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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2826_Библиотеки_им_академика_М_И_Перельмана.pdf
Haemostasis and Thrombosis 233
Haemophilia A
This is the result of a deficiency of factor VIII (p. 228). It is inherited as an
X-linked recessive, affecting 1 in 5000 males.
Clinical features
Clinical features depend on the plasma levels of factor VIII.
• Levels <1 IU/dL (severe disease) are associated with frequent spontaneous
bleeding into muscles and joints that can lead to a crippling arthropathy.
• Levels 1–5 IU/dL are associated with severe bleeding following injury
and occasional apparently spontaneous episodes.
• Levels >5 IU/dL produce mild disease with bleeding only with trauma or surgery.
Cerebral haemorrhage is much more frequent than in the general population.
Investigations
There is a prolonged APTT and reduced plasma level of factor VIII. The PT,
bleeding time and vWF are normal.
Management
• Intravenous infusion of recombinant factor VIII concentrate is the treatment
possible. It is given as prophylaxis, e.g. before and after surgery, or to treat
an acute bleeding episode. Patients with severe haemophilia are given
prophylaxis three times weekly from early childhood to prevent permanent
joint damage. Many patients also have a supply of factor VIII concentrate at
home to inject at the first sign of bleeding.
• Synthetic vasopressin (desmopressin) – intravenous, subcutaneous or
intranasal administration – raises the level of factor VIII and is used to
treat some patients with mild haemophilia.
• Patients should be vaccinated against hepatitis A and B and encouraged
to take part in exercise regimens that avoid contact sport.
Complications
Recurrent bleeding into joints leads to deformity and arthritis. The risk of
infection (hepatitis C and HIV) from multiple transfusions of plasma-derived
clotting factor concentrates has been virtually eliminated because of the
exclusion of high-risk blood donors, screening of donors and heat treatment of factor VIII concentrates. Ten per cent of people with haemophilia
develop antibodies to factor VIII, and may need massive doses to overcome
this. Recombinant factor VIIa is also used to ‘bypass’ the inhibitor.
Haemophilia B (Christmas disease)
This is the result of a deficiency of factor IX, and affects 1 in 30 000
males. Inheritance and clinical features are the same as for haemophilia A.
Treatment is with factor IX concentrates. Desmopressin is ineffective.
234 Haematological disease
von Willebrand’s disease
vWF contributes to platelet adhesion to damaged subendothelium and stabilization of factor VIII in plasma. Deficiency of vWF leads to defective platelet
function (p. 230) and factor VIII deficiency (p. 228).
Clinical features
Types 1 and 2 are mild forms, with autosomal dominant inheritance, and
characterized by mucosal bleeding (nose bleeds and gastrointestinal bleeding) and prolonged bleeding after dental treatment or surgery.
Type 3 patients (recessively inherited) have more severe bleeding, but
rarely experience the joint and muscle bleeds seen in haemophilia A.
Investigations
Prolonged bleeding time reflects a defect in platelet adhesion. There is a
prolonged APTT, normal PT and decreased plasma levels of VIII: C and vWF.
Management
This depends on the severity of the bleeding, and includes treatment with
desmopressin and factor VIII concentrates, which contain vWF.
Acquired coagulation disorders
Vitamin K deficiency
Vitamin K is needed for the formation of active factors II (prothrombin), VII, IX
and X. Deficiency occurs with malnutrition, malabsorption and with warfarin
treatment (an inhibitor of vitamin K synthesis). There is an increase in PT and
APTT. Treatment is with phytomenadione (vitamin K, p. 240).
Disseminated intravascular coagulation (DIC)
DIC involves widespread generation of fibrin within blood vessels, caused by
initiation of the coagulation pathway. Consumption of platelets and coagulation
factors occurs, as well as secondary activation of fibrinolysis, leading to production of FDPs, which contribute to bleeding by inhibiting fibrin polymerization.
Aetiology
DIC results from massive activation of the clotting cascade. The major initiating factors are the release or expression of tissue factor, extensive damage to
vascular endothelium exposing tissue factor or enhanced expression of tissue
factor by monocytes in response to cytokines. The most common causes are
sepsis, major trauma and tissue destruction (surgery, burns), advanced cancer and obstetric complications (amniotic fluid embolism, placental abruption
DIC occurs in most cases of acute promyelocytic leukaemia due to generation
of procoagulant substances in the blood.
Thrombosis 235
Clinical features
The presentation varies from no bleeding at all to complete haemostatic failure,
with bleeding from venepuncture sites and the nose and mouth. Thrombotic
events may occur as a result of vessel occlusion by platelets and fibrin.
Investigations
The diagnosis is suggested by the history (e.g. severe sepsis, trauma, malignancy),
the clinical presentation and the presence of severe thrombocytopenia. It is confirmed by finding a prolonged PT, APTT and TT, decreased fibrinogen and elevated
FDPs. The blood film shows fragmented red cells. In mild cases with compensatory
increase of coagulation factors, the only abnormality may be an increase in the
FDPs, or in the D-dimer fragment reflecting accelerated fibrinolysis.
Management
• Treat the underlying condition.
• Platelets concentrates (to maintain count >50 × 109/L), FFP,
cryoprecipitate and red cell concentrates are indicated in patients who
are bleeding.
Liver disease
Liver disease results in a number of defects of haemostasis: vitamin K deficiency in cholestasis, reduced synthesis of clotting factors, thrombocytopenia
and functional abnormalities of platelets. DIC may occur in acute liver failure.
THROMBOSIS
A thrombus is defined as a solid mass formed in the circulation from the
constituents of the blood. Fragments of thrombi (emboli) may break off and
block vessels downstream.
Arterial thrombosis
Arterial thrombosis is usually the result of atheroma, which forms particularly
in areas of turbulent blood flow, such as the bifurcation of arteries. Platelets
adhere to the damaged vascular endothelium and aggregate in response to
ADP and thromboxane A2. This may stimulate blood coagulation, leading to
complete occlusion of the vessel, or embolization resulting in distal obstruction.
Arterial emboli may also form in the left ventricle after myocardial infarction,
in the left atrium in mitral valve disease, or on the surface of prosthetic valves.
Prevention
• Prevention of arterial thrombosis is achieved by minimizing risk factors
associated with atherosclerosis (p. 437) and with antiplatelet drugs.
236 Haematological disease
Aspirin (p. 240) irreversibly inhibits cyclo-oxygenase, reducing platelet
production of thromboxane A2 (p. 228). It is the most commonly used
antiplatelet drug.
• Clopidogrel (p. 241) and prasugrel block platelet aggregation and prolong
platelet survival by inhibiting the binding of ADP to its platelet receptor.
• Antibodies (e.g. abciximab), peptides (e.g. eptifibatide) and non-peptide
antagonists (e.g. tirofiban) block the receptor of GpIIb/IIIa, inhibiting the
final common pathway of platelet aggregation (p. 228). They are used
as an adjunct in invasive coronary artery intervention and as primary
medical therapy in coronary artery disease. Excessive bleeding has
beena problem.
• Epoprostenol is a prostacyclin which is used to inhibit platelet
aggregation during renal dialysis (with or without heparin) and is also
used in primary pulmonary hypertension.
Treatment
Treatment is with thrombolytic therapy (p. 246). Streptokinase is a purified
fraction of the filtrate obtained from cultures of haemolytic streptococci. It
forms a complex with plasminogen, which activates other plasminogen molecules to form plasmin. Tissue-type plasminogen activators such as alteplase
(t-PA), tenecteplase (TNK-PA) and reteplase (r-PA) are produced using
recombinant gene technology. Unlike streptokinase, they are not antigenic
and do not produce allergic reactions, though they have a slightly higher risk
of intracerebral haemorrhage. The use of thrombolytic therapy in myocardial
infarction, pulmonary embolism and ischaemic stroke is discussed on pages
455, 476, and 751, respectively.
Venous thrombosis
Unlike arterial thrombosis, venous thrombosis usually occurs in normal vessels, often in the deep veins of the leg. It originates around the valves as red
thrombi consisting of red cells and fibrin. Propagation occurs, inducing a risk of
embolization to the pulmonary vessels. Chronic venous obstruction in the leg
results in a permanently swollen leg which is prone to ulceration (post-phlebitic
syndrome). Heparin (p. 242), warfarin (p. 243) and the direct oral anticoagulants
(p. 245) are used in the prevention and treatment of thromboembolism.
Prevention
About 25 000 people in the UK die from preventable, hospital-acquired
venous thromboembolism every year. All patients should be assessed on
admission to hospital for their risk of developing venous thromboembolism.
Prophylactic measures include early mobilization, leg elevation and compression stockings. Thromboprophylaxis with low molecular weight heparin
(LMWH) is indicated in medical inpatients (i.e. non-surgical) with any of the
risk factors listed in Table 5.18. Recent long-distance, sedentary travel is an
Thrombosis 237
additional risk factor to consider in outpatients presenting with suspected
venous thromboembolism. Prophylaxis of venous thromboembolism in
surgical patients depends on the type of surgery and other risk factors
(see Table 5.18). Patients undergoing minor surgery (anaesthetic <60 min)
with no risk factors for venous thrombosis are not usually given LMWH.
Patients with risk factors and/or undergoing major surgery (anaesthetic >60
min) should receive LMWH (p. 242).
Treatment
Clinical features and investigation of deep venous thrombosis (DVT) and
pulmonary embolism (PE) are discussed on pages 488 and 473, respectively.
Treatment of established thromboembolism
• Obtain objective evidence of thrombosis as soon as possible; heparin
treatment is often started on the basis of clinical suspicion.
• Perform a coagulation screen and platelet count before starting
treatment to exclude a pre-existing thrombotic tendency.
• LMWH (p. 242). Where feasible, selected patients can be safely treated
as outpatients.
• Warfarin (p. 243) is started at the same time as heparin.
• The dose of warfarin is adjusted to maintain the INR, usually at two to
three times the control value.
Table 5.18 Risk factors for venous thromboembolism in
hospital inpatients
Major abdominal/pelvic surgery
Active cancer
Trauma, especially lower limb/pelvis
Pregnancy
Use of oestrogen-containing contraceptive/hormone replacement therapy
Age >60 years
One or more significant medical comorbidities, e.g. heart disease, respiratory
failure, acute infectious disease
Obesity (body mass index >30 kg/m2)
Significant immobility (including recent long haul travel >4 h)
Varicose veins with phlebitis
Hyperosmolar hyperglycaemic states (p. 657)
Personal history or first-degree relative with a history of venous thromboem-
bolism
Thrombophilia (p. 229), antiphospholipid syndrome
Inflammatory bowel disease
Nephrotic syndrome
Ethnicity: highest risk in people of African descent, intermediate in white
people and lowest in Asians
238 Haematological disease
Table 5.19 Indications for oral anticoagulation and target
international normalized ratio (INR)
Target INR
2.5 Pulmonary embolism, deep vein thrombosis, symptomatic inherited
thrombophilia, atrial fibrillation, cardioversion, mural thrombus,
cardiomyopathy
3.0 Prevention of embolization after insertion of mechanical prosthetic
aortic valves
3.5 Recurrence of venous thromboembolism while on warfarin therapy,
antiphospholipid syndrome, prevention of embolization after insertion of
mechanical prosthetic mitral valves, coronary artery graft thrombosis
• Heparin is overlapped with warfarin for a minimum of 5 days and
continued until the INR is in the therapeutic range (Table 5.19).
• Major side effects of heparin therapy are bleeding and thrombocytopenia.
The platelet count should be measured in all patients receiving heparin
for more than 5 days.
• Direct oral anticoagulants (DOACs) are an alternative to warfarin
and have had a major impact on the management of venous
thromboembolism. Four DOACs are currently licensed for venous
thromboembolism treatment: three direct factor Xa inhibitors (apixaban,
edoxaban and rivaroxaban) and one direct thrombin inhibitor (dabigatran)
(see pages 245).
Anticoagulation for a minimum of 3 months is sufficient for patients
after their first thrombosis with a precipitating cause, provided there are no
persisting risk factors. Long-term anticoagulation is required for those with
repeated episodes or continuing risk factors.
THERAPEUTICS
Oral iron
Reference nutrient intake is 8.7 mg for men, 14.8 mg for women.
Indications
Treatment of iron deficiency, prophylaxis in patients with risk factors for iron
deficiency, e.g. malabsorption, menorrhagia, pregnancy and post-gastrectomy. Adding a 250 mg ascorbic acid tablet at the time of iron administration
enhances the degree of iron absorption (iron is best absorbed as the ferrous
[Fe2+] ion in a mildly acidic environment). Tannins in tea inhibit iron absorption and should be avoided. Iron and folic acid combination preparations are
used in pregnancy for women who are at risk of developing iron and folic
acid deficiency.
Therapeutics 239
Preparations and dose
Ferrous sulphate has a higher concentration of elemental iron than ferrous
gluconate.
Ferrous sulphate. Tablets: 200 mg (60 mg elemental iron).
Treatment: 200 mg three times daily is expected to raise the haemoglobin level by approximately 10 g/L/week. Oral iron should be continued for
3months following a normal Hb result; prophylactic dose: 200 mg daily.
Side effects
Constipation and diarrhoea. Nausea and epigastric pain are related to the
amount of elemental iron ingested and are lower with preparations containing a low elemental iron content, e.g. ferrous gluconate.
Cautions/contraindications
Avoid long-term use unless indicated; excretion of iron is fixed at 1–2 mg of
iron per day through gastrointestinal loss, and prolonged use may result in
iron overload.
Folic acid
Reference nutrient intake is 200 μg/day.
Indications
Folate-deficient megaloblastic anaemia, prevention of folic acid deficiency in
chronic haemolytic states, renal dialysis and pregnancy, prevention of neural
tube defects.
Preparations and dose
Folic acid. To prevent first neural tube defect: 400 μg daily before
conception and during pregnancy.
To prevent recurrence of neural tube defect or in mothers with diabetes:
5 mg daily before conception and during pregnancy.
Side effects
Very rarely allergic reactions.
Cautions/contraindications
Folic acid should not be used in undiagnosed megaloblastic anaemia unless
vitamin B12 is administered concurrently; otherwise, neuropathy may be
precipitated.
Vitamin B
Reference nutrient intake is 1.5 μg/day.
12
240 Haematological disease
Indications
Vitamin B12 deficiency.
Preparations and dose
Hydroxocobalamin. Injection: 1 mg/mL.
Vitamin B12 deficiency without neurological involvement: 1 mg intramus-
cularly three times a week for 2 weeks, then 1 mg every 3 months lifelong.
Vitamin B12 deficiency with neurological involvement: 1 mg intramuscu-
larly daily for 6 days, then 1 mg every 2 months.
Cyanocobalamin. Tablets: 50 μg; Liquid: 35 μg/5 mL.
Vitamin B12 deficiency of dietary origin: 50–150 μg or more daily taken
between meals.
Side effects
Itching, fever, nausea, dizziness, anaphylaxis after injection. Hypokalaemia,
sometimes fatal, is due to intracellular potassium shift on anaemia resolution
after treatment of severe vitamin B12 deficiency.
Cautions/contraindications
Contraindicated if hypersensitivity to hydroxocobalamin or any component
of preparation.
Vitamin K
Mechanism of action
Vitamin K is a fat-soluble vitamin necessary for the production of blood
clotting factors and proteins necessary for the normal calcification of bone;
reference nutrient intake 1 μg/kg body weight.
Indications
Water-soluble form used to prevent deficiency in patients with fat malabsorption (especially biliary obstruction or hepatic disease); intravenous form for
excessive anticoagulation with warfarin and in patients with prolonged INR
prior to invasive procedures (e.g. endoscopic retrograde cholangiopancreatography [ERCP] or liver biopsy) or in whom there is bleeding.
Preparations and dose
Phytomenadione. Vitamin K1 tablets: 10 mg; Injection: 10 mg/mL.
Oral. Excessive anticoagulation (INR >8.0): 0.5–2.5 mg.
IV. Excessive anticoagulation and major bleeding (any INR value): 5 mg over
10 minutes together with prothrombin complex concentrate or FFP (15 mL/kg).
Menadiol sodium phosphate
Water-soluble tablets: 10 mg. For prevention of vitamin K deficiency in
patients with fat malabsorption: 10 mg daily.
Therapeutics 241
Side effects
Anaphylaxis with i.v. preparation.
Cautions/contraindications
Caution with menadiol in G6PD deficiency and vitamin E deficiency (risk of
haemolysis).
Drugs affecting haemostasis
Antiplatelet agents
• Aspirin
• Clopidogrel, prasugrel, ticagrelor
• Glycoprotein GP11b/111a inhibitor.
Mechanism of action
Decrease platelet aggregation and inhibit thrombus formation in the arterial circulation, where anticoagulants have little effect. Aspirin irreversibly inhibits the
enzyme cyclo-oxygenase, reducing production of thromboxane A2, a stimulator
of platelet aggregation. Clopidogrel is a pro-drug that is metabolized by the
liver, partly by cytochrome P450 2C19, before it is biologically active. It blocks
binding of ADP to platelet receptors and thus inhibits activation of the GpIIb/
IIIa complex and platelet activation. Prasugrel, a novel thienopyridine, is similar
to clopidogrel. Glycoprotein GpIIb/IIIa inhibitors (e.g. abciximab, eptifibatide,
tirofiban) prevent platelet aggregation by blocking the binding of fibrinogen to
receptors on platelets. They are used as an adjunct to percutaneous coronary
intervention in selected patients with acute coronary syndromes.
Indications
Aspirin. Secondary prevention of thrombotic cerebrovascular or cardiova-
scular disease: 300 mg chewed followed by maintenance dose of 75 mg daily.
Primary prevention when estimated 10-year cardiovascular risk is ≥ 20%
(p.437), provided that blood pressure is controlled.
After coronary artery bypass grafting.
In combination with clopidogrel – see below.
Atrial fibrillation (selected cases, p. 419).
Transient musculoskeletal pain and pyrexia (see Chapter 7).
Clopidogrel. Where aspirin is contraindicated for the prevention of
atherosclerotic events in patients with history of ischaemic stroke, myocardial
infarction or established peripheral artery disease.
Following coronary artery stent insertion: 300 mg daily, then 75 mg daily
with aspirin 75 mg daily. Continue clopidogrel for 6 weeks; 12 months if a
drug-eluting stent. Continue aspirin indefinitely.
Acute coronary syndrome: 300 mg, then 75 mg daily in addition to aspirin
and other treatments. Continue clopidogrel for 12 months.
242 Haematological disease
Side effects
An increased risk of bleeding is the main risk with all antiplatelet agents.
Aspirin causes peptic ulceration. Patients with a past history of ulceration
should be co-prescribed a proton pump inhibitor (PPI) with aspirin, to prevent
recurrent ulceration. In patients with a history of peptic ulcer bleeding while
taking aspirin, co-administration of a PPI is associated with a reduced rate of
re-bleeding compared with administration of clopidogrel alone.
The effects of aspirin and clopidogrel last for the duration of the platelet life,
i.e. 7–10 days. For surgical interventions: stop aspirin if indicated for primary
prevention and continue if indicated for secondary prevention. Clopidogrel is
likely to have been given for a high-risk indication, e.g. to prevent coronary stent
thrombosis, and should not be stopped perioperatively without prior discussion
with the cardiology team. However, the risk of bleeding perioperatively is high
if clopidogrel is continued, and non-urgent surgery should be delayed until
such time that clopidogrel can be stopped. For urgent surgery, excessive and
uncontrolled bleeding is treated with platelet transfusion.
Cautions/contraindications
Active bleeding, haemophilia and other bleeding disorders are contraindications. Aspirin also causes bronchospasm and must be prescribed with caution
to patients with asthma. Aspirin interacts with a number of other drugs, and
its interaction with warfarin is a special hazard (refer to National Formulary for
details). Drugs that inhibit CYP2C19 (fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine
and chloramphenicol) reduce the efficacy of clopidogrel and should be avoided.
Thrombin inhibitors
• Heparin
• Fondaparinux
• Bivalirudin.
Mechanism of action
Unfractionated heparin is not a single substance but a mixture of polysaccharides
which bind to and activate antithrombin (AT), which inactivates thrombin and
other proteases involved in blood clotting, particularly factor Xa. Usually, LMWH
is used, due to its superior bioavailability and longer half-life. Fondaparinux
binds to AT and inhibits only factor Xa. Hirudins are direct thrombin inhibitors.
Bivalirudin is used in percutaneous coronary interventions and lepirudin is used
for anticoagulation in patients with heparin-induced thrombocytopenia.
Indications
LMWH, produced by the enzymatic or chemical breakdown of the heparin
molecule, is almost always used for the prevention and treatment of DVT
and pulmonary embolism, myocardial infarction and acute coronary syn-