THROMBOSIS

A thrombus is defined as a solid mass formed in the circulation from the constituents of the blood during life. 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 obstruc-tion. Arterial emboli may also form in the left ventricle after myocardial infarc-tion, 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 asso-ciated with atherosclerosis (p. 445) and with antiplatelet drugs.

■ Aspirin (p. 243) irreversibly inhibits cyclo-oxygenase, reducing platelet production of thromboxane A2 (p. 228). It is the most commonly used antiplatelet drug.

■ Dipyridamole inhibits phosphodiesterase-mediated breakdown of cyclic AMP, which prevents platelet activation.

■ Clopidogrel (p. 243) blocks platelet aggregation and prolongs platelet survival by inhibiting the binding of ADP to its platelet receptor. Prasugrel is similar and is undergoing trials.

■ 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 been a 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

This is with thrombolytic therapy (p. 247). 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 intra-cerebral haemorrhage. The use of thrombolytic therapy in myocardial infarc-tion, pulmonary embolism and ischaemic stroke is discussed on pages 455, 475, and 748, 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. 244) and warfarin (p. 246) are the two drugs used most frequently in the prevention and treatment of thromboembolism.

Ximelagatran This oral direct thrombin inhibitor is a potential alternative to warfarin and has already been evaluated in patients with venous thrombo-embolism, atrial fibrillation and myocardial infarction. It has a rapid onset of action and can be administered in a fixed dose without the need for moni-toring. There are also fewer drug interactions than for warfarin but elimination is primarily renal, and abnormalities of liver function have been described during its use.

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 compres-sion 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 additional risk factor to consider in outpatients presenting with suspected venous thromboembolism. Prophylaxis of venous thromboembolism in surgi-cal patients depends on the type of surgery and other risk factors (Table 5.18). Patients undergoing minor surgery (anaesthetic <60 min) with no risk factors for venous thrombosis are not usually given LMWH. Patients undergo-ing major surgery (anaesthetic >60 min) but without risk factors for venous thrombosis or patients undergoing minor surgery but with risk factors are at moderate risk and should receive LMWH (20 mg, p. 245). Patients undergoing major surgery and with risk factors are at high risk and should receive LWMH (40 mg).

Treatment

Clinical features and investigation of deep venous thrombosis and pulmonary embolism are discussed on pages 487 and 475, respectively.

Table 5.18 Risk factors for venous thromboembolism in hospital inpatients
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)
Major abdominal/pelvic surgery
Active cancer
Pregnancy
Use of oestrogen containing contraceptive/hormone replacement therapy
Significant immobility
Varicose veins with phlebitis
Diabetic coma
Personal history or first-degree relative with a history of venous
thromboembolism
Thrombophilia (p. 229)
Inflammatory bowel disease
Nephrotic syndrome

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. 244). Where feasible selected patients can be safely treated as outpatients.

■ Warfarin (p. 246) 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.

■ Heparin is overlapped with warfarin for a minimum of 5 days and con-tinued 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.

Anticoagulation for 6 weeks is sufficient for patients after their first throm- bosis 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.

Other anticoagulant drugs

These are new anticoagulants and not yet in widespread use.

■ Fondaparinux - a synthetic pentasaccharide that inhibits factor X and is similar to the LMWHs.

■ Hirudins are direct thrombin inhibitors. Bivalirudin is used in percutane-ous coronary interventions and lepirudin is used for anticoagulation in patients with heparin-induced thrombocytopenia (p. 245).

■ Dabigatran (direct thrombin inhibitor) and rivaroxaban (inhibitor of factor X) are both given orally and an option for the prophylaxis of venous thromboembolism after total hip or knee replacement surgery.

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

3.5

Recurrence of venous thromboembolism while on warfarin therapy, antiphospholipid syndrome, mechanical prosthetic heart valve, coronary artery graft thrombosis

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
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NEUROENDOCRINE TUMOURS OF THE PANCREAS

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Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
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Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
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THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
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AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
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WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

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Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
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ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

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COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

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Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
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DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
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THE EAR
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THE THROAT
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MUSCLE DISEASES
MYOTONIAS
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Dermatology

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