Anticoagulant and antithrombotic therapy

ANTICOAGULANT THERAPY

Dr.musa kassiem hussien Assistant professor Dep. of internal medicine
4-4-2016

Inherited abnormalities of coagulation

Several inherited conditions predispose to VTE, with several points in common which are worth noting:
1-None of them is strongly associated with arterial thrombosis. 2-All are associated with a slightly increased incidence of adverse outcome of pregnancy, including recurrent early fetal loss, but there are no data to indicate that any specific intervention changes that outcome.


3-Apart from in antithrombin deficiency and homozygous factor V Leiden, most carriers of these genes will never have an episode of VTE; if they do, it will be associated with the presence of an additional temporary risk factor. 4-There is little evidence that detection of these abnormalities predicts recurrence of VTE. 5-None of these conditions per se requires treatment with anticoagulants.

Antithrombin deficiency

Antithrombin (AT) is a serine protease inhibitor (SERPIN) which inactivates factors IIa, IXa, Xa and XIa. Heparins, fondaparinux and idraparinux achieve their therapeutic effect by potentiating the activity of AT. Familial deficiency of AT is inherited as an autosomal dominant; homozygosity for mutant alleles is not compatible with life


Around 70% of affected individuals will have an episode of VTE before the age of 60 years and the relative risk for thrombosis compared with the background population is 10-20. .

Pregnancy is a high-risk period for VTE and this requires fairly aggressive management with doses of LMWH which are greater than the usual prophylactic doses (≥ 100 U/kg/day). Antithrombin concentrate (either plasma-derived or recombinant) is available; this is required for cardiopulmonary bypass and may be used as an adjunct to heparin in surgical prophylaxis.


Protein C and S deficiencies
Protein C and S are vitamin K-dependent natural anticoagulants involved in switching off coagulation factor activation and thrombin generation . Inherited deficiency of either protein C or S results in a prothrombotic state with a five-fold relative risk of VTE compared with the background population

Antiphospholipid antibody syndrome

Antiphospholipid syndrome (APS) is aclinicopathological entity in which a constellation of clinical conditions, alone or in combination, is found in association with a persistently positive test for an antiphospholipid antibody. The antiphospholipid antibodies are heterogeneous and typically are directed against proteins which bind to phospholipids . Although causal roles for these antibodies have been proposed, the mechanisms underlying the clinical features of APS are not clear.

In clinical practice, two types of test are used, which detect:

1-antibodies which bind to negatively charged phospholipid on an ELISA plate (called an anticardiolipin antibody test) 2-those which interfere with phospholipid-dependent coagulation tests like the APPT or the dilute Russell viper venom time (DRVVT; called a lupus anticoagulant test).

The term antiphospholipid antibody Encompasses both a lupus anticoagulant And an anticardiolipin antibody. Some individuals are only positive for one Of these activities, whereas in others both Are present.

Clinical manifestations

1-Adverse pregnancy outcome *Recurrent first trimester abortion (≥ 3) *Unexplained death of morphologically normal fetus after 10 weeks' gestation *Severe early pre-eclampsia 2-Venous thromboembolism 3-Arterial thromboembolism 4-Livedo reticularis, catastrophic APS, transverse myelitis, skin necrosis, chorea

*SLE *Rheumatoid arthritis *systemic sclerosis Bahcets syndrom *Temporal artritis *Sjogrens syndrom*
Conditions associated with secondary APS

Targets for antiphospholipid antibodies

*β2-glycoprotein 1 *Protein C *Annexin V *Prothrombin (may result in haemorrhagic presentation)


APS may present in isolation (primary APS) or in association with one of the conditions above, most typically SLE (secondary APS). Most patients present with a single manifestation and APS is now most frequently diagnosed in women with adverse outcomes of pregnancy.

It is extremely important to make the diagnosis in patients with APS, whatever the manifestation, because it affects the prognosis and management of arterial thrombosis, VTE and pregnancy.

Arterial thrombosis, typically stroke, associated with APS should be treated with warfarin as opposed to aspirin. APS-associated VTE is one of the situations where the predicted recurrence rate is high enough to indicate long-term anticoagulation after a first event.

ANTICOAGULANT THERAPY

There are numerous indications for anticoagulant and antithrombotic medications . Broadly speaking, antiplatelet medications are of greater efficacy in the prevention of arterial thrombosis and of less value in the prevention of VTE. Thus, antiplatelet agents, such as aspirin and clopidogrel, are the drugs of choice in acute coronary events and in ischaemic cerebrovascular disease, while warfarin and other anticoagulants are favoured in VTE. In some extremely prothrombotic situations,such as coronary artery stenting, a combination of anticoagulant and antiplatelet drugs is used.

A range of anticoagulant and antithrombotic drugs is used in clinical practice . Newer agents allow predictable anticoagulation without the need for frequent monitoring and dose titration. Although warfarin remains the mainstay for oralanticoagulation, Newer oral anticoagulants (dabigatran, rivaroxaban and apixaban),which can be given at fixed doses with predictable effects and no need for monitoring, have now been approved for the prevention of perioperative VTE, the treatment of established VTE and the prevention of cardioembolic stroke in patients with atrial fibrillation.

Indications for anticoagulation

Heparin
1-Prevention and treatment of VTE 2-Percutaneous coronary intervention 3-Post thrombolysis for myocardial infarction 4-Unstable angina pectoris 5-Non-Q wave myocardial infarction 6-Acute peripheral arterial occlusion 7-Cardiopulmonary bypass 8-Haemodialysis and haemofiltration

Unfractionated heparin (UFH) and low molecular weight heparins (LMWH) both act by binding via a specific pentasaccharide to antithrombin which potentiatesits natural anticoagulant activity . Increased cleavage of activated proteases, particularly factor Xa and thrombin (IIa), accounts for the anticoagulant effect. LMWHs preferentially augment antithrombin activity against factor Xa.
Heparins



LMWHs are at least as efficacious as UFH but have several advantages.
1-LMWHs are nearly 100% bioavailable and therefore produce reliable dose-dependent anticoagulation. 2-LMWHs do not require monitoring of their anticoagulant effect (except possibly in patients with very low body weight and with GFR < 30 mL/min). 3-LMWHs have a half-life of around 4 hours when given subcutaneously, compared with 1 hour for UFH. This permits once-daily dosing by the subcutaneous route, rather than the therapeutic continuous intravenous infusion or prophylactic twice-daily subcutaneous administration required for UFH. .

4-While rates of bleeding are similar between products, the risk of osteoporosis and heparin-induced thrombocytopenia is much lower for LMWH. 5-However, UFH is more completely reversed by protamine sulphate in the event of bleeding and at the end of cardiopulmonary bypass, for which UFH remains the drug of choice


Unfractionated heparin (UFH) should be started with loading dose of 5000 U i.v Followed by a continuous infusion of 20U/Kg/hr Initially . The level of anticoagulant should be assessed by the APTT after 6 hours and, if satisfactory , daily thereaftre. It is usual to aim for a patient time which is 1.5-2.5 time the Control of the test.

The half life of I.V heparin is about one hour and if Patient bleeds, it is usually sufficient just to discontinue The infusion, however , if bleeding is sever , the excess Can be neutralised with I.V protamine. Treatment should continue for 6-8 days, depending upon The extent of the thrombous.


in most patients it is appropriate to start Warfarin therapy at the same time as heparin, as it takes several days to decrease the concentration of vitamin k-dependent clotting factors. Heparin should continued until the INR IS>2.0 FOR 2 CONSECUTIVE DAYS.


The more recently developed low molecular weight Heparin (LMWHs) augment antithrombin activity Against factor Xa, it dose not prolong the APTT.If its plasma level needs to be measured this is Done by using a specific anti-Xa based assay.Because of its high bioavaibility after S.C injection ,It is given as either a standard or weight –related Dose.normally , therefore, the plasma LMWH levelDose not to be measured.


LMWHs are widely used for the prevention and treatment of VTE, the management of acute coronary syndromes . In some situations, UFH is still favoured by some clinicians, though there is little evidence that it is advantageous, except when rapid reversibility is required. UFH is useful in patients with a high risk of bleeding: for example, those who have peptic ulceration or may require surgery.


UFH is also favoured in the treatment of life-threatening thromboembolism: for example, major PE with significant hypoxaemia, hypotension and right sided heart strain. In this situation, UFH is started with a loading intravenous dose of 80 U/kg., followed by a continuous infusion of 18 U/kg/hr initially. The level of anticoagulation should be assessed by the APTT after 6 hours and, if satisfactory, twice daily thereafter.
It is usual to aim for a patient APTT which is 1.5–2.5 times the control time of the test.


Heparin-induced thrombocytopenia Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin therapy, caused by induction of anti-heparin/PF4 antibodies which bind to and activate platelets via an Fc receptor. This results in platelet activation and a prothrombotic state, with a paradoxical thrombocytopenia. HIT is more common in surgical than medical patients (especially cardiac and orthopaedic patients), with use of UFH rather than LMWH, and with higher doses of heparin.


Clinical featuresPatients present, typically 5–14 days after starting heparin treatment, with a fall in platelet count of more than 30% from baseline. The count may still be in the reference range. They may be asymptomatic, or develop venous or arterial thrombosis and skin lesions, including overt skin necrosis. Affected patients may complain of pain or itch at injection sites and of systemic symptoms, such as shivering, following heparin injections. Patients who have received heparin in the preceding 100 daysand who have preformed antibodies may develop acute systemic symptoms and an abrupt fall in platelet count in the first 24 hours after re-exposure.

InvestigationsThe pre-test probability of the diagnosis is assessedusing the 4Ts scoring system. This assigns a scorebased on:• the thrombocytopenia• the timing of the fall in platelet count• the presence of new thrombosis• the likelihood of another cause for thethrombocytopenia.Individuals at low risk need no further test; thosewith intermediate and high likelihood scores shouldhave the diagnosis confirmed or refuted using an anti-PF4 enzyme-linked immunosorbent assay (ELISA).

Management Heparin should be discontinued as soon as HIT is diagnosed and an alternative anticoagulant which does not cross-react with the antibody substituted. Argatroban (a direct thrombin inhibitor) and danaparoid (a heparin analogue) are licensed for use in the UK. In asymptomatic patients with HIT who do not receive an alternative anticoagulant, around 50% will sustain a thrombosis in the subsequent 30 days. Patients with established thrombosis have a poor prognosis.

Coumarins (e.g. warfarin)

Although several coumarin anticoagulants are used around the world, warfarin is the most common. Coumarins inhibit the vitamin K-dependent post-translational carboxylation of factors II, VII, IX and X in the liver. This results in anticoagulation due to an effective deficiency of these factors. This is monitored by the INR, a standardised test based on measurement of the prothrombin time.

Coumarins (warfarin etc.) indications:

Prevention and treatment of VTE Arterial embolism Atrial fibrillation with specific stroke risk factors . Mobile mural thrombus post-myocardial infarction Extensive anterior myocardial infarction Dilated cardiomyopathy Cardioversion Ischaemic stroke in antiphospholipid syndrome Mitral stenosis and mitral regurgitation with atrial fibrillation
Therapeutic INR 2.5

*Recurrent venous thrombosis whilst on warfarin *Mechanical prosthetic cardiac valves

INR=3.5



Warfarin anticoagulation typically takes more than 3 days to become established, even using initial loading doses. Patients who require rapid initiation of therapy may receive higher initiation doses of warfarin. A typical regime is to give 10 mg warfarin on the first and second days, with 5 mg on the third day; subsequent doses are titrated against the INR. Patients with risk factors requiring prophylactic anticoagulation (e.g. atrial fibrillation) can have warfarin introduced slowly using lower doses.


Low-dose regimens are associated with a lower risk of the patient developing a supratherapeutic INR, and hence a lower bleeding risk. The duration of warfarin therapy depends on the clinical indication, and while treatment of DVT or preparation for cardioversion requires a limited duration, anticoagulation to prevent cardioembolic stroke in atrial fibrillation or from heart valve disease is long-term.

The major problems with warfarin are:• a narrow therapeutic window• metabolism that is affected by many factors• numerous drug interactions.Drug interactions are common through proteinbinding and metabolism by the cytochrome P450 system.Inter-individual differences in warfarin doses requiredto achieve a therapeutic INR are mostly accounted forby naturally occurring polymorphisms in the CYP2C9and the VKORC1 genes and dietary intake of vitamin K.

Major bleeding is the most common serious side-effect of warfarin and occurs in about 1.0% of patients each year. Fatal haemorrhage, which is most commonly intracranial, occurs in about 0.25% per annum. There are scoring systems which predict the annual bleeding risk and these can be used to help compare the risks and benefits of warfarin for an individual patient .

Bleeding risk score

1-Age > 65 years (1 point) 2-Previous gastrointestinal bleed (1 point) 3-Previous stroke (1 point) 4-Medical illness (1 point) Recent myocardial infarction Renal failure Anaemia Diabetes mellitus Score: annual rate of major haemorrhage

0=3% 1-2=12% 3-4=30-48%

Management of warfarin includes strategies for over-anticoagulation and for bleeding.
1-If the INR is above the therapeutic level, warfarin should be withheld or the dose reduced. If the patient is not bleeding, it may be appropriate to give a small dose of vitamin K either orally or intravenously (1-2.5 mg), especially if the INR is > 8.

2-In the event of bleeding, withhold further warfarin. Minor bleeding can be treated with 1-2.5 mg of vitamin K intravenously. Major haemorrhage should be treated as an emergency with vitamin K 5-10 mg slowly i.v., combined with coagulation factor replacement. This should optimally be a prothrombin complex concentrate (30-50 U/kg) which contains factors II, VII, IX and X; if that is not available, fresh frozen plasma (15-30 mL/kg) should be given.



CONTRAINDICATIONS TO ANTICOAGULATION *recent surgery especially to eye or CNS. *pre-existing haemorrhagic state e.g.liver disease, Renal failure,haemophilia, thrombocytopenia. *pre-existing structural lesions e.g.peptic ulcer. Recent cerebral haemorrhage. *uncontrolled hypertension. *cognitive impairment. *frequent falls in old age.

Rivaroxaban

It is an orally active direct factor Xa inhibitor . Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects lasts 8 to 12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.


There is currently no specific way to reverse the anticoagulant effect of rivaroxaban in the event of a major bleeding event, unlike warfarin.


Indications of Rivaroxaban 1-prevention and treatment of VTE 2-Aterial fibrillation with risk factor Stroke.

Dabigatran

Ingested orally, dabigatran is a competitive and reversible direct thrombin inhibitor. Thrombin plays a role in the last step of blood coagulation.
150 mg orally twice daily



Dabigatran inactivates both fibrin-bound and free thrombin through binding to the active site; proving more effective than indirect thrombin inhibitors such as unfractionated heparin (which cannot inhibit fibrin-bound thrombin).


Dabigatran can be used for the prevention of stroke in patients with atrial fibrillation. The drug was developed as an alternative to warfarin, since it does not require maintenance of INRor monitoring by frequent blood tests, while offering similar efficacy in preventing ischemic events


Dosing modifications CrCl>50 mL/min: Dose adjustment not necessary CrCl >30-50 mL/min if patient not being treated with a P-glycoprotein (P-gp) inhibitor (eg, dronedarone, ketoconazole): No dosage adjustment required CrCl 30-50 mL/min plus P-gp inhibitor (eg, dronedarone, ketoconazole): Decrease dose to 75 mg PO twice daily

Apixaban

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as:1- prior stroke or transient ischaemic attack (TIA);2- age≥ 75 years;3- hypertension; 4-diabetes mellitus; 5-symptomatic heart failure (NYHA Class ≥ II).Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults .

Mechanism of action Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation