L11 Blood Thrombosis 2

Overview

This lecture covers venous thrombosis: how a thrombus differs from an embolus, the cellular mechanism that initiates deep venous thrombosis (DVT) in stasis, how thrombi propagate and embolise to the lungs, the risk factors (age, surgery, cancer, antiphospholipid syndrome, oral contraceptives, heritable thrombophilia), how DVT and pulmonary embolism (PE) are diagnosed (Wells score, D-dimer, compression ultrasound, CT pulmonary angiography), the anticoagulants used to treat VTE, how recurrence risk determines treatment duration, and the chronic complications of venous thrombosis.

Thrombus vs embolus, venous vs arterial

• A thrombus is a solid mass in a blood vessel or the heart; thrombosis is the pathological process forming it.
• Thrombi are made of platelets, fibrin clot, neutrophils/monocytes, and trapped red cells.
• An embolus is a free-floating mass inside blood vessels that can travel from one site to another; it is usually made of thrombus, but less commonly can be fat, amniotic fluid, gas, or tumour. Plural: emboli. Embolism is the lodging of an embolus (e.g. pulmonary embolism).
• Venous and arterial thrombosis are very different:
  • Venous: usually in deep veins of the leg; initiated by stasis; the thrombus is fibrin clot + cells; treated mainly with anticoagulants.
  • Arterial: occurs in atherosclerotic arteries; initiated by damaged endothelium and platelet adhesion, followed by recruitment of coagulation; treated mainly with anti-platelet drugs.
• Other thrombotic processes exist beyond typical leg DVT: left atrial appendage thrombus in atrial fibrillation, venous thrombosis in unusual sites (cerebral venous, abdominal veins, upper limb), superficial thrombophlebitis, and cardiac mural thrombus.

Initiation of deep venous thrombosis

• Major risk factors for DVT (trauma/fracture, leg surgery, immobility, nursing home confinement, obesity, pregnancy/puerperium, age) share a common mechanism: reduced blood pumping causes stasis.
• Stasis occurs in calf veins during surgery or immobility, with low or intermittent flow especially in deep calf veins (particularly soleal veins). This makes the endothelium hypoxic, especially around valves, activating endothelial cells.
• Stasis leads to adhesion of neutrophils and monocytes to the vessel wall (demonstrated in a mouse inferior vena cava model: adherent leukocytes appear on the vessel wall 6 h after an 80% reduction in blood flow, versus none at baseline).
• Neutrophils and monocytes may be the major initiating cells for DVT:
  • Hypoxia and/or local inflammation increases selectin expression on endothelial cells.
  • Neutrophils adhere via P-selectin and undergo NETosis, releasing DNA (neutrophil extracellular traps).
  • The released DNA activates Factor XII, driving the intrinsic pathway (FXII → FXI → FIX(a) → common pathway).
  • Meanwhile monocytes adhere to the selectins and express Tissue Factor (TF), activating the extrinsic pathway (TF/FVIIa → FX).
• Integrated pathway: Neutrophil NETosis → FXIIa → FXIa → FIXa (intrinsic); Monocyte TF and activated endothelial cell TF (uncertain link) → FVIIa (extrinsic), which also feeds into FIXa; FIXa and FVIIa both converge on FXa (common pathway) → thrombin → fibrin.

Development and consequences: propagation and pulmonary embolism

• Thrombosis is a dynamic process: the thrombus propagates (extends) towards the upper leg and pelvis, and may extend considerable distances in the direction of flow.
• A propagating thrombus is not well attached to the vein wall, so fragments may break off and become an embolus.
• Pulmonary emboli lodge in branches of the pulmonary artery; a large “saddle” embolus (arising from a large ileo-femoral vein) can obstruct both left and right pulmonary arteries and cause death.
• Histologically, a venous thrombus/embolus in a pulmonary artery shows a varied, layered appearance (lines of Zahn), with alternating fibrin/platelet-rich and red cell-rich bands, since thrombus contents vary as they form.
• DVT vs PE presentation:
  • DVT: unilateral leg swelling, pain, warmth, skin discolouration; can occur suddenly or over days to weeks.
  • PE: shortness of breath, chest pain (classically worse with breathing), non-productive cough, haemoptysis.
• PE severity:
  • Massive PE: causes sudden death or haemodynamic instability.
  • Submassive PE: normal arterial blood pressure but right ventricular dysfunction (seen on ECG, echo, CT).

Risk factors for VTE

• Strong risk factors:
  • Persistent: age, active cancer, antiphospholipid syndrome.
  • Transient: Caesarean section, hospitalisation for acute illness, major trauma or fracture, prolonged immobility (e.g. bedridden >3 days), surgery >30 min, heparin-induced thrombocytopenia.
• Weak risk factors:
  • Persistent: chronic inflammatory disorders, nursing home confinement, obesity, personal or family history of VTE.
  • Transient: brief immobility (e.g. travel >4 h), oestrogen therapy, infection, minor trauma or fracture, pregnancy or puerperium, surgery <30 min, venous catheterisation.
  • Risk factors are broadly either mainly immobilisation-related or related to activated/increased coagulation.
• Age is a strong, continuous risk factor: absolute risk of first venous thrombosis rises roughly exponentially with age (overall total risk 1-4/1000/year; men 1-3/1000/year; women 1-6/1000/year).
• Possible explanations for increased risk with age: rising procoagulant (clotting factor) levels, rising markers of coagulation such as D-dimer indicating a persistent hypercoagulable state, increased body mass, decreased activity with increased co-morbidities/frailty and periods of immobilisation due to illness, and increased frequency of acute serious infections.
• Model of VTE causation: everyone’s baseline thrombosis potential rises with age. People with congenital thrombophilia have a higher baseline curve than the general population, crossing the “thrombosis threshold” (causing VTE) at an older age purely from that rise. Adding a transient risk factor (e.g. contraceptives, major surgery) produces a temporary spike on top of the baseline, which can push a person over the threshold earlier than baseline rise alone would. Venous thrombosis is thus often caused by disturbances in plasma coagulation combining baseline/genetic risk with transient triggers.
• Risk after major orthopaedic surgery without prophylaxis (DVT/PE %, based on mandatory venography since 1980):
  • Hip arthroplasty: DVT total 42-57% (proximal 18-36%); PE total 0.9-28% (fatal 0.1-2.0%).
  • Knee arthroplasty: DVT total 41-85% (proximal 5-22%); PE total 1.5-10% (fatal 0.1-1.7%).
  • Hip fracture surgery: DVT total 46-60% (proximal 23-30%); PE total 3-11% (fatal 2.5-7.5%).
  • Arthroscopic ACL repair: 30-40% distal DVT, of which ~1/3 extend to proximal DVT and ~1/3 are symptomatic; <1% PE.
• Cancer: 5-20% of cancer patients get a VTE; 20% of VTE patients have cancer. Risk is multifactorial: chemotherapy, surgery, immobility, and a prothrombotic state.
• Antiphospholipid syndrome: an autoimmune condition with antibodies against phospholipid-associated proteins; causes a marked increase in venous (and arterial) thrombosis and increased late-pregnancy fetal loss.
• Oral contraceptives: used by up to a third of women of fertile age; increase VTE risk, highest in the first months, gradually decreasing over the first year but remaining 3-8x baseline risk. People with a personal history of VTE should not be recommended an OCP.
• Heritable thrombophilia: suspected with VTE at a young age (<40/50 years), a strong family history (first-degree relative with onset <50 years), VTE occurring despite only weak risk factors, recurrent VTE events, or VTE at unusual sites (splanchnic/cerebral veins). Main strong examples: antithrombin deficiency, protein C deficiency, protein S deficiency. Mechanism: antithrombin normally inhibits Factors XIa, IXa, Xa and thrombin; protein C and protein S normally inhibit Factors VIIIa and Va. Deficiency of any of these natural anticoagulants removes inhibition of coagulation factors, increasing fibrin formation and thrombosis risk.

Diagnosis of DVT and PE

• Diagnosing DVT combines a clinical probability score, D-dimer, and imaging:
  • The Wells score is widely used to estimate clinical probability.
  • D-dimer provides evidence of recent fibrin production.
  • Compression ultrasound imaging follows if appropriate.
• Wells score clinical variables (1 point each unless noted): active cancer; paralysis/paresis or recent immobilisation of a lower limb; recently bedridden >3 days or major surgery in the past 12 weeks; localised tenderness along the deep veins; swelling of the entire leg; calf swelling >3 cm larger than the other leg (measured 10 cm below the tibial tubercle); pitting oedema confined to the affected leg; collateral superficial veins evident (not varicosities); previously documented DVT; an alternative diagnosis at least as likely as DVT scores -2. Total >2 = high probability of DVT; <2 = low probability.
• Wells score investigation strategy:
  • High probability: go straight to compression ultrasound; D-dimer is not needed.
  • Low probability: request D-dimer. If negative, reassure and discharge without further investigation. If positive, proceed to compression ultrasound.
• D-dimer formation requires degradation of crosslinked fibrin: fibrinogen → (thrombin cleavage, loss of fibrinopeptides A and B) → fibrin polymer → (Factor XIIIa crosslinking) → crosslinked fibrin → (plasmin cleavage) → fibrin degradation products, one fragment of which is D-dimer (two D domains plus an E domain).
• Compression ultrasound: a normal vein is compressible; a vein containing DVT is non-compressible because the thrombus fills the lumen.
• CT pulmonary angiography is used to diagnose PE, showing filling defects (emboli) within pulmonary artery branches.

Other venous thromboses

• Upper limb thrombosis: presents with swelling and pain in the upper limb.
• Intra-abdominal thrombosis: very non-specific symptoms; pain; liver impairment if the hepatic vein is involved; portal hypertension if the portal vein is involved.
• Cerebral venous and sinus thrombosis: presents with headaches, seizures, cranial nerve palsies, and visual disturbance.

Treatment

• Acute treatment of VTE is anticoagulation, to prevent extension of the thrombus:
  • Direct oral anticoagulants (DOACs) are preferred, having a lower risk of intracranial and fatal bleeding than warfarin.
  • Low molecular weight heparin (LMWH).
  • Warfarin.
  • Thrombolysis (fibrinolysis).
• DOAC mechanisms: dabigatran is a direct thrombin inhibitor; rivaroxaban is a direct anti-Factor Xa inhibitor. On the intrinsic/extrinsic/common pathway diagram, rivaroxaban blocks FXa and dabigatran blocks thrombin.
• There is considerable interest in direct Factor XI inhibitors: FXI appears critical for DVT formation, yet relatively unimportant for normal haemostasis, making it an attractive target that may reduce bleeding risk compared with existing anticoagulants.

Recurrence and duration of anticoagulation

• Provoked thrombosis: an identifiable risk event contributed to the thrombus (surgery, pregnancy, bedrest, major trauma, inflammation, lower limb immobility in a plaster cast, paralysis after spinal cord injury). Future risk depends on whether the risk factor ceases or persists; risk to other family members is nil.
• Unprovoked thrombosis: no previous risk event. A family history of unprovoked thrombosis may be present, and there is a greater risk of repeat thromboses. Consider investigating for heritable risk factors if the patient is aged under ~40 years.
• Recurrence rates (after stopping anticoagulation) inform how long to treat:
  • First VTE provoked by major surgery/trauma: 1% at 1 year, 3% at 5 years.
  • First VTE provoked by a transient non-surgical risk factor: 5% at 1 year, 15% at 5 years.
  • Provoked VTE with a persistent risk factor (e.g. active cancer): 15% at 1 year, 45% at 5 years.
  • First unprovoked distal DVT: 5% at 1 year, 15% at 5 years.
  • First unprovoked proximal DVT or PE: 10% at 1 year, 30% at 5 years.
  • Second episode of unprovoked VTE: 15% at 1 year, 45% at 5 years.
• Treatment duration decisions form a spectrum from short-term (3 months) low-risk treatment for VTE due to a transient risk factor, up to long-term anticoagulation for the highest-risk groups (e.g. men with unprovoked DVT or PE), factoring in bleeding risk, fluctuating INRs, lifestyle impact, and patient preference.

Complications of venous thrombosis

• Venous insufficiency: inadequate venous drainage after thrombosis causes loss of valves in the affected vein, leading to skin trophic changes, chronic soft tissue swelling, pain, and risk of chronic ulceration.
• Acute consequences: local oedema causing pain from reduced venous drainage (thrombus is cleared by fibrinolysis over months); pulmonary embolism may occur.
• Chronic consequences (post-phlebitic syndrome): raised venous pressure from loss of valves; varicose veins (dilated and tortuous); chronic ankle ulcers after minimal trauma, due to chronically raised venous pressure affecting skin blood flow and nutrition; swelling (oedema); chronic leg pain, especially when standing.

Self-test

1. Define a thrombus and list its typical constituents.
2. Distinguish a thrombus from an embolus.
3. Distinguish venous thrombosis from arterial thrombosis in terms of site, initiating trigger, composition, and main treatment.
4. Describe the steps by which stasis in the calf veins initiates DVT, from endothelial hypoxia through to fibrin formation, including the roles of neutrophils and monocytes.
5. Explain why a propagating thrombus is prone to embolising.
6. A patient develops sudden shortness of breath, pleuritic chest pain, and haemoptysis. What is the likely diagnosis, and how does its presentation differ from that of a DVT in the same leg?
7. Distinguish massive from submassive pulmonary embolism.
8. List the strong persistent, strong transient, weak persistent, and weak transient risk factors for VTE given in the lecture.
9. Explain, using the “thrombosis threshold” model, why a person with congenital thrombophilia who also undergoes major surgery may develop VTE earlier than either factor would predict alone.
10. What clinical features would make you suspect a heritable thrombophilia rather than a provoked thrombosis?
11. Describe how deficiency of antithrombin, protein C, or protein S increases thrombosis risk.
12. A patient has a Wells score of 3. What is the next investigation, and why?
13. A patient has a Wells score of 1. Describe the recommended investigation pathway from this point.
14. Describe how a D-dimer is generated from fibrinogen.
15. Explain the ultrasound finding that distinguishes a normal vein from one with DVT.
16. Distinguish dabigatran from rivaroxaban in terms of mechanism of action.
17. Why is Factor XI considered an attractive target for a new anticoagulant?
18. Distinguish a provoked from an unprovoked thrombosis, including their implications for future risk and duration of treatment.
19. Describe the chronic complications that can follow venous thrombosis and explain the underlying mechanism.
20. Integrative: trace the pathway from stasis in a calf vein, through thrombus initiation and propagation, to a possible pulmonary embolism, and explain how each stage is targeted by a different clinical test or treatment discussed in the lecture.

Answers

Reveal answers

1. A thrombus is a solid mass in a blood vessel or the heart. Its constituents are platelets, fibrin clot, neutrophils/monocytes, and trapped red cells.
2. A thrombus is the solid mass that forms in a vessel or the heart. An embolus is a free-floating mass (usually made of thrombus, but sometimes fat, amniotic fluid, gas or tumour) that has broken free and travels through the bloodstream to lodge elsewhere.
3. Venous thrombosis occurs mainly in the deep veins of the leg, is initiated by stasis, is composed of fibrin clot plus cells, and is treated mainly with anticoagulants. Arterial thrombosis occurs in atherosclerotic arteries, is initiated by damaged endothelium and platelet adhesion followed by recruitment of coagulation, and is treated mainly with anti-platelet drugs.
4. Stasis (from reduced blood pumping, e.g. due to immobility or surgery) causes low/intermittent flow in the calf veins, making the endothelium hypoxic, especially around valves, and activating endothelial cells, which increase selectin expression. Neutrophils adhere via selectins and undergo NETosis, releasing DNA that activates Factor XII, driving the intrinsic pathway (FXIIa → FXIa → FIXa). Monocytes also adhere to the selectins and express Tissue Factor, activating the extrinsic pathway (TF/FVIIa). Both pathways converge on FXa, generating thrombin and then fibrin.
5. A propagating thrombus extends in the direction of flow but is not well attached to the vein wall, so pieces can break off and travel in the bloodstream as an embolus.
6. Pulmonary embolism. PE presents with shortness of breath, chest pain classically worse on breathing, a non-productive cough, and haemoptysis, whereas DVT in the leg presents with unilateral swelling, pain, warmth, and skin discolouration, which can develop suddenly or over days to weeks.
7. Massive PE causes sudden death or haemodynamic instability. Submassive PE occurs with normal arterial blood pressure but with right ventricular dysfunction seen on ECG, echo, or CT.
8. Strong persistent: age, active cancer, antiphospholipid syndrome. Strong transient: Caesarean section, hospitalisation for acute illness, major trauma or fracture, prolonged immobility (>3 days bedridden), surgery >30 min, heparin-induced thrombocytopenia. Weak persistent: chronic inflammatory disorders, nursing home confinement, obesity, personal/family history of VTE. Weak transient: brief immobility (travel >4 h), oestrogen therapy, infection, minor trauma or fracture, pregnancy/puerperium, surgery <30 min, venous catheterisation.
9. Everyone’s baseline thrombosis potential rises with age; a person with congenital thrombophilia has a higher baseline curve than the general population and would eventually cross the thrombosis threshold from age alone. Major surgery adds a temporary spike in thrombosis potential on top of that already-elevated baseline, pushing the combined level over the threshold sooner than either the genetic predisposition or the surgery would alone.
10. Suspect heritable thrombophilia if VTE occurs at a young age (<40/50 years), there is a strong family history (first-degree relative with onset <50 years), VTE occurs despite only weak risk factors, VTE is recurrent, or VTE occurs at an unusual site (splanchnic or cerebral veins).
11. Antithrombin normally inhibits Factors XIa, IXa, Xa and thrombin; protein C and protein S normally inhibit Factors VIIIa and Va. A deficiency in any of these natural anticoagulants removes this inhibition, allowing coagulation factors to remain active and increasing fibrin formation and thrombosis risk.
12. A Wells score of 3 (>2) indicates high probability of DVT, so the next step is compression ultrasound directly; D-dimer is not needed in this pathway.
13. A Wells score of 1 (<2) indicates low probability, so a D-dimer test should be requested. If the D-dimer is negative, the patient can be reassured and discharged without further investigation. If positive, proceed to compression ultrasound.
14. Thrombin cleaves fibrinogen, removing fibrinopeptides A and B to form fibrin, which polymerises. Factor XIIIa crosslinks the fibrin polymer. Plasmin then cleaves the crosslinked fibrin into fibrin degradation products, one of which is the D-dimer fragment (two D domains plus an E domain), which can only form from crosslinked (not simple) fibrin.
15. A normal vein is compressible under ultrasound probe pressure and collapses. A vein containing DVT is non-compressible, because the thrombus fills the lumen and prevents collapse.
16. Dabigatran is a direct thrombin inhibitor, blocking the conversion of fibrinogen to fibrin at the final common step. Rivaroxaban is a direct Factor Xa inhibitor, blocking the common pathway one step earlier, before prothrombin is converted to thrombin.
17. Factor XI appears to be critical for DVT formation but relatively unimportant for normal haemostasis, so inhibiting it could reduce thrombosis while carrying a lower bleeding risk than existing anticoagulants.
18. A provoked thrombosis has an identifiable risk event (e.g. surgery, pregnancy, bedrest, trauma, immobility, spinal cord injury); future risk depends on whether that risk factor ceases or persists, and family risk is nil, generally allowing shorter treatment. An unprovoked thrombosis has no identifiable trigger, may have a family history, and carries a greater risk of recurrence, generally warranting longer-term anticoagulation and consideration of investigating for heritable risk factors if the patient is young.
19. Loss of venous valves after thrombosis causes venous insufficiency: raised venous pressure leads to varicose veins, chronic soft tissue swelling/oedema, skin trophic changes, chronic ulceration at the ankle after minimal trauma (due to chronically impaired skin blood flow and nutrition), and chronic leg pain, especially on standing. Together these constitute the post-phlebitic syndrome.
20. Stasis in a calf vein (e.g. from immobility or surgery) causes endothelial hypoxia and activation, leading to neutrophil NETosis and monocyte tissue factor expression, which together drive fibrin formation via the intrinsic and extrinsic pathways, forming a thrombus (detectable clinically via the Wells score, D-dimer, and confirmed with compression ultrasound). The thrombus may propagate, and being poorly attached, can fragment and embolise to the lungs as a pulmonary embolism (diagnosed with CT pulmonary angiography, and potentially fatal if a large saddle embolus occludes both pulmonary arteries). Acute treatment at any stage is anticoagulation (DOACs, LMWH, warfarin, or thrombolysis) targeting different points in this pathway (e.g. rivaroxaban blocking FXa, dabigatran blocking thrombin), while longer-term management depends on whether the thrombosis was provoked or unprovoked and the associated recurrence risk.