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also: look back to lectures!

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- Definition: host defense mechanism that protects this integrity after injury to the vessel wall and tissue injury.

- Primary & Secondary:

Primary: vasoconstriction, primary response to injury, platelet plug

Secondary: recruitment of clotting factors

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What is the role of the vessel wall? - normally prevents platelet adhesion and thrombus formation via endothelium lining. Injury causes reflex vasoconstriction, endothelium damage results in loss of antithrombic properties, activation of platelets, and coagulation and inhibition of fibrinolysis.

Platelets

Platelets adhesion:

Platelet release:

Platelet aggregation:

Platelet coagulation:

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Coagulation cascade

Coagulation factors: synthesized in the liver. Factor II = prothrombin.

Coagulation pathway (explain): Xa initiated by the extrinsic pathway, amplified by the intrinsic pathway.

VWF & factor VIII: VWF is a glycoprotein, released from platelet granules and endothelial cells. Prevent premature Factor VIII breakdown.

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Antithrombin

Activated protein C

Protein S

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What is fibrinolysis? (explain)

Hemostatic response that helps restore vessel patency after vascular damage.

Principle component is the serine protease plasmin, which can break down fibrinogen and fibrin to fibrin (and fibrinogen) degradation products.

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Vascular/platelet bleeding: characterized by bruising and spontaneous bleeding from small vessels. Bleeding into the skin--purpura. Bleeding also occurs from mucous membranes.

Coagulation disorders: typically associated with bleeding after injury or surgery. Short delay between precipitating event and overt haemmorhage or haematoma formation.

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definition: caused by reduced platelet production in the bone marrow, excessive peripheral destruction of platelets, or sequestration in an enlarged spleen.

investigations: examine bone marrow (to check number of megakaryocytes)

treatment: no treatment needed unless severe.

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definition: increased platelet count (acute-phase reaction)

causes: slenectomy, malignant disease, inflammatory disorders (eg rheumatoid arthritis, inflammatory bowel disease), major surgery + post haemorrhage, myeloproliferative disorders, iron deficiency

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Aetiology: lack of factor VIII while the VWF is normal.

Inheritance: genetic defect. Inversion in intron 22. X-linked disorder.

Prevalence: 1 in 5,0000 of the male population.

Clinical and laboratory features: severe, moderate, and mild. Ask about the nature of bleeding: severe begins spontaneously, moderate is severe bleeding following an injury, mild is only bleeding after an injury.

measure the prothrombin time, thrombin time. (PT, bleeding time.)

Treatment: administration of factor VIII.

Complications: development of antibodies to factor VIII in 30% of people with severe haemophilia.

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Deficiency of factor IX. Inheritance and clinical features identical to haemophilia a, but incidence is only about 1 in 30,000 males.

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Aetiology: defective platelet function as well as factor VIII deficiency, both due to a deficiency or abnormality in VWF.

Types: Located on chromosome 12.

Type 1 is partial quantitative deficiency of VWF and
significant type 1 VWD is usually inherited as an
autosomal dominant.

Type 2 is due to a qualitative abnormality of VWF, and it too is usually inherited as an autosomal dominant.

Type 3 is recessively inherited and patients have
virtually complete deficiency of VWF. Their parents are often phenotypically normal.

Clinical features: Type 3 patients severe bleeding, joint and muscle pains. Types 1 + 2 usually mild clinical factors. Rarely experience joint and muscle bleeds seen in haemophilia A.

Treatment: desmopressin, replacement therapy (surgery) in type 3 (severe).

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What role does vitamin K play? - without it, factors II, VII, IX, and X cannot bind to calcium.

Aetiology: inadequate stores, malabsorption of vitamin K, oral anticoagulant drugs.

Newborn babies? - low levels of vitamin K, all babies given a prophylactic dose of vitamin K.

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A solid mass formed in the circulation. Fragments (emboli) may break off and block vessels.

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Explanation: "white thrombus," unlike "red thrombus" in venous thrombi. Plaque rupture leads to exposure of blood containing factor VIIa to tissue factor within the plaque, which may trigger blood coagulation and thrombus formation.

Prevention and treatment of arterial thrombosis: minimizing factors predisposing to atherosclerosis. Treatment includes antiplatelet drugs + thrombolytic therapy.

Antiplatelet drugs:

aspirin: COX inhibitor

dipyridamole: inhibits platelet phosphodiesterase, causing increase in cAMP.

glycoprotein IIb/IIIa receptor antagonists: block receptor on platelet for fibrinogen and von Willebrand factor.

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Where does it occur?

Major causes of venous thrombosis?

How does it differ from arterial thrombosis? ("red thrombus")

Risk factors (table 8.26)

Inherited

Thrombophilia

Coagulation abnormalities

Acquired

Investigations

Haemostatic screening test: full blood count (including platelet count). Coagulation screen (including fibrinogen level) will detect erythrocytes, thrombocytosis, and dysfibrinogenaemia.

Testing for specific causes of thrombophilia: Assays for naturally occurring anticoagulants, assay for activated protein C and molecular testing for factor V Leiden and the prothrombin variant, screen for coagulation factor

Prevention and treatment of venous thrombosis

Anticoagulants

Heparin: mixture of polysaccharides, initially extracted from the liver. Binds to antithrombin, which increases inhibitory activity of antithrombin.

LMW heparin: potentiation of thrombin inhibition.

Direct thrombin inhibitors

Oral anticoagulants (characteristics, contraindications, and complications)

contraindications: severe uncontrolled hypertension, non-thromboembolic strokes, peptic ulceration, severe liver and renal disease, pre-existing haemostatic defects, non-compliance, pregnancy

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When and where? immobility, pregnancy, risk factors (diagram below)

Factors leading to DVT

Check Virchow's triad: https://www.ncbi.nlm.nih.gov/books/NBK539697/

Clinical features: figure below

Investigations: D-dimer level, confirmed with CT or V:Q scan. Wells criteria can be used to determine risk of pulmonary embolism.

Venography in the lower leg

Treatment: anticoagulants

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Definition

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are manifestations of the same pathological entity, called venous thromboembolism (VTE).

An embolus is any intravascular material that migrates from its original location to occlude a distal vessel. Although the embolus can be a blood clot (thrombus), fat, air, amniotic fluid, or tumour, a PE is usually caused by a thrombus originating from the deep veins in the legs (deep venous thrombosis, DVT).

Arterial vs. venous thrombosis

The coagulation cascade is an essential part of hemostasis. However, the same coagulation factors can give rise to clot formation in the circulation that is inappropriate (i.e. not for hemostasis). Thrombi can form in both the arteries and veins, but they have different pathophysiology and lead to different outcomes. This chapter is about venous thrombosis.

Venous thromboembolism is associated with Virchow's triad: three conditions that predispose to thrombus formation.

1. Hypercoagulability

2. Stasis

3. Endothelial damage

VTE often arise from the synergistic effects of multiple risk factors, for example, when a patient with inherited factor V Leiden mutation uses oral contraceptives (acquired risk on genetic risk background).

Triad component Associated risk factors

Changes in blood coagulation pathway, shifting balance toward coagulation

Hereditary factors (inherited thrombophilia)

Factor V Leiden*: Activated factor V (FVa) is a cofactor for activated factor X, and together, they lead to thrombin generation from its zymogen, prothrombin. Thrombin is a serine protease that cleaves soluble fibrinogen into insoluble fibrin and activates other factors that amplify the coagulation cascade. To regulate coagulation and protect against clot formation, activated protein C (aPC) cleaves and inactivates FVa. Factor V Leiden is a mutation at one of the aPC cleavage sites, rendering factor Va resistant to inactivation, thus predisposing to clot formation and VTE. Individuals with this mutation are at a 5-fold increased risk for developing a first VTE.

Prothrombin G20210A*: Mutation at nucleotide 20210 from guanine to adenine. The mutation is in the 3' untranslated region of the prothrombin and therefore does not alter the structure of the protein, but causes increased production of prothrombin (factor II). Individuals with this mutation are at a 2-4 fold increased risk for developing a first VTE.

Deficiencies in antithrombin (AT), protein C (PC) and protein S (PS), plasminogen (Pg):
AT, PS and PC are the major anticoagulation proteins and genetic defects can lead to qualitative or quantitative defects in their structure predisposing patients to developing VTE.

*The 2 most common hereditary factors; autosomal dominant risk inheritance

Cancer: Cancer cells induce a prothrombotic state through a variety of mechanisms. Some cancer cells express (i) procoagulant proteins and (ii) cause the release of microparticles (soluble fragments of tumour cell membranes) leading to a systemic hypercoagulable state. Two common procoagulant proteins are tissue factor, which indirectly activates factor X by complexing with factor VII, and cancer procoagulant, which directly activates factor X. Tumour-induced hypoxia and release of inflammatory cytokines have also been speculated to cause a prothrombotic state.
Pathophysiol Haemost Thromb. 2006;35(1-2):103-10.
Best Pract Res Clin Haematol. 2009 Mar;22(1):49-60.

Chemotherapy: Chemotherapy drugs have been shown to induce TF in tumor cells as well as monocytes, downregulation of protein C and S (natural anticoagulation mechanism), direct damage to the vascular endothelium, and platelet activation. Anti-angiogenic agents (bevacizumab) have platelet and endothelial activation properties leading to a prothrombotic state.
Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):316-20.

Oral contraceptives and hormone replacement therapy: Hyperestrogenemia causes increased hepatic synthesis of procoagulant proteins and decreased synthesis of anticoagulant and fibrinolytic proteins.
Thromb Res. 2010 Jul;126(1):5-11.

Pregnancy and postpartum period: High estrogen like OCP/HRT and stasis due to obstruction of inferior vena cava by fetus.

Central obesity: Mechanisms include procoagulant effects of adipocytokines (leptin and adiponectin), increased activity of coagulation cascade, increased inflammation, oxidative stress, and endothelial dysfunction.
Eur J Vasc Endovasc Surg. 2007 Feb;33(2):223-33.

Heparin-induced thrombocytopenia (HIT): Heparin binds platelet factor 4 (PF4) and exposes a previously masked epitope, leading to the production of IgG antibody in some heparin treated patients. IgG binds to the heparin-PF4 complex, forming immune complexes that bind and activate platelets. This leads to a hypercoagulable state and thrombocytopenia. Platelet activation also induces endothelial cell injury.
Blood. 2007 Dec 15;110(13):4253-60.

The slowing or stopping of blood flow

Reduced mobility: Increases length of contact of coagulation factors with endothelium.
Examples: Long-haul air travel, hospitalization

Polycythemia: Hyperviscosity, due to excessive overproduction of red blood cells, leads to stasis of blood in the veins.

Endothelial injury: Stasis directly damages the endothelium as well as reduces the natural fibrinolysis.

Congestive heart failure: Failure to pump blood forward results in venous stasis and elevated central venous pressure.

Endothelial damage
Normal endothelium is antithrombotic.

Endothelial dysfunction: Shifts the balance between clot generation and breakdown towards thrombosis due to decreased synthesis of nitric oxide and prostacyclin and increased endothelin-1.

Hypertension

Cigarette smoking

Endothelial damage: Exposure of subendothelial tissue factor and collagen, which offer a substrate for platelet binding, activation and aggregation; leading to clot formation.

Chronic indwelling central venous catheter (catheters also directly activate the intrinsic pathway)

Major surgery

Trauma

Pathophysiology of DVT

Deep venous thrombosis usually arises in the lower extremities. Most DVTs form in the calf veins, particularly in the soleus sinusoids and cusps of the valves.

Venous valves are avascular, which, in conjunction with reduced flow of oxygenated blood in veins, predisposes the endothelium to be hypoxemic. The endothelium around valves responds by expressing adhesion molecules that attract leukocytes. These cells transfer tissue factor to the endothelium, which can complex with activated factor VII to begin the coagulation cascade via the extrinsic pathway. The main component of these venous thrombi is fibrin (as product of coagulation cascade) and red blood cells, which get trapped in the clot. Platelets also contribute, but to a lesser extent.

The skeletal muscle pump helps prevent DVT by moving blood past the valves (i.e. reducing venous stasis), which washes away activated clotting factors that can otherwise propagate the initial thrombus.

If a clot forms and does not resolve (see below), it will extend proximally into the popliteal and femoral veins ("proximal veins"). 25% of calf DVTs will extend proximally within 7 days. While calf DVTs are usually asymptomatic and do not give rise to significant PEs, proximal DVTs are more likely symptomatic and can embolize to form dangerous PEs.

By the numbers

96% arise in the lower extremities; 4% arise in the upper extremities.
Chest. 2008 Jan;133(1):143-8.

Of symptomatic lower-extremity DVTs, 88% involve the proximal veins; the rest only involve the calf veins. Almost all lower-extremity DVTs arise from the calf veins and extend proximally.
Arch Intern Med. 1993 Dec 27;153(24):2777-80.

90% of PEs arise from DVTs.

50% of symptomatic proximal lower-extremity DVTs have asymptomatic PEs.

70% of PEs have asymptomatic DVTs.

28% of symptomatic DVTs will have post-thrombotic syndrome after 5 years.

Resolution and consequences

The initial thrombus can lead to complete resolution, clot extension/embolization, or organization.

Complete resolution: Fibrinolysis is a dynamic process where plasminogen is converted into plasmin, an enzyme that degrades fibrin into soluble peptides. Fibrinolysis starts within hours, and it can lead to complete or partial resolution of the thrombus. Partial resolution may lead to any one of these 3 consequences.

Clot extension and embolization: Proximal flow of the venous blood sweeps the thrombus in the same direction, extending it into the proximal veins.

Organization: Thrombi that do not resolve begin to retract within days. At the same time, inflammatory cells infiltrate the thrombi and cause remodeling. The residual clot is incorporated into the vessel wall and a layer of endothelial cells forms on top (re-endothelialization). This process, called organization, allows some blood flow to resume, but it destroys valves along the length of the clot and causes scarring of the veins. The hemodynamic changes to the vein causes post-thrombotic syndrome.
Post-thrombotic syndrome is a consequence of DVTs, and the clinical features include pain, leg edema, and other signs of venous insufficiency. It occurs in approximately 1/3 of DVT cases. The cause is a combination of venous obstruction by residual clots or venous scarring and venous reflux due to valve destruction. Prevention of this sequela includes adequate anticoagulation to prevent VTE recurrence and compression stockings to improve venous return.

Pathophysiology of PE

Hellenic J Cardiol. 2007 Mar-Apr;48(2):94-107.
Circulation. 2003 Dec 2;108(22):2726-9.

Effects of mechanical occlusion

Increased alveolar (physiologic) dead space: decreased perfusion of alveoli distal to thrombus causes the alveoli to be ventilated but not perfused, resulting in V/Q mismatch (high V/Q) and increased dead space

Increased minute ventilation: patient compensates for dead space and responds to chemical irritation by hyperventilation.

Hypocapnia: increased minute ventilation causes decreased blood CO2 and respiratory alkalosis. Hypocapnia exacerbates alveolar hypoxemia by causing secondary bronchoconstriction.

Increased pulmonary vascular resistance: due to vascular obstruction by thrombus and chemical mediators from platelets (see below)

Decreased surfactant and atelectasis: vascular compromise beyond thrombus reduces surfactant production and thus predisposes distal region to atelectasis

Effects of chemical mediators

Platelets from the thrombus secrete chemical mediators such as histamine and serotonin, which causes pulmonary vasoconstriction and bronchoconstriction.

Bronchoconstriction leads to alveolar hypoxemia, which in turn causes more vasoconstriction and increased vascular resistance.

Hemodynamic consequences

Increased right ventricular afterload: from increased pulmonary vascular resistance.

Right ventricular dilatation and hypertrophy: parasternal heave, loud P2

Right-sided (backward) heart failure: increased jugular venous pressure (JVP)

Decreased left ventricular filling: because of bowing of interventricular septum to left side from RV hypertrophy
Left-sided (forward) heart failure: hypotension, syncope, cardiogenic shock

Resolution

Intrinsic thrombolytic mechanisms (plasmin) start to lyse clots: D-dimer (breakdown product of fibrin) levels increase in serum.

Symptomatic PE is treated with anticoagulation therapy (oral or parenteral), thrombolytic therapy (for massive PE causing cardiogenic shock), or inferior vena cava filter (if anticoagulation is contraindicated). See Treatment section for details.

Untreated large PE causes death by acute increase in right ventricular pressure, leading to RV failure.

Clinical features of DVT

Clinicians accurately diagnose DVT using clinical features in approximately 25% of cases because the signs and symptoms are neither sensitive nor specific. Therefore, it is important to confirm clinical findings using additional testing, such as compression ultrasonography. The signs and symptoms of DVT arise from (i) venous obstruction and (ii) inflammation of the veins. Patients may also present with features of pulmonary embolism.

Clinical features of PE

PEs are frequently asymptomatic. Symptomatic patients most commonly present with dyspnea. Signs of DVT are only found in about 1/3 of PE patients.

Diagnosis of DVT

JAMA. 2006 Jan 11;295(2):199-207. (Discussion of Wells DVT score here)

Chest. 2012 Feb;141(2 Suppl):e351S-418S. (2012 Chest Guidelines)

Diagnosis starts with history (risk factors) and physical, which can be used to generate a pretest probability using a validated clinical prediction rule, such as the Wells DVT score (see JAMA reference above). Patients with high likelihood of DVT can be further tested with compression ultrasonography, where the length of the proximal veins (popliteal and femoral) is sequentially compressed with the ultrasound probe. Normal veins are easily occluded with moderate external compression, but a DVT will prevent occlusion of the vein lumen. Ultrasonography is both sensitive and specific for DVTs.

A D-dimer level can be done to rule-out DVT in individuals with low pretest probability (see discussion in Diagnosis of PE).

Contrast venography is considered the gold standard for diagnosis of DVT, although this is rarely done because it is invasive, expensive, and not readily available. Contrast is injected into the dorsal foot vein, and the leg is imaged with CT scan or MRI.

Diagnosis of PE

JAMA. 2003 Dec 3;290(21):2849-58.

Diagnosis is based on history and physical, and confirmed with CT or V:Q scan if the clinical suspicion is high. The Wells criteria can be used to determine risk (pretest probability) of PE.

Note on D-dimer: In low-risk patients with symptoms that suggest PE, a D-dimer can be used to rule out PE if negative (high sensitivity, low specificity). D-dimer level is measured in the blood. As explained above, it is a degradation product of fibrin, which is elevated if a coagulation and fibrinolysis reaction happens in the body. In PE, endogenous fibrinolytic mechanisms try to dissolve the clot, which is the basis of an elevated D-dimer. However, the D-dimer level not specific and is elevated in any type of inflammatory process. Its clinical utility is limited to ruling out PE in those with a low pretest probability.

Treatment

Chest. 2012 Feb;141(2 Suppl):e419S-94S.

The goals of treatment for VTE are (i) anticoagulation to prevent further clot generation and (ii) thrombolysis if the thrombus is large enough to cause hemodynamic compromise.

Anticoagulation: Reduces further clot formation

Anticoagulation with parenteral (intravenous or subcutaneous) and oral anticoagulants is the mainstay of VTE therapy. Typically, one of the parenteral agents (e.g. heparin, LMWH, or fondaparinux) or a new oral anticoagulant (e.g. rivaroxaban) is started first. The patient may be transitioned to a traditional oral anticoagulant (e.g. warfarin) for chronic anticoagulation.

Unfractionated heparin (UFH): Inhibits the function of thrombin as well as Xa by inducing conformational changes in antithrombin, allowing it to bind the enzymes better.

Low molecular weight heparin (LMWH): Functions similar to UFH, but due to the smaller average heparin chain length, accelerates the bridging of AT with Xa only, and not thrombin.

Fondaparinux: A pentasaccharide sequence that directly binds to AT (at an allosteric site) and induces a conformational change allowing it to bind and inhibit factor Xa only.

Rivaroxaban: A new oral anticoagulant that inhibits factor Xa by binding to its active site.

Chronic anticoagulation: For prophylaxis against future VTE

Any of the agents for acute anticoagulation can be used for chronic anticoagulation, but they are less convenient for outpatients due to the need for daily injections. Oral anticoagulation drugs are the mainstay for outpatient anticoagulation. Vitamin K antagonists (e.g. warfarin) were traditionally used, but newer agents, such as dabigatran and rivaroxaban, can also be used. In addition, aspirin is an antiplatelet agent that has been shown to reduce VTE events in recent trials.

Vitamin K antagonists (e.g. warfarin): Warfarin inhibits the vitamin K dependent synthesis of calcium dependent clotting factors (II, VII, IX and X). Furthermore, warfarin also inhibits PS and PC (part of the endogenous anticoagulation pathway).
The inhibition of PC and PS occurs faster than the other clotting factors, making warfarin acutely a procoagulant. Therefore, warfarin must be given concomitantly with acute anticoagulants at first (a process known as "overlapping") to (i) prevent acute procoagulant effect and (ii) allow time for inhibition of vitamin K dependent factors. Once the patient's international normalized ratio (INR) is therapeutic (2-3), acute anticoagulants can be discontinued.

Warfarin has been the mainstay of chronic VTE therapy for over 50 years, but there are several issues with its use: (i) increased bleeding risk, (ii) teratogenicity in pregnancy, (iii) interaction with many foods and drugs, and (iii) close monitoring required because anticoagulation effect is not reliably predictable by dosage. New antithrombotic medications have been developed that are potentially safer than warfarin.

Direct thrombin inhibitors (e.g. dabigatran): Directly block thrombin function by blocking the active site. Dabigatran is equivalent to warfarin in both prevention of recurrent clots and bleeding risk in patients with acute VTE, but it does not require monitoring due to its predictable therapeutic effect (RE-COVER trial).
N Engl J Med. 2009 Dec 10;361(24):2342-52.

Direct Xa inhibitors (e.g. rivaroxaban): Directly inhibit the function of Xa by blocking the active site. Unlike warfarin and dabigatran, rivaroxaban does not require overlapping with heparins. Rivaroxaban is equivalent to warfarin in short- and long-term prevention of PE in symptomatic patients, but it does not require monitoring or overlapping, and has significantly lower bleeding risk compared to warfarin (EINSTEIN-PE trial).
N Engl J Med. 2012 Apr 5;366(14):1287-97.

Aspirin: Although this antiplatelet agent is classically used to prevent arterial thrombosis, new evidence suggests that it can also be used for recurrent VTE prevention. Daily aspirin (100mg/day used in trials) can reduce VTE recurrence by approximately 1/3. Aspirin, although not as effective as other anticoagulants, may be used if the patient is intolerant of anticoagulants.
N Engl J Med. 2012 Nov 22;367(21):2039-41.

Thrombolysis: Breaks down the thrombus

Tissue plasminogen activator (tPA): activates plasminogen (Pg) to plasmin (Pn), which cleaves the thrombus, generating soluble D-dimer products.

Contraindications to anticoagulation

Thrombectomy: If a large thrombus creates hemodynamic compromise, and there are contraindications to thrombolysis, the clot can be surgically removed or by interventional radiology.

Inferior vena cava (IVC) filter: Temporary IVC filters can be placed to stop the movement of clots from the deep veins of the lower extremity from travelling to the pulmonary vasculature.

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Deep vein thrombosis (DVT) and pulmonary embolism (PE) are manifestations of the same pathological entity, called venous thromboembolism (VTE). An embolus is any intravascular material that migrates from its original location to occlude a distal vessel.

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Look at terminology mentioned in problem (e.g. prothrombin time).

Look at the lecture (very important) and study drugs mentioned there.