT; parenteral vitamin K is given electively for biliary obstruction or malabsorption but is useless in hepatocellular failure; and bridging, though suggested by CHEST 2012, increased major bleeding without reducing thromboembolism in recent studies, so it is reserved for high-risk indications (mechanical valves, infarction, stroke or embolism within 30 days) with heparin stopped 4–6 hours before and restarted 12–24 hours after the procedure, while older events, thrombophilia and atrial fibrillation need no such stringency [9].
• Cardiopulmonary bypass activates platelets and factors on circuit surfaces, causing fibrinolysis, quantitative and qualitative platelet defects (sequestration, degranulation, fragments) compounded by shear, hypothermia, dilution and anticoagulation; activated clotting times are followed on pump, conventional tests wait until rewarming and protamine, TEG gauges the coagulopathy and predicts transfusion, empiric FFP and cryoprecipitate lack thresholds, indiscriminate platelets give no advantage, and ε-aminocaproic acid or tranexamic acid at induction, aprotinin and desmopressin (releasing endothelial factor VIII) cut bleeding and reoperation [9].

Damage control resuscitation and massive transfusion in Schwartz's account

• Sequential crystalloid-then-red-cells-then-plasma resuscitation from the 1970s rested on no quality data; damage control resuscitation, permissive hypotension, minimal crystalloid and artificial colloid, immediate balanced red cells, plasma and platelets in whole-blood-like ratios, and haemostatic adjuncts alongside mechanical control, followed a 2007 review of 246 military casualties in which a plasma:red cell ratio of 1:1.4 cut mortality from 65% (at 1:8) to 19%; PROMMTT showed haemorrhagic death at a median 2–3 hours with higher plasma (HR 0.31) and platelet (HR 0.55) ratios reducing 6-hour mortality; PROPPR randomised 680 patients at 12 centres to 1:1:1 versus 1:1:2 plasma:platelets:red cells with no difference in 24-hour (13% vs 17%) or 30-day (22% vs 26%) mortality but fewer haemorrhagic deaths at 24 hours (9% vs 15%), more haemostasis (86% vs 78%) and no excess in 23 secondary outcomes; the EAST meta-analysis found mortality 31% vs 38% for high versus low plasma ratios in 5292 patients and 28% vs 43% for platelet ratios in 1607, recommending ratios of 1:1 or more; plasma repairs the endothelial glycocalyx, whose shed syndecan-1 tracks severity, coagulopathy and death, whereas crystalloid raises hydrostatic pressure without repair [9].
• Substantial bleeding is 3 or more red cell units in any hour and massive transfusion traditionally 10 units in 24 hours, but the critical administration threshold (3 units within 60 minutes, additive each time it recurs) predicts death better (twofold per positive) and earlier; about 25% of severe trauma admissions receive early blood, only a few a massive transfusion (double in the military); prediction models (McLaughlin, Yücel, Moore, Schreiber; AUC 0.80–0.89) need laboratory or severity data, while the ABC score (heart rate, blood pressure, FAST, penetrating mechanism; AUC 0.83–0.90) misses under 5% of massive transfusion patients and identifies 85% of major trauma [9].
• Schwartz's guideline: O-negative uncrossmatched immediately (then O-negative for females, O-positive for males), type-specific uncrossmatched in 5–10 minutes, crossmatched in 40 minutes; unstable patients or non-responders after 1–2 units trigger the protocol, coolers of 6 red cells, 6 FFP and a 6-pack of platelets arrive in 1:1:1 from the first 2 units, platelets are kept over 100,000, fibrinogen is checked after 6 red cells and 20 units of cryoprecipitate (2 g) given if 200 mg/dL or less, laboratory (CBC, INR, fibrinogen, pH or base deficit, TEG) repeats after each cooler, and the protocol stops when bleeding stops [9].
• Fibrinogen is the first factor to fall critically, drops prehospital and predicts death, so early cryoprecipitate (feasible, raising levels without mortality change in a pilot) or room-temperature lyophilised, virally inactivated fibrinogen concentrate (not FDA-approved) is advocated; moving four thawed universal plasma units to the emergency department cut product use and raised 30-day survival, in-flight plasma in 1677 patients improved admission physiology and early mortality, and military prehospital protocols reduced deaths [9].
• Whole blood, over 10,000 units in Iraq and Afghanistan, higher haematocrit, factor activity and platelets than 1:1:1 components, better survival than components in two military series, low-titre universal use in Vietnam with 1 haemolytic reaction per 9600 units, haemostatic potential preserved 14 days cold, is returning through civilian pilot trials of leukoreduced platelet-poor crossmatched and low-titre platelet-containing uncrossmatched products [9].
• Tranexamic acid occupies plasminogen's lysine-binding sites, is 10 times more potent than aminocaproic acid, leaves platelets and coagulation tests unchanged, has a 2-hour half-life and renal excretion, reduces transfusion in bypass, liver transplantation and arthroplasty, is conditionally recommended by EAST early after severe injury (empiric versus TEG-documented hyperfibrinolysis remaining contested, thrombotic risk uncertain) and is withheld with active intravascular clotting or alongside activated prothrombin complex or factor IX concentrates [9].

Procedural interventions

Fibrinolysis after prostate surgery is a specific and easily missed cause of postoperative bleeding: prostatic surgery can release urokinase, which activates plasminogen and produces thrombolysis, treated with epsilon-aminocaproic acid, an inhibitor of fibrinolysis [1].

Local haemostatic measures used in theatre include the biological agents topical thrombin, fibrin sealant and tranexamic acid [16].

Polycythaemia vera requires preoperative preparation in its own right: keep the haematocrit below 48 and the platelet count below 400 before surgery, with treatment by phlebotomy, aspirin and hydroxycarbamide [11].

Local haemostasis in Schwartz's account

Direct digital pressure (at the site or proximally, as with a tourniquet or the Pringle manoeuvre) is the oldest and least traumatic method; small vessels take simple ligature, large pulsating arteries a transfixion suture, diffuse raw surfaces gauze or laparotomy pad packing, and cut bone bone wax; electrocautery coagulates by induced heat at an amplitude high enough for prompt coagulation but below arcing (protecting monitoring leads, pacemakers and defibrillators), needs a grounding plate to avoid burns and is explosive with ether, divinyl ether, ethyl chloride, ethylene and cyclopropane, while direct current of 20–100 mA and argon gas control raw-surface oozing by attracting negatively charged blood elements to the anode [9]. Topical agents are adjuncts, never substitutes for technique, used sparingly: absorbable gelatin foam (Gelfoam) and oxidised cellulose (Surgicel) provide a clotting matrix and microfibrillar collagen (Avitene) activates platelets; biological topical thrombin (human or recombinant preferred to bovine, which is immunogenic and can worsen coagulopathy; never into large vessels, where systemic thrombin risks DIC or death), cryoprecipitate-derived fibrin sealants (FloSeal, a fibrin patch controlled hepatectomy parenchymal bleeding in a randomised multicentre trial) and platelet sealants (Vitagel; collagen, thrombin and the patient's centrifuged fibrinogen and platelets) act at defined cascade steps; the ideal agent is potent, non-reactive, non-antigenic, biodegradable, sterilisable and cheap [9].

Complications

Haemolytic reactions

• Acute haemolysis follows ABO incompatibility and is antibody-mediated, a type II hypersensitivity reaction [10].
• It presents with back pain, chills, tachycardia, fever and haemoglobinuria, and can lead to acute tubular necrosis, DIC and shock [10].
• Management is fluids, diuretics, bicarbonate and pressors [10].
• The Oxford Handbook adds the immediate practical steps: stop the transfusion, give basic life support if needed, keep the bag and giving set for analysis and inform haematology, give crystalloid and furosemide to encourage diuresis, and be prepared for dialysis [2].

Delayed haemolysis is antibody-mediated against minor donor antigens and produces mild jaundice; if the patient is stable, observe [10]. The Oxford Handbook describes it as accelerated destruction of transfused red cells 7 to 10 days after transfusion, usually by antibodies to Rh E, Kell, Duffy or Kidd present at levels too low to detect beforehand; because the haemolysis is extravascular, haemoglobinaemia and haemoglobinuria are uncommon, and it shows instead as an unexpected fall in haematocrit a few days after transfusion, with hyperbilirubinaemia and a positive Coombs' test [2].

Non-immune haemolysis results from squeezed blood and is treated with fluids and diuretics [10].

Non-haemolytic reactions

• Febrile non-haemolytic transfusion reaction is the most common transfusion reaction, usually a recipient antibody reaction against donor white cells with cytokine release [17].
• The transfusion should be discontinued if the patient has had previous transfusions or if the reaction occurs soon after starting, and white cell filters used subsequently [17].
• Pyrexia typically begins over an hour after the transfusion is started, the severity is proportional to the number of leucocytes transfused and the rate of transfusion, and paracetamol 1 g limits the fever while antihistamines do not help [2].
• Bailey & Love notes that this reaction is rare with leukodepleted blood [3].

Urticaria is usually a reaction of recipient antibodies against donor plasma proteins, or against IgA in an IgA-deficient patient, and is treated with histamine blockers and supportive care [17].

Anaphylaxis presents with bronchospasm, hypotension, angio-oedema and urticaria, usually from recipient antibodies against donor IgA in an IgA-deficient recipient; it can be an airway emergency, treated with adrenaline, fluids, pressors, steroids and histamine blockers [17]. The Oxford Handbook gives the doses: stop the transfusion and disconnect the tubing, then adrenaline 0.5 mL of 1:1000 IM, chlorphenamine 10 mg IV and hydrocortisone 100 mg IV [2].

• Transfusion-related acute lung injury is rare but is the most common cause of death from a transfusion reaction [17].
• It is caused by donor antibodies to the recipient's white cells, which clot in the pulmonary capillaries and produce non-cardiogenic pulmonary oedema within 6 hours [17].
• The Oxford Handbook describes the same mechanism as recipient antibodies against donor HLA, with activated recipient leucocytes migrating to the lung and releasing proteolytic enzymes that cause a localised capillary leak [2].
• Bailey & Love notes it usually follows FFP [3].

Transfusion-related circulatory overload is a separate entity, characterised by acute dyspnoea, a high central venous pressure and hypoxia; stop the transfusion, and give high-flow oxygen and a loop diuretic such as furosemide 40 mg IV [2].

Infection

All blood products carry a risk of HIV and hepatitis except albumin and serum globulins, which are heat treated [4]. Donated blood is screened for HIV, hepatitis B, hepatitis C, HTLV, syphilis and West Nile virus [4]. CMV-negative blood is used in low-birthweight infants, bone marrow transplant recipients and other transplant patients [4].

The Oxford Handbook adds the window that screening cannot close: HIV and hepatitis C can be transmitted by an infective but seronegative donor for 15 to 20 days after infection [2]. CMV is common in the donor population at 40 to 60% [2]. Malaria may be transmitted by transfusion, as may new-variant Creutzfeldt-Jakob disease [2], and Chagas' disease can also be transmitted [7].

• Platelets are the blood product most often contaminated, because they are not refrigerated, and the most common bacterial contaminants are Gram-negative rods, usually E. coli [7].
• The Oxford Handbook names Staphylococcus, Enterobacter, Yersinia and Pseudomonas species and describes the presentation, pyrexia above 40°C with hypotension, during or hours after the transfusion, and, unlike a febrile transfusion reaction, not self-limiting [2].
• Management is volume resuscitation, culture of the patient with the bag and giving sets sent to microbiology, and empirical broad-spectrum antibiotics [2].

Complications of massive transfusion

Bailey & Love lists these as coagulopathy, hypocalcaemia, hyperkalaemia, hypokalaemia and hypothermia [3]. Patients transfused repeatedly over long periods, as in thalassaemia, may develop iron overload; each transfused unit of red cells contains approximately 250 mg of elemental iron [3].

Complications of a single transfusion, by contrast, are incompatibility haemolytic reaction, febrile reaction, allergic reaction, infection (bacterial, usually from faulty storage, hepatitis, HIV and malaria) air embolism, thrombophlebitis and transfusion-related acute lung injury [3].

Reaction rates and disease transmission in Schwartz's figures

• Transfusion-related events occur in about 10% of transfusions, under 0.5% serious, with deaths from TRALI, ABO haemolysis and bacterially contaminated platelets.
• Febrile non-haemolytic reactions (temperature rise over 1°C; 0.5–1.5%) from preformed cytokines and anti-leukocyte antibodies are prevented by leukoreduction and platelets stored under 5 days and softened by paracetamol; bacterial contamination (under 0.01% of red cells, under 0.05% of platelets; Gram-negatives grow at 4°C, but room-temperature apheresis platelets and FFP thawed in contaminated baths are the usual sources) kills up to 25% and is treated by stopping, culturing, oxygen, adrenergic blockade and antibiotics; allergic reactions (0.1–0.3% of units, up to 1% of transfusions, mostly with FFP and platelets) take antihistamines, adrenaline or steroids; TACO (1:200–1:10,000; rapid infusion into older cardiac patients) shows rising venous pressure, dyspnoea, cough and basal crackles and is treated by diuresis, slowing and restricting fluids; TRALI, non-cardiogenic oedema with hypoxaemia, fever, rigors and bilateral infiltrates within 1–2 hours and virtually always under 6, from anti-HLA class II or anti-HNA antibodies, fell below 1 in 10,000 units after plasma from female donors was restricted and is managed by stopping transfusion, notifying the service and supporting the lungs [9].
• Acute haemolysis (1:33,000–1:1,500,000 units; ABO incompatibility from clerical or technical error) is fatal in up to 6%, causing haemoglobinaemia, haemoglobinuria, DIC through factor XII and complement activation and tubular necrosis, presenting awake with infusion-site pain, flushing, back and chest pain, fever, dyspnoea, hypotension and tachycardia and under anaesthesia as diffuse bleeding and hypotension; the transfusion stops, recipient blood and the unit return to the bank, a positive Coombs' test is diagnostic and hydration protects the tubules; delayed haemolysis at 2–10 days is anamnestic IgG extravascular clearance with mild anaemia, unconjugated bilirubin, low haptoglobin, fever and a positive Coombs', needing antigen identification rather than treatment [9].
• Transmission: malaria (all components, usually P. malariae, incubation 8–100 days), Chagas', brucellosis, rarely syphilis, CMV mononucleosis; HCV and HIV-1 residual risk is under 1 per million donations and HBV about 1 per 300,000, hepatitis A almost never (no carrier state), West Nile virus is targeted by pathogen-inactivation trials, prions are transmissible with no inactivation, and Zika, detected in up to 2.8% of donors in endemic areas, transmitted by platelets in Brazil, causing microcephaly, cannot be screened by questionnaire and is tested under IND [9].

Outcomes

Stored blood is low in 2,3-DPG, which shifts the oxyhaemoglobin dissociation curve to the left and increases the affinity of haemoglobin for oxygen, so transfused blood does not immediately deliver oxygen as well as the patient's own [4]. The Oxford Handbook makes the same point about massive transfusion: large volumes of stored blood leave a circulating volume with poor oxygen-carrying capacity, raised potassium, hypothermia if not warmed, and coagulopathy from calcium sequestration, compounded by depletion of clotting factors from the blood loss itself [2].

Correction of coagulopathy is not necessary if there is no active bleeding and no haemorrhage is anticipated, a patient not due for surgery does not need their numbers normalised [3]. During major haemorrhage the opposite applies: coagulopathy should be anticipated and managed actively [3].

Blood substitutes remain investigational. Several oxygen-carrying substitutes, either biomimetic or abiotic, are under investigation in experimental animal or early clinical trials [3].

Saved on this device only — sign in to keep it if you switch devices.