What it is:Clot in the venous circulation. Shows up as deep vein thrombosis (DVT), pulmonary embolism (PE), or both. Same disease, same treatment.
Why it kills:Most venous thrombi start in the leg. Isolated calf clots rarely embolize. Clots in the popliteal vein and aboveare the dangerous ones - they break off, lodge in the pulmonary artery, block gas exchange, and can cause fatal circulatory collapse.
Treatment in one line:Confirm it objectively, start a rapid-acting anticoagulant immediately, treat for at least 3 months, then decide whether to extend.
Every VTE decision reduces to: can this patient take an oral drug right now, or do they need a parenteral bridge first?Rivaroxaban and apixaban go straight to oral. Dabigatran and edoxaban require 5 days of parenteral first. Warfarin requires overlapuntil INR ≥2. That split explains most of the chapter.
| Component | Examples |
|---|---|
| Blood stasis | Immobility, obesity, long travel, hospitalization, paralysis |
| Vascular injury | Surgery, trauma, venous catheters |
| Hypercoagulability | Malignancy, coagulation factor abnormalities, antiphospholipid antibodies, certain drugs (estrogens) |
Plus increasing ageand prior VTE, which are independent risk factors sitting outside the triad.
| Disorder | Prevalence | VTE risk increase |
|---|---|---|
| Activated protein C resistance(mostly factor V Leiden) - the most common | 2–7% | 3× |
| Prothrombin G20210A mutation- second most common | 2–4% | 3× |
| Protein C, protein S, or antithrombin deficiency | <1% | Up to 7×lifetime |
Common mutations, modest risk. Rare deficiencies, big risk.Factor V Leiden is a mutation making factor V resistant to degradation by activated protein C. Prothrombin G20210A increases circulating prothrombin, which increases thrombin generation. Both roughly triple risk. The rare deficiencies (protein C, S, antithrombin) hit under 1% of people but can raise lifetime risk sevenfold.
Modern model is cell-surface based, not the old intrinsic/extrinsic diagram.
Then:thrombin converts fibrinogen to fibrin monomers, which polymerize into strands. Factor XIIIa cross-links them into a mesh that traps platelets and red cells - the stabilized clot.
Natural brakes:thrombomodulin converts protein C to activated protein C, which teams with protein S to inactivate Va and VIIIa. Antithrombin inhibits thrombin and Xa, accelerated by heparan sulfate from endothelium. These confine clotting to the injured zone.
Clot breakdown:tPA converts plasminogen to plasmin, which degrades fibrin into soluble products including D-dimer. That's why D-dimer is a marker of active clot turnover.
| DVT | PE | |
|---|---|---|
| Symptoms | Unilateralleg swelling, pain, tenderness, erythema, warmth. Some patients asymptomatic | Cough, chest pain or tightness, shortness of breath, palpitations, hemoptysis, dizziness, lightheadedness |
| Signs | Palpable cord, positive Homan sign | Tachypnea, tachycardia, diaphoresis, cyanosis, hypotension, shock, cardiovascular collapse |
Bilateral leg swelling is usually heart failure, venous insufficiency, or kidney disease. One swollen, warm, tender calfis the DVT picture.
Postthrombotic syndromeis the long-term complication: chronic lower extremity swelling, pain, tenderness, skin discoloration, and ulceration. Preventing it is one of the treatment goals.
| Test | Role |
|---|---|
| Compression ultrasound (CUS) | Initial test for suspected DVT |
| CT pulmonary angiography (CTPA) | Initial test for suspected PE |
| D-dimer | Nearly always elevated in VTE. A value <500 ng/mLcombined with a low clinical probability score is useful to rule outVTE |
| Wells score | Clinical probability checklist - sorts patients into likely vs unlikely before imaging |
| V/Q scan | Alternative for PE when CTPA isn't suitable (contrast allergy, renal impairment) |
| Venography / pulmonary angiography | Most accurate and reliable, but expensive, invasive, and hard to perform and interpret. Rarely used |
It rises in infection, surgery, trauma, pregnancy, malignancy, and old age - so a high value proves nothing. Its value is the negative: low D-dimer plus low Wells probability lets you safely skip imaging.
Early ambulation, graduated compression stockings, intermittent pneumatic compression (IPC) devices, and IVC filters. Use mechanical methods when drugs are contraindicated.
| Population | Prophylaxis | Duration |
|---|---|---|
| Hospitalized / acutely ill medical, high VTE risk + low bleeding risk | Low-dose UFH, LMWH, fondaparinux, or rivaroxaban | During hospitalization or until fully ambulatory |
| Low-risk medical patients | Routine pharmacologic prophylaxis not warranted | - |
| General, gynecologic, cardiac, vascular surgery | LMWH or low-dose UFH. If drugs contraindicated → IPC or compression stockings | Through the period of increased risk |
| Joint replacement (hip or knee) | Aspirin, adjusted-dose warfarin, LDUH, LMWH, fondaparinux, dabigatran, apixaban, or rivaroxaban | At least 10 days; trials support 15–42 days |
| Major surgery generally | Per above | Extended prophylaxis supported up to 42 days |
| Drug | Dose | Timing & duration |
|---|---|---|
| Rivaroxaban | 10 mg PO daily | Start 6–10 h post-op after hemostasis. 12 days (knee) / 35 days (hip) |
| Apixaban | 2.5 mg PO BID | Start 12–24 h post-op. 12 days (knee) / 35 days (hip) |
| Dabigatran (hip only) | 110 mg day 1, then 220 mg daily | Start 1–4 h post-op after hemostasis. 28–35 days. No dosing if CrCl ≤30 |
| Betrixaban | 160 mg once, then 80 mg daily with food | Acute medical illness, 35–42 days |
DVT and PE are treated the same way. Work down these questions in order.
| Question | If YES |
|---|---|
| 1.PE with severe cardiopulmonary compromise, or DVT with high risk of limb loss? | Thrombolytic therapy, then anticoagulate with UFH or LMWH |
| 2.Active bleeding or contraindication to anticoagulation? | Place IVC filter.Start anticoagulation once the bleeding or contraindication resolves. Remove the filter as soon as clinically acceptable |
| 3.PE with poor prognosis, or DVT unsuitable for outpatient management? | Hospitalizefor treatment |
| 4.CrCl <30 mL/min? | UFH × 5 days overlapped with warfarin until INR >2 |
| Otherwise | Outpatient treatment- see the four options below |
"Which DOAC can be started without a parenteral anticoagulant?" → Rivaroxaban and apixaban only.They're the ones with a built-in loading phase (15 mg BID × 21 d, 10 mg BID × 7 d). Dabigatran and edoxaban have no loading phase, which is exactly why they need 5 days of parenteral coverage up front.
Only when anticoagulants are contraindicated due to active bleeding. They are not an alternative to anticoagulation for convenience, and should be removed as soon as it's safe.
Encourage ambulation as symptoms permit. Ambulation plus graduated compression stockings reduces pain and swelling faster than strict bedrest, with no increase in embolization. Thrombolysis or thrombectomy is reserved for life- or limb-threatening DVT.
| Drug | Target | Acute VTE treatment | Extended risk reduction |
|---|---|---|---|
| Rivaroxaban(Xarelto) | Factor Xa | 15 mg BID with food × 21 d → 20 mg daily with food | 10 mg daily |
| Apixaban(Eliquis) | Factor Xa | 10 mg BID × 7 d → 5 mg BID | 2.5 mg BID |
| Edoxaban(Savaysa) | Factor Xa | 60 mg daily after ≥5 d parenteral. 30 mgif CrCl 15–50, weight ≤60 kg, or on certain P-gp inhibitors | Not approved |
| Dabigatran(Pradaxa) | Factor IIa(thrombin) | 150 mg BID after ≥5 d parenteral | 150 mg BID |
Three end in "-xaban" and hit factor Xa. Dabigatranis the odd one out - a direct thrombin (IIa)inhibitor. That difference drives the reversal agent: idarucizumab for dabigatran, andexanet alfa for the Xa inhibitors.
Adding aspirin to a DOAC nearly doubles bleeding ratesand should be avoided in most VTE patients. Always ask whether there's a real ongoing indication for the aspirin, or whether it's just leftover.
| LMWH | UFH | Fondaparinux | |
|---|---|---|---|
| Target | Xa > IIa, via antithrombin | IXa, Xa, XIIa, IIa, via antithrombin | Xa only, via antithrombin |
| Route | SC, fixed weight-based | IV infusion (or SC) | SC once daily |
| Monitoring | None routinely | aPTT(or anti-Xa) | None routinely |
| HIT risk | ⅓ that of UFH | Highest | Very low |
| Reversal | Protamine (partial) | Protamine (full) | No antidote |
| Renal | Caution; monitor anti-Xa if impaired | Preferred if CrCl <30 | Contraindicated if CrCl <30 |
LMWHs are depolymerized UFH fragments, roughly one-third the mean molecular weight. Same mechanism: accelerate antithrombin.
Six advantages over UFH:predictable dose response · improved SC bioavailability · dose-independent clearance · longer biologic half-life · lower thrombocytopenia incidence · less need for routine lab monitoring.
Dosing (actual body weight):
Monitoring:baseline CBC with platelets and serum creatinine. Then CBC every 5–10 days for the first 2 weeks and every 2–4 weeks after, watching for occult bleeding. Anti-factor Xa is the monitoring assay but is unnecessary in stable, uncomplicated patients- consider it in significant renal impairment, morbid obesity, or pregnancy.
In patients without cancer, LMWH usually transitions to long-term warfarin after 5–10 days.
UFH binds antithrombin, causing a conformational change that dramatically increases inhibition of IXa, Xa, XIIa, and IIa. Largely replaced by LMWH, fondaparinux, and DOACs, but still the drug of choice in CrCl <30 and in unstable patientsbecause it's titratable and fully reversible.
Weight-based IV dosing for DVT/PE:loading dose 80–100 units/kg(max 10,000 units), then infusion at 17–20 units/kg/h(max 2300 units/h). Use actual body weight; adjusted body weight if >130% of ideal.
| aPTT (sec) | Anti-Xa (unit/mL) | Adjustment |
|---|---|---|
| <37 | <0.20 | 80 units/kg bolus, increase infusion by 4 units/kg/h |
| 37–47 | 0.20–0.29 | 40 units/kg bolus, increase by 2 units/kg/h |
| 48–71 | 0.30–0.70 | Therapeutic - no change |
| 72–93 | 0.71–1.0 | Decrease by 1–2 units/kg/h |
| >93 | >1.0 | Hold 1 hour, then decrease by 3 units/kg/h |
Check aPTT before starting and 6 hoursafter initiation or any dose change. Therapeutic ranges must be institution-specific.
SC option:333 units/kg initially, then 250 units/kg q12h. Osteoporosis riskwith ≥20,000 units/day for over 6 months, especially in pregnancy.
Indirectly inhibits factor Xa onlythrough antithrombin. Safe and effective alternative to LMWH for acute VTE, then followed by long-term warfarin.
Weight-based once-daily SC dosing:
No routine coagulation testing. Check baseline kidney function - contraindicated if CrCl <30. CBC at baseline and periodically for occult bleeding. No specific antidote exists.
Mechanism:inhibits the enzymes that cyclically regenerate reduced vitamin K in the liver. Reduced vitamin K is the cofactor needed to carboxylate factors II, VII, IX, Xand the anticoagulant proteins C and S. Without it, those proteins are produced with reduced activity.
Onset depends on how fast existing factors clear. Factor VII half-life is ~6 hours; prothrombin is ~72 hours.So the INR rises early on the strength of factor VII depletion alone, while prothrombin is still circulating. Full antithrombotic effect takes at least 6 days.Proteins C and S are also short-lived, so their early loss can create a brief procoagulant window. That is exactly why you overlap with a rapid-acting parenteral agent.
Overlap rule:continue the parenteral anticoagulant for at least 5 days AND until INR ≥2 for at least 24 hours.Both conditions must be met.
| Situation | Starting dose |
|---|---|
| Most patients | 5–10 mg daily |
| Age >60, interacting medications, or high bleeding risk | Consider 2.5 mg |
| Age <60, no interacting meds, low bleeding risk | Consider 7.5–10 mg |
Measure PT/INR on day 2 or 3 if daily monitoring is available, otherwise day 3–4, then adjust. Typical target INR for VTE is 2–3.
Range is mild to life-threatening. It's also a CYP2C9 and VKORC1-sensitive drug with an enormous interaction list - antibiotics, amiodarone, azoles, NSAIDs, and dietary vitamin K all shift the INR.
| Anticoagulant | Reversal | Details |
|---|---|---|
| UFH | Protamine sulfate | 1 mg per 100 unitsof UFH infused in the previous 4 hours. Max 50 mg. Slow IV over 10 min |
| Enoxaparin | Protamine (partialonly) | 1 mg per 1 mgenoxaparin given in previous 8 h. Second dose 0.5 mg/mg if bleeding continues. Not recommended if >12 h since dose |
| Dalteparin | Protamine (partial) | 1 mg per 100 anti-Xa units in previous 8 h |
| Fondaparinux | None | No specific antidote |
| Dabigatran | Idarucizumab(Praxbind) | 5 g IV. Rapid reversal for life-threatening bleeding or urgent surgery |
| Rivaroxaban / apixaban | Andexanet alfa(Andexxa) | Recombinant factor Xa decoy. For life-threatening bleeding |
| Warfarin | Vitamin K ± 4-factor PCC / FFP | Depends on INR and bleeding severity |
Idarucizumab → dabigatran (both have the "d-a" and both are the thrombin story). Andexanet→ the -xabans. And protamine only fully reverses UFH; against LMWH it's partial, and against fondaparinux it does nothing.
| Scenario | Duration | Reasoning |
|---|---|---|
| First acute VTE, any patient | 3 months minimum | Appropriate initial duration for all |
| Provokedby a major transient or reversible risk factor (surgery, hospitalization) | 3 months, then stop | The trigger is gone; recurrence risk drops |
| First unprovoked / idiopathic VTE | Consider extended therapy beyond 3 monthswhen feasible | Relatively high recurrence rate with no removable cause |
| VTE with active cancer | Extended therapy, rarely stopped | High recurrence risk that persists as long as the cancer does |
Provoked = there was a clear temporary reason (post-op, immobilized, hospitalized). Treat 3 months and stop. Unprovoked = it happened for no visible reason, so the underlying risk is still there. That's when extended therapy enters the discussion, using reduced-dose rivaroxaban 10 mg daily or apixaban 2.5 mg BID.
A rare immunologicreaction that requires immediate intervention and can be fatal. Counterintuitively, the most common complication of HIT is thrombosis, not bleeding- usually VTE, less often arterial.
| T | What it asks |
|---|---|
| Thrombocytopenia | How large is the platelet drop? |
| Timing | When did the platelet fall or thrombosis occur relative to heparin exposure? |
| Thrombosis | Is there new thrombosis? |
| oTher causes | Is there another explanation for the low platelets? |
Thrombocytopenia is the most common manifestation, but serologic confirmation of heparin antibodies is required for diagnosis.If new thrombosis appears alongside falling platelets with a moderate or high 4Ts score: discontinue ALL heparin(including flushes and LMWH) and start a direct thrombin inhibitor. Do not simply switch UFH to LMWH - cross-reactivity is the whole problem.
LMWH carries roughly one-thirdthe HIT incidence of UFH, and a lower osteoporosis risk.
| Drug | Test | Frequency |
|---|---|---|
| UFH | aPTT (or anti-Xa) | Baseline, 6 h after start and after every dose change |
| LMWH | Anti-Xa only if indicated | Not routine. Consider in renal impairment, morbid obesity, pregnancy |
| All heparins | CBC with platelets | Baseline, then q5–10 days for 2 weeks, then q2–4 weeks |
| Warfarin | PT/INR | Frequent during initiation, then stable-interval monitoring. Target 2–3 |
| DOACs | None routinely | Check renal functionperiodically - it drives dosing and eligibility |
| All agents | Signs of bleeding, hemoglobin | Daily inpatient; every visit outpatient |