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Blood Transfusion 223
Usually 1 unit (250 mL of plasma containing >40 × 109/L platelets) is given,
and the platelet count should rise by >20 × 109/L.
Fresh frozen plasma is separated from blood cells and frozen for
storage. It contains all the coagulation factors and is used in acquired
coagulation factor deficiencies, such as massive haemorrhage or DIC.
Cryoprecipitate is the supernatant obtained after thawing of FFP at 4°C.
It contains factor VIII: C, von Willebrand factor (vWF) and fibrinogen and is
used in DIC where the fibrinogen level is very low (<1.0 g/L).
Factor VIII and IX concentrates are used for the treatment of haemophilia
and von Willebrand’s disease where recombinant factor concentrates are
unavailable.
Albumin (4.5% and 20%) is given to patients with acute severe
hypoalbuminaemia and to patients with liver disease and nephrotic syndrome
(20% solution) who are fluid overloaded and resistant to diuretics.
Immunoglobulins are used in patients with hypogammaglobulinaemia to
prevent infection and in patients with idiopathic thrombocytopenic purpura.
Specific immunoglobulin, e.g. anti-hepatitis B, is used after exposure of a
non-immune patient to infections.
Blood groups
The blood groups are determined by antigens on the surface of red cells.
The ABO and rhesus (Rh) systems are the two major blood groups. In the
ABO groups, individuals produce antibodies against the antigens that are not
present on their own red cells (Table 5.14). If red cells carrying A or B antigens are transfused to someone who has antibodies to these then a severe
immune reaction will occur, leading to shock and DIC (p. 233), which may
be fatal within minutes to hours. Patients with blood group AB can receive
blood of any other ABO group and are known as universal recipients. Most of
the population carry RhD antigens (Rh +ve) on their red cells and they can
receive any RhD type blood. RhD –ve patients should receive RhD –ve blood.
Exposure to RhD +ve blood through transfusion or pregnancy will lead to
development of anti-D.
Table 5.14 The ABO system: antigens and antibodies
Blood group Red cell antigen Antibody in patient’s plasma
A
B
AB
O
Blood groups O and A are the most common in the UK.
A
B
AB
No A or B
Anti-B
Anti-A
No antibodies to A or B
Anti-A and anti-B
224 Haematological disease
Procedure for blood transfusion
Compatibility testing is performed by the transfusion service in order to select
donor blood of the correct ABO and Rh group for the recipient and to screen
the patient’s serum or plasma for antibodies against other red cell antigens
(such as Kell and Duffy) that may cause a transfusion reaction. After a massive bleed when immediate transfusion is necessary, O RhD –ve blood can
be given without any transfusion investigations being undertaken. It should
need to be used only on rare occasions.
Many hospitals have guidelines for the ordering of blood for elective
surgery. Operations in which blood is required only occasionally can be
classified as ‘group and save’, in order to conserve blood usage. In this
case, ABO and Rh testing is performed along with the antibody screen.
Should blood unexpectedly be required during the course of the procedure,
compatible units can be released within a matter of minutes after an
immediate spin cross-match, whereby the patient’s serum or plasma is
incubated with the donor red cells to confirm compatibility.
Blood transfusion is a potentially hazardous procedure, which should
only be undertaken when the benefits outweigh the risks. Stringent
procedures need to be followed to ensure that the correct blood is given to
the correct patient and that any adverse reactions are dealt with promptly
and efficiently (Table 5.15). The temperature, pulse rate and blood pressure
should be recorded before the start of each unit, 15 minutes after the start
and at hourly intervals during the transfusion. A temperature rise of 1°C
or greater above baseline may indicate an acute haemolytic transfusion
reaction due to blood group incompatibility and is an indication to stop
the transfusion.
Complications of transfusing red blood cells
• ABO incompatibility is the most serious complication. It usually results
from errors in sample labelling or patient identification. Within minutes of
starting the transfusion there is pyrexia, rigors, dyspnoea, hypotension,
loin and back pain. Intravascular haemolysis leads to dark urine. The
transfusion must be stopped and the donor units returned to the blood
transfusion laboratory for testing with a new blood sample from the
patient. Emergency treatment may be needed to maintain the blood
pressure (p. 560). Autoimmune haemolysis may develop about a week
after transfusion in patients alloimmunized by previous transfusions in
whom the antibody level is too low to be detected during compatibility
testing.
• Febrile reactions are usually the result of anti-leucocyte antibodies in
the recipient acting against transfused leucocytes, leading to the release
of pyrogens. These reactions are less common since the introduction of
leucocyte-depleted blood.
Blood Transfusion 225
Table 5.15 Care of the patient receiving a blood transfusion
orblood products
1 Taking the blood sample for cross-matching
Identify patient positively by asking their surname, forename, date of birth
Confirm ID details on hospital wrist band match those on transfusion
request form
Label sample tube after blood has been added with patient identification
(full name, date of birth, hospital number), patient location, date of
sample and signature of person taking blood
2 Procedure for patient identification before transfusion
Check the blood bag is not leaking or wet and has a compatibility label
attached
Check patient identity (full name, sex, date of birth, hospital number)
matches that on the blood transfusion request form and compatibility
label attached to the blood pack. This is now usually done by a handheld
computer reading a barcode on the patient’s wristband and the
compatibility label and ensuring a match.
Check intravenous fluid prescription chart
3 Blood checks
Check expiry date of the blood on compatibility label and blood bag
Check blood group and blood pack donation number on blood transfusion
request form, blood pack and compatibility label
Record the blood pack donation number on intravenous fluid prescription
chart
Date, time and signature on blood transfusion request form, compatibility
label, intravenous fluid prescription chart
• Urticarial reactions are common but rarely severe. Treatment involves
slowing or stopping the transfusion and administering chlorphenamine
10 mg intravenously (i.v.).
• Anaphylactic reactions are seen in patients lacking IgA but who produce
anti-IgA that reacts with IgA in the transfused blood. This is a medical
emergency (p. 559).
• Transmission of infection has decreased now that donated blood is
tested for hepatitis B surface antigen and antibodies to hepatitis C,
human immunodeficiency virus (HIV)-1 and human T-cell lymphotropic
virus (HTLV)-1. Cytomegalovirus (CMV)-seronegative blood is given to
immunosuppressed patients who are susceptible to acquiring CMV
infection.
• Heart failure may occur, particularly in elderly people and those having
large transfusions.
226 Haematological disease
• Complications of massive transfusion (>10 units within 24 hours) include
hypocalcaemia, hyperkalaemia and hypothermia. Bleeding may occur as
a result of depletion of platelets and clotting factors in stored blood.
Concerns about the safety of blood transfusion have led to increased
interest in strategies for avoiding or reducing the use of donor blood. These
include artificial Hb solutions and autologous blood transfusion. The latter is
more popular in developing countries and involves collection of blood from
the donor/patient either pre-operatively or by intraoperative blood salvage.
THE WHITE CELL
The five types of leucocytes (white cells) found in peripheral blood are
neutrophils, eosinophils and basophils (which are all called granulocytes)
and lymphocytes and monocytes. Leucocytosis and leucopenia describe an
increase (>11 × 109/L) and a decrease (<4.0 × 109/L), respectively, in the
total circulating white cells.
Neutrophils
The prime function of neutrophils is to ingest and kill bacteria, fungi and
damaged cells.
Neutrophil leucocytosis is an increase in circulating neutrophils in
the peripheral blood (>10 × 109/L). It occurs in bacterial infection, tissue
necrosis, inflammation, corticosteroid therapy, myeloproliferative disease,
acute haemorrhage, haemolysis, leukaemoid reaction (excessive leucocytosis
characterized by the presence of immature cells in the peripheral blood) and
leucoerythroblastic anaemia (immature red and white cells appear in the
peripheral blood in marrow infiltration, e.g. malignancy, myeloid leukaemia,
severe anaemia). A ‘left shift’ describes the presence of immature white cells
(promyelocytes, myelocytes and metamyelocytes) in the peripheral blood and
occurs with infection and in leucoerythroblastic anaemia.
Neutropenia is a decrease in circulating neutrophils in the peripheral
blood (<1.5 × 109/L). Causes include race (in black Africans), viral infection,
severe bacterial infection, megaloblastic anaemia, pancytopenia, drugs
(marrow aplasia or immune destruction) and inherited abnormalities. An
absolute neutrophil count of <0.5 × 109/L is regarded as severe neutropenia
and may be associated with life-threatening infections. The management of
neutropenic sepsis is summarized in Emergency Box 5.1.
Eosinophils
Eosinophils play a part in allergic responses and in the defence against infections with helminths and protozoa. Eosinophilia (normal range 0.04–0.44 ×
109/L, 1%–6% of total white cells) occurs in asthma and allergic disorders,
parasitic infections (e.g. Ascaris), skin disorders (urticaria, pemphigus and
Haemostasis and Thrombosis 227
eczema), malignancy and the hypereosinophilic syndrome (restrictive cardiomyopathy hepatosplenomegaly and very high eosinophil count).
Monocytes
Monocytes are precursors of tissue macrophages. Monocytosis (normal
range 0.04–0.44 × 109/L, 1%–6% of total white cells) occurs in chronic
bacterial infections (e.g. tuberculosis), myelodysplasia and malignancy, particularly chronic myelomonocytic leukaemia.
Lymphocytes
There are two types: T and B lymphocytes. Lymphocytosis occurs in response
to viral infection, chronic infections (e.g. tuberculosis and toxoplasmosis),
chronic lymphocytic leukaemia and some lymphomas.
HAEMOSTASIS AND THROMBOSIS
A bleeding disorder is suggested when the patient has unexplained (i.e. no
history of trauma) bruising or bleeding, or prolonged bleeding in response to
injury or surgery, e.g. after tooth extraction.
Haemostasis
Haemostasis is the process of blood clot formation at the site of vessel injury.
When a blood vessel wall breaks, the haemostatic response must be quick,
localized to the site of injury, and carefully regulated. Abnormal bleeding or
a propensity to non-physiological thrombosis (i.e. thrombosis not required
for haemostatic regulation) may occur when specific elements of these
processes are missing or dysfunctional.
Haemostasis is a complex process and depends on interactions between
the vessel wall, platelets and coagulation and fibrinolytic mechanisms.
• Vessel wall. Platelet adhesion and thrombus formation is inhibited on
the intact endothelium by its negative charge and also by antithrombotic
factors (thrombomodulin, heparin sulphate, prostacyclin, nitric
oxide, plasminogen activator). Injury to vessels leads to immediate
vasoconstriction, thus reducing blood flow to the injured area, and
endothelial damage results in loss of antithrombotic properties.
• Platelets. Intimal injury and exposure of subendothelial elements leads to
platelet adherence to collagen and vWF in the subendothelial matrix via
the platelet membrane receptor glycoprotein (Gp) Ib. GpIIb/IIIa receptor
on the platelet surface is then exposed, forming a second binding site for
vWF. Deficiency of GPIb or vWF leads to congenital bleeding disorders:
Bernard–Soulier disease and von Willebrand’s disease, respectively.
Following adhesion, platelets spread along the subendothelium and
228 Haematological disease
release the contents of their cytoplasmic granules containing adenosine
diphosphate (ADP), serotonin, thromboxane A2, fibrinogen and other
factors. ADP leads to a conformational change in the GpIIb/IIIa receptor,
allowing it to bind to fibrinogen, a dimer that acts as a bridge between
platelets and so binds them into aggregates (platelet aggregation).
During aggregation, platelet membrane receptors are exposed, providing
a surface for the interaction of coagulation factors and ultimately the
formation of a stable haemostatic plug.
• Coagulation. Coagulation involves a series of enzymatic reactions leading
to the conversion of soluble plasma fibrinogen to fibrin clot (Fig. 5.5).
The local generation of fibrin enmeshes and reinforces the platelet
plug. Coagulation is initiated by tissue damage. This exposes tissue
factor (TF), which binds to factor VII. and this complex has the dual
effect of converting factor X to factor Xa (‘a’ indicates active) and factor
IX to factor IXa. Generation of factor Xa alone is insufficient to allow
haemostasis to proceed to completion. Factor VIII consists of a molecule
with coagulant activity (VIII: C) associated with vWF, which prevents
premature breakdown of VIII: C. Factor VIII increases the activity of factor
Injury
IX IX
VIIa
TF
IXa
VIIIa
TFPI
XIa
XI
Thrombotic
activation
XXaVa
Prothrombin
Fibrinogen
Fig. 5.5 Coagulation mechanism. The in vivo pathway begins with the activation
of factor X by the complex formed by factor VIIa and tissue factor. Factor XI is
activated by thrombin. TF, tissue factor; TFPI, tissue factor pathway inhibitor.
Thrombin
Fibrin
Haemostasis and Thrombosis 229
IXa by 200 000-fold. All of the coagulation factors are synthesized in the
liver and vWF is synthesized by endothelial cells and megakaryocytes. The
vitamin K-dependent enzymes are prothrombin and factors VII, IX and X.
• Physiological limitation of coagulation. Coagulation would lead to
dangerous occlusion of blood vessels if it was not limited to the site
of injury by protective mechanisms. Antithrombin binds to and forms
complexes with coagulation factors, thereby inactivating them. Its
activity is increased by heparin. Activated protein C inactivates factors
V and VIII and this is enhanced by the cofactor protein S. Inherited
deficiency or abnormality of these natural anticoagulant proteins is
termed thrombophilia and places the patient at increased risk of venous
thromboembolism (p. 236).
• Fibrinolysis. Fibrinolysis is a normal haemostatic response that helps
to restore vessel patency after vascular damage. The plasma protein
plasminogen is converted to plasmin by activators (principally tissue
plasminogen activator, tPA) released from endothelial cells. Plasmin
breaks down fibrin and fibrinogen into fragments collectively known as
fibrin degradation products (FDPs), which include D-dimers.
Bleeding disorders are therefore the result of a defect in vessels, platelets
or the coagulation pathway (Table 5.16).
Investigation of bleeding disorders
The most appropriate initial investigations may be suggested by the history
and examination. Bleeding from multiple sites suggests a generalized haemostatic defect. Enquiries should be made about family history, intercurrent
disease, alcohol consumption and drugs.
Vascular/platelet bleeding is characterized by bruising of the skin and
bleeding from mucosal membranes. Bleeding into the skin is manifest as
petechiae (small capillary haemorrhages, a few millimetres in diameter) and
superficial ecchymoses (larger areas of bleeding).
Coagulation disorders (e.g. haemophilia A and B) are typically
associated with bleeding after injury or surgery, spontaneous haemarthroses
(bleeding into joints) and muscle haematomas. The most common cause of
abnormal bleeding is thrombocytopenia.
• Platelet count and blood film will show the number and morphology of
platelets and any blood disorder such as leukaemia.
• Coagulation tests are abnormal with deficiencies or inhibitors of the
clotting factors. If the abnormal result is corrected by the addition of
normal plasma to the patient’s plasma in the assay, then the result is
abnormal as a result of deficiency and not of inhibitors.
• The prothrombin time (PT) is prolonged with abnormalities of factors VII,
X, V, II or I, liver disease, or if the patient is on warfarin. The international
normalized ratio (INR) is the ratio of the patient’s PT to a normal control
when using the international reference preparation. The advantage of the
230 Haematological disease
Table 5.16 Classification of bleeding disorders
Blood vessel defect
Hereditary
Hereditary haemorrhagic telangiectasia
Connective tissue disorders, e.g. Marfan’s, Ehlers–Danlos syndromes
Acquired
Severe infections, e.g. meningococcal, typhoid
Drugs: steroids, sulphonamides
Allergic: Henoch–Schönlein purpura, autoimmune rheumatic disorders
Others: scurvy, senile purpura, easy bruising syndrome
Platelet defect
Thrombocytopenia (Table 5.17)
Platelet dysfunction
Inherited, e.g. Bernard–Soulier syndrome
Acquired: renal and liver disease, paraproteinaemias, platelet inhibitory
drugs, e.g. aspirin
Coagulation defect
Hereditary: haemophilia A or B, von Willebrand’s disease
Acquired: anticoagulant treatment, liver disease, disseminated intravascular
coagulation
INR over the PT is that it uses international standards and thus allows
international comparison of results.
• The activated partial thromboplastin time (APTT) is prolonged with
deficiencies or inhibitors of one or more of the following factors: XII, XI,
IX, VIII, X, V or I (but not factor VII). Heparin prolongs the APTT.
• Thrombin time (TT) is prolonged with fibrinogen deficiency,
dysfibrinogenaemia (normal levels but abnormal function), heparin
treatment or DIC.
• The bleeding time is a measure of the interaction of platelets with the
blood vessel wall and is abnormal in von Willebrand’s disease, in blood
vessel defects, and when there is a decrease in the number or function
of platelets.
These tests will localize the site of the problem. Further specialized
investigations (e.g. platelet aggregation studies and measurement of
fibrinogen, FDPs and individual clotting factors), will be necessary to identify
the exact haemostatic defect correctly.
Platelet disorders
Platelet disorders are the result of thrombocytopenia (platelet count <150 ×
109/L; see Table 5.17) or disorders of platelet function, e.g. those occurring
Haemostasis and Thrombosis 231
Table 5.17 Causes of thrombocytopenia
Impaired production Excessive destruction
Bone marrow failure Immune
Megaloblastic anaemia Autoimmune – ITP
Leukaemia Secondary immune (SLE, CLL, viruses,
drugs, e.g. heparin)
Myeloma Post-transfusion purpura
Myelofibrosis Other
Myelodysplasia Disseminated intravascular coagulation
Solid tumour infiltration Thrombotic thrombocytopenic purpura
Aplastic anaemia (see Table 5.6) Haemolytic uraemic syndrome
HIV infection Sequestration
Hypersplenism
Dilutional
Massive transfusion
Thrombocytopenia due to impaired production is selective megakaryocyte depression (drugs,
chemicals) or more often also associated with failure of red and white cell production.
CLL, chronic lymphocytic leukaemia; ITP, immune thrombocytopenic purpura; SLE,
systemic lupus erythematosus.
with aspirin treatment and uraemia. Congenital abnormalities of platelet
number (e.g. Fanconi’s anaemia, Wiskott–Aldrich syndrome) or function (e.g.
Bernard–Soulier syndrome) are all extremely rare.
Mild thrombocytopenia can be artefactual and due to platelet clumping or
a blood clot in the sample. This is excluded by asking the haematologist to
confirm an unexpectedly low count by manual differentiation. Spontaneous
bleeding from skin and mucous membranes is unlikely to occur with platelet
counts above 20 × 109/L. Increased destruction or decreased production can
be differentiated by bone marrow examination, which will show, respectively,
increased or decreased numbers of megakaryocytes (platelet precursors).
Platelet transfusion is usually indicated when the platelet count is very low
(<10 × 109/L) or to maintain a platelet count of >50 × 109/L in the presence
of active bleeding or prior to an invasive procedure.
Immune thrombocytopenic purpura (ITP)
This describes immune destruction of platelets.
• ITP in children often follows viral infection. There is rapid onset of
purpura, which is usually self-limiting.
• ITP in adults is usually less acute than in children and is characteristically
seen in young women. It may occur with other autoimmune disorders,
232 Haematological disease
e.g. systemic lupus erythematosus (SLE) and thyroid disease, in patients
with chronic lymphatic leukaemia and after infection with some viruses,
e.g. HIV. There is a fluctuating course, with easy bruising, epistaxis and
menorrhagia. Major haemorrhage is rare.
Investigation
There is thrombocytopenia with normal or increased megakaryocytes on
bone marrow examination. The detection of platelet autoantibodies (present
in 60%–70%) is not essential for diagnosis, which often depends on exclusion of other causes of excessive destruction of platelets.
Management
Patients with platelet counts greater than 30 × 109/L require no treatment
unless they are about to undergo a surgical procedure. Platelet transfusions
are reserved for intracranial or other extreme haemorrhage.
First-line therapy. Oral corticosteroids produce a response in two-thirds
of patients but relapse is common when the dose is reduced. Intravenous
immunoglobulin (i.v. IgG) is useful where a rapid rise in platelet count is
desired, especially before surgery.
Second-line therapy is splenectomy, to which the majority of patients
respond. In cases where splenectomy is not successful, possible treatments
include immunosuppressive agents such as rituximab. Thrombopoietin
receptor agonists, such as romiplostim and eltrombopag, drive increased
platelet production and may be used in refractory ITP.
Thrombotic thrombocytopenic purpura (TTP)
Widespread adhesion and aggregation of platelets lead to microvascular thrombosis and profound thrombocytopenia. This occurs due to
deficiency of ADAMTS 13, a protease which is normally responsible
for degradation of vWF. ADAMTS 13 deficiency is congenital, sporadic
or autoantibody mediated (pregnancy, SLE, infection, drug treatment
(e.g. clopidogrel)). There is florid purpura, fever, fluctuating cerebral
dysfunction and haemolytic anaemia with red cell fragmentation, often
accompanied by renal failure. The coagulation screen is usually normal but lactate dehydrogenase levels are markedly raised as a result
of haemolysis. Treatment is with plasma exchange (to remove the
antibody to ADAMTS 13), methylprednisolone and rituximab. Platelet
concentrates are contraindicated. Caplacizumab is an immunoglobulin
which inhibits the vWF interaction with glycoprotein Ib. It speeds up
normalization of the platelet count and reduces recurrent TTP.
Inherited coagulation disorders
Inherited disorders usually involve a deficiency of only one coagulation factor,
whereas acquired disorders usually involve a deficiency of several factors.