ANNE ROBINSON

• Haemostasis, DVT and PE

• Ellie Raby • Jesse Nwachukwu THE CASE

Presentation Additional Hx • 56 y/o female PMHx varicose veins in right leg • Acute She is on HRT Both mother and grandmother • Difficulty have had DVT

Hx of presenting complaint • Returned from holiday 3 days ago • Pain in right calf • Woken up by pain in left side of chest • Coughed up bright red blood • Pain worse on deep breaths • Severe SOB BLOOD VESSEL ANATOMY

• Layers of the blood vessel: • Tunica Interna/Intima • Endothelial cells -> basement membrane -> subendothelial collagen • Tunica Media • Smooth muscle cells - have receptors so responsive to your Symp NS / body’s needs -> controls size of lumen • Tunica Externa/adventitia • Made of collagen and elastic connective tissue. • Responsible for support and anchoring the vessels to adjacent organs. HAEMOSTASIS

Haemostasis – “how the body prevents blood loss when a blood vessel is injured/broken”

There are 3 stages: • Primary Haemostasis (platelet plug formation) • Secondary Haemostasis (clotting cascade -> fibrin mesh formation) • Fibrinolysis (breaking down the clot) PRIMARY HAEMOSTASIS

“Where platelets clump together and form a plug around the injury”

5 stages: 1) Endothelial injury • SM vascular spasm + Endothelin 2) Exposure • Release of vWF. Collagen binds. 3) Adhesion • Platelets bind to vWF 4) Activation • Platelets activated -> +ve feedback loop 5) Aggregation • ADP + TXA2 -> lots of GP2b/3a surface proteins -> links two platelets together SECONDARY HAEMOSTASIS

• Intrinsic pathway • 12 -> 11 -> (X) -> 9 -> 8 • Factor XII contacts subendothelial collagen • PTT (playing table tennis). Heparin. • Extrinsic pathway • III + VII • Trauma -> exposes tunica adventitia (which have TF - Factor 3 - in their membrane) • PT (playing tennis)/INR. Warfarin. • Common pathway • X x V x II x I • Formation of the fibrin mesh

Things to keep in mind… • Most Factors produced by the liver • Factors II, VII, VIII, IX, X, XI, XIII need Ca to function • Factors II, VII, IX, X need Vitamin K

DEEP VEIN THROMBOSIS (DVT)

• Definition: “DVT is the formation of a blood clot in a deep vein resulting in impaired venous blood flow and consequent leg swelling and pain”. • Common sites: Legs (below the knee), thigh, pelvic region • Risk factors: Virchow’s triad • Clinical features: • Unilateral • calf swelling. • Pitting oedema. • Increase in skin temperature/warmth • Skin discolouration (erythema or occasionally purple / cyanosed) • localized pain and tenderness along deep venous system • Homan sign: calf pain on dorsal flexion of the foot • Prominent superficial veins • Mild fever VIRCHOW'S TRIAD:

Highly regulated system -> so slight disturbances -> bleeding or thrombosis. There are 3 factors that, individually or together, can disrupt this system -> thrombus. These can be remembered by “HE'SVirchow”:

1. Hypercoagulability: • E.g. increased platelet adhesion, medications (COCP increase clotting factors and decreases anticoagulation factors like Protein C and antithrombin), illness, cancer, IBD, nephrotic syndrome, sepsis, blood transfusion, genetics (i.e. thrombophilia's), dehydration, • Increased clotting factors -> increase primary or secondary haemostasis -> activation of clotting cascade. 2. Endothelial damage: • E.g. Infections, chronic inflammatory, toxins, trauma, surgery, central venous catherisation and previous DVT. • This exposes tissue factor and collagen -> activation of clotting cascade 3. Stasis (venous): • E.g. >40yo, paralysis, varicose veins, external pressure on the extremity, prolonged immobilization in bed, long flights, car trips, or in pregnancy. • If blood flow becomes turbulent -> linear flow is disrupted and slow or static pockets of blood are formed. During stasis, platelets and other clotting factors contact the endothelium -> prolonged interaction -> platelet adhesion -> activation of clotting cascade LETS LOOK BACK AT THE CASE

Presentation • 56 – RF for DVT • Acute chest pain • Difficulty breathing

Hx of presenting complaint • Returned from holiday 3 days ago – RF for DVT • Pain in right calf – sign of DVT • Woken up by pain in left side of chest • Coughed up bright red blood • Pain worse on deep breaths • Severe SOB

Additional Hx • PMHx varicose veins in right leg – RF for DVT • She is on HRT – RF for DVT • Both mother and grandmother have had DVT – RF for DVT THE FATES OF THROMBI

• Thrombus = aggregation of platelets. Erythrocytes, WBC’s – trapped in a mass of fibrin sheets. • Once a thrombus has occurred it can do various things… 1) Propagation - growing along the vessel wall 2) Organisation - organise within the vessel layers 3) Recanulisation - forming holes within the thrombus 4) Embolism - dislodgement of the thrombus 5) Resolution - thrombus broken down by plasmin

Clot forms in DVs -> embolises -> IVC -> right atrium -> right ventricle -> pulmonary artery -> lodges

Affects on CV and Resp system TYPES OF EMBOLUS

• Thrombus vs embolus: A thrombus is a blood clot that forms in a vein. An embolus is an object that is carried in the blood stream and can lodge in a vessel, causing an embolism. Types of embolus: - FAT BAT: Fat Air Thrombus Bacteria Amniotic fluid Tumour

Rare for thrombi to develop de novo in pulmonary vasculature – clots usually form in deep venous system of lower extremities & embolise. Approx 50% of DVT lead to PE. (PE)

PE is a life threatening condition caused by the obstruction of one or more pulmonary arteries by solid, liquid, or gaseous masses, leading to respiratory dysfunction In most cases, the embolism is caused by blood thrombi, which arise from DVT and embolize to the lungs Other symptoms: Suspect pulmonary embolism • Retrosternal chest pain (due to right ventricular (PE) in a person with: ischaemia). • & haemoptysis. •Dyspnoea • Dizziness and/or syncope (due to right ventricular failure) •Tachypnoea – severe cases •Other signs: •Pleuritic chest pain • Tachycardia HR > 100bpm •and/or features of DVT– leg pain • Hypoxia & swelling (usually unilateral), lower • Pyrexia abdominal pain, redness, increased • Elevated JVP temperature, and venous distension. • Gallop rhythm • Pleural rub. • Hypotension & cardiogenic shock (rare) • The symptoms and signs of PE are not specific + they differ depending on the location of the obstruction • PE may be completely asymptomatic and be discovered incidentally when assessing for another condition EFFECT ON RESP SYSTEM

Ventilation(v) = air moving in and out of the lungs Perfusion (q) = blood flow to and out of the lungs

PE obstruction -> 1) Infarction and Inflammation of lungs and pleura -> -> pleuritic chest pain and haemoptysis (coughing up blood) -> cytokines released -> bronchoconstriction -> decreases O2 coming in (-> - decreased PaO2) -> and tachypnoea -> respiratory alkalosis with (decreased PaCO2)

2) V/Q mismatch (abnormal gas exchange) – here there is abnormal perfusion but there is ventilation. The severity of v/q mismatch depends on the number, size and location of the obstruction. Reduced perfusion -> decreases O2 exchange (-> hypoxemia) -> hyperventilation -> hypocapnia i.e. respiratory alkalosis EFFECTS ON CV SYSTEM

Embolism -> increased pulmonary vascular pressure -> backflow of blood to the right side of the heart -> pulmonary hypertension -> right ventricular hypertrophy -> right sided HF -> decreased SV -> decreased CO -> decreased BP -> compensatory tachycardia + whatever happens on the RHS affects the LHS -> also get decreased CO from left ventricle -> detected by baroreceptors - > stimulates sympathetic response -> tachycardia + vasoconstriction (tries to increased BP but it won't work. Even if you constrict your vessels to increase pressure, because you have the pulmonary emboli you will still get a decrease in CO -> decreased BP). + For patients who have an atrial septal defect the embolism can go from right atrium -> left ventricle -> aorta -> embolic stroke DIFFERENTIALS

DVT PE Cellulitis Respiratory: Thrombophlebitis • Pneumothorax Arthritis • Pneumonia Asymmetric peripheral oedema secondary • Acute exacerbation of COPD to heart failure, renal disease or liver disease Haematoma Cardiac: Lymphoedema • Acute coronary syndrome Ruptured backers cyst • Decompensated heart failure Varicose veins • Dissecting/rupturing aortic aneurysm • Pericarditis

Musculoskeletal chest pain: Note that CP with chest wall palpation occurs in up to 20% of people with confirmed PE.

Other: • GORD • Any cause for collapse, such as vasovagal syncope, orthostatic hypotension, cardiac arrhythmias, seizures & cerebrovascular disorders. BACK TO THE CASE

Presentation Physical examination • 56 – RF for DVT SOB – sign of PE • Acute chest pain – sign of PE High BMI – RF for DVT • Difficulty breathing – sign of PE High RR – sign of PE Hx of presenting complaint Low SATS – sign of PE • Returned from holiday 3 days ago – RF for DVT • Pain in right calf – sign of DVT Laboratory findings: • Woken up by pain in left side of chest – sign of PE Low Pao2 – sign of PE • Coughed up bright red blood – sign of PE Low PaCO2 – sign of PE • Pain worse on deep breaths – sign of PE Low sats – sign of PE • Severe SOB – sign of PE

Additional Hx • PMHx varicose veins in right leg – RF for DVT • She is on HRT – RF for DVT • Both mother and grand mother have had DVT – RF for DVT INVESTIGATIONS - DVT

D-dimer: low specificity and high sensitivity. Can rule out DVT but can give false positive, i.e following surgery. D dimers are protein fragments produced during the degradation of fibrin.

Duplex ultrasound: US that looks at speed off blood flow and detects turbulence/ occluded flow from clot INVESTIGATIONS – PE

2-level PE Well’s score to estimate clinical probability of PE

Clinical feature Points CTPA: CT pulmonary angiogram Clinical signs & sympts of DVT (minimum of leg swelling & pain 3 – uses a die to view the with palpation of the deep veins) pulmonary vessels.

An alternative diagnosis is less likely than PE 3 V/Q scan: ventilation perfusion scan. Uses radioactive material to HR>100bpm 1.5 measure ventilation when the substance is breathed in and Immobilisation for >3 days or surgery in last 4 weeks 1.5 perfusion when the material is injected. Images taken during both Previous DVT/PE 1.5 procedures are then compared. Haemoptysis 1 Malignancy (on tx, tx in last 6 months, or palliative) 1

PE likely= >4 points - organise immediate CTPA, if there's a delay in getting CTPA then anticoagulation until scan is performed. PE unlikely= 4 points or less - arrange D-dimer, if +ive arrange immediate CTPA - give anticoagulation if delay getting scan. If patient has allergy to contrast media or renal impairment, a V/Q scan should be used instead OTHER INVESTIGATIONS

• History - assess for risk factors

• CXR – useful for ruling out other pathology. CXR is neither sensitive nor specific for confirming PE, mainly useful DDx e.g. pneumonia, pneumothorax. Described chest radiographic signs include: • Fleischner sign: enlarged pulmonary artery (20%) • : peripheral wedge of airspace opacity and implies lung infarction (20%) • Westermark sign: regional oligaemia and highest positive predictive value (10%)

• ECG – may show sinus tachycardia; non-specific ST segment & T wave abnormalities; right axis deviation; RBBB & less commonly ‘S1Q3T3’

• ABG: Most commonly shows hypoxemia and hypocapnea (respiratory alkalosis) due to hyperventilation: • type 1 respiratory failure • ↓PaO2 and ↓PaCO2

MANAGEMENT

• Haemodynamically stable → oxygen therapy if hypoxic and analgesia (paracetomol) if in pain. RivaroXaban or ApiXaban (DOACs that inhibit Xa) should be given initially after PE is diagnosed and while awaiting confirmation of PE. • If neither apixaban nor rivaroxaban is suitable offer: • Low molecular weight heparin (LMWH) - if patient is breastfeeding, pregnant or has active cancer • Use unfractioined IV heparin if patient has high risk of death PE • Continue anticoagulation for a least 3 months - assess risk & benefits of extending treatment • If PE was provoked: • Consider stopping after 3 months of treatment • If PE was unprovoked: • Consider continuing after 3 months of treatment - may imply patient has tendency to thrombosis For patients with active Cancer - use LMWH for 6 months

• Haemodynamically unstable (massive PE – low BP <90 systolic or a drop >40 in 15 mins) → offer continuous Unfractionated heparin (UFH) infusion • Consider thrombolysis → fibrinolytics = tPA • Alteplase (manufactured form of tPA) – bind to fibrin proteins on the clot. • Streptokinase, urokinase (bacteria derived) - works by binding to circulating or fibrin proteins on the clot • Surgical thrombectomy (uncommon, high mortality)

• Patients who have repeat PEs despite anticoagulation may be considered for IVC filters. These work by stopping clots formed in the deep veins of leg from moving to the pulmonary arteries. IVC filter use is supported by NICE but other studies suggest a weak evidence base. Drug MOA C/I S/E

Warfarin Inhibits hepatic production of vitamin k dependant - Risk of haemorrhage - Bleeding coagulation factors (factors 11, V11,IX and X and proteins C - Pregnancy and S). by inhibiting vitamin k epoxide reductase, the enzyme - Liver disease - Use heparin for bridging during hypercoagulable phase responsible for restoring vitamin k to it's reduced form, - Caution when taking CYP of treatment. Aim for INR 2.5 (2-3) Needs monitoring necessary as cofactor in synthesis of clotting factors. inducers/inhibitors as will - Warfarin can be reversed with phyto menadione (vit increase/decrease warfarin effects. K) diSCo 1972 X, IX, VII, II + protein C and S - Some antibiotics may kill gut flora that synthesise vit k – increases warfarin effect Heparin Large molecules/unfractioned promote inactivation of factors - Clotting disorders - haemorrhage, bruising at injection site Fondaparinux 11a and xa whereas LMWH (smaller) is more specific to - Severe hypertension - Hyperkalaemia Enoxparin factor Xa (clotting factor). - Recent surgery/trauma Dalteparin LMWH more specific - Use UFH in renal failure, pregnancy and obesity UFH needs monitoring. aPTT range 1.5-2.5 - UFH reversible using protamine sulphate Doac’s The Doac's act on the final common pathway of the - Active bleeding - bleeding, particularly epistaxis and GI Apixaban coagulation cascade, comprising factor X, thrombin and fibrin. - Hepatic or renal disease - Anaemia Dabigatran The drugs with an X in work on Xa, preventing conversion of - Pregnancy - Dizziness Edoxaban prothrombin to thrombin. Dabigatran directly inhibits - GI upset Rivaroxaban thrombin, preventing conversion of fibrinogen to fibrin. - No monitoring required - Elevated liver enzymes

Thrombolytics Catalyse conversion of plasminogen to plasmin Not to be used in patients with: - Nausea/vomiting Stroptokinase Plasmin dissolves fibrinous clots and re-canalise occluded Increased bleed risk - Bruising around injection site Atelplase vessels so affected tissue can be perfused Previous streptokinase treatment - Hypotension Used in caution with: - Serious bleeding Anticoagulants and antiplatelets - Allergic reaction - Cardiogenic shock

Antiplatelets - Aspirin - Bleeding - Don’t use in active bleeding Clopidogrel Irreversibly inhibits Cox1 and prevents formation of TXA2 - GI upset - Use in caution with renal and hepatic impairment and Aspirin used in platelet aggregation - Thrombocytopenia anticoagulants. - Clopidogrel - Use in caution with other nsaids Prevents platelet aggregation as binds irreversibly to ADP Anti-platelets (‘anti 1o haemostasis’) – used receptors for prevention of stroke etc but not VTE

PT (playing tennis): extrinsic pathway time. Citrate CLOTTING TESTS added to prevent clotting (binds to calcium). Centrifuged to separate clotting factors. Calcium, thromboplastin and tissue factor are added. Time taken for clot to form = PT.

PTT (playing table tennis): intrinsic pathway time. Identical to PT method, but partial thromboplastin (without tissue factor) is added with calcium + an activating agent i.e silicone. Increased PTT when on anticoagulation, haemophilia, sepsis

TT: fibrinogen to fibrin time. Increased when def in fibrinogen i.e in liver failure

Mixing studies: if prolonged PT or PTT. Look to see if there is a deficiency in clotting factor or an inhibitor of factor activity. 50:50 plasma from patient and normal plasma. If clotting normalises = factor deficiency (normal blood adds the missing factor). If does not normalise, there may be a clotting inhibitor in the patients blood, i.e antiphospholipid antibodies SBA’S A TALL, THIN 25-YEAR-OLD LADY PRESENTS TO THE GP WITH PLEURITIC CHEST PAIN FOLLOWING A 12-HOUR FLIGHT BACK FROM SINGAPORE. SHE IS TAKING THE COCP. WHICH OF THE FOLLOWING WOULD MAKE YOU QUESTION A DIAGNOSIS OF ACUTE PULMONARY EMBOLISM?

A. Sinus tachycardia on ECG B. Normal chest x-ray C. Heart rate >100 bpm D. Hyper-resonance to of chest E. ABG showing ↓PaO2 and ↓PaCO2 A 40-YEAR-OLD MAN PRESENTS TO THE GP WITH PAIN IN HIS CALF FOLLOWING A GOLF GAME. HE IS GENERALLY ACTIVE, DOES NOT SMOKE OR DRINK AND MAINTAINS A LOW BMI. HE HAS HAD NO RECENT SURGERY AND THE CALF SHOWS NO SWELLING OR OEDEMA. HE HAS NO SIGNIFICANT MEDICAL HISTORY. WHAT IS THE MOST APPROPRIATE INVESTIGATION TO RULE OUT A DVT?

A. CTPA B. Doppler ultrasound C. D-dimer D. Venogram E. FBC A 62-YEAR-OLD MAN COMES TO THE EMERGENCY DEPARTMENT BECAUSE OF ACUTE ONSET AND LIGHT HEADEDNESS FOR THE PAST HOUR. HE UNDERWENT A TOTAL KNEE REPLACEMENT SURGERY A MONTH AGO. HE REPORTS THAT HE EXPERIENCES CHEST PAIN UPON DEEP INSPIRATION. HIS TEMPERATURE IS 36.4°C (97.5°F), PULSE IS 120/MIN, RESPIRATIONS ARE 22/MIN, AND BLOOD PRESSURE IS 140/85 MM HG. WHICH OF THE FOLLOWING IS THE MOST LIKELY DIAGNOSIS?

A. Aortic dissection B. Cardiac tamponade C. Mediastinitis D. Myocardial infarction E. Pulmonary embolism A DELIGHTED NEW MOTHER HAS JUST GIVEN BIRTH TO A HEALTHY BABY BOY AFTER AN ELECTIVE C-SECTION AND IS RECOVERING IN THE POSTPARTUM UNIT. DESPITE HER JOY SHE HAS BEEN EXPERIENCING AN ACUTE ONSET OF SHORTNESS OF BREATH. SHE SAYS THAT SHE IS STILL IN EXTREME PAIN FROM THE OPERATION AND HAS ONLY LEFT HER BED A FEW TIMES TO USE THE RESTROOM. PHYSICAL EXAMINATION SHOWS CLEAR LUNG FIELDS BILATERALLY AND A SWOLLEN, TENDER, AND ERYTHEMATOUS LEFT CALF. WHICH OF THE FOLLOWING WOULD MOST LIKELY HAVE PREVENTED THIS PATIENT'S COMPLICATION?

A. Appropriate pain control with morphine B. Incentive spirometer use C. Postpartum antibiotic administration D. Postpartum early ambulation E. Postpartum magnesium sulphate A 41-YEAR-OLD WOMAN IS REFERRED FOR ASSESSMENT AFTER SUFFERING A SECOND PULMONARY EMBOLUS WITHIN A YEAR. SHE HAS NOT BEEN TRAVELLING RECENTLY, HAS NOT HAD ANY SURGERY, DOES NOT SMOKE AND DOES NOT TAKE THE ORAL CONTRACEPTIVE PILL. SHE IS NOT CURRENTLY ON ANY MEDICATION AS THE DIAGNOSIS IS RETROSPECTIVE AND SHE IS NOW ASYMPTOMATIC. WHAT SHOULD BE THE NEXT STEP IN HER MANAGEMENT?

A. Initiation of warfarin therapy B. ECG C. Thrombophilia screen D. Insertion of inferior vena cava filter E. Duplex scan of lower limb veins and pelvic ultrasound THANKS J FEEDBACK

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