Veins and venous return
Veins are the body's blood reservoir and its return road - they store most of the circulating volume at low pressure and, with the help of one-way valves and the calf muscles, push it back uphill to the right side of the heart.
What it normally does
Veins are thin-walled and distensible, and the systemic venous system holds roughly two thirds of the total blood volume at low pressure (capacitance vessels). Their smooth muscle, under sympathetic alpha-1 control, can tighten and squeeze that reserve back towards the heart, so venous tone, circulating volume and the skeletal muscle pump together set venous return - and over any sustained period the heart can only eject what is returned to it.
anything that strands blood in the veins (standing still, a blunted baroreflex, a venodilating drug) or empties them (bleeding, dehydration) drops filling and therefore stroke volume, which is why postural hypotension and nitrate-induced hypotension look the same at the bedside.
Standing turns the veins below the heart into a hydrostatic column. The vertical distance from right atrium to ankle in an adult is a little over a metre, so quiet standing puts an ankle venous pressure of roughly 80 to 90 mmHg on the leg veins. Contracting the calf empties the deep veins upward and the one-way valves stop the blood falling back, so within a few steps ambulatory ankle venous pressure falls to about 20 to 30 mmHg. The calf muscle pump is effectively a second heart.
if the valves fail the pressure no longer falls on walking (ambulatory venous hypertension), and that sustained pressure - not the clot itself - is what produces oedema, pigmentation and the venous ulcer.
Venous return runs on a tiny pressure gradient: roughly 12 to 18 mmHg in the venules, about 8 to 10 mmHg in the large peripheral veins, down to a mean right atrial pressure of about 0 to 5 mmHg. Flow is therefore slow and easily stalled, and it depends on external help - the muscle pump, the valves, and the fall in intrathoracic pressure with inspiration.
immobility alone is enough to bring venous flow close to stasis, which is the first arm of Virchow's triad and the reason hospitalised and post-operative patients form deep vein thrombosis.
The systemic veins converge on the right heart and then the lungs. Two qualifications matter: the pulmonary veins are not systemic veins and carry oxygenated blood to the LEFT atrium, and the splanchnic veins drain first into the portal vein and the liver (so portal-system clot lodges in the liver, not the lung) before hepatic venous blood joins the inferior vena cava.
a clot released from a limb or pelvic vein is delivered to the pulmonary arteries rather than the brain - so a swollen leg and sudden breathlessness are one disease in two places, whereas a clot formed in the left atrium is pumped into the systemic arteries instead.
The leg has two venous systems. The superficial veins (great saphenous up the medial leg and thigh, small saphenous in the posterior calf) lie outside the deep fascia in subcutaneous fat; the deep veins lie within the fascia where contracting muscle can compress them. Perforating veins connect the two, and their valves normally direct flow superficial to deep (some foot perforators are the recognised exception).
the superficial veins have no muscle to pump or support them, so once perforator and saphenous valves become incompetent, blood refluxes outward and downward into vessels that cannot empty themselves - varicose veins, and eventually skin damage.
What goes wrong
- Orthostatic (postural) hypotension← from “Veins are thin-walled and distensible, and the…”
Standing shifts roughly 500 to 800 mL of blood into the leg and splanchnic veins. Normally the baroreflex answers within seconds: venous tone tightens and squeezes that volume back, while heart rate and arteriolar tone rise. If the reflex is blunted - age, autonomic neuropathy in diabetes or Parkinson disease, hypovolaemia, or a drug that relaxes veins or blocks the reflex - the blood stays in the legs, filling falls, and the blood pressure drops on standing.
Lying-to-standing blood pressure with a timed three-minute reading, plus a medication review, is the whole assessment; a blunted heart rate response suggests autonomic failure, a brisk one suggests hypovolaemia.
You would find: A fall of 20 mmHg or more systolic, or 10 mmHg or more diastolic, within three minutes of standing, with dizziness or a near-faint. Common in older Australians and in anyone on antihypertensives, diuretics, nitrates, alpha-blockers or tricyclics. A heart rate that fails to rise with the fall points to autonomic failure rather than simple volume loss.
- Deep vein thrombosis← from “Venous return runs on a tiny pressure gradient…”
Stop the calf pump - surgery, a plaster cast, a long-haul flight, a stroke, a hospital bed - and the already slow venous flow stalls. Stasis is one arm of Virchow's triad; add hypercoagulability (pregnancy and the puerperium, combined oral contraceptive, cancer, inherited thrombophilia) or endothelial injury, and thrombus forms in the deep calf veins and propagates proximally.
Wells score decides whether D-dimer is useful at all; D-dimer is sensitive but not specific, so a positive result in a likely patient adds nothing and ultrasound is the test.
You would find: One calf swollen, warm and tender, with a calf circumference 3 cm or more greater than the other side. Score the pre-test probability (Wells) first: if DVT is unlikely a negative D-dimer excludes it, and if DVT is likely go straight to compression ultrasound - you cannot diagnose or exclude it by inspection. Formal VTE risk assessment on hospital admission is standard Australian practice because this is a leading preventable cause of in-hospital death.
- Pulmonary embolism← from “The systemic veins converge on the right heart…”
Thrombus that breaks free from a leg or pelvic vein follows the systemic venous drainage into the right atrium and ventricle and lodges in the pulmonary arteries. It blocks perfusion of ventilated lung (dead space, hypoxaemia) and raises right ventricular afterload; if the load is large enough the right ventricle dilates and fails, and cardiac output falls. Rarely a clot crosses a patent foramen ovale instead and embolises to the systemic circulation (paradoxical embolus).
Breathless plus hypoxic plus tachycardic with a clear chest X-ray is PE until excluded; hypotension marks massive PE, where thrombolysis rather than anticoagulation alone is considered.
You would find: Sudden breathlessness, pleuritic chest pain, tachycardia and low oxygen saturation - often with no leg symptoms at all, because the clot has left the leg. Sinus tachycardia is the commonest ECG finding (S1Q3T3 is classic but uncommon); look for right heart strain on ECG or echocardiogram and confirm with CT pulmonary angiogram. An age-adjusted D-dimer cut-off (age x 10 micrograms/L above the age of 50) is used to reduce false positives in older patients.
- Varicose veins← from “The leg has two venous systems. The superficia…”
Valves in the superficial veins and perforators become incompetent, so blood refluxes back down and outward instead of inward and upward. The full standing hydrostatic column now lands on superficial veins that lie outside the deep fascia with no surrounding skeletal muscle to support or empty them. They dilate, elongate and become tortuous, and the dilatation pulls further valve cusps apart - the problem feeds itself.
Cosmetic in most, but look for the skin changes that mark venous hypertension rather than simple varicosity - pigmentation, eczema, lipodermatosclerosis - because those change management.
You would find: Visible dilated, tortuous veins down the medial leg and thigh (great saphenous distribution) or the posterior calf (small saphenous), with aching and heaviness worst at the end of a day standing and relieved by elevation. Duplex ultrasound maps where the reflux starts.
- Chronic venous insufficiency and venous ulceration← from “Standing turns the veins below the heart into …”
When the valves are destroyed - most often by a previous DVT (post-thrombotic syndrome), sometimes by long-standing superficial reflux - walking no longer drops the ankle venous pressure. It stays high all day (ambulatory venous hypertension). That pressure is transmitted back to the capillaries, so fluid, red cells and protein leak into the skin. Iron from broken-down red cells is deposited as haemosiderin, the tissue fibroses, and the skin eventually breaks down into a venous ulcer.
Compression is the treatment for a venous ulcer and the danger for an arterial one, so the ankle-brachial index is checked before the bandage goes on; a medial gaiter ulcer with normal pulses is venous until proven otherwise, but mixed arterial and venous disease is common in older patients.
You would find: Ankle swelling, brown haemosiderin staining, tight woody skin (lipodermatosclerosis) and a shallow, exudative ulcer over the medial gaiter area just above the medial malleolus, with foot pulses present. Measure the ankle-brachial index before compression bandaging: significant arterial disease (ABI below about 0.8) makes full compression unsafe.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- antithrombin III, bound through the pentasaccharide sequence carried on the heparin chain
- Which does
- the conformational change accelerates antithrombin's inactivation of factor Xa by around a thousandfold; the chains are mostly shorter than the 18 saccharides needed to bridge antithrombin onto thrombin, so anti-IIa activity is much weaker (anti-Xa to anti-IIa roughly 3 to 4 to 1 for enoxaparin)
- So you see
- thrombin generation falls and existing thrombus stops extending; the response is predictable enough that routine APTT or INR monitoring is not used
- And the same mechanism causes
- bleeding, because antithrombin-mediated suppression of factor Xa acts at every site of haemostasis and not only in the calf vein; and heparin-induced thrombocytopenia, which follows specifically from heparin binding platelet factor 4 and provoking antibodies against that complex (less common with low molecular weight than with unfractionated heparin, and paradoxically prothrombotic).
- Handling
- renally cleared, so it accumulates in significant renal impairment (reduced dosing or anti-Xa monitoring is used below a creatinine clearance of about 30 mL/min); it is a large polysaccharide and does not cross the placenta, which is why it is the anticoagulant of choice in pregnancy - warfarin crosses and is teratogenic, and the direct oral agents are small molecules avoided in pregnancy for lack of safety data
Catches people out: Bleeding risk climbs with renal impairment because of accumulation. Protamine reverses only part of the anti-Xa effect, unlike its complete reversal of unfractionated heparin. Falling platelets after about day 5 of exposure should raise heparin-induced thrombocytopenia rather than prompting more heparin.
- Binds
- the active site of factor Xa (direct, reversible, competitive inhibition - no antithrombin cofactor required)
- Which does
- factor Xa can no longer cleave prothrombin, so the prothrombinase burst that amplifies coagulation is blocked
- So you see
- anticoagulation within hours of the first dose, predictable enough that no routine monitoring is needed; the clot stops growing while the body's own fibrinolysis clears it over weeks
- And the same mechanism causes
- bleeding is the direct extension of systemic Xa blockade, gastrointestinal bleeding being the characteristic site; and because the half-lives are hours rather than days, missed doses leave a patient unprotected far faster than they would on warfarin. Reversal relies on prothrombin complex concentrate, with a specific agent (andexanet alfa) registered but not stocked everywhere.
- Handling
- partly renally cleared (rivaroxaban more than apixaban), so both are avoided in severe renal impairment; rivaroxaban treatment doses need food for reliable absorption; both are avoided in pregnancy and breastfeeding, and they perform worse than warfarin in mechanical prosthetic valves and in triple-positive antiphospholipid syndrome
Catches people out: They stop the clot growing and stop new clot forming; they do not dissolve the clot already sitting there - the body does that over weeks, and residual ultrasound changes are not treatment failure.
- Binds
- the VKORC1 subunit of vitamin K epoxide reductase in hepatocytes
- Which does
- reduced vitamin K cannot be regenerated, so gamma-carboxylation of factors II, VII, IX and X - and of the natural anticoagulants protein C and protein S - fails; the proteins are still secreted but cannot bind calcium and phospholipid, so they are functionally inert
- So you see
- the INR climbs over several days as already-carboxylated factors decay; the usual target range in venous thromboembolism is an INR of 2 to 3
- And the same mechanism causes
- an early, transient prothrombotic window, because protein C has a half-life of about 8 hours and is depleted long before prothrombin is - this is exactly why parenteral cover is overlapped, and unopposed it can cause warfarin-induced skin necrosis; then bleeding, once the vitamin K-dependent factors have actually fallen.
- Handling
- onset is set by the half-lives of the existing factors - factor VII falls within hours but prothrombin takes two to three days - so a fast-acting anticoagulant is overlapped for at least five days and until the INR is in range on consecutive days. Effect is reversed with vitamin K, and urgently with prothrombin complex concentrate. Metabolism through CYP2C9 and dependence on dietary vitamin K make it heavily interaction-prone, and it crosses the placenta and is teratogenic.
Catches people out: It takes days to work, so it never covers the acute clot on its own. Narrow therapeutic index with frequent INR monitoring, and both diet and interacting drugs move the INR.
- Binds
- no receptor - the molecule is bioactivated inside vascular smooth muscle (largely by mitochondrial aldehyde dehydrogenase-2) to release nitric oxide, which binds soluble guanylate cyclase
- Which does
- cyclic GMP rises, protein kinase G lowers intracellular calcium and dephosphorylates myosin light chains, and the smooth muscle relaxes; venous capacitance vessels are considerably more sensitive than arterioles at ordinary doses, with epicardial coronary dilatation as well
- So you see
- venous return and preload fall, so left ventricular volume and wall stress fall, angina eases and pulmonary congestion clears; higher doses add arterial dilatation and drop afterload too
- And the same mechanism causes
- throbbing headache and flushing, from the same cGMP-mediated dilatation acting on meningeal and cutaneous vessels; postural hypotension with reflex tachycardia when preload falls too far - dangerous precisely in the patients whose output depends on filling.
- Handling
- tolerance develops within about 24 hours of continuous exposure, so a nitrate-free interval is built into long-acting regimens; it is contraindicated with PDE5 inhibitors such as sildenafil or tadalafil, because blocking cGMP breakdown while driving cGMP production causes profound and sustained hypotension
Catches people out: In anyone who depends on preload - severe aortic stenosis, right ventricular infarction, hypovolaemia - dropping venous return drops the blood pressure hard. Combining it with a PDE5 inhibitor is contraindicated for the same reason, amplified.
Swollen leg plus breathless equals one disease in two places, because blood in a limb or pelvic vein is delivered to the right heart and then the lungs. Contrast a clot from the left atrium, which is pumped out through the left ventricle into the systemic arteries - most notoriously to the brain, but equally to gut, kidney or limb. Same clot, different plumbing, completely different presentation. Two exceptions are worth holding: splanchnic vein clot goes to the liver through the portal vein, and venous clot reaches the systemic side only if a patent foramen ovale lets it cross. At the ankle, an ulcer in the medial gaiter area with palpable foot pulses is venous until proven otherwise and is treated with compression, while one with absent pulses is arterial and compression will make it worse - so the ankle-brachial index is checked first.
Now test whether it stuck
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