Holding Heparin for Surgery

Timing of Heparin Interruption

For neuraxial anesthesia (spinal/epidural), the thresholds are more conservative:

• IV UFH: stop ≥6 hours before block; confirm normal aPTT
• Therapeutic LMWH: stop ≥24 hours before block
• Prophylactic LMWH: stop ≥12 hours before block

— Miller's Anesthesia, 10e, p. 3988–3989

Who Needs Bridging? (Deciding Whether to Bridge)

High-Thrombotic-Risk → Bridge

• Mechanical heart valve (especially mitral position)
• Recent ischemic stroke or TIA (<3 months)
• Recent VTE (<3 months)
• Hypercoagulable disorders
• CHA₂DS₂-VASc ≥7–8 (very high AF risk)

Low-to-Moderate Risk → No Bridge

• Atrial fibrillation (most patients): The BRIDGE trial (double-blind, placebo-controlled RCT) showed forgoing LMWH bridging in AF patients does not increase arterial thromboembolism and decreases major bleeding risk
• VTE >3 months ago
• Remote TIA/stroke (>3 months, no high-risk source)

— Sabiston Textbook of Surgery, p. 305–306; Mulholland & Greenfield's Surgery, p. 896

Bridging Protocol (When Indicated)

1. Hold warfarin 5 days before surgery
2. Start LMWH (or UFH) 24 hours after stopping warfarin (once INR <2.0)
3. Continue bridging through Day −2
4. Last dose of LMWH 24 hours before surgery (Day −1 = no LMWH)
5. Day 0 = Surgery

• Low-bleeding-risk surgery: Resume LMWH 24 hours postoperatively; restart warfarin same night if no bleeding
• High-bleeding-risk surgery: Resume therapeutic LMWH at 48–72 hours postoperatively
• Continue bridging until INR is therapeutic on two consecutive checks

— K.J. Lee's Essential Otolaryngology; Sabiston Textbook of Surgery; Miller's Anesthesia, 10e

LMWH Dosing for Bridging

• Enoxaparin: 1 mg/kg SQ BID or 1.5 mg/kg SQ daily (treatment dose)
• Renal impairment (eGFR <30 mL/min): Prefer IV UFH over LMWH for bridging
• HIT history: Heparin and LMWH are contraindicated; use argatroban, bivalirudin, fondaparinux, or a DOAC (with hematology consultation)

DOACs — No Bridging Needed

Key Principles Summary

1. IV UFH off 4–6 h pre-op; LMWH off 24 h pre-op (therapeutic dose)
2. Most AF patients do NOT need bridging (BRIDGE trial evidence)
3. Bridge when thrombotic risk is very high: mechanical valves, recent stroke/VTE, severe hypercoagulable states
4. Restart heparin/LMWH 24–72 h postoperatively depending on bleeding risk
5. Neuraxial anesthesia requires stricter hold times than general surgery

• Miller's Anesthesia, 10e, pp. 3988–3989
• Sabiston Textbook of Surgery, pp. 305–306
• Mulholland & Greenfield's Surgery, 7e, p. 896
• K.J. Lee's Essential Otolaryngology, p. 142
• BRIDGE trial (PMID: 26095867); PAUSE trial

Restarting Heparin Post-Surgery

IV Unfractionated Heparin (UFH)

Restart without a bolus dose to avoid sudden anticoagulant surges. — Miller's Anesthesia, 10e

LMWH (e.g., Enoxaparin, Dalteparin)

— Miller's Anesthesia, 10e; Sabiston Textbook of Surgery

Warfarin (VKA) — Restart Timeline

• Resume warfarin 12–24 hours postoperatively if hemostasis is adequate (most surgeries)
• Then bridge with heparin/LMWH until INR is therapeutic on two consecutive readings
• Expect 8–9 days of subtherapeutic INR even if warfarin is restarted the same night

— Washington Manual of Medical Therapeutics; Miller's Anesthesia, 10e

High Bleeding Risk Procedures — Special Cases

— Washington Manual of Medical Therapeutics

General Principles

1. Always confirm hemostasis before restarting — no strict time rule overrides active bleeding
2. UFH restarts sooner than LMWH (12 h vs. 24 h for low-risk), but LMWH is preferred for bridging due to predictable pharmacokinetics
3. No bolus when restarting UFH — start at maintenance infusion rate only
4. Renal function matters — if eGFR <30 mL/min, prefer IV UFH over LMWH (LMWH accumulates)
5. HIT history: avoid all heparin products; use argatroban, bivalirudin, or fondaparinux instead
6. DOACs: resume 1 day after low-risk surgery, 2 days after high-risk surgery — no bridging needed

Target Hemoglobin in Heart Failure

The Short Answer: There Is No Proven Hb Target to Aim For

What the Major Trials Show

RED-HF Trial (Key Evidence)

• Enrolled 2,278 patients with systolic HF and mild-to-moderate anemia (Hb 9.0–12.0 g/dL)
• Randomized to darbepoetin alfa (to normalize Hb) vs. placebo
• Result: No significant difference in death from any cause or HF hospitalization (HR 1.01, 95% CI 0.90–1.13; P = 0.87)
• Additional harm: Darbepoetin alfa increased thromboembolism-related adverse events
• Conclusion: ESAs should NOT be used to target a higher Hb in HF

— Braunwald's Heart Disease, 15e; Harrison's Principles of Internal Medicine, 22e

Earlier Epoetin Trials

• Patients with ischemic heart disease or CHF receiving epoetin alfa targeting normal hematocrit (42%) had higher rates of CVD events than those with a lower target hematocrit
• Targeting higher Hb with ESAs is potentially harmful in HF

— Goodman & Gilman's Pharmacological Basis of Therapeutics

Prevalence and Significance of Anemia in HF

• Affects 30–60% of patients with heart failure
• WHO definition: Hb <13 g/dL (men), <12 g/dL (women)
• Anemia reduces tissue O₂ delivery, worsens NYHA functional class, and is associated with increased HF hospitalizations and mortality
• Common causes in HF: iron deficiency, renal dysfunction (relative EPO deficiency), malnutrition, GI blood loss, hemodilution

What TO Do: Treat the Cause

1. Iron Deficiency (Most Actionable)

⚠️ The HEART-FID trial (3,065 patients) showed no benefit on death, HF hospitalization, or 6-min walk — benefits likely confined to symptom reduction and possibly fewer HF hospitalizations in iron-deficient patients

2. SGLT2 Inhibitors

• Dapagliflozin and empagliflozin increase hemoglobin and hematocrit as a side effect, possibly through plasma volume reduction and increased erythropoiesis — this may partly explain their benefit in HF

3. Treat Other Contributing Causes

• Vitamin B12 / folate deficiency
• Optimize renal function
• Manage CKD anemia per KDIGO guidelines (target Hb 10–11.5 g/dL with ESAs in CKD, though this is a CKD-specific target, not HF-specific)

Transfusion in Decompensated HF

• Transfuse to relieve symptomatic anemia or when Hb causes hemodynamic compromise
• A restrictive transfusion strategy (transfuse at Hb ~7–8 g/dL) is generally preferred — liberal transfusion risks volume overload in HF
• If acute decompensated HF with severe anemia: loop diuretic + transfusion may be needed together

Summary

Aplastic Anaemia

Definition

— Harrison's Principles of Internal Medicine, 22e; Robbins & Kumar Basic Pathology

Classification

Epidemiology

• Incidence: 2 per million/year in Europe; 5–7 per million/year in Asia (Thailand, China)
• Equal sex distribution
• Bimodal age peak: teens/twenties and older adults

Etiology & Causes

Pathophysiology

1. Immune-mediated (primary): Activated Th1/cytotoxic T cells produce interferon-γ and TNF → suppress and destroy hematopoietic stem cells. This is why immunosuppression restores hematopoiesis in 60–70% of patients.
2. Intrinsic stem cell defect: 5–10% have inherited telomerase mutations → premature stem cell senescence. An additional 50% have abnormally short telomeres. Genetically altered stem cells may also express neoantigens → triggering T-cell attack.

Clinical Features

• Anaemia: insidious weakness, pallor, dyspnea
• Thrombocytopenia: petechiae, ecchymoses, mucosal bleeding
• Neutropenia: serious bacterial and fungal infections
• No splenomegaly — if present, suspect alternative diagnosis

Severity Classification (Camitta Criteria)

Diagnosis

• CBC: pancytopenia with low reticulocytes (hypoproliferative)
• Peripheral smear: normocytic/macrocytic RBCs, no dysplasia
• Bone marrow biopsy (essential): hypocellular marrow with fat replacement, absent/markedly reduced hematopoietic cells
• Flow cytometry: reduced CD34+ cells; rule out PNH clone (GPI-anchored protein deficiency — present in ~50% of AA)
• Cytogenetics: rule out MDS, Fanconi (chromosomal fragility test with diepoxybutane)
• Genomic testing: telomere length, germline mutation screen in younger patients

Treatment

1. Hematopoietic Stem Cell Transplantation (HSCT)

• Matched sibling: long-term survival ~90%+ in children; slightly lower in adults (higher GVHD/infection risk)
• Matched unrelated donor (MUD): outcomes similar to sibling in well-matched cases; used upfront in children, as salvage in adults
• Haploidentical donor: increasingly used; post-transplant cyclophosphamide for GVHD prevention
• No radiation in conditioning (to avoid late malignancy)
• ⚠️ Avoid family member blood transfusions before transplant (sensitisation risk)
• HLA typing should be ordered immediately on diagnosis in all transplant-eligible patients

2. Immunosuppressive Therapy (IST) — For non-transplant candidates

Horse ATG + Cyclosporine + Eltrombopag

• Granulocyte improvement typically apparent within 2 months
• MCV remains elevated; marrow cellularity recovers slowly
• Relapse is frequent when cyclosporine/eltrombopag is tapered — most respond to reinstitution
• Children respond well to IST; eltrombopag adds less benefit in children than in adults
• Glucocorticoids alone are NOT effective as primary therapy and increase fungal infection risk

3. Supportive Care

• RBC transfusions: for symptomatic anaemia (minimise in transplant candidates)
• Platelet transfusions: for bleeding or prophylaxis at low counts
• Antibacterial/antifungal prophylaxis: especially during neutropenia (ANC <500)
• G-CSF: limited utility in immune aplastic anaemia
• Iron chelation: if transfusion-dependent long-term

Complications & Associated Disorders

• Clonal evolution: ~15% develop PNH, MDS, or AML over time (especially after IST)
• PNH clone: found in ~50% at diagnosis; monitor with flow cytometry
• Relapse: common during IST tapering
• Long-term survivors of IST have elevated risk of late myeloid malignancy

Prognosis