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CPD 63: BLOOD CLOTS Biography - Dolupo Okuboyejo graduated from Obafemi Awolowo University, Ile-Ife Nigeria in 2001 and completed her Pre-registration training in National Orthopaedics Hospital, Lagos Nigeria in 2002. After practising for a couple of years in Nigeria, she relocated to Ireland and completed her Irish Pharmacist Adaptation at Riverforest pharmacy, Leixlip Co Kildare in 2011. She registered with PSI in 2012 and is currently working as a Community Pharmacist in Co Dublin and environs. She obtained a Post Graduate Diploma in Healthcare management from RCSI in 2014 and recently completed a module in Cardiology in Clinical Pharmacy Practice with a Distinction in Trinity College Dublin. 1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice. 2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area. 3. PLAN - If I have identified a knowledge gap

- will this article satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs?

Haemostasis is the arrest of blood loss from damaged vessels, which is essential to life. The ability of the body to control the flow of blood following vascular injury is paramount to continued survival. The clotting process is a complicated one that requires the interaction of platelets, clotting factors and fibrinolytic factors. In normal haemostasis, the body first responds to an injury by constricting the blood vessels to reduce the amount of blood loss. The next step involves formation of a temporary loose platelet plug, which begins with platelet adhesion. Vascular injury to endothelial cells of the vessel wall exposes the underlying matrix, which contains collagen and a glycoprotein called von Willebrand factor (vWF). Circulating platelets adhere to exposed collagen and to vWF to stabilize the adhesion. The platelets then release thromboxane A2 (TXA2) and Adenosine Diphosphate (ADP), which binds with ADPspecific surface receptors (P2Y1, P2Y12). TXA2 and ADP activate and recruit additional circulating platelets to the site of injury, where they aggregate to form a temporary plug. Aggregation also involves Fibrinogen binding to glycoprotein IIb/IIIa receptors, which are also exposed following activation of platelets. The transformation from a temporary platelet plug to a permanent fibrin mesh is achieved through the activation of clotting factors of the intrinsic and extrinsic pathways. Fibrin forms the framework of the blood clot. Finally, following tissue repair, dissolution of the blood clot occurs through the action of Plasmin to allow normal blood circulation1-3. Clots can however form inside blood vessels (arteries and veins) without an obvious injury or they do not dissolve naturally. A thrombus is a solid mass, composed of platelets and fibrin that forms within a blood vessel. The formation of a blood thrombus inside blood vessels is referred to as Thrombosis. When this occurs, it can obstruct and slow down the blood flow in the vessels or, if large enough, a thrombus can totally occlude the blood supply to the

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Blood Clots INTRODUCTION

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organs in which they have formed. As the clot propagates, fragments known as emboli may dislodge and travel in the bloodstream to distant sites, lodging in other vessels. Embolism refers to when an embolus lodges within the blood vessel and blocks the blood supply to that organ/tissue leading to tissue damage or death. Other forms of emboli are fat and air but a blood clot embolus is known as thromboembolus3-5. Thrombosis is classified into several different types, according to the location of the thrombus. The two broad classifications are venous thrombosis and arterial thrombosis, depending on whether the clot was developed in an artery or a vein. Causes of arterial thrombosis differ from causes of venous thrombosis. ARTERIAL THROMBOSIS The formation of a thrombus within an artery is known as Arterial Thrombosis. The major cause of arterial thrombosis is Atherosclerosis, which damages the inner linings of the arteries through the formation of plaques. The plaques are formed where fatty or calcium deposits cause the arterial walls to thicken. Blood flow within an artery is at a high speed and these Atherosclerotic Plaques, which tend to form at areas of turbulent blood flow inside the vessels may rupture, causing platelet aggregation which triggers blood coagulation, subsequently leading to thrombus formation. Thrombi in an artery is composed mainly of platelets with little fibrin. This platelet-rich clot can lead to occlusion of the vessel or embolism could result, obstructing blood flow in major organs. Arterial thrombosis could potentially lead to life threatening conditions such as Myocardial Infarction; when circulation to the heart is suddenly blocked due to a thrombus in the coronary arteries or stroke; when circulation to the brain is cut off, due to occlusion of the cerebral arteries. The risk factors for developing arterial thrombosis could be linked to the risk factors for developing atherosclerosis. These include

60 Second Summary A blood clot is the body’s healthy response to injury to prevent bleeding, however it may pathologically form within the arteries or veins, this is referred to as thrombosis. The clot formed may partially obstruct blood flow or can totally occlude the blood supply to the organs in which they have formed, leading to organ damage. Fragments known as emboli may also dislodge and travel in the bloodstream to distant sites lodging, in other vessels. Arterial thrombosis results mainly from atherosclerosis which damages the inner linings of the arteries through the formation of plaques which could potentially lead to myocardial infarction or stroke. Risk factors include smoking, obesity, physical inactivity, Hyperlipidaemia, Hypertension and Diabetes. Venous thrombosis is mainly caused by abnormal blood flow states like stasis and hypercoaguability. It most commonly occurs in the deep veins of the legs and can lead to fatal pulmonary embolism. Risk factors include surgery, immobility, malignancy and obesity, pregnancy, and haematological disorders. Antiplatelets and Anticoagulants are the mainstay of treatment for arterial and venous thrombosis respectively.

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CPD 63: BLOOD CLOTS

age, male sex, Hyperlipidaemia, Hypertension, Diabetes, Smoking, Obesity and/or a sedentary lifestyle.

major surgery (lasting between 1-1.5 hours), medical illness or trauma, prolonged journeys, use of plaster cast

Congestive Heart failure, recent Myocardial Infarction, Nephrotic Syndrome, inflammatory bowel disease, pelvic, hip or lower limb trauma.

PREVENTION AND TREATMENT OF ARTERIAL THROMBOSIS

• Endothelial Injury - could result from Chemotherapy, varicose veins, catheter/Drip insertions or intravenous drug users

Surgical factors are related to the type and duration of the procedure. These include orthopaedic surgeries of the Pelvis, hip or leg.

• Hypercoaguability - could result from genetic or acquired thrombophilias

Haematological disorders that increase thromboembolic risks are due to defects of haemostasis. Thrombophilia is the term used to describe Inherited or Acquired defects of haemostasis leading to a predisposition to venous thromboembolism. They include Activated Protein C Resistance (most commonly Factor V Leiden variant), Prothrombin variant, Antithrombin III deficiency, Protein C or Protein S Deficiency and Antiphospholid antibodies (Lupus anticoagulant and Anticardiolipin antibodies). The strength of individual risk factors and the cumulative weight of all risk factors applicable to a particular patient have to be taken into consideration in assessing whether prophylaxis is indicated7, 10, 11.

Attempts to prevent or reduce arterial thrombosis are directed mainly at minimizing factors predisposing to atherosclerosis. Treatment of established arterial thrombosis includes the use of Antiplatelet drugs and Thrombolytic therapy3. ANTIPLATELET DRUGS Platelet activation at the site of vascular damage is crucial to the development of arterial thrombosis. Antiplatelets decrease platelet aggregation and inhibit thrombus formation in the arterial circulation by various mechanisms. Drugs in this class include Aspirin, Clopidogrel, Prasugel, Ticagrelor and Dipyridamole VENOUS THROMBOSIS Unlike arterial thrombosis, venous thrombosis often occurs in normal vessels. They are particularly prone to occur where blood flow is sluggish because the slow flow permits activated clotting factors to accumulate instead of being washed away. Major causes are stasis and hypercoaguablity. The propagating thrombus is formed of fibrin and platelets and is particularly liable to embolise. The majority of venous thrombi occur in the deep veins of the leg3. VENOUS THROMBOEMBOLISM

These risk factors for developing venous thromboembolism can be divided into a number of categories, including patient-related factors, disease states, surgical factors and haematological disorders. Patient related factors include age >40 years, obesity, smoking, varicose veins, oestrogen therapy (Oral Contraceptives or Hormone Replacement Therapy) pregnancy and postpartum period, immobility, prolonged bed rest, spinal cord injury with paralysis Disease States that confer increased risk include respiratory failure, malignancy,

RISK FACTORS FOR VTE10 Strong Risk Factor (odds ratio >10) Fracture (hip or leg) Hip or knee replacement Major general surgery Major trauma Spinal cord injury

The condition in which a thrombus forms in the deep veins of the legs or pelvis, is referred to as Deep Vein Thrombosis (DVT). The thrombus can dislodge and travel in the blood circulation, particularly to the pulmonary arteries. This is known as Pulmonary Embolism (PE). The term Venous Thromboembolism (VTE) includes both DVT and PE7.

Moderate Risk Factors (odds ratio 2–9) Arthroscopic knee surgery Central venous lines Chemotherapy Malignancy Hormone replacement therapy Oral contraceptive therapy Congestive heart or respiratory failure Paralytic stroke Pregnancy[postpartum] Previous venous thromboembolism Thrombophilia

Weak Risk Factors (odds ratio <2) Bed rest >3 days Immobility due to sitting (e.g. prolonged car or air travel) Increasing age Laparoscopic surgery (e.g. cholecystectomy) Obesity Pregnancy[antepartum] Varicose veins

PUBLIC HEALTH IMPACT VTE is a leading cause of death and disability worldwide. According to statistics published by the International Society on Thrombosis and Haemostasis (ISTH), every year there are approximately 10 million cases of deaths of VTE worldwide. It is estimated that annually there are 100,000-300,000 VTE-related deaths in the United States of America and in Europe, there are 544,000 VTE-related deaths. In the U.S and Europe, VTE-related events kill more people than AIDS, breast cancer, prostate cancer and motor vehicle crashes combined. Up to 60% of VTE cases occur during or after hospitalization, making it a leading preventable cause of hospital death.8 In UK alone it has been estimated that 25,000 people die every year from preventable hospital-acquired VTE. Non-fatal VTE is also important because it can cause serious longer-term conditions, such as post-thrombotic syndrome and chronic thrmboembolic pulmonary hypertension9. RISK FACTORS Thromboembolic disease occurs when one or more of the following three elements known as Virchow’s Triad are present: • Abnormal blood flow - this result from stasis in veins due to immobility. Instances of immobility that lead to sluggish blood flow are

DEEP VEIN THROMBOSIS Typical symptoms associated with DVT include leg pain and tenderness along the line of the deep veins and swelling of the calf or thigh. On physical examination, signs include increased warmth, pitting oedema, erythema (occasionally purple or cyanosed), distension of the superficial veins, and hard, thickened palpable vein12. One of the commonly used tools that uses clinical scores for evaluating the probability of DVT is known as the Wells’ Score for Prediction of DVT. It is used to quantify the likelihood of an individual patient having DVT based on their medical history and physical examination. Clinical judgement, therefore plays a critical role in DVT diagnosis because certain risk factors and markers of DVT can be assessed early in the diagnosis process13. If a patient presents with signs or symptoms of deep vein thrombosis (DVT), an assessment of their general medical history and a physical examination has to be carried out to exclude other causes. NICE guidelines in the UK recommend that, for a suspected DVT the twolevel DVT Wells score in the table below should be used to estimate the clinical probability of DVT. If the patient scores 2 or more points, DVT is likely but with a score of 1 or less, DVT is unlikely6.

TWO-LEVEL DVT WELLS SCORE Clinical Feature Active cancer (treatment ongoing or within previous 6 months or palliative) Paralysis, paresis or recent plaster immobilization of lower extremities Recently bedridden for more than 3 days or major surgery within 4 weeks Localised tenderness along distribution of the deep vein system Entire leg swollen Calf swelling by more than 3 cm when compared with asymptomatic leg Pitting oedema Collateral superficial veins Alternative diagnosis as likely or greater than that of DVT Clinical probability simplified score DVT likely DVT unlikely

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Points

1 1

1 1 1

1 1 1 -2 2 points or more 1 point or less


CPD 63: BLOOD CLOTS However, clinical information alone (history and physical examination) is insufficient to diagnose DVT. In addition to the clinical probability pre-test, objective diagnostic tests, such as compression (venous) ultrasound, venography or MRI or a D-Dimer test (which detects fragments produced by clot lysis) have to be performed to have a definitive diagnosis. PULMONARY EMBOLISM (PE) PE is a potentially life threatening condition and, in severe cases the occurrence of circulatory collapse and cardiac arrest may result in sudden death. Early fatality occurs in up to 15% of patients and, thus rapid diagnosis is crucial. However, the diagnosis of PE can be missed because of its non-specific clinical symptoms14. Common signs and symptoms include Dyspnoea, Pleuritic chest pain, cough, substernal chest pain, fever, tachypnoea, haemoptysis, tachycardia, syncope, unilateral leg pain and signs of DVT (unilateral extremity swelling). These symptoms are not specifically diagnostic of PE. Hence, the diagnostic process and decisions regarding the need for imaging tests specifically designed to detect PE, should be based on a careful assessment of clinical probability. If a patient presents with signs or symptoms of pulmonary embolism (PE), it is best to carry out an assessment of their general medical history, a physical examination and a chest X-ray to exclude other causes. If PE is suspected, the UK NICE guidelines recommend the use of the two-level PE Wells score in the table below to estimate the clinical probability of PE. A score of more than 4 points indicates that PE is likely and a score of 4 points or less indicates that PE is unlikely. In order to diagnose PE, imaging techniques, using computed tomography pulmonary angiogram (CTPA) (or where unsuitable, a ventilation/ perfusion single photon emission computed tomography (V/Q SPECT) scan or a Planar Scan) have to be carried out to make a firm diagnosis of PE6, 14. It is important to note that patients can present with signs or symptoms of both DVT (for example, a swollen and/or painful leg) and PE (for example chest pain, shortness of breath or haemoptysis) A clinician should maintain a high index of suspicion for this condition because prompt treatment of PE can dramatically reduce the levels of morbidity and mortality associated with PE.

TWO LEVEL PE WELLS SCORE Clinical Feature

Points

Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins)

3

An alternative diagnosis is less likely than PE

3

Heart rate >100beats per minute

1.5

Immobilisation for more than 3 days or surgery in the previous 4 weeks

1.5

Previous DVT/PE

1.5

Haemoptysis

1

Malignancy (on treatment, treated in the last 6 months or palliative)

1

Clinical probability simplified scores PE likely

More than 4points

PE unlikely 4points or less

PHARMACOLOGICAL TREATMENT7 The goals of pharmacotherapy for DVT are to reduce morbidity, prevent the development of a potentially fatal PE or other long-term complications, such as post-thrombotic syndrome (characterized by swelling, chronic leg pain, redness and ulcer, resulting from damage to the valves of the vein) and chronic thromboembolic pulmonary hypertension. It is also important to reduce the risk of recurrence of both DVT and PE. Risk stratification is essential for managing acute PE. The clinical examination (including blood pressure, heart rate, and oxygen saturation) biomarkers (troponin, BNP) and echocardiography to assess the right ventricle and PE size should all be used to assist in the acute management of PE. If the patient is normotensive and the right ventricle size and function are normal, standard anticoagulation is advised. If the patient is normotensive but the right ventricle is abnormal and biomarkers are elevated, treatment is more controversial. The recommendation for patients that are haemodynamically unstable is to consider thrombolysis or pulmonary embolectomy ANTICOAGULANTS14-16 PARENTERAL ANTICOAGULANTS Immediate anticoagulation can be achieved with fast acting parenterals, such as low molecular weight heparins (LMWH) (e.g Tinzaparin and Enoxaparin) and unfractionated heparin. They are used to ensure rapid anticoagulation for the initial acute-phase treatment of DVT and PE, thus preventing further clot formation. Unfractionated Heparin (UFH): acts by inhibiting thrombin and by potentiating the naturally occurring inhibitors of activated factor X (Xa). It is usually given as an intravenous injection loading dose (5000 units or 75units/kg) followed by continuous intravenous infusion (18 units/kg/ hr) or, alternatively by intermittent subcutaneous injection (15,000 units every 12 hours for the treatment of DVT). Laboratory monitoring for unfractionated heparin, preferably on a daily basis, is essential by determining the Activated Partial Thromboplastin Time (APTT). It has a short duration of action and its effect can be terminated rapidly and therefore used in patients at high risk of bleeding. UFH is recommended for patients in, as well as for those with serious renal impairment (creatinine clearance, 30 mL/min), or severe obesity. These recommendations are based on the short half-life of UFH, the ease of monitoring its anticoagulant effects and its rapid reversal by protamine. Low Molecular Weight Heparins (LMWH): They are derived from UFH by enzymatic/ chemical degradation. They act by potentiating the inhibition of several activated coagulation factors, especially factor Xa and by increasing antithrombin III activity. Each LMWH agent has a specific molecular weight distribution that determines its anticoagulant activity and duration of action, so one agent cannot be substituted for another. They include Enoxaparin, and Tinzaparin. They are generally preferred for routine use over unfractionated Heparin in the treatment of DVT and PE because they carry a lower risk of inducing major bleeding and heparin-induced thrombocytopenia. They also have a more consistent pharmacological profile and are more easily administered by subcutaneous injection. Dosage is usually weight based. Enoxaparin is usually given at a dose of 1.5 mg/kg/day or 150 units/kg once daily or, alternatively 1mg/kg twice daily. Tinzaparin is

usually given at a dose of 175 units/kg once daily. Routine monitoring is usually not required but periodic measurement of anti-factor Xa activity (anti-Xa levels) may be necessary in patients with increased risk of bleeding (e.g. in renal impairment, those who are underweight or overweight) and in pregnancy. SIDE EFFECTS OF UFH AND LMWHS • Haemorrhage- If haemorrhage occurs, it is usually sufficient to withdraw UFH and the LMWH but if rapid reversal of the effects of the heparin is required, Protamine sulphate is a specific antidote (but only partially reverses the effects of low molecular weight heparins). • Hyperkalaemia (due to inhibition of aldosterone secretion) • Thrombocytopenia-(clinically important immune mediated Heparin Induced Thrombocytopaenia (HIT) develops 5-10 days and can be complicated by thrombosis. (rarely seen in LMWH) • Osteoporosis-(Risk lower with LMWH) • Alopecia (prolonged use) • Injection site reactions • Skin Necrosis • Hypersensitivity reactions (including urticaria, angiodema, and anaphylaxis) Other available alternative parenteral anticoagulants are Fondaparinux (a synthetic pentasaccharide that inhibits activated factor X) and Danaparoid (used with development/history of HIT) ORAL ANTICOAGULANTS The standard duration of anticoagulation should cover at least 3 months. Traditionally, within this period, acute-phase treatment consists of administering a parenteral anticoagulant over first 5–10 days and overlapping with the initiation of a vitamin K antagonist (VKA)-most commonly Warfarin. Because Warfarin has a delayed onset of action, the transition requires close monitoring of the international normalized ratio (INR), with parenteral anticoagulation continued for a minimum of 5 days and until the INR is 2.0 or above for at least 24 hours. Frequent coagulation monitoring and dose adjustment is continued throughout Warfarin treatment in order to maintain a narrow therapeutic range (INR 2.0–3.0)14,16. Recently, however, the Novel Oral Anticoagulants (NOACs) - Dabigatran, Rivaroxaban, Apixaban and Edoxaban have been approved for use in the treatment of DVT and PE. ESC guidelines recommend that Parenteral anticoagulant can be followed by administration of Dabigatran. If Rivaroxaban or Apixaban is given instead, oral treatment with one of these agents should be started directly or after a 1–2 day administration of UFH or LMWH. In this latter case, acutephase treatment consists of an increased dose of the oral anticoagulant over the first 3 weeks (for Rivaroxaban), or over the first 7 days (for Apixaban).14 The latest NOAC approved for treatment of of DVT and PE; Edoxaban (newly licensed in Ireland) is approved in patients who have been treated with a parenteral anticoagulant for at least 5 days14. NOACs remain under close scrutiny but many reviews suggest their advantages over warfarin (most importantly the lack of necessity for monitoring, rapid onset and fewer drug interactions and diet restrictions) outweigh disadvantages (particularly cost and the lack of an immediately acting antidote).

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CPD 63: BLOOD CLOTS ANTICOAGULANTS

WARFARIN

DABIGATRAN PradaxaR

RIVAROXABAN XareltoR

APIXABAN EliquisR

EDOXABAN LixianaR

Time to reach Max Conc after oral admin(CMax)

2-3 days

1-2 hours

2-4 hours

3-4hours

1-2hours

Half- life

40 hours

12-14 hours(prolonged in renal impairment

5-9 hours(young) 11-13hrs(elderly)

8-15 hours

10-14hours

Dosage (DVT/PE Treatment

Variable dosing Starting dose - 5-10mg, subsequent dosing to target INR (Usual maintenance dose- 3-9mg once daily)

Fixed dosing 150mg twice daily 110 twice daily (Elderly and high risk of bleeding)

Fixed dosing 15mg twice daily (Day1-21) 20mg once daily (Day22 onwards)

Fixed Dosing 10mg twice daily (1-7days) 5mg twice daily(Day 8 onwards)

Fixed Dosing 60mg once daily 30mg once daily(moderate to severe renal impairment and low body weight

Routine Monitoring

Frequent testing ( INR) required to determine anticoagulation effect

None

None

None

None

Contraindications

Haemorrhagic stroke Significant bleeding Within 48 hours postpartum

Active Bleeding Impaired Haemostasis

Active bleeding

Active bleeding

Active bleeding

Possible Side effects

Haemorrhage Alopecia Nausea Vomiting Diarrhoea Hepatic dysfunction Skin necrosis Purple toes syndrome

Haemorrhage Nausea Dyspepsia Abdominal pain Dysphagia GI ulcer

Haemorrhage Nausea Constipation Dyspepsia Dizziness Headache Hypotension Oedema Renal impairment

Haemorrhage Nausea Anaemia Hypotension

Haemorrhage, Anaemia Nausea Rash Hepatobiliary disorders Abnormal liver function test

Drug Interactions

Inducers and Inhibitors of CYP3A4, CYP2C9,CYP1A2 metabolic pathways, Thrombin Inhibitors Anticoagulants, Antiplatelets, Thrombolytic agents, NSAIDS, SSRIs, SNRIs, Herbal Drugs. Anticoagulation control affected by Vitamin K containing foods e.g. green leafy vegetables, keep diet consistent. INR affected by cranberry, grapefruit juice and alcohol (Avoid Binge drinking and Chronic use).

P-glycoprotein inhibitors and inducers Also with: Amiodarone/verapamil, dronaderone Cyclosporine, Carbamazepine, Phenytoin, Antiplatelets, SSRIs, NSAIDS

Potent dual CYP 3A4 and P-glycoprotein inhibitors e.g. Azole antibiotics. Also with: Rifampicin, Clarithromycin, Carbamazepine, Phenytoin, Antiplatelet, SSRIs, NSAIDS

Potent dual CYP 3A4 and P-glycoprotein inhibitors e.g. Azole antibiotics. Also with: Rifampicin, Clarithromycin, Carbamazepine, Phenytoin, Antiplatelet, SSRIs, NSAIDS

P-glycoprotein inhibitors e.g ciclosporin, dronaderone, erythromycin, quinidine, ketoconazole NSAIDS

FIBRINOLYTICS3, 15 Fibrinolytic drugs act as thrombolytics by activating plasminogen to form plasmin, which degrades fibrin and so break up thrombi. They are used in patients with massive pulmonary embolism, haemodynamically unstable patients and in patients with extensive deep vein thrombi. They are also used in myocardial infarction, which can result from arterial thrombosis. Drugs in the class include Streptokinase, Alteplase, Tenecteplase and Reteplase. Streptokinase is a purified fraction of the filtrate obtained from cultures of haemolytic streptococci. It is antigenic and leads to development of antibodies that cause allergic reactions, limiting its use. It is unlicensed in Ireland. The others are made by recombinant technology (tissue type plasminogen activators) and are not antigenic. The main risk of thrombolytic therapy is bleeding and is contraindicated in patients with recent haemorrhage, surgery, haemorrhagic stroke or any other recent invasive procedures.

COAGULATION CASCADE SHOWING DRUG ACTION

References on request

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