EM guidemap - Transfusion medicine

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Introduction

Red cell transfusion

Fresh frozen plasma

Cryoprecipitate

Platelet transfusion

Management of patients taking oral anticoagulants

Management of major bleeding following fibrinolytic therapy

Appendix

Introduction

- this guidemap contains some basic information related to the use of red blood cells and other blood component products used in transfusion therapy

Red cell transfusion

- all red cells have multiple antigens, some of which can result in a major transfusion reaction if a patient receives an incompatible blood transfusion

- the major red cell antigens are antigens of the the ABO and the Rh type

- the ABO antigens are present at birth and reciprocal antibodies are present by 6 - 12 months of age

(anti-ABO antibodies are IgM antibodies that bind complement and cause agglutination and destruction of red cells => immediate intravascular hemolysis)

- the major Rh system antigen is the D antigen and it is found in 85% of the population

- the D antigen is very immunogenic and > 80% of Rh negative patients will develop anti-D antibodies if they are exposed to Rh positive blood

(anti-D antibodies are IgG antibodies that bind to the surface of the red cells => deformed red cells, which are then sequestered in the spleen => delayed extravascular hemolysis)

ABO system and blood selection
Blood group  RBC antigen RBC antibody RBC choice Plasma choice
A A  anti-B A, O A, AB
B B anti-A B, O B, AB
AB A, B none A, B, AB, O AB
O H anti a, anti B O O, A, B, AB
Rh group and blood selection
Rh group Rh antigen Rh antibody RBC choice Plasma choice Platelet choice
Rh positive D positive none pos or neg either either
Rh negative D negative anti D negative either neg or either

* Rh-negative blood products should always be given to Rh-negative females of child bearing age to prevent the formation of anti-D antibodies

(Rh-immunoglobulin should be given concurrently to a Rh-negative female when Rh-positive blood has to be emergently transfused because of an acute, life-threatening bleeding situation eg. ruptured ectopic pregnancy)

- Rh-negative males and elderly Rh-negative females can be given Rh-positive blood if emergent transfusion is required and there is insufficient Rh-negative blood available

(however, Rh-positive blood should preferably not be given to a Rh-negative patient who has previously received Rh-positive blood, because the patient will have pre-formed anti-D antibodies that may result in early/delayed hemolysis of the donor cells and decreased donor cell survival)

- a complete type and crossmatch should always be performed if time permits - it usually takes 30 - 45 minutes to completely type-and-crossmatch blood

- type-specific blood should only be used if blood needs to be transfused within 10 - 15 minutes of ED arrival and there is insufficient time to completely cross match blood

- if there is more time available prior to initiating an emergency blood transfusion, an abbreviated cross match is a much safer option than simply using type-specific blood (without any antibody screening testing)

(it takes 5 - 10 minutes to simply type blood for ABO and Rh compatability, but a type-and-screen - which also includes an immediate-spin cross match - can be performed in 20 - 30 minutes => it may be better to wait the additional 10 - 20 minutes to obtain partially cross matched blood if the patient needs a "relatively stat" blood transfusion - rather than take the risk of using type-specific blood, which is released by the blood bank without performing an immediate-spin cross matching of the patient's serum and the donor's RBCs to check for unexpected antibodies)

- type O (universal donor) blood is only used in the most critical situations - a life-threatening bleed requiring an immediate blood transfusion within a few minutes of ED arrival (major trauma, ruptured ectopic pregnancy or ruptured abdominal aortic aneurysm not responding to crystalloid recuscitation in the field)

(whole blood should not be used because the donor plasma contains anti-A and anti-B antibodies, which will cause agglutination of the recipient's red blood cells, and if  > 2 units of type O whole blood have been given => one needs to continue to use type O  whole blood for recuscitation; however, this should not be a problem if packed red cells are used because pRBC's contain little plasma, and there is insufficient amounts of anti-A/anti-B antibodies  present to cause red cell hemolysis if packed red cells of the patient's original blood group are subsequently transfused)

- the amount of blood ordered depends on the size of the patient, the initial hematocrit and the rate of ongoing blood loss

(massive transfusions given rapidly require the use of blood warmers to prevent iatrogenic hypothermia)

- in stable patients, who do not require an immediate blood transfusion, a type-and-screen should be ordered if there is a possible need for a blood transfusion, and a type-and-crossmatch should only be performed if transfusion seems inevitable

- the ideal blood use ratio is 1.5 crossmatched units/transfused units

(cross matched blood is reserved for a particular patient for 48 hours, and is therefore out-of-circulation and not available to other patients during that time period)

- a ratio of 2 is acceptable, while a ratio > 3 - 4 suggests that a physician should have a higher threshold for cross-matching blood

- indications for blood transfusion include:-

(there are really no 'fixed' rules as to when an acutely bleeding patient should receive a blood transfusion and the "target" hemoglobin level should be flexible - it depends on multiple factors such as the underlying health of the patient, the initial hematocrit value, the rate of ongoing bleeding, and the efficacy of the patient's physiological compensatory mechanisms - ? the "target" hemoglobin level should probably be ~ 7 - 8 g/dl in a healthy patient and ~ 10 g/dl in an elderly patient with cardiac and/or cerebral ischemia; also, many patients with a chronic anemia can tolerate a Hb in the 4 - 6 g/dl range => asymptomatic patients with chronic anemia do not necessarily require a blood transfusion if there in no evidence of a progressive anemia + no evidence of impaired cardio-respiratory or bone marrow function)

- blood is administered as packed red cells and 1 unit of packed red cells has a volume of  ~ 250 ml and a hematocrit of ~ 60 - 70%, and the packed cells should be administered over 1 - 2 hours (2 - 3 ml/kg/hour) in a stable patient

(the packed cells can be diluted with normal saline to allow faster administration through a smaller gauge needle (22 - 24g) if it is not possible to obtain vascular access with a larger IV catheter; the packed cells should always be administered within 30 minutes of thawing or the unit should be returned to the blood bank for proper storage; and the total transfusion time should be < 4 hours)

- the packed cells are administered through a standard blood filter, which should be replaced after 2 - 3 units have been administered

(some physcians use microaggregate filters in patients who have compromised lung function and who are going to receive multiple units of packed cells - to decrease the likelihood of "shock lung" from accumulated aggregated debris in the packed red cells - and these filters have to be changed after each unit of packed cells)

- one unit of packed cells should increase the Hb by ~ 1g/dl in the average adult (or a 3% increase in the Hct), and every 1 ml/kg of packed cells should increase the hematocrit by 1% in pediatric patients

(red cell viability decreases by ~ 1% per day during proper storage and > 70% of the transfused red cells should remain viable for 24 hours if the blood has been properly stored => the hematocrit should be measured about one hour after the transfusion is completed - the hematocrit will depend on the viability of the transfused red cells + rate of ongoing blood loss)

- leucocyte-reduced packed cells are given when it is important to i) decrease the likelihood of a non-hemolytic febrile reaction secondary to anti-leucocyte/platelet antibodies, ii) reduce the risk of transmitting a viral infection (especially CMV) to immuno-compromised patients, and iii) decrease the chance of a graft-versus-host reaction in immuno-compromised patients eg. bone marrow transplant patients

(one simple way of reducing the amount of leucocytes transfused is to use special, leucocyte-reducing blood filters)

- blood should only be mixed with normal saline and no medications should be added to the IV line, which is solely dedicated to the blood transfusion

- adverse reactions to blood transfusions include:-

Acute hemolytic reaction

- usually due to an ABO incompatability, and usually due to a clerical error and patient-blood product misassignment (1/7,000 transfusions)

- should be suspected when the patient complains of fever, chills, burning sensation at the transfusion site, severe joint or low back pain, chest constriction, respiratory distress, anxiety or a sense of impending doom

- these symptoms may be accompanied by tachycardia and hypotension, and the severity of the reaction is often proportional to the amount of blood transfused

(it is important to always transfuse blood slowly for the first 15 minutes and to recheck the patient's clinical status and vital signs  every 5 minutes during the first15 minutes - so as to receive early warning of a major ABO incompatability reaction)

- a severe reaction will often include DIC, hemoglobinuria, cardiogenic shock and renal failure

(hypotension and blood oozing from mucosal surfaces may be the only signs of a major hemolytic reaction in an anesthetised or unconscious patient)

- treatment should be targeted toward maintaining hemodynamic stability (crystalloids +/- vasodepressors), maintaining  adequate renal blood flow (low-dose dopamine infusion) and ensuring an urine output of  >100cc/hour (IV fluids + loop diuretics)  - after immediately stopping the transfusion and replacing the IV tubing

(blood specimens should be taken for repeat compatibility testing, repeat hematocrit, coagulation studies, direct and indirect Coombs testing, serum haptoglobin levels, free serum hemoglobin level and serum bilirubin; and the urine should be tested for hemoglobinuria)

Delayed hemolytic reaction

- most often caused by Rh, Kell, Kidd or Duffy antibodies that bind to the surface of the red cells => deformation of the red cells => splenic squestration of the deformed red cells => extravascular hemolysis

(> 25% of patients receiving > 5 units of type O blood during an emergency transfusion will develop hyperbilirubinemia secondary to a minor hemoltyic reaction - from the small amounts of anti-A/anti-B antibodies in the donor's plasma)

- seen 2 - 10 days after a blood transfusion when the patient presents with fever, jaundice, hemoglobinemia and hemoglobinuria

- there is no specific treatment and the reaction is usually mild

Febrile non-hemolytic reaction

- usually due to anti-leucocyte and anti-platelet antibodies, or due to cytokines produced in platelet concentrates during storage

- most commonly seen in multi-transfused or multiparous individuals and occurs in 1:200 transfusions

- the patient usually presents with fever, chills, headache and malaise within 1 - 2 hours of transfusion, and the symptoms usually last a few hours

- the present blood transfusion should be stopped, because it is not possible to differentiate a febrile non-hemolytic transfusion reaction from a more serious immediate hemolytic reaction (or a bacterial contamination reaction causing sepsis)

(formal tests should be performed to exclude a hemolytic transfusion reaction or bacterial sepsis - pink plasma, which can be detected in a centrifuged blood sample at the bedside before laboratory testing can be completed, is an early sign of a major hemolytic reaction)

- the fever is treated empirically with acetaminophen while waiting the results of laboratory testing

- only ~ 15% of patients have a second febrile reaction and the patient can be pre-treated with acetaminophen => a patient with a history of  > 2x previous febrile reactions should receive leucocyte-reduced red cells

Allergic reaction

- immediate anaphylactic reactions are rare and suggest an Ig-A deficient patient

(anaphylactic reactions are treated in the standard manner with epinephrine, anti-histamines and steroids; and Ig-A deficient patients should either receive future blood products from other Ig-A deficient individuals or receive only saline-washed red cells)

- most allergic reactions are minor and include erythema, hives and itching

- with minor reactions => the blood transfusion can be continued, but it should be temporarily slowed + anti-histamines should be administered

- anti-histamines can also be used prophylactically if the patient has a previous history of minor allergic reactions

Dilutional coagulopathy

- due to the rapid transfusion of multiple units of blood causing a dilutional effect on the platelet count and the level of labile coagulation factors

(a transfusion-induced coagulopathy is more likely to be due to an iatrogenic dilutional thromboctopenia than a dilution of the coagulation factors)

- blood still coagulates normally if the level of coagulation factors are > 20 - 30% of normal and if the serum fibrinogen is > 75 mg/%

- replacement of the entire blood volume (80 ml/kg) leaves the patient with ~ 33% of the original concentration of coagulation factors, which may be sufficient to allow adequate blood coagulation

- there is no evidence to justify routine administration of FFP or platelet transfusions according to a pre-determined formulae => the patient should only be treated if there is objective evidence of a dilutional coagulopathy causing ongoing bleeding

- a repeat platelet count should be measured after 5 - 10 units of blood have been transfused, and platelet transfusions are only indicated if there is significant thrombocytopenia (platelet count < 50,000 cu.mm) + clinical evidence of microvascular bleeding

- FFP should be administered if clotting studies are abnormal (PT/PTT > 1.5 - 1.8 normal) , or after 5 - 10 units of rapid administration of blood - if clotting studies (PTT and aPTT) are not readily available + there is clinical evidence of microvascular bleeding

- cryoprecipitate should only be administered if the serum fibrinogen remains < 100 mg/dl despite adequate FFP administration

(1 unit of cryoprecipitate increases the serum fibrinogen by ~ 10 mg/% in the average-sized adult - unless massive bleeding continues)

Hypocalcemia (citrate toxicity)

- citrate accumulation only occurs when blood is transfused faster than one unit of blood every 5 minutes

- rare when using packed red cells, which has lower citrate concentrations in the added anticoagulant solution

- citrate accumulation is more common in patients with liver disease and associated hypotension

- clinical signs of citrate toxicity include peri-oral paresthesias, skeletal muscle tremors and a prolonged QT interval

- symptomatic citrate-induced hypocalcemia is treated with 1 - 10 ml of 10% calcium chloride by slow IV infusion

Transfusion-related acute lung injury (TRALI)

- due to leukoagglutinins (anti-WBC donor antibodies) that react with recipient WBC's => leucocyte aggregates and complement activation in the lungs => non-cardiogenic pulmonary edema within 1 - 4 hours of transfusion

- the diagnosis is made on clinical grounds and there is no objective test to differentiate TRALI from other causes of acute non-cardiogenic pulmonary edema

- treatment is empirical with steroids and respiratory support

- the condition usually subsides within 48 - 96 hours

- leucocyte-reduced red cells should be used for future transfusions

Graft-versus-host disease

- occurs when transfused donor lymphocytes multiply in an immuno-compromised recipient eg. bone marrow transplant patient, leukemic patient treated with chemotherapy, intra-uterine fetus receiving an intra-uterine blood transfusion

- causes bone marrow depression and sepsis

- presents with fever, anorexia, nausea, vomiting, diarrhea, rashes and pancytopenia days after the blood transfusion

- there is no effective treatment and fatality is common

- prevention is by exclusively using gamma-irradiated blood cell components

- indications for using irradiated blood components:-

- relative indications for using irradiated blood components include:- Infection

- all blood is pre-tested for antibodies against hepatitis B/C, HIV, and HTLV viruses and syphilis bacteriae; and for hepatitis B and HIV viral antigens

- the risk of infection from a single blood transfusion:-

- Hepatitis A = 1/1,000,000
- Hepatitis B = 1/30,000 - 1/250,000
- Hepatitis C = 1/30,000 - 1/150,000
- HIV = 1/200,000 - 1/2,000,000
- HTLV = 1/250,000 - 1/2,000,000
- Parvovirus B19 = 1/ 10,000
- Bacterial infection = 1/500,000

- blood that is also serologically negative for CMV and EBV should be used for serologically negative recipients in high risk groups - pregnant females, premature or low birth weight newborns, immunosuppressed and transplant patients

Fresh frozen plasma

- FFP is usually derived from a single donor and is no longer prepared from pooled plasma - because of the high risk of transmission of hepatitis and HIV viruses

(a single unit of FFP has the same risk of viral transmission as any other single donor blood product)

- the plasma is usually collected by centrifugation or plasmapharesis (from a single donor) and frozen within 6 hours of collection

- FFP contains labile coagulation factors that have a shelf life of ~ 1 year if stored at - 18°C

- the volume of each FFP unit is ~ 250 ml (~ 400 ml when collected by apheresis)

- PLAS + SD is a new product - pooled plasma, solvent/detergent treated - and it is the first product to use viral inactivation technology to markedly decrease the risk of viral transmission

(PLAS + SD was approved by the FDA in May 1998 and is now commercially available)

- indications for FFP include:-

(Cryoprecipitate is a better source of fibrinogen than FFP because less volume will be required and there is less risk of volume overload - 5 units of FFP with a volume of ~ 1250 ml contains the same amount of fibrinogen as 10 units of cryoprecipitate with a volume of ~ 100 - 250 ml and they should both increase the serum fibrinogen by 75 - 100 mg/dl)

- the required dose of FFP is dependent on the patient's clinical condition, the degree of depletion of the patient's coagulation factors and the rate of ongoing depletion of the patient's coagulation factors

- it is usually only necessary to increase the level of coagulation factors to > 20% of normal to ensure an adequate level

- dose of FFP = 5 - 20 ml/kg given slowly over > 10 minutes by IV infusion

- start with 2 units of FFP in the average-sized adult => repeat the PT/aPTT ~ 1 hour after the transfusion and give additional FFP if the PT/PTT > 1.5 x normal

(if platelets are being transfused, remember that for every 5 - 6 units of platelets, or 1 plateletpheresis unit, the patient is receiving the volume equivalent of 1 unit of FFP)

- the FFP is thawed at 37°C and must be given within 24 hours through a special filter

- the FFP should be ABO compatible, but cross matching is not required

- FFP should not be used as a volume expander, nutritional supplement, or source of immunoglobulin; and it should not be used to treat protein-losing states or hypoalbuminemia

Cryoprecipitate

- cryoprecipitate is prepared from a single unit of FFP by slowly thawing the FFP at 4°C and then harvesting the precipitant by centrifugation

- each unit of cryoprecipitate (volume = 10 - 25 ml/bag) contains 100 - 120 IU of factor VIII:C (anti-hemophiliac factor), 100 - 250 mg of fibrinogen, 40 - 70% of the original amount of factor VIII:vWF (von Willebrands factor) and 20 - 30% of the original amount of factor XIII

- cryoprecipitate is used to treat bleeding associated with:-

(desmopressin is used for mild/moderate type I von Willlebrands disease, but tachyphylaxis and the need for repeated doses of factor VIII:vWF minimize the role of desmopressin in severe type I von Willebrands disease)

- cryoprecipitate should preferably be ABO/Rh compatible, but it does not have to be cross-matched

- cryoprecipitate is administered in a dose of 1 - 2 units/10kg at a rate of 5 - 10 ml/min and ~ 10 bags are usually required for the average-sized adult

- each bag of cryoprecipitate increases the serum fibrinogen by ~ 10 mg/dl in the average-sized adult

(the amount of cryoprecipitate required depends on the degree of coagulopathy and the degree of bleeding - in patients with DIC and consumptive coagulopathy, the frequency and duration of therapy will depend on the rate of fibrinogen degradation => periodic measurement of the fibrinogen level is appropriate - a serum fibrinogen of 50 - 100 mg/dl is required for adequate coagulation)

- a single unit of cryoprecipitate carries the same risk of viral transmission as a single unit of FFP

Platelet transfusion

- platelets are derived from random single donors and prepared from whole blood by centrifugation and extraction of the platelet-rich supernatant, which is then expressed into a satellite bag and re-suspended with 50 - 60 ml of plasma

- platelets can also be derived from the buffy coat or obtained from a single donor by apheresis

- one bag of apheresis-derived platelets has a volume of ~ 300ml and is equivalent to 6 units of random donor platelets

- single donor apheresis-derived platelets are useful for patients, who have allo-antibodies against platelets -  to increase the platelet survival rate by ensuring that only allo-compatible platelets are transfused

- platelets cannot be refrigerated and are stored at room temperature for up to 5 days

- the efficacy of stored platelets is difficult to assess and usually ~ 66% of transfused platelets survive in the circulation, while ~ 33% get sequestered in the spleen

- platelets usually survive for ~ 5 days in a recipient, who does not have platelet antibodies or a consumptive coagulopathy

- ABO-compatible platelets survive longer, although it is not essential to give ABO-compatible platelets

(multiple platelet transfusions can result in a small degree of hemolysis of the recipient's red cells if they are not ABO-compatible, because the platelet transfusion units have a small amount of anti-AB red cell agglutinins in the associated plasma)

- the donor platelets only have to be Rh-compatible in Rh-negative females of child-bearing age

(Rh immunoglobulin should be given if the only available platelets are from Rh-positive donors - one vial of rhogam is sufficient to cover 30 units of Rh-positive platelets)

- the platelet units must be administered within 4 hours of preperation through a standard blood filter, or through a leukoreduction (third generation) platelet filter

(microaggregate blood filters cannot be used because they trap platelets)

- clinical indications for platelet infusions are:-

- at counts of < 5,000/cu.mm, a high likelihood of spontaneous hemorrhage exits and hemorrhage is extremely likely with trauma, surgery or an invasive procedure
- at counts between 5,000 - 10,000/c.mm, there is an increased likelihood of spontaneous hemorrhage and a high likelihood of bleeding with trauma, surgery or an invasive procedure
- at counts between 10,00 - 50,000/cu.mm there is a variably increased risk of bleeding with trauma, surgery or an invasive procedure
- at counts above 50,000/cu.mm bleeding due to platelet deficiency is extremely unlikely

- platelet transfusions are indicated i) if there is evidence of active bleeding or when major surgery is anticipated in a thrombocytopenic patient, who has a platelet count < 50,000/cu.mm; ii) prophylactically if the platelet count is < 5,000/cu.mm or iii) if the platelet count is > 5,000/cu.mm but < 50,000/cu.mm - on the basis of a significant risk of bleeding - if the patient complains of headaches, has significant GIT blood loss, develops confluent petechiae as opposed to scattered petechiae, or displays significant continuous bleeding from a wound or other site

(scattered mucosal hemorrhage, petechiae or traces of blood in the stool or urine do not necessarily indicate a higher risk of bleeding; however, increasing retinal hemorrhages is a sign of increased risk requiring platelet transfusion - the need for prophylactic platelets increases as the count gets closer to 5,000/cu.mm and decreases as the count gets closer to 50,00/cu.mm)

- platelet transfusions have limited usefulness when platelet destruction, either by antibodies or by consumption, is the cause of the thrombocytopenia; however, platelets should be considered when the platelet count is < 50,000/cu.mm and there is active bleeding

- platelets are usually contra-indicated in TTP, and should be limited to major surgery with excessive bleeding or life-threatening bleeding in ITP

(in ITP, the platelet transfusion should be preceded by the administration of IV immunoglobulin to increase platelet survival; also, remember that platelets may exacerbate the thrombotic tendencies in patients with heparin-induced thrombocytopenia)

- the amount and duration of of platelet therapy depends on the clinical situation - the platelet count should be maintained > 50,000/ml for at least 3 consecutive days if a thrombocytopenic patient undergoes major surgery

- the usual platelet dose = 1 unit of random single-donor platelets/10 kg administed at 5 - 10 ml/min IV

- the platelet count should be measured 1 hour after transfusion to determine whether further platelet transfusion units are necessary; and again in 16 - 24 hours to assess for platelet viability

- an individual unit of platelets increases the platelet count by 5,000 - 10,000/cu.mm in the average adult, unless continued bleeding or continued platelet consumption/destruction exists

- platelet allo-antibodies develop in 20 - 70% of patients who receive multiple platelet transfusions and they have a variable effect on the survivability of transfused platelets

- platelet refractoriness is defined as < 5,000 increase in platelet count 1 hour after transfusion of 6 units of random donor platelets (or a single unit of apheresis-derived platelets)

- platelet refractoriness may be related to fever, infection, DIC, splenomegaly, excessive bleeding, various drugs and anti-platelet antibodies

- refractory patients may require repeat platelet transfusions every 6 - 12 hours

- refractory patients may also require fresh platelets or a more careful selection of donor platelets based on HLA-typing

- if HLA-typed platelet transfusions are not effective, complex platelet cross-match testing may be required

- a bleeding time cannot be used to assess whether a thrombocytopenic patient requires a platelet transfusion

Management of a patient on oral anticoagulants

Introduction

- warfarin (coumadin) is the most common oral anticoagulant used in clinical practice

- warfarin produces an anticoagulant effect by interfering with the cyclic-interconversion of vitamin K and vitamin K epoxide in the liver, which leads to a depletion of vitamin K-dependent coagulant proteins - factor II, factor VII, factor IX and factor X

- warfarin produces an anticoagulant effect within 1 - 2 days by first affecting the level of factor VII (which has a short half-life of ~ 8 hours)

- however, it takes > 5 days for warfarin to have a substantial anti-thrombotic effect, which is mainly due to a reduction of the serum level of factor II (half-life of 72 hours) +/- factor X

- warfarin may cause an initial pro-thrombotic effect because it decreases the serum level of the endogenous anticoagulant protein factor C (serum half-life of ~ 6 - 8 hours) before it affects the serum levels of the coagulant factors (factors II, VII, IX and X) => transient state of increased thrombogenesis that lasts 24 - 36 hours

- an increase in the PT is a measure of warfarin's anticoagulant effect and the standardised PT measurement is the INR

- the therapeutic INR range = 2 - 3 for most conditions requiring oral anticoagulant therapy

- the therapeutic INR range = 2.5 - 3.5 in patients with prosthetic heart valves, the antiphospholipid syndrome and when warfarin is used for the prevention of recurrent MI's

(the European Society of Cardiology recommends an INR = 3.0 - 4.5 for first generation valves, an INR = 3.0 - 3.5 for second generation valves in the mitral position and an INR = 2.5 - 3.0 for second-generation valves in the aortic position)

- it takes ~ 5 days for warfarin to reach its full antithrombotic effect (factor II and factor X have a long serum half-life of > 2 days and it takes 5 days for the serum level of all the warfarin-dependent coagulation factors to be reduced to < 20%), although the INR may be in the therapeutic range before 5 days (because warfarin rapidly decreases the serum factor VII level to < 20%)

- heparin should be given to patients who require an immediate anti-thrombotic effect (DVT/PE and patients with mechanical valves), and there should be an overlap of ~ 2 days between the anti-thrombotic influences of heparin and warfarin

- there is room for flexibility in selecting the starting dose of warfarin - some physicians prefer to use a larger starting dose of 7.5 - 10 mg, but lower starting doses (5 mg) may be more appropriate in the elderly and in patients at high risk of bleeding

- PT monitoring is performed daily until the therapeutic range is reached and maintained for at least two consecutive days => then performed 2 - 3 x weekly for 1 - 2 weeks => then less frequently depending on the stability of the PT results

- it may be difficult to stabilise a patient's INR because many factors influence warfarin's anticoagulant effect

- unexpected fluctuations in dose response could be due to changes in diet, inaccuracy in PT testing, undisclosed drug use, poor patient compliance, surreptitious self-medication or intermittent alcohol consumption

- fluctuating levels of dietary vitamin K affect long-term warfarin therapy and an increased intake of vitamin K (weight reduction diets rich in green vegetables or vitamin K-containing dietary supplements) can decrease the effect of warfarin, while warfarin's effect may be increased in patients with poor vitamin K intake or in states of fat malabsorption

- the effect of warfarin can be overcome by low doses of vitamin K because the oxidised form of the vitamin can be reduced through a different warfarin-resistant vitamin K reductase system => the patient can become resistant to warfarin for up to a week or more if given large doses of vitamin K

-many drugs can influence the effect of warfarin by various mechanisms

Drug and food interactions with warfarin - based on the level of evidence
Level of evidence Potentiation Inhibition No effect
I
  • alcohol (if concomitant liver disease)
  • amiodarone
  • cimetidine
  • clofibrate
  • cotrimazole
  • erythromicin
  • fluconazole
  • isonoazid
  • metronidazole
  • miconazole
  • omeprazole
  • phenylbutazone
  • piroxicam
  • propanolol
  • sulfinpyrazone
  • barbiturates
  • carbamazepine
  • chordiazepoxide
  • cholestyramine
  • griseofulvin
  • nafcillin
  • rifampin
  • sucralfate
  • high vitamin K foods
  • large amounts of avocado
  • alcohol
  • antacids
  • atenolol
  • bumetadine
  • enoxacin
  • famotidine
  • fluoxetine
  • ketorolac
  • metoprolol
  • naproxen
  • nizatidine
  • psyllium
  • ranitidine
II
  • acetaminophen
  • chloral hydrate
  • ciprofloxacin
  • dextropropoxyphene
  • disulfuram
  • itraconazole
  • quinidine
  • phenytoin
  • tamoxifen
  • tetracycline
  • flu vaccine
  • dicloxacillin
  • ibuprofen 
  • ketoconazole
III
  • acetylsalicylic acid
  • diisopyramide
  • fluoroucail
  • ketoprofen
  • lovastatin
  • metozalone
  • moricizine
  • nalidixic acid
  • norfloxacin
  • ofloxacin
  • propoxyphene
  • sulindac
  • tolmetin
  • topical salicylates
  • azathioprine
  • cyclosporine
  • etretinate
  • trazodone
  
IV
  • cefamandole
  • cefazolin
  • gemfibrizol
  • heparin
  • indomethacin
  • sulfisoxazole
  
  • diltiazem
  • tobacco
  • vancomycin

Management of patients with high INR values with/without bleeding

- if a patient has an elevated INR and is not bleeding or does not require surgery, then it is reasonable to reduce the INR to a safer level of < 5.0 either by omitting a dose of warfarin or by administering vitamin K

(* it is controversial whether po vitamin K or sc vitamin K should be used - proponents of po therapy argue that sc vitamin K is poorly absorbed, while other investigators regard the situation as reversed and they believe that po vitamin K is poorly absorbed)

- avoid high doses of vitamin K if the INR is only slightly elevated because it can lead to warfarin resistance for up to 1 week

- if continuing warfarin therapy is critically indicated after high doses of vitamin K have been administered - a patient with a mechanical heart valve - then heparin should be given until the effects of the administered vitamin K have worn-off and the patient again becomes responsive to warfarin therapy

- if the patient has serious bleeding or requires major surgery, the INR should be reduced to 1.0 - 1.5 as soon as possible

(the sc route of administration of vitamin K is not recommended because the effect of vitamin K may be delayed and unpredictable; rapid IV bolus administration of vitamin K can cause anapylactoid reactions and vitamin K should be administered by slow IV infusion when rapid reversal of warfarin's effect is necessary - IV vitamin K should cause reversal of warfarin's effect in 6 - 24 hours)

- if a patient receiving long-term warfarin therapy requires elective or urgent surgery, it is reasonable to reduce the INR to the 1.0 - 1.5 range at the time of surgery

- there are a number of approaches that can be adopted prior to elective/urgent surgery, depending on the likelihood of major bleeding during surgery and the risk of thrombosis if the patient is inadequately anticoagulated

- simply discontinuing warfarin therapy will return the INR to the normal range in about 4 days if the INR was in the 2.0 - 3.0 range, and different supplemental approaches include:-

(the optimum approach usually requires a consultation with an appropriate specialist)

Management of major bleeding following fibrinolytic therapy

- if a patient has a significant bleed following fibrinolytic (tpa or retaplase or streptokinase) therapy => immediately discontinue the fibrinolytic agent and any heparin therapy

- tpa has a very short half-life and the effect wears off within a few minutes

- check the hematocrit, serum fibrinogen, thrombin time, aPTT and platelet count and type-and-cross blood

- most cases will not require further therapy => however, 10 bags of cryoprecipitate should be used to replenish the serum fibrinogen if the bleeding continues or if the serum fibrinogen level is < 100 mg/dl

- the dose of cryoprecipitate should be repeated if the serum fibrinogen is < 100mg/dl after administration of the cryoprecipitate

- FFP can be used to replenish fibrinogen if cryoprecipitate is not available -  5 units of FFP is equivalent to 10 bags of cryoprecipitate

- 2 units of FFP should also be administered (to replenish other coagulation factors) if bleeding continues and the serum fibrinogen > 100 mg/dl

- protamine (1mg per 100 units of heparin) should be given slowly IV (over 1 - 3 minutes and not to exceed 50 mg in any 10 minute period) if heparin has been infused in the previous 4 hours

- an anti-fibrinolytic agent can also be used if the bleeding continues after appropriate cryoprecipitate and FFP therapy eg. epsilon-amino-caproic acid - 5g over 60 minutes IV followed by 1 g/h for 8 hours, or tranexamic acid - 10 mg/kg IV q 8 hourly

- volume replacement with crystalloids and packed cells should be used prn

- if the patient has a life-threatening bleed or ICH => empirically administer cryoprecipitate, FFP and an anti-fibrinolytic agent +/- platelets if the platelet count is low

Appendix

Replacement therapy in inherited coagulation disorders (for major surgery or severe trauma and major bleeding)
Disorder Therapeutic product Loading dose Maintenance dose
Von Willebrands disease Humate P None recommended 30 units/kg q 12h for 2 days then 30 units/kg/day
  Cryoprecipitate None recommended 1 bag/10kg/day
Fibrinogen deficiency Cryoprecipitate 1 - 2 bags/10kg 1 bag/10mg every other day
  Purified fibrinogen 50 - 100 mg/kg 20 mg/kg every other day
Prothrombin deficiency or dysfibrinogenemia FFP 15 ml/kg 5 - 10 ml/kg/day
  Purified prothrombin concentrate 20 units/kg 10 units/kg/day
Factor V deficiency FFP 20 ml/kg 10 ml/kg q 12 - 24h
  Purified prothrombin concentrate 30 units/kg 10 - 20 units/kg q 6 - 24h
Factor VII deficiency FFP 20 ml/kg  5 ml/kg q 6 - 24h 
  Purified prothrombin concentrate 30 units/kg 10 20 units/kg q 6 - 24h
Factor X deficiency  FFP 15 - 20 ml/kg 5 ml/kg/day
  Purified prothrombin concentrates 15 units/kg 10 units/kg/day
Factor XI deficiency FFP 15 - 20 ml/kg 5 ml/kg q 12 - 24h
Factor XIII deficiency FFP 5ml/kg q 1 - 2 weeks Not usually required

(see the "hemophilia" guidemap for details on factor VIII and factor IX replacement therapy)