Haematology

Haematology

Clinical haematology is the branch of medicine that focuses on the diagnosis, prognosis, treatment, and prevention of diseases (both benign and malignant) of red and white blood cells, platelets, and the coagulation system. Haematological diseases include anaemia, sickle cell disease, haemophilias, and cancers like leukaemias, lymphomas and myelomas. This module concentrates on the conditions for which there are clinically approved pharmacological interventions. There is overlap with the Therapeutics/Oncology module in this section of the PEP.

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Venous thromboembolism

Venous thromboembolism (VTE) is a blood clot in a vein. VTEs can partially or completely obstruct blood flow. The most frequent types of VTE are

  • deep-vein thrombosis (DVT) and
  • pulmonary embolism (PE)

Pharmacological VTE prophylaxis and treatment relies on the use of different classes of drugs; anti-coagulants, antiplatelet drugs and thrombolytic/fibrinolytic agents.

Anti-coagulant drugs are used to prevent thrombus formation or extension of an existing thrombus in the venous circulation. Anticoagulation can be achieved with either parenteral (injectable) or oral anticoagulants.

Parenteral anticoagulants include unfractionated heparin, low molecular weight heparins and fondaparinux.

Oral anticoagulants include the Vitamin K antagonists e.g. warfarin sodium, and non-vitamin K dependent oral anticoagulants (NOACs). Warfarin antagonises the effects of Vitamin K, preventing the activation of numerous clotting factors. The anticoagulant effects of warfarin take 48 to 72h to fully develop so if immediate effects are required, unfractionated or low molecular weight heparin are usually administered concomitantly.

NOACs include direct factor Xa inhibitors e.g., edoxaban, rivaroxaban, apixaban, and direct thrombin inhibitors e.g., dabigatran etexilate. In most situations where warfarin is used NOACs have a similar or greater efficacy, with lower risk of bleeding, therefore there is increased use of these drugs in place of warfarin. All of these drugs prevent thrombus formation.

Antiplatelet drugs (clopidogrel, prasugrel, ticagrelor, cangrelor, aspirin) act to dissolve intravascular clots. Clopidogrel, prasugrel, ticagrelor and cangrelor are P2Y12 receptor antagonists, that act to disrupt platelet aggregation.

Thrombolytic/fibrinolytic agents (alteplase, tenecteplase, reteplase, urokinase, streptokinase) also act to dissolve intravascular clots. Alteplase, tenecteplase and reteplase are recombinant versions of the endogenous serine protease, tissue plasminogen activator (tPA), which converts plasminogen to plasmin in blood vessels.

Urokinase (urokinase-type plasminogen activator, or uPA) is another endogenous serine protease within the proteolytic cascade that regulates fibrinolysis. Like tPA, uPA generates plasmin from plasminogen to elicit a pro-thrombolytic effect. Urokinase is used to treat PE.

Streptokinase is a bacteria-derived enzyme. It acts to increase plasmin levels. Its use has largely been replaced by newer fibrinolytic agents, but it remains on the WHO's list of essential medicines. Streptokinase can be use to treat patients post-MI, to treat PE and DVT, and to prevent occlusion in arteriovenous cannulae.

The choice of drug (or drug combinations) depends on the aim of treatment; prophylaxis (pre/post surgery, patients with CVD at risk of VTE), or treatment of confirmed VTE? The patient's existing conditions (bleeding disorders, cancer, pregnancy, renal impairment etc.) and body weight will all influence the prescriber's choice of drug/s. Many of these drugs are also used to treat or prevent clotting in patients with cardio-vascular conditions (acute MI, acute ischemic stroke, etc.). The UK’s National Institute for Health and Care Excellence (NICE) guidelines on ‘Venous thromboembolic diseases: diagnosis, management and thrombophilia testing’ can be found here.

Drugs and blood clotting

This session covers the basic pharmacodynamics and pharmacokinetics of drugs developed to prevent and/or reverse thrombus (blood clot) formation. It includes an overview of anticoagulants, antiplatelet agents and thrombolytic agents. It is aimed at preclinical medical or dental students, or students in their early years of a pharmacology degree.

Provided by Dr Clare Guilding, Newcastle University Medicine Malaysia

Average: 3.8 (17 votes)

Sickle cell disease

Sickle cell anaemia is a potentially life-threatening genetic condition that is caused by inheritance of genes that encode abnormal beta-globin proteins. The sickle haemoglobin (or HbS) variant produces haemoglobin that polymerises into a distorted conformation when in the deoxygenated state. This results in erythrocyte deformation into the classic sickle shape. A sickle cell crisis ensues when the misshapen and rigid erythrocytes form clumps that block blood vessels. Symptoms include intense pain, anaemia (due to haemolysis), splenomegaly, dactylitis (swollen digits), stroke, infections and acute chest syndrome (tachypnoea, low oxygen saturation).

Genetics

Individuals who are homozygous for sickle haemoglobin will suffer from sickle cell anaemia, which is the most common, and the most severe form of the disease. Heterozygotes, with one sickle haemoglobin gene and a normal haemoglobin gene have sickle cell trait, and will rarely develop symptomatic disease. They can however, pass their sickle haemoglobin gene onto their children. People of African or African-Caribbean ethnicity are in the high-risk group for sickle cell diseases. In the UK, all newborn babies are screened for sickle cell disease. Anyone who is pregnant is also offered screening.

Management

Patients should be provided with an individual care plan that includes regular follow-ups, alongside self-management guidance on measures to prevent (or reduce the risk of) complications of sickle cell disease, plus clear indications of when urgent medical attention should be sought. Patients should be advised to avoid triggers, such as exposure to cold or windy weather, excessive physical activity and dehydration.

Acute sickle crises: Standard pain medications such as paracetamol or ibuprofen can be useful for self-management during a sickle crisis. For those presenting with fever (temperature >38°C) should be offered empirical broad-spectrum antibiotic treatment with choice guided by local microbiological guidelines.

Chronic treatment: Patients with sickle cell disease should be offered appropriate immunisations (e.g., pneumococcus, meningococcus). Penicillin prophylaxis should be offered to all children with sickle cell disease, started by 3 months of age and continued until the child is 5 years old. Hydroxycarbamide (hydroxyurea) may be recommended for those who experience regular episodes of pain.

Regular blood transfusions (preferably exchange transfusions) that are used to keep the sickle haemoglobin percentage below 30%, may be recommended, particularly if anaemia becomes severe or persistent.

Two novel therapeutics were recently approved for preventing sickle cell anaemia and crises:

  1. Voxelotor is an orally administered drug that is taken daily. It is indicated as a treatment for sickle cell disease (in individuals ≥ 4 years old). It locks sickle haemoglobin into its oxygen-binding conformation, and thus reduces abnormal polymerisation and erythrocyte sickling.
  2. Crizanlizumab is an anti-selectin P monoclonal antibody has been approved as a preventative therapy for sickle cell crises. Inhibition of the interaction between selectin P and its primary ligand P-selectin glycoprotein ligand-1 (PSGL-1), produces an antithrombotic effect that is exploited to reduce the vaso-occlusive damage caused by sickled erythrocytes.

What is Sickle Cell Disease?

This is an online resource that is maintained by the Centers for Disease Control and Prevention (CDC) in the United States. It provides easy to understand information that is a useful introduction to the sickle cell diseases.

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Sickle cell anaemia is a potentially life-threatening genetic condition that is caused by inheritance of genes that encode abnormal beta-globin proteins. The sickle haemoglobin (or HbS) variant produces haemoglobin that polymerises into a distorted conformation when in the deoxygenated state. This results in erythrocyte deformation into the classic sickle shape. A sickle cell crisis ensues when the misshapen and rigid erythrocytes form clumps that block blood vessels. Symptoms include intense pain, anaemia (due to haemolysis), splenomegaly, dactylitis (swollen digits), stroke, infections and acute chest syndrome (tachypnoea, low oxygen saturation).

Genetics

Individuals who are homozygous for sickle haemoglobin will suffer from sickle cell anaemia, which is the most common, and the most severe form of the disease. Heterozygotes, with one sickle haemoglobin gene and a normal haemoglobin gene have sickle cell trait, and will rarely develop symptomatic disease. They can however, pass their sickle haemoglobin gene onto their children. People of African or African-Caribbean ethnicity are in the high-risk group for sickle cell diseases. In the UK, all newborn babies are screened for sickle cell disease. Anyone who is pregnant is also offered screening.

Management

Patients should be provided with an individual care plan that includes regular follow-ups, alongside self-management guidance on measures to prevent (or reduce the risk of) complications of sickle cell disease, plus clear indications of when urgent medical attention should be sought. Patients should be advised to avoid triggers, such as exposure to cold or windy weather, excessive physical activity and dehydration.

Acute sickle crises: Standard pain medications such as paracetamol or ibuprofen can be useful for self-management during a sickle crisis. For those presenting with fever (temperature >38°C) should be offered empirical broad-spectrum antibiotic treatment with choice guided by local microbiological guidelines.

Chronic treatment: Patients with sickle cell disease should be offered appropriate immunisations (e.g., pneumococcus, meningococcus). Penicillin prophylaxis should be offered to all children with sickle cell disease, started by 3 months of age and continued until the child is 5 years old. Hydroxycarbamide (hydroxyurea) may be recommended for those who experience regular episodes of pain.

Regular blood transfusions (preferably exchange transfusions) that are used to keep the sickle haemoglobin percentage below 30%, may be recommended, particularly if anaemia becomes severe or persistent.

Two novel therapeutics were recently approved for preventing sickle cell anaemia and crises:

  1. Voxelotor is an orally administered drug that is taken daily. It is indicated as a treatment for sickle cell disease (in individuals ≥ 4 years old). It locks sickle haemoglobin into its oxygen-binding conformation, and thus reduces abnormal polymerisation and erythrocyte sickling.
  2. Crizanlizumab is an anti-selectin P monoclonal antibody has been approved as a preventative therapy for sickle cell crises. Inhibition of the interaction between selectin P and its primary ligand P-selectin glycoprotein ligand-1 (PSGL-1), produces an antithrombotic effect that is exploited to reduce the vaso-occlusive damage caused by sickled erythrocytes.

Videos and Podcasts on Sickle Cell Disease

This webpage provides a set of short video resources that are produced by the Centers for Disease Control and Prevention (CDC) in the United States. The individual videos contain information about sickle cell diseases that are suitable for either patients or healthcare professionals.

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