Heparins and fondaparinux

01Purpose and principlesWhat the treatment does and how it fits into care.

UFH is a heterogeneous polysaccharide that accelerates antithrombin inhibition of thrombin and factor Xa. It has rapid onset, a short half-life and variable protein binding, so therapeutic infusion needs a validated APTT-ratio or anti-Xa nomogram. LMWH has a stronger and more predictable anti-Xa effect, longer half-life and renal clearance, making fixed weight-based subcutaneous dosing practical. Fondaparinux is a synthetic pentasaccharide that selectively enhances antithrombin-mediated factor Xa inhibition. It is once daily, renally cleared and rarely cross-reacts with HIT antibodies, but lacks a specific antidote.

Match agent to the clinical trajectory. Stable DVT and PE usually suit LMWH or a DOAC pathway. UFH is valuable in haemodynamic instability, severe renal dysfunction where accumulation is unacceptable, or when an invasive procedure may require rapid cessation. Cancer and pregnancy commonly use LMWH, but cancer-associated VTE choice also incorporates oral options, tumour site, platelets and interactions. Fondaparinux is an alternative for stable VTE and prophylaxis, and may be used in selected HIT pathways with specialist oversight, but it should not replace reperfusion planning in unstable PE.

Dose from actual body weight unless the product or protocol states otherwise. Enoxaparin treatment is commonly 1 mg/kg every 12 hours; its SmPC permits 1.5 mg/kg once daily for uncomplicated, low-recurrence-risk VTE and specifically favours twice-daily treatment in obesity, symptomatic PE, cancer, recurrence or proximal iliac thrombosis. Prophylaxis is typically 40 mg SC daily for medical or high-risk surgical patients, with 20 mg daily in severe renal impairment under the product schedule. The surgical start time and duration depend on procedure and anaesthesia.

A common UFH VTE nomogram uses an 80 units/kg IV bolus then 18 units/kg/hour, followed by APTT or anti-Xa titration. This is not universal: acute coronary syndrome, stroke, extracorporeal circuits and pregnancy protocols differ. Check baseline FBC, PT, APTT, renal function and actual weight. An unexpectedly prolonged baseline APTT from lupus anticoagulant or factor deficiency makes anti-Xa monitoring preferable. Once steady, monitor at the nomogram interval and after every adjustment; a fixed rate without repeat testing is unsafe.

HIT is a prothrombotic immune complication, not simply thrombocytopenia. Use the 4Ts score before laboratory testing. A low score makes HIT unlikely; an intermediate or high score requires all heparin to stop, PF4-heparin immunoassay and a non-heparin anticoagulant if clinically safe, with functional confirmation according to the laboratory pathway. Do not wait for the platelet count to recover before protecting against thrombosis. Avoid platelet transfusion unless bleeding or an invasive indication exists, and do not start warfarin until platelet recovery because early monotherapy can cause venous limb gangrene.

For major UFH bleeding, stop the infusion and use protamine based on recent dose. The SmPC states that 1 mg protamine neutralises about 100 IU of recently administered UFH; less is needed as time elapses. For an infusion, stopping and 25–50 mg slow IV may be used according to exposure. Enoxaparin reversal is incomplete: many protocols use 1 mg protamine per 1 mg enoxaparin given within 8 hours, then 0.5 mg per 1 mg if bleeding persists; later doses are smaller or unnecessary. Give over about 10 minutes, maximum 50 mg, because hypotension, pulmonary vasoconstriction and anaphylactoid reactions can occur.

Key points

LMWH is preferred for most stable VTE treatment because its weight-based effect is predictable and routine APTT monitoring is unnecessary.
UFH is useful when rapid titration and short offset are needed, in selected severe renal failure, or when thrombolysis, embolectomy or imminent surgery is possible.
For acute VTE, enoxaparin 1 mg/kg SC every 12 hours is preferred in symptomatic PE, obesity, cancer, recurrent VTE or proximal iliac thrombosis; 1.5 mg/kg once daily is reserved for uncomplicated lower-risk patients.
Fondaparinux treats DVT or stable PE once daily by weight: 5 mg below 50 kg, 7.5 mg at 50–100 kg and 10 mg above 100 kg, after renal and bleeding assessment.
Fondaparinux treatment of DVT or PE is contraindicated when creatinine clearance is below 30 mL/min and has no specific antidote; it is not the default for haemodynamically unstable PE.
UFH treatment commonly starts 80 units/kg IV then 18 units/kg/hour, but use the validated local nomogram and reduce or omit the bolus when bleeding risk is high.
Protamine rapidly reverses UFH and only partially neutralises LMWH; dose from the actual heparin received and elapsed time, administer slowly, and do not exceed 50 mg in one dose.
Suspected HIT requires immediate cessation of UFH, LMWH, heparin flushes and heparin-coated devices and initiation of a therapeutic non-heparin anticoagulant when bleeding risk permits.
Anti-Xa monitoring is selective rather than routine: consider it in severe renal impairment, pregnancy, extremes of weight, unexpected bleeding or thrombosis and prolonged therapeutic exposure.

02Indications, selection and cautionsWho may benefit, who needs urgent treatment and important alternatives.

Need for rapid offset

Unstable PE, imminent operation, thrombolysis or high bleeding risk may favour titratable short-acting UFH over a longer subcutaneous agent.

Renal accumulation

Rising creatinine, oliguria, low body weight and prolonged dosing increase LMWH or fondaparinux exposure and demand prompt regimen review.

HIT timing

A greater than 50% platelet fall around days 5–10, rapid fall after recent exposure or new thrombosis is more informative than an absolute count threshold.

Occult bleeding

Flank, groin, back or abdominal pain, hypotension, neurological symptoms or falling haemoglobin may indicate retroperitoneal, muscular or intracranial haemorrhage.

Dose mismatch

A prophylactic dose in established VTE, a once-daily regimen in high-recurrence-risk disease or an unadjusted renal dose produces preventable failure or toxicity.

Red flags requiring action

New thrombosis, skin necrosis, systemic reaction after an IV heparin bolus or a platelet fall of more than 50% typically 5–10 days after exposure suggests immune HIT even if the count remains normal.
Retroperitoneal pain, hypotension, neurological change or a rapid haemoglobin fall during therapeutic heparin requires immediate cessation and major-bleeding assessment.
Acute kidney injury during therapeutic LMWH or fondaparinux can cause accumulation, while an apparently therapeutic dose selected from estimated rather than actual weight can be unsafe.

03Assessment before treatmentTests and checks that guide safe selection.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: FBC, renal function and actual weightFirst stepFirst line
Why
Select dose, establish platelets and haemoglobin and anticipate renal accumulation.
Interpretation and limitations
Trend platelets against baseline rather than waiting for a count below 150 × 10⁹/L. Calculate Cockcroft–Gault where the product uses creatinine clearance.
02
UFH APTT ratio or calibrated anti-Xa
Why
Titrate therapeutic infusion to the validated local target.
Interpretation and limitations
Use the same nomogram and laboratory method. Lupus anticoagulant, factor deficiency, inflammation and very high factor VIII can make APTT discordant; anti-Xa may then be preferable.
03
Selective LMWH anti-Xa level
Why
Assess exposure when predictable pharmacokinetics cannot be assumed.
Interpretation and limitations
Take at the protocol-defined post-dose time, usually around 4 hours for a peak, and interpret against agent, indication and dosing frequency rather than a universal range.
04
HIT probability and laboratory pathway
Why
Avoid both missed immune HIT and unnecessary cessation from indiscriminate antibody testing.
Interpretation and limitations
Calculate 4Ts first. Intermediate or high probability prompts PF4-dependent immunoassay and functional confirmation where required while treatment decisions proceed.
05
Bleeding-source assessment
Why
Identify anatomical haemorrhage and additional haemostatic defects.
Interpretation and limitations
Use serial FBC, PT, APTT, fibrinogen, renal profile, group samples and site-specific imaging; anti-Xa can support residual exposure but should not delay source control.

04Treatment approachPreparation, options, escalation and aftercare.

01Stable acute VTEStart weight-based LMWHFirst stepDVT or PE is confirmed without haemodynamic instability or immediate procedure.

1Record actual weight, renal function, platelets, bleeding risk, cancer, pregnancy and intended oral-transition pathway.
2Give the indication-appropriate treatment dose, favouring enoxaparin 1 mg/kg twice daily in symptomatic PE or high-recurrence contexts.
3Review renal trajectory, injection technique, platelets and transition or duration before discharge.

02UFH infusionTitrate through one nomogramRapidly adjustable therapeutic anticoagulation is clinically preferable.

1Obtain baseline tests and choose APTT or anti-Xa monitoring, reducing or omitting the bolus when the protocol and bleeding risk require.
2Start the indication-specific weight-based rate and repeat the assay at the nomogram interval after initiation and every change.
3Adjust only through the validated table, investigate discordance or heparin resistance and plan the transition before stopping.

03Possible HITStop all heparin and protect from thrombosisPlatelets fall in a compatible timing or new thrombosis, skin lesion or bolus reaction occurs.

1Calculate 4Ts and identify every UFH, LMWH, flush and coated-device exposure.
2If probability is intermediate or high, stop all heparin, send the laboratory pathway and begin a therapeutic non-heparin anticoagulant when safe.
3Image for clinically suspected thrombosis, avoid premature warfarin and document future heparin avoidance if HIT is confirmed.

04Major heparin bleedingStop, reverse selectively and control sourceUFH or LMWH accompanies critical-site, haemodynamic or uncontrolled bleeding.

1Stop anticoagulant, resuscitate, obtain last dose or infusion exposure, renal function and coagulation tests and activate source control.
2Give slow IV protamine using the actual recent UFH or LMWH dose and elapsed-time formula, recognising LMWH reversal is incomplete.
3Reassess haemostasis and protamine toxicity, avoid reflex redosing and create a thrombosis-prevention and restart plan.

05Regimens, contraindications and interactionsTreatment details and the circumstances that modify them.

Predictable weight-based first-line parenteral treatment for many stable adults with DVT or PE and a standard option in pregnancy and cancer pathways.

Enoxaparin for acute VTE

Give 1 mg/kg subcutaneously every 12 hours for obesity, symptomatic PE, cancer, recurrent VTE or proximal iliac thrombosis; 1.5 mg/kg once daily is an option for uncomplicated patients at low recurrence risk.

Use actual weight and product-specific renal adjustment; severe renal impairment increases exposure. Review platelets, bleeding, neuraxial timing and recent heparin exposure. Avoid all heparin in suspected immune HIT and use pregnancy or thrombocytopenia protocols.

Prevents hospital-associated VTE when risk assessment shows thrombosis benefit exceeds bleeding risk.

Enoxaparin prophylaxis

For medical or high-risk surgical prophylaxis a common regimen is 40 mg subcutaneously once daily; in severe renal impairment the SmPC regimen is 20 mg once daily, with start time and duration set by procedure and mobility.

Do not mistake prophylaxis for treatment. Account for neuraxial catheter timing, surgery type, weight extremes, renal function, active bleeding and platelet trend; local obstetric and orthopaedic protocols may use different weight bands.

Short-acting anticoagulation when rapid titration, rapid interruption or selected severe renal failure and procedural flexibility are important.

Unfractionated heparin infusion

A common acute VTE regimen is 80 units/kg IV bolus then 18 units/kg/hour, titrated to a locally validated APTT ratio or anti-Xa target; reduce or omit the bolus when the indication or bleeding risk requires.

Never run without timely assay-based adjustment. Monitor platelets and bleeding, investigate apparent resistance or APTT discordance and stop all exposure if immune HIT is suspected. Dosing differs for ACS, stroke and extracorporeal circuits.

Once-daily synthetic factor Xa inhibition for selected stable DVT or PE and a specialist option in some HIT contexts.

Fondaparinux treatment

Give 5 mg subcutaneously once daily below 50 kg, 7.5 mg once daily at 50–100 kg or 10 mg once daily above 100 kg for DVT or stable PE, generally for at least 5 days and until the planned oral treatment is established.

For the DVT or PE treatment strengths, use is contraindicated when creatinine clearance is below 30 mL/min and active major bleeding is present. There is no specific antidote; it is unsuitable as sole management of unstable PE and needs careful neuraxial and procedural timing.

Specific cationic neutralisation of UFH and partial reversal of LMWH during clinically important bleeding or urgent surgery.

Protamine sulfate

Give by slow IV injection over about 10 minutes, never more than 50 mg in one dose; approximately 1 mg neutralises 100 IU recent UFH, while recent enoxaparin is only partially reversed using an elapsed-time protocol.

Calculate from actual recent exposure because excess protamine is anticoagulant. Rapid administration can cause severe hypotension, pulmonary vasoconstriction, bradycardia and anaphylactoid reactions, with higher sensitivity after prior protamine or some fish allergy contexts.

06Complications, monitoring and follow-upAdverse effects, response and longer-term review.

Obtain baseline and serial FBC, with platelet trend during the HIT risk window; investigate a proportional fall even when the absolute count remains within the laboratory range.
For UFH, repeat APTT or anti-Xa at the nomogram interval after starting and after each rate change, then at least daily once stable; never mix nomograms and targets.
For therapeutic LMWH or fondaparinux, monitor renal function during acute illness and prolonged courses; use selected anti-Xa measurement only with an agent-specific question and sampling time.
Inspect injection and procedural sites, ask about occult bleeding and verify dose against current actual weight, renal function, indication and treatment versus prophylaxis phase.
After protamine, follow clinical haemostasis, coagulation, haemoglobin and cardiopulmonary observations; persistent bleeding may reflect incomplete LMWH reversal or an anatomical source rather than inadequate protamine.

07Special situationsVariants, exceptions and circumstances that change the usual approach.

HIT is thrombosis first

The platelet fall is a clue to explosive thrombin generation. Giving platelets or withholding alternative anticoagulation without a bleeding reason can worsen the central hazard.

APTT can be misleading

Inflammation raises factor VIII and shortens APTT, whereas lupus anticoagulant prolongs it. A calibrated anti-Xa approach can resolve clinically important discordance.

Protamine has its own anticoagulation

More is not better: excess protamine impairs platelets and coagulation, while rapid dosing causes cardiovascular collapse. Use recent exposure and elapsed time.

Once daily is selective

Enoxaparin 1.5 mg/kg once daily is convenient but is not the preferred regimen for symptomatic PE, obesity, active cancer, recurrence or proximal iliac clot.

Fondaparinux is different

Its negligible HIT cross-reactivity is useful, but renal dependence, long effect and absent antidote make it a poor automatic substitute in unstable or bleeding patients.

08Common pitfallsFrequent interpretation and management errors.

01
Do not prescribe enoxaparin 40 mg daily to treat established DVT or PE; that is a common prophylactic dose, not therapeutic anticoagulation.
02
Do not diagnose HIT from thrombocytopenia alone or send antibodies in a low-probability presentation; use 4Ts to reduce harmful false-positive interpretation.
03
Do not wait for a HIT immunoassay before stopping every heparin source in an intermediate- or high-probability case with thrombosis risk.
04
Do not monitor UFH by APTT when a markedly abnormal baseline makes the result uninterpretable without considering anti-Xa and the underlying cause.
05
Do not use fondaparinux below its renal limit or assume dialysis removes its bleeding risk.
06
Do not repeat protamine solely because an anti-Xa remains measurable after LMWH; clinical haemostasis, time and incomplete neutralisation must guide senior review.