Thrombo Prophylaxis

7/31/2019 Thrombo Prophylaxis

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THROMBO

PROPHYLAXIS


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1. Which of the following statements iscorrect?

a. The annual incidence of venousthromboembolism is 20/100,000

b. The risk of a DVT after a hip replacement isaround 50%

c. 90-day mortality from a treated PE is 10%

d. Factor II is also known as prothrombin


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2. Are proteins C and S

pro-coagulant oranticoagulant?


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3. Which of the following aremajor risks factors for venous

thromboembolism? a. Malignancy

b. Varicose veins

c. Post-operative intensive care

d. Thoracic surgery


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4. Which of the following statements iscorrect:

a. In cases of HIT, it is recommended totransfuse platelets once below 20,000 !109/L.

b. Patients with HIT should beanticoagulated.

c. HIT should only be treated if the patienttests positive for HIT antibodies.

d. Patients with HIT are allergic to heparin.


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5. In a patient with HITT

(which includes thrombosis),

why should you reverse any

existing warfarin therapy?


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6. Which of the following is not adirect thrombin inhibitor?

a. Fondaparinux b. Lepirudin

c. Argatroban d. Bivalirudin

e. Danaparoid


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INTRODUCTION

Venous thromboembolism (VTE),comprising deep vein thrombosis (DVT) andpulmonary embolism

(PE), has an annual incidence in Europe of60 -70 per 1000, 000 inhabitants.

Half of these occur in hospitalised patients

or those in care homes, and 25% in peoplewith no recognised risk factors.


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The risk in the post-operative populationis higher still, with the incidence ofsubclinical DVT after total kneearthroplasty or hip fracture surgerybetween 40-60% and an incidence of PEin the same group of 4-10%.

In the UK, patients with a PE whoreceive treatment, have 14- and 90-daymortality rates of approximately 10%and 20%, respectively.


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The House of Commons Health Committeereported in 2005 that an estimated 25,000people in the UK die from preventable hospital-acquired VTE every year.

It is our duty to do what we can to reduce theincidence of VTE by both understanding themechanism of formation, and ensuring correctprophylaxis is received.

There have recently been a number of advancesin the prevention of VTE, and this two-part seriesaims to summarise these, as well as reviewingolder prophylactic strategies.


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This first tutorial will discuss thepathophysiology of VTE, identification ofhigh risk populations, and the presentationof DVT and PE.

It will then briefly cover the treatment ofthese conditions.

In the second tutorial, the mechanical andpharmacological methods of prevention

will be discussed.


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THROMBOGENESIS

Thrombogenesis is a normal mechanism bywhich the body maintains haemostasis isresponse to injury.

Venous thromboembolism, however, is theabnormal development and propagation of aclot which is not useful.

The thrombus can cause local problems relatingto mechanical obstruction or blood flow.

In this situation, fragments of the thrombus canbreak off and cause further harm by similar

means.


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The formation of a thrombus and its subsequentembolisation was first described by RudolphVirchow in 1856.

He subsequently described the eponymouslynamed Virchows triad.

In an environment where one or more of the

following conditions are met, there is a risk ofthrombogenesis; venous stasis, damage ordysfunction of the endothelium anhypercoagulability.


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Activation of the

coagulation cascade

Tissue factor is located in the smooth muscle andadventitial layers or vessel walls; collagen is locatedin the subendothelial matrix.

When the endothelium is disrupted, the revelation ofeither of these compounds can initiate thrombusformation via platelet activation.

Coagulation can also be activated inappropriately,not just by trauma to the endothelium, but by

disruption, such as that caused by atheroscleroticplaques, turbulent blood flow or accumulation ofactivated clotting factors which may precipitatethrombus formation. immunological damage.Stagnant blood allows


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Platelets Platelets are formed from the fragmentation

of a precursor called a megakaryocyte andhave a life span

of only 5 -9 days. The main function of aplatelet is to maintain haemostasis. Plateletsare responsible

for synthesis of Thromboxane A2 and withinthe cell there are granules containing many of

the mediators of coagulation; calcium, ADP, von

Willebrand Factor, fibrinogen, factors V andXIII.


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The initial tethering of platelets to thesite of injury is mediated by glycoproteinIb receptors and Von Willebrand Factor

(vWF).

As the platelet plug forms there is aconformational change cause by actin

and myosin filaments within the cell. Contraction of the plug acts to reduce

the size of the vessel defect and stabilise

the plug.


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Von Willebrand Factor Von Willebrand Factor (vWF) is found in

plasma, the endothelium and

megakaryocytes.

The binding of vWF to collagen or plateletglycoprotein complexes, facilitates the

formation of a thrombus. Absence of vWF factor causes a defect in

primary haemostasis and coagulation as

seen in von Willebrand Factor deficiency.


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Formation of the thrombus

After initial adhesion of platelets to the site ofinjury, amplification of the coagulation

process must occur for a stable plug to form. The platelet integrin, glycoprotein IIb/IIIa, is

the main receptor for adhesion and

aggregation but other autocrine andparacrine mediators, including thrombin,thromboxane A2, epinephrine and adenosinediphosphate aid the haemostatic process.


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The formation of thrombin

Thrombin is a potent initiator and

amplifier of the coagulation

cascade. When tissue factor is exposed, three

substrates, factor VII, factor IX and

factor X interact to form factor Xawhich converts prothrombin to

thrombin.


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Thrombin then activates the flowingfactors; V, VIII, XI, as well as initiating theconversion of fibrinogen to fibrin.

Factor Va amplifies the conversion ofprothrombin to thrombin.

In its absence, the generation of thrombin

is 1% the rate of generation when factor Vais present.


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Fibrinogen Fibrinogen, a soluble plasma

glycoprotein, is converted to fibrin

by the action of thrombin and plays

a great role in providing stability tothe platelet plug by bridging

glycoprotein IIb/IIIa integrins.


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Modulators Calcium is an important co-factor in the

coagulation cascade without which haemostasis

would falter. It is only in the presence of both calcium and

factor Va that factor Xa can convert prothrombinto

thrombin on the cell membrane. Vitamin K is a fat soluble vitamin that is involved

in the carboxylation of glutamate residues onfactors

II, VII, IX, X and proteins C and S.


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Negative feedback and

inhibition

Haemostasis is an incredibly careful balance

between pro- and anti-coagulant factors that

are omnipotent within the plasma and

endothelium.

As soon as the coagulation cascade is initiated,

the inhibitory mechanism is also activated.

When bound to thrombomodulin (found in theendothelium), thrombin activates protein C,

an inhibitor of the coagulation cascade and inthis way provides negative feedback, halting

the haemostatic process.


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The action of Protein C

(inactivation of factors Va and

VIIIa) is slightly increased in thepresence of Protein S.

Antithrombin III, circulating inplasma, is also a potent

inactivator of thrombin.


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Plasmin, derived from the

cleavage of plasminogen by tissue

plasminogen activator (t-PA) inthe endothelium, is responsible

for fragmenting fibrin and

destabilising the thrombus.


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ASSESSMENT OF RISK

The National Institute of ClinicalExcellence (NICE) recently passed

guidance relating to VTE.

All patients admitted to hospital inthe United Kingdom should have

their risk of VTE assessed onadmission, allowing adequate

thromboprophylaxis to be instituted

immediately.


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DIAGNOSIS OF VTE VTE has a variety of clinical

presentations and is often

asymptomatic. Symptomatic venous thrombosis

carries a considerable risk of long

term morbidity, due to venousulceration and development of post-

thrombotic limb secondary to

venous insufficiency.


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Signs and symptoms of

DVT and PE Signs and symptoms of a DVT or PE may bevery subtle and unless actively searchedfor, can easily be missed.

Symptoms of a DVT include painful, red,swollen limb.

On examination the limb may be tender on

palpation, hardened or distended veinsmay be identified and there may be

discolouration or cyanosis.


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The clinical presentation of a pulmonaryembolus may be even more vague.

Symptoms and signs include dyspnoea,

tachypnoea, chest pain, cough,haemoptysis, tachycardia, raised jugularvenous pressure, cyanosis, fever andcirculatory collapse.

There are a number of scoring systems tohelp guide investigation of a suspected PE,the one reproduced in the box below is thatwhich is recommended by the British

Thoracic Society (BTS)1:


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The patient must have clinical features compatiblewith PE breathlessness and/or tachypnoea with orwithout pleuritic chest pain and/or haemoptysis

plus two other factors: (a) the absence of another reasonable clinical

explanation

(b) the presence of a major risk factor.

Where (a) and (b) are both true the probability ishigh; if only one is true

the probability is intermediate; and if neither is truethe probability is low.


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Investigations

Leg Ultrasound

For suspected DVT, duplex ultrasonography of

femoral and popliteal veins has a sensitivity and specificity of around 97% in a symptomatic patient5.

Unfortunately there is limited accuracy in

compression ultrasound in detecting asymptomatic

proximal DVT and a single normal leg ultrasound, should not therefore, be used to exclude a subclinical

thrombus1.


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D-dimer

D-dimer is a degradation product of cross-linkedfibrin. Raised D-dimer levels do not infer VTE as they

are present in many conditions such as pregnancy,peripheral vascular disease, cancer, inflammatoryconditions and hosptalised patients.

Newer second generation rapid D-dimer tests showsensitivities of 87-98% and combined with a lowclinical probability (using a scoring system such asthe one discussed earlier), a negative D-dimer canhave a negative predictive value of 97%.


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If all patients with high, intermediate and lowclinical probabilities are included, then thenegative predictive value drops to 85% (usingthe SimpliRED assay)1.

The BTS recommend that the D-dimer is onlyused in cases where clinic suspicion of a PE or

DVT is low.


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Isotope Lung Scanning

Isotope tests are reported as having high,

intermediate and low probability ofpulmonary embolism.

A normal or low probability isotope orventilation/perfusion scan, reliably excludes a

PE.

A high probability lung scan is not, however,diagnostic of one1.


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The BTS recommends that an isotope scanshould only be the initial imaging investigation ifthere is: a normal, contemporaneous chest x-ray,no significant, symptomatic cardiopulmonarydisease, facilities are available on site,standardized reporting criteria are used and anon-diagnositc test is followed by furtherimaging.

This technique is useful in those patients whowould benefit from the lower radiation exposureas compared to the CTPA, such as obstetricpatients.


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Computed tomography pulmonary angiogram(CTPA)

The availability of fast multi-slice scanners

has increased in the northern hemisphere andit is now the recommended first line imagingtechnique for PE.

Its superiority to the isotope scan is not onlythat it has a greater sensitivity and specificityfor PE but that, in the advent of a negativescan, it often reveals the true diagnosis.


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The CTPA identifies a greater number ofemboli, but without improving outcome,when compared to the ventilation/perfusionscan.

A proximal clot can be reliably identified inaround 95% of studies and if the CTPA is

negative further treatment is not required.


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Echocardiography ECHO can be diagnostic in

massive PE and may give

prognostic information,

however, it is less useful in mostother cases.


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Other Investigations

Contrast venography is the gold standarfor PE diagnosisbut there is inter-observer

disagreement in up to a third of subsegmental thrombi. It is

still, however, more sensitive tosubsegmental thrombi than a CTPAd for DVT diagnosis in

all veins but is rarely carried out.

Alternate investigations include measurement of thethrombus burden, using radionuclide venography

and impedance plethysmography. Both are sensitive indetecting proximal but not distal thrombosis.

\

Pulmonary angiography is seen as the gold standard.


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In patients with a PE the electrocardiogramoften demonstrates only a tachycardia.Infrequently there

may be right axis deviation, large S deflectionin lead I, a Q wave in lead III and inverted Twave in

lead III. T wave inversion in inferior andanterioseptal leads may also be indicative ofPE.


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Chest X-ray is invariably unhelpful in thediagnosis of a PE although it candemonstrate Westermark sign (proximaldilation and distal constriction of the

pulmonary vasculature) and HamptonsHump (wedge shaped opacificationassociated with pulmonary infarction).

Although rare, if seen, these signs have highspecificities for PE.

Although it may not be of use in diagnosis ofPE, a chest x-ray may well elucidate an

alternative diagnosis.


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TREATMENT OF VTE The initial treatment of any patient follows the

ABC approach .

Patients suspected VTE may need supportivetherapy and treatment based on clinical

judgement prior to definitive diagnosis.

Therapy may include: oxygen, fluid, inotropesand analgesia.

In the future there may be a place for pulmonaryvasodilators in treatment of a massive PE butcurrently, along with supportive management,the goals of treatment are to prevent furtherthrombus formation, and in some circumstances

precipitate breakdown of the thrombus.


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These recommendations for treatment of anacute VTE are taken from the AmericanCollege of Chest Physicians2 (ACCP) who

issued guidelines in 2008.

The British Thoracic Society guidelines datefrom 2003 and differ only slightly.

NICE are in the process of developingguidelines for the treatment of VTE.


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Anticoagulation

The ACCP guidelines state that anticoagulationwith unfractionated heparin (UFH), lowmolecular heparin (LMWH) and factor Xainhibitors is better than no anticoagulation for anacute PE or DVT.

The treatment of choice, however, is LMWHwithout regular factor Xa assays.

Direct thrombin inhibitors are also useful as theinitial treatment of VTE, although these are notmentioned in the guidelines


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. If LMWH is unavailable and there is noability to monitor anti-Xa activity thensubcutaneous, fixed dose UFH can be used

(initial dose 333U/Kg followed twice daily250U/Kg).

A vitamin K antagonist (VKA) should be

started on day one and dual therapycontinued until the international normalised

ratio (INR) is > 2 for more than 24 hours.


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In the case of massive PE then an IV bolus ofUFH may be given immediately as it is morerapid in onset than the LMWH.

Where the clinical suspicion of VTE is high,then treatment should be started beforedefinitive diagnosis.

In renal failure there is some evidence tosuggest that UFH is safer than LMWH.


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Thrombolysis

For the majority of patients with VTE, thrombolysisis not recommended, however, the cliniciansdecision must be based on severity of the condition,

prognosis and risk of bleeding. There is a small population of patients that may

benefit from thrombolysis, namely any patient withhaemodynamic compromise including cardiacarrest, unless contraindicated due to bleeding risk.

If administering thrombolysis then a peripheral veinis preferred to a central catheter.

50mg Altepalase (a plasminogen activator) isrecommended by the BTS in the emergent situation.


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Caval filters and embolectomy

In highly compromised patients who cannotreceive thrombolytic therapy then catheter

extraction or embolectomy may beconsidered.

The routine placement of a vena caval filter isnot recommended but in a patient with a highrisk of bleeding, obviating the use ofanticoagulation, then an inferior vena cavalfilter may be used.


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Long term treatment

VKA, most commonly warfarin, provide themainstay of long term prophylaxis againstfurther VTE.

Anticoagulation with VKA for at least 3 months,with a target INR 2.5, is recommended for allpatients (BTS advise 6 weeks in those with norisk factors).

Long term anticoagulation must be assessed inconjunction with the individual patients risk ofbleeding and on-going risk factors for VTE.


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IMPORTANT POINTS/SUMMARY BOX

VTE is a major cause of mortality andmorbidity

Appropriate thromboprophylaxis should beconsidered for patient admitted into hospital

Appropriate diagnostic tests and imagingdepends on the findings of a targeted clinical

history and examination


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ANSWERS TO QUESTIONS

1. F/T/F/T

2. Proteins C and S are anticoagulant co-factors

3. malignancy, varicose veins, post-operative

intensive care


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Heparin induced

thrombocytopaenia (type II)is a life-threatening syndrome that may occur after

exposure to unfractionated or (in rare cases) low-molecular-weight heparin. HITis usually suspected

after an incidental finding of thrombocytopaenia following administration ofheparin, where there is no

clear alternative cause for the fall in platelet count. Detection of thethrombocytopaenia and accurate

diagnosis (or strong clinical suspicion), are key aspects in the management ofHIT. Once the diagnosis

has been committed to, treatment must be immediately initiated to combatsome of the potentially

catastrophic effects of the disorder. The principal goal of managing heparininduced

thrombocytopaenia is to reduce the risk of thrombosis by decreasing furtherplatelet activation and

thrombin generation.


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There are seven key aspects of treating hit:

1. Discontinue heparin.

2. Continue to monitor platelet counts.

3. Avoid giving warfarin until platelet counts recover.4. Test for HIT antibodies (if not already tested for).

5. Evaluate for the presence of deep veinthrombosis.

6. Platelet transfusions are ONLY given to treatbleeding, NOT the thrombocytopaenia.

7. Anticoagulate with a non-heparin regimen.


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DISCONTINUE ALL HEPARIN

In most cases, patients with HIT have recently been exposed to a heparin source: heparin flushes,intraoperative

anticoagulation, subcutateous injection for thrombophrophylaxis, or haemodialysis.

Whatever the situation, once your suspicion of HIT has been adequately confirmed; ensure allsources

of heparin are discontinued, and notify all caregivers. Interestingly, a retrospective analysis2

demonstrated that timely discontinuation of heparin was no more effective in reducing morbidityand

mortality than late heparin cessation. This demonstrates that, while ceasing heparin is a vital partof

management, multimodal therapy is important in ultimately decreasing the morbidity andmortality.

The thrombocytopaenia associated with HIT may continue to worsen, even after discontinuingheparin

administration. Recovery of the platelet count is a good sign that HIT has regressed and isresponding

to therapeutic measures.


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HIT is usually suspected and investigated afteran incidental platelet count reveals

thrombocytopaenia.

Until the nadir of the patients platelet count hasbeen established, and there is a clear rise in the

platelet count, the patients platelet levelsshould be evaluated daily (when resources

allow). In severe

cases of thrombocytopaenia, haemoglobin levelsshould also be monitored for signs of subclinical

bleeding.


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WARFARIN AND LOW MOLECULARWEIGHT HEPARIN (LMWH)

LOW MOLECULAR WEIGHT HEPARIN

Low molecular weight heparin is not anappropriate alternative for anticoagulation in

HIT. There is an

in-vivo cross-reactivity between UFH andLWMH in approximately 50% of cases.


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WARFARIN

Warfarin monotherapy in active heparin inducedthrombocytopaenia is contraindicated, based on

multiple reports of warfarin induced skin necrosis and

venous gangrene in the limbs. Affected patientstypically have a supratherapeutic INR (typically above 4.0).

The risk of thrombosis in HIT patients

started on warfarin is 38-76% within the first month despitecomplete discontinuation of heparin. For

this reason it is recommended that warfarin not be starteduntil adequate resolution of the patients

thrombocytopaenia has occurred (preferably, plateletcounts above 150,000 ! 109/L).


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In some cases, HIT is diagnosed after warfarintherapy has already been initiated. In this situation,

it is

recommended to reverse warfarin anticoagulationwith vitamin K. This reversal reduces the risk of

warfarin necrosis, and minimizes the risk of directthrombin inhibitor (DTI) underdosing, as warfarin

prolongs the activated partial thromboplastin time(aPTT), which is used to monitor DTI levels, as well

as the PT.


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REVERSAL OF HEPARIN

The reversal of vitamin K antagonists (warfarin), should be conducted byadministering vitamin K 5-10

mg orally or iv. Evaluation of the International Normalised Ratio (INR) and aPTTshould be done

roughly 6 hours later to evaluate the effectiveness of the vitamin K dosing. Thedoes can be repeated,

if necessary.

HIT ANTIBODIES

In a patient with clinically suspected HIT (where the pre-test probability is high),more definitive

confirmation by testing for the presence of HIT antibodies helps to guidetreatment and prevents

missing an alternative diagnosis. Specifics on the types of testing available aredetailed inpart 1 of this

tutorial.


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DEEP-VEIN THROMBOSES

Anticoagulation is required for at least 2 to 3 monthsafter the resolution of HIT (see below) to prevent

and treat thrombosis. Thrombosis in HIT is one ofthe more serious complications, and as a result

requires vigilance in monitoring and prompttreatment if detected. In patients with HIT who

develop

thrombosis, there is an associated mortality ofapproximately 2030%, and an equal percentage will

become permanently disabled by amputation,stroke or other causes.


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Thromboembolic complications can bevenous, arterial (or both) and include:

1. Deep venous thrombosis (DVT)

2. Pulmonary embolism (PE)

3. Myocardial infarction (MI)

4. Thrombosis and ischemia of limbs via

arterial occlusion.


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The type and site of thrombosis varies depending on the patientand some of their inherent risk factors.

DVTs and PEs are most common in postoperative patients. Whilethe incidence of deep vein

thrombosis in orthopaedic patients who received heparin forthromboprophylaxis was 17.8%, those

with HIT have a DVT incidence that approaches 89%. Even afterdiscontinuation of heparin, patients

with HIT have a 38-76% risk of developing thromboticcomplications in the first month.

Therefore, an essential component to treatment of the patientwith HIT is vigilance in monitoring for

the development or existence of thrombi, and optimizingtreatment to prevent further occurrence.

PLATELET


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PLATELET TRANSFUSIONS

Even though patients with HIT can be severelythrombocytopaenic, the transfusion of platelets in an

attempt to avoid bleeding is generally unnecessary. Even

when severe throbocytopenia occurs in HIT,petechiae and other mucocutaneous bleeding that would

typically be found in patients with non-HIT

thrombocytopaenia are rare. Paradoxically, platelettransfusions have been linked with thrombotic

events in some reports. When the diagnosis of HIT is uncertainand there is a high bleeding risk (as

judged by the clinician), or if significant bleeding occurs,platelet transfusions may be appropriate.


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ALTERNATIVE ANTICOAGULATION

As mentioned above, the thrombotic aspect of HIT is aserious comorbidity that should be prevented,

monitored, and treated if discovered. The pathophysiology

of HIT involves extensive plateletactivation, and thrombocytopaenia secondary to platelet

clumping/consumption. Hence, once the

diagnosis of HIT is committed to, and heparin isdiscontinued, alternative thromboprophylaxis should

be initiated.Until it is safe to restart heparin or warfarin, a range of

newer and developing anticoagulants may be

utilized for thromboprophylaxis.


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INITIATION OF ALTERNATIVE ANTICOAGULATION

Non heparin alternate anticoagulants should be given for at least 14 days totreat and prevent

thrombosis. Preferred alternatives are lepirudin or argatroban.

1. Special monitoring tests are required for these medications.

2. Doses should be reduced in cases of renal and hepatic insufficiency.

3. Once the platelet count rises above 150,000 ! 109/L, oral warfarin may beinitiated with careful

overlapping with a nonheparin anticoagulant for at least 5 days.

4. If a life saving procedure like coronary artery bypass graft (CABG),percutaneous coronary

intervention (PCI) or haemodialysis is required during acute HIT, the alternative,nonheparin

anticoagulant of choice will depend upon the resources at your facility(availability of medication

and ability to monitor levels of anticoagulation).


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DIRECT THROMBIN INHIBITORS

Direct thrombin inhibitors work in the final commonpathway of the clotting cascade (see figure 1).

They directly bind and inactivate thrombin (alsoknown as factor IIa). This prevents the conversion of

fibrinogen to fibrin (a key component to theproduction of a hemostatic plug or clot).

Direct thrombin inhibitors have short half-lives,show no cross-reactivity to heparin, and unlike

heparin, do not require antithrombin to function.


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Lepirudin

Lepirudin is recombinant hirudin (originally produced by leeches),which directly inhibits thrombin by

irreversibly binding to it. In patients with HIT, studies havedemonstrated that anticoagulation with

lepirudin significantly lowered mortality, new thromboembolism,and limb amputation.

Of note, lepirudin is renally cleared, and caution should be takenin those with renal dysfunction.

Antibodies to lepirudin develop in 30% of patients after initial

exposure and in 70% of patients afterrepeated exposure. Because fatal anaphylaxis has been

reported upon repeat administration of

lepirudin,patients should not be treated with this agent morethan once.


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Argatroban

This is an arginine-based synthetic anticoagulant, which directly inhibitsthrombin and reversibly binds

the catalytic site of thrombin. Of note, Argatroban is hepatically cleared, andcaution should be taken in

patients with liver dysfunction. In these patients, it is recommended to reducethe dose by 75%.

Bivalirudin

Bivalirudin is another synthetic thrombin inhibitor that has been approved forpercutaneous coronary

intervention in patients who have, or are at risk for, heparin-inducedthrombocytopaenia (table 2).

Because of its short half-life, bivalirudin shows promise as a potentialanticoagulant in cardiac bypass

surgery, but its use in treating heparin-induced thrombocytopaenia has not beenstudied in clinical

trials.


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FACTOR Xa INHIBITORS

Danaparoid

Danaparoid is a mixture of three glycosaminoglycans(heparin sulphate, dermatan sulphate and

chondroitin sulphate) which, via antithrombin, inhibits anti-factor Xa activity. Recent studies in HIT

associated thrombosis showed a 90% treatment successrate with danaparoid. Danaparoid has a long

anti-factor Xa half-life of roughly 25 hours. Danaparoid can

be given intravenously (see table) orsubcutaneously if the intravenous route is not practicable.

In this case it can be given as 1250U

subcutaneously followed by 2000U twice a day.


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The dose should be adjusted to maintainplasma anti-Xa levels within 0.50.8 U/mL

(this requires

facilities that have the ability to rapidly testfactor Xa levels). If surgery or other invasive

procedures

are planned, danaparoid should be stoppeduntil the anti-Xa level is less than 0.4.


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Fondaparinux

Fondaparinux is a synthetic heparin pentasaccharide thatdoes not cross-react with HIT antibodies, and

is a favourable candidate for anticoagulation in patients

with HIT. It has a long half-life of roughly 17hours, and is recommended as prophylaxis for post-

operative thrombosis by daily subcutaneous

injection of 2.5mg. Despite its theoretical potential, thereare few publications supporting the use of

fondaparinux in HIT and other thrombocytopenicsituations. Further studies are required before a

definitive recommendation can be made on its use in HIT.


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ALTERNATIVE ANTICOAGULATION IN LATER STAGES OF HIT

Subacute HIT

At this stage, platelets have generally recovered and are stable at levelsof 150,000!109/L or above, but

the patient is still HIT antibody positive.

1. Avoid reintroduction of heparin for at least 100 days to minimize theincreased risk of thrombosis.

2. Alternative anticoagulation may be utilized in emergency situations(CABG, PCI, dialysis)

Previous HIT, but normal platelet count, and no detectable HIT antibodies

1. Short-term exposure to heparin may be safe, but should be utilizedonly in emergency situations.

2. Alternative anticoagulants may be used if there is a concern of HITrecurrence.

3. Bivalirudin may be considered as drug of choice for PCI.


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SUMMARY

If HIT is confirmed or seriously suspected:stop all heparin.

Follow platelet trends

Evaluate and monitor for arterial and/orvenous thrombosis

Commence alternative anticoagulation


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ANSWERS TO QUESTIONS

1a: FALSE. Platelet transfusion should bereserved for patients with documentedbleeding, as further platelet loads areassociated with thrombosis in HIT.

1b: TRUE. Because of the incidence and

morbidity/mortality of HIT associatedthrombosis, prophylaxis should be initiatedafter discontinuation of heparin.


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1c: FALSE. Because of the sensitivity of theHIT antibody test, it serves as an excellent testto rule out HIT.

Likewise, the availability of a HIT antibody testis not essential for diagnosing HIT.

A diagnosis of HIT can be made on clinicalgrounds if an antibody test is not available.

1d: FALSE. HIT is not an allergic condition.

While HIT is an antibody mediated condition,it does not involve systemic histamine release oranaphylactic/anaphylactoid characteristics.

.


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2: When utilizing warfarin in HIT patients, asevere reduction in protein C can develop,resulting in a failure to control thrombingeneration.

As a result, thrombosis in HIT patients startedon warfarin can reach 38-76% within the firstmonth, despite complete discontinuation of

heparin. 3: a and e. Fondaparinux and danaparoid are

NOT direct thrombin inhibitors but anti-factorXa agents


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Anticoagulation is a very common form of medical intervention

which is increasingly used for primary or secondary prevention

of thromboembolic complications of vascular disease. Oralanticoagulation

with vitamin K antagonists (VKAs), mainly warfarin,is almost the unique tool for chronic anticoagulant treatment

in clinical practice, although newer anticoagulants have already

been approved or evaluated in clinical studies. Anticoagulation

with VKAs has been shown to be effective in the prevention and

treatment of thrombotic complications in various clinicalsettings,

including atrial fibrillation, venous thromboembolism

(VTE), acute coronary syndromes and after invasive cardiacprocedures.


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In spite of the sharp increase in the number of anticoagulated

subjects which has occurred in recent years (an increase

of 45% of warfarin prescriptions between 1998 and 2004

has been recorded in the USA [1]), numerous studies have documented

an under-use of anticoagulation in subjects, especially

elderly, who would benefit from this therapy (2, 3). Adequate

treatment with VKAs is rather demanding, for both the patients

and the health care systems, because periodic laboratory monitoring

is necessary to maintain the effect of the drug in a therapeutic

range and to minimize adverse events (46). Bleeding is

the most important complication of VKAs and a major concern

for both physicians and patients.


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The incidence of bleeding varies widely inpublished studies. In

part, the difference in reported rates can be

attributed to the diverse

classification of bleeding events (major, life-threatening

and minor) adopted in single studies.


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randomised clinical trials record lower rates ofbleeding than observational

studies because they usually include only highly

selected patients.Very elderly patients are almost always

excluded in these studies

Up to one third of patients evaluated for

participation in clinical trials on VKAs use in atrialfibrillation were judged for a high perceived

bleeding risk (7, 8).


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It is, in fact, well known that the first few months of

treatment are associated with a higher rate of complications (9,

10.)

Such studies may therefore underestimate the rate of bleeding

by missing early complications and early cessation of VKA

in patients at a high risk of bleeding. In a recent analysis of clinical

studies characterised by careful monitoring of anticoagulant

intensity, it has been calculated that VKA treatment increases the

risk of major bleeding by 0.3 0.5% per year. In these studies the

risk of intracranial hemorrhage (ICH), which is the major if not

the exclusive cause of death and disability associated with VKA

treatment (11), is increased by approximately 0.2% per year

when compared to controls (12).


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The absolute risk of major bleeding complications in specialised

anticoagulation services ranged from 0.32% to 2.1% per

year, and of fatal bleeding from 0% to 0.25% per year (13). Asignificant

clinical impact of bleeding in patients anticoagulated for

VTE has been demonstrated in a recent meta-analysis ofavailable

clinical trials that reported a case-fatality rate of major

bleeding of 13.4% in all patients (95% confidence interval [CI],

9.4% to 17.4%), with a rate of ICH of 1.15% patient-years (95%CI, 2.5% to 21.7%) (14).


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Major bleeding with VKA treatment can be not onlylifethreatening,

such as ICH, but also associated with significant

morbidity, while even minor bleedings may be important for the

related inconvenience to the patients. Altogether, the risk of

bleeding associated with VKAs limits their more widespread use

and denies many patients the benefits of a useful therapy. It has

been shown (15) that the occurrence of VKA-associated adverse

events has an impact on the prescription of this treatment, since

physicians are less likely to prescribe VKAs after observing

major bleeding during VKA treatment in their patients.


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Intensity of anticoagulation

The intensity and duration of anticoagulation are main factors

associated with the risk of bleeding. A strong relationship between

the intensity of anticoagulation and the risk of bleeding

has been demonstrated by several experimental trials (in various

clinical conditions) in which patients were randomised to different

anticoagulation levels (12). Though bleeding is not always related

to a high intensity of anticoagulation and may occur even in

association with very low international normalised ratio (INR)

values (< 2.0), the intended intensity of anticoagulation and especially

the actually achieved intensity are major determinants

of anticoagulation-induced bleeding.


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The increase in bleeding

incidence becomes exponential for INR values > 4.5,while the

lowest rate is associated with INR results between

2.0 to 3.0 INR(9). The risk of death is also strongly related to the

INR level,

with a minimum risk at 2.2 INR. High INR values are

associatedwith an excess mortality as well: for one unit INR

increase above

2.5 there is a two-fold risk increase (19).


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Timing from starting of anticoagulation

The first period of anticoagulation and inparticular the first 90

days are associated with a higher rate ofhaemorrhages (9, 10).

This can be attributed to different factors: occultlesions can be

unmasked at the beginning of anticoagulanttherapy, and/or the

dose adjustment may be less adequate in thatperiod.


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Quality of monitoring

A poor control of anticoagulation is undoubtedly an important

factor leading to an increased risk of complications. A way to

evaluate the quality of anticoagulation control is to calculate the

time spent within the therapeutic range (time-in-range). A strongrelationship between time-in-range and bleeding or

thromboembolic

rates has been observed in many studies, involving different

patient populations and different target ranges (20).


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Higher

rates of annual mortality and major bleedingevents have been

recorded in a poor control group of patients(4.20% and 3.85%,

respectively) compared to a good control

group (1.69% and

1.58( )%21.)


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Many factors may affect the quality of anticoagulation

monitoring. A better overall quality of treatment and a

more stable anticoagulation has been reported by using coumarin

drugs with long-lasting action, such as warfarin (22) or phenprocoumon

(23), versus the short half-life drug acenocoumarol.

Patient information and education and the systems adopted for

INR control are also factors affecting the quality of treatment. A

better quality control in patients who had received a satisfactory

education has been reported (24), as well as an improvement in

their time-in-range in highly unstable patients after a supplementary

education course (25).

For personal


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Person-dependent factors

Genetic factors

Though for decades VKAs have been the most usedantithrombotic

drugs, only recently our understanding of their mechanismsof action and of the broad inter-individual variability in

the sensitivity to these drugs has greatly improved thanksto the

knowledge on their pharmacogenetics (for a complete

review see[30.)]


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At least 30 genes have been associated with themetabolism

and action of warfarin. Some polymorphisms of genes thatencode

for the vitamin K epoxide reductase enzyme (VKORC1)and for the cytochrome P-4502C9 enzyme (CYP2C9) are

responsible

for the large inter-individual variations in doserequirements,

and can predispose to overdosage conditions and a higherrisk of bleeding (31, 32).


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Age

Throughout most (9, 4649), though not all (50, 51),studies age

is generally regarded as a risk factor for bleeding

during VKAtreatment. A recent review of the studies (52)

reported rates of

3.2% and 0.64% patient-years, for major and fatal

bleeding respectivelyin subjects aged 69 years or older compared to 0.6%

and 0.12% patient-years in subjects aged 40 years orless.


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The

risk of ICH, the most important and feared type of haemorrhage

during VKA, is particularly increased in advanced age (47). Its

incidence is estimated to be 0.2% to 1.0% patient-years in all

anticoagulated patients (53), but increases to 1.1% patient-yearsin patients above 75 years (54). A recent study (55) reported an

adjusted odds ratio of 2.5 (95% CI, 134.7) of ICH in patients

aged 85 or more versus a reference group of patients of 7074

years. In line with previous reports (54), this study showed that

values of INR less than 2.0 were not associated with lower risk ofICH compared with values between 2.0 and 3.0.


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Elderly subjects are exposed to higher risk for bleedingcomplications

during VKA for several reasons. They require lower

anticoagulant doses than younger subjects, mainly because ofreduced

metabolic clearance (56) especially in older women. It hasbeen recently shown that, when warfarin is being initiated, the

commonly used starting daily dose of 5 mg per day may lead to

overanticoagulation for the majority of elderly patients and a

lower initiation and maintenance dose has been recommendedfor these patients (57).


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Elderly patients have a higher prevalence

of co-morbid conditions (58) and are more likely to be takinginteracting

drugs. They more frequently have pathological changes

in cerebral vessels, such as leukoaraiosis and amyloid angiopathy,

that may increase the risk of ICH (59, 60). They are at

higher risk for falls with a subsequent substantially increased

risk of intracranial haemorrhage (61). The incidence ofgastrointestinal

haemorrhage increases sharply with age (62), due to themorefrequent presence of diverticulosis, malignancy, angiodysplasias,

and ischaemic colitis, all more common in the elderly

population.


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Although reported to be similar in elderly and

younger patients (63), non-compliance to VKAs maycontribute

to the complexity of the drug regimen and a higher

instability ofanticoagulation levels. A lack of a clear

understanding of the purpose

and mechanisms of this treatment by the elderly (25)

whoare also prone to mental impairment (64) may also

contribute to

a low compliance with the treatment.


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It can be concluded that elderly patients shouldnot be excluded

from anticoagulation therapy only because oftheir age if

they are otherwise good candidate to thetreatment. These subjects

should, however, be monitored carefully andfrequently to

maximise their stability during anticoagulationand to reduce the

risk of complications.


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Gender

A greater risk of bleeding (66) or of borderline significance(67)

was reported in women than in men treated for atrialfibrillation,

although no significant difference in bleeding rate between

males and females was found in observational studiesenrolling

patients with various indications for VKA (9). Pengo et al.

(68)found a higher frequency of major bleeding in females

treated for

atrial fibrillation at univariate analysis.


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Non-compliant patients

were found to be more frequently young, male and not havingalready

experienced a thromboembolic event (63). Unstable patients,

more frequently than stable ones, reported they were

poorly informed on the reasons and the clinical importance of

anticoagulation for their health; many of them also hadinsufficient

knowledge of VKA mechanism of action, the rules of treatment-

monitoring, and the risk of thrombotic and bleedingcomplications

(25.)


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A relationship between patient knowledge of

anticoagulation mechanisms and quality of control has beenreported

(69, 70). Moreover, patient education on VKAs andanticoagulation

training has been effective in reducing the risk ofmajor bleeding in older patients (71). These data indicate that

patient

knowledge of VKAs treatment and its management is a primary

determinant of the quality of anticoagulation control and

that appropriate education and information of patients is one of

the most important tasks of services dedicated toanticoagulation

monitoring.


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Dietary modification has long been recognised as a key factor

for instability of anticoagulated patients. Patients who increase

their dietary vitamin K intake may become resistant to

VKA effect (72, 73). On the contrary, a lower intake of vitamin K

has been demonstrated to increase sensitivity to VKAs (74, 75).A reduction in dietary vitamin K intake should be expected in

sick patients who are treated with antibiotics and intravenous

fluids without vitamin K supplementation and in patients who

have states of fat malabsorption.


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It is possible that at least part of

the instability of anticoagulation control in patientson VKA

therapy is attributable to a low dietary intake and/orlow reserves

of vitamin K. A low-dose vitamin K supplementation(100 to 200

mcg daily) proved to be effective in improving thequality of anticoagulation

control (76, 77), a result that has been confirmed by

two recent trials (78, 79).


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Fever or other hypermetabolic states, such as hyperthyroidism,

may increase VKAs responsiveness, probably by increasing

the catabolism of vitamin K-dependent coagulation factors.

The use of nutritional supplements and/or herbal products is

particularly problematic in VKA-treated patients for the little orno standardisation of their content and for the possible effects

on

anticoagulation stability. Unfortunately, such products arefrequently

taken by patients monitored in anticoagulation clinics

(80) often without informing the doctors in charge.


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Co-morbid conditions

The presence of co-morbidities may represent a significant risk

factor for bleeding during treatment. A recent analysis of results

of a clinical trial on treatment of patients with AF (the AFFIRM

Study [81]) reported that congestive heart failure, hepatic orrenal disease and diabetes were conditions, among others,

significantly

associated with major bleeding. A history of bleeding

(especially in the gastro-intestinal tract) is the patient relatedfactor

most frequently reported to be predictive for the risk of

further bleeding complications (82).


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Liver diseases potentiate

the response to VKAs by impairing synthesis of coagulationfactors

and usually make a good control of anticoagulation more

difficult. In a recent review (83) of the available studies,several

possible predisposing factors have been analysed: historyof

bleeding, history of myocardial infarction and previous

cerebrovascularevents were all factors associated with higher risk

of bleeding complications.


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Blood pressure control is a critical factor for bleedingcomplications

during VKA. A higher prevalence of history of hypertension

in anticoagulated patients with bleeding versus patients

without bleeding complications was found in some (84), though

not all studies (55). No relationship was found between quartiles

of systolic blood pressure and bleeding complications in the

SPORTIF cohorts (85). These result can reflect the optimalmanagement

and close monitoring typical of a clinical trial setting. It

has been reported that a modest blood pressure-lowering halves

the occurrence of ICH during antiplatelet therapy (and likely

during anticoagulation) (86).


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The association between malignancy and VTE is wellestablished.

The ISCOAT study showed that a malignant disease was

significantly more common in patients who started oralanticoagulation

for VTE than in patients who were treated with

VKAs for other indications (11.3% vs. 2.9%, respectively; p

Thrombo Prophylaxis

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