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 pro-cesses 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 (thombomodulin, heparin sulphate, prostacyclin, nitric oxide, plas-minogen 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, via the platelet membrane receptor glycoprotein Ib (Gplb), to collagen and vWF in the subendothelial matrix. GplIb/IIIa recep-tor 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. Fol-lowing adhesion, platelets spread along the subendothelium and release the contents of their cytoplasmic granules containing adenosine diphos-phate (ADP), serotonin, thromboxane A2, fibrinogen and other factors. ADP leads to a conformational change in the glycoprotein (Gp)IIb/IIIa receptor allowing it to bind to fibrinogen, a dimer that acts as a bridge between platelets and so binds them into aggregates (plateletaggregatiorì). During aggregation, platelet membrane receptors are exposed, providing a surface for the interaction of coagulation factors and ultimately the forma-tion 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

Fig. 5.5 Coagulation mechanism. The in vivo pathway begins with tissue factor-factor VlIa complex activating factor X and also factor IX. Factor XI is activated by thrombin. TF, tissue factor; TFPI, tissue factor pathway inhibitor.

proceed to completion. Factor VIII consists of a molecule with coagulant activity (VIII : C) associated with vWF, which prevents premature break-down of VIII : C. Factor VIII increases the activity of factor IXa by about 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, factors VII, IX and X.

■ Physiological limitation of coagulation Coagulation would lead to danger-ous 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. 237).

■ Fibrinolysis Fibrinolysis is a normal haemostatic response that helps to restore vessel patency after vascular damage. The plasma protein plas-minogen is converted to plasmin by activators (principally tissue plas-minogen activator, tPA) released from endothelial cells. Plasmin breaks

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 (see 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

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 nature of the defect and therefore the most appropriate initial investiga-tions may be suggested by the history and examination, e.g. family history, intercurrent disease, alcohol consumption, drugs. Vascular/platelet bleeding is characterized by bruising of the skin and bleeding from mucosal mem-branes. Bleeding into the skin is manifest as petechiae (small capillary haemorrhages, a few millimetres in diameter) and superficial ecchymoses (larger areas of bleeding). Haemophilia A and B are typically associated with 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 clot-ting 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 INR over the PT is that it uses international standards and thus anticoagulant control in different hospitals across the world can be compared.

■ 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 normal ranges of these tests vary from laboratory to laboratory, and patient results must be compared with the testing laboratory's reference range.

■ 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 investiga-tions, e.g. platelet aggregation studies and measurement of fibrinogen, FDPs and individual clotting factors, will be necessary to identify the exact haemo-static defect correctly.

Platelet disorders

Platelet disorders are the result of thrombocytopenia (platelet count <150 X 109/L; Table 5.17) or disorders of platelet function, e.g. those occurring 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 X 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 X 109/L) or to maintain a platelet count of >50 X 109/L in the presence of active bleeding or prior to an invasive procedure.

Table 5.17 Causes of thrombocytopenia

Impaired production

Excessive destruction

Bone marrow íailure

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 iníiltration

Thrombotic thrombocytopenic purpura

Aplastic anaemia (Table 5.6) Haemolytic uraemic syndrome
HIV infection Sequestration
  Hypersplenism
  Dilutional
  Massive transfusion

ITP, immune thrombocytopenic purpura; SLE, systemic lupus erythematosus; CLL, chronic lymphocytic leukaemia.

Thrombocytopenia due to impaired production is selective megakaiyocyte depression (drugs, chemicals) or more often also associated with failure of red and white cell production.

Immune thrombocytopenic purpura (ITP)

There is 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, e.g. systemic lupus erythematosus 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 X 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 1 mg/kg body weight produces 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. For those that fail splenectomy possible treatments include high-dose corticosteroids, i.v. IgG, intravenous anti-D, vinca alkaloids, danazol and immunosuppressive agents such as azathioprine, ciclosporin and dapsone. There is also interest in the use of rituximab and romiplostim, a thrombo-poiesis protein.

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, systemic lupus erythematosus, 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 dehydro-genase levels are markedly raised as a result of haemolysis. Treatment is with plasma exchange (to remove the antibody to ADAMTS 13), methylpred-nisolone and rituximab. Platelet concentrates are contraindicated.

Inherited coagulation disorders

Inherited disorders usually involve a deficiency of only one coagulation factor,

whereas acquired disorders involve a deficiency of several factors.

Haemophilia A

This is the result of a deficiency of factor VIII : C (p. 229). 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 : C.

■ Levels <1 IU/dL (severe disease) are associated with frequent spontane-ous bleeding into muscles and joints that can lead to a crippling arthropathy.

■ Levels 1-5 lU/dL are associated with severe bleeding following injury and occasional apparently spontaneous episodes.

■ Levels >5 lU/dL produce mild disease with bleeding only with trauma or surgery.

HIV and liver disease (due to hepatitis C) are common as a result of transmis-sion from infected factor concentrates that were given prior to 1986. Since 1986 plasma-derived products are all virally inactivated. Cerebral haemor-rhage 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 of choice and is used in preference to plasma-derived concen-trates where 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 child-hood 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. Treat-ment is with factor IX concentrates. Desmopressin is ineffective.

von Willebrand’s disease

Deficiency of vWF leads to defective platelet function (p. 228) as well as factor VIII deficiency (p. 229).

Clinical features

Types 1 and 2 are mild forms, with autosomal dominant inheritance, and characterized by mucosal bleeding (nose bleeds and gastrointestinal bleed-ing) 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, VII, IX and X. Defi-ciency 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. 242).

Disseminated intravascular coagulation (DIC)

There is widespread generation of fibrin within blood vessels, caused by initiation of the coagulation pathway. There is consumption of platelets and coagulation factors, and secondary activation of fibrinolysis, leading to pro-duction of FDPs, which contribute to coagulation by inhibiting fibrin polymerization.

Aetiology

DIC results from massive activation of the clotting cascade. The major initiat-ing 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, abruptio placentae). DIC occurs in most cases of acute promyelocytic leu-kaemia due to generation of procoagulant substances in the blood.

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, malig-nancy), the clinical presentation and the presence of severe thrombocyto-penia. 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 X 109/L), FFP, cryo-precipitate 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 defi-ciency in cholestasis, reduced synthesis of clotting factors, thrombocytopenia and functional abnormalities of platelets. DIC may occur in acute liver failure.

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
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

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
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

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

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
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

10. Cardiovascular disease

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

11. Respiratory disease


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
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology

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