Week of 20–26 July 2026¶
What is the mechanism of iron-induced hypophosphatemia?¶
Answer: IV iron — chiefly ferric carboxymaltose (FCM) — causes hypophosphatemia by driving FGF23-mediated renal phosphate wasting.
- FCM infusion acutely raises circulating FGF23 3- to 6-fold. FGF23, along with 1,25-dihydroxyvitamin D and PTH, is one of the main regulators of serum phosphate.
- The FGF23 spike reduces proximal tubular reabsorption of filtered phosphate, causing inappropriate urinary phosphate excretion. Phosphate typically reaches its nadir about 2 weeks after the initial infusion.
- FGF23 also lowers 1,25-dihydroxyvitamin D, which decreases gut phosphate absorption and serum calcium, secondarily raising PTH.
- Because PTH also increases renal phosphate excretion, a second wave of PTH-mediated wasting sustains the hypophosphatemia beyond the initial period of FGF23 elevation.
Risk factors: FCM above all; also normal kidney function, more severe iron deficiency, lower body weight, baseline hypophosphatemia, and repeated IV iron doses.
Symptoms are fatigue and myalgia, which overlap with the symptoms of iron deficiency itself — so prevention, by choosing another formulation, beats trying to detect it.
Treatment is difficult: the mechanism is renal wasting, so supplementation is largely excreted rather than retained.
Selected trials
| Study | Design | Key finding |
|---|---|---|
| Magagnoli, AJH 2025 | Systematic review | 50–92% (FCM) vs 2–8% with other formulations |
| Richards, JAMA Open 2025 | RCT, surgical patients | 26% (FCM) vs 4.5% (placebo); longer stay, 12 vs 9 days |
| Wolf, JAMA 2020 | RCT | 75% (FCM) vs 8% (FD) |
| Wolf, JCI 2018 | RCT | 50% (FCM) vs 1% (ferumoxytol) |
| Zoller, Gut 2023 | RCT, IBD | 51% (FCM) vs 8% (FD) |
FCM = ferric carboxymaltose; FD = ferric derisomaltose.
Can patients with persistent or chronic ITP eventually stop treatment with TPO-RAs?¶
Answer: Yes. STOPAGO — an open prospective multi-center study of 48 patients who had achieved a CR for more than 1 year — showed the following:
At 12 months:
At 12 months, 25 (52.1%; 95% confidence interval [CI], 37.2-66.7) and 14 of 48 patients (29.2%; 95% CI, 17.2-42.3) achieved sustained response off treatment (SROT >30) and sustained CR off treatment (SCROT >100), respectively
— STOPAGO
- Most relapses occurred within 4 weeks after TPO-RA discontinuation, with no major bleeding.
At 4 years:
results show that almost 50% of patients with persistent or chronic ITP who achieved stable CR with TPO-RAs can maintain a sustained response off treatment >4 years after TPO-RA discontinuation, and late relapses are rare.
there were no bleeding events in patients with relapse (nor short or late relapse), and all but 2 patients (1 early and 1 late relapse) achieved CR after rechallenge with TPO-RAs.
— STOPAGO long-term follow-up
Source: Long-term follow-up of the STOPAGO study
Can you use TPO-RAs in patients with ITP and positive APLAs?¶
Answer: Carefully and with important considerations.
The largest study is retrospective, from the French CARMEN registry — 80 patients with ITP secondary to SLE and/or APS. Thrombotic event (TE) rates after starting a TPO-RA:
- SLE without APLA — 8.1%
- SLE with APLA — 22.2%
-
APS — 50%, all of whom had previous thrombosis; this subgroup also produced 3 cases of catastrophic APS (CAPS)
-
LAC was present in the majority of patients with thrombosis.
- Limitations are real: small numbers, selection bias.
On whether the drug must be stopped after a TE:
Among patients who continued TPO-RAs after a TE with anticoagulation, only 1 of 9 experienced a recurrent event
The authors read that as reassuring. One in nine is still a high failure rate.
Related: 0008 — IVIG in ITP and thrombosis risk — the same question in a different drug: does treating the ITP raise thrombotic risk, or does the untreated disease?
What is the difference between hemophilia carriers and hemophilia?¶
Answer: Hemophilia experts, in consultation with patient advocacy groups, replaced the old "carrier vs. hemophilia" split with a five-category nomenclature keyed to factor level and bleeding phenotype.
The term "hemophilia carrier" (HC) understates bleeding symptoms in women/girls. A new HC nomenclature was defined by hemophilia experts consulting with patient advocacy groups.
Five new HC categories are: severe/moderate/mild hemophilia, symptomatic and asymptomatic HC.
By FVIII/FIX level:
- Severe hemophilia — <0.01 IU/mL
- Moderate hemophilia — 0.01–0.05 IU/mL
- Mild hemophilia — >0.05 and <0.40 IU/mL
- Level ≥0.40 IU/mL with a bleeding phenotype — symptomatic carrier
- Level ≥0.40 IU/mL without a bleeding phenotype — asymptomatic carrier
Genetics and bleeding: In most instances, as in men, hemophilia in women results from an inherited variant on a single X chromosome, though the relationship between mutation type and factor level in carriers is poorly understood. Rarely, a woman inherits an affected X chromosome from both parents, or has an extremely skewed X-inactivation pattern, producing moderate or severe hemophilia. About one in four carriers with normal factor levels (>0.50 IU/mL) still have an increased bleeding tendency — in hemophilia A carriers partly from an impaired FVIII response to hemostatic stress — typically manifesting as mucocutaneous bleeding; bleeding after dental work, surgery, or childbirth; and joint bleeds with consequent poor joint health and quality of life.
Related: 0013 — FVIII levels and bleeding in hemophilia A carriers — what determines whether a carrier bleeds.
What is the correlation between factor VIII levels and bleeding in carriers of hemophilia A?¶
Answer: The Canadian Hemophilia Carriers (CHiC) study evaluated the determinants of FVIII/FIX levels, bleeding score, and health-related quality of life in 92 hemophilia A carriers. Key findings:
- More bleeding with lower factor: the Self-BAT bleeding score correlated inversely with FVIII:C (rs = −0.298, 95% CI −0.482 to −0.09).
- VWF is a major driver: VWF:Ag correlated with FVIII:C (rs = 0.622, 95% CI 0.47 to 0.737) and with Self-BAT (rs = 0.255, 95% CI 0.043 to 0.445).
- VWF:Ag tracked with category: lower in mild hemophilia A (mean 82.8 IU/dL) than in symptomatic (129.6) or asymptomatic carriers (164.2).
- Blood type: present in 83.3% of mild hemophilia A, 59.1% of symptomatic, and 37.5% of asymptomatic carriers; associated with 29.8% lower VWF:Ag, 15.2% lower FVIII:C, and a 1.44-fold higher VWFpp/VWF:Ag.
- Multivariable analysis confirmed the links between FVIII:C and VWF:Ag (B 0.26, 95% CI 0.17 to 0.34), Self-BAT and FVIII:C (B −0.06, 95% CI −0.1 to −0.01), and Self-BAT and ABO (B −2.73, 95% CI −5.41 to −0.04).
- Quality of life: the SF-36v2 Physical Component Summary correlated with Self-BAT (rs = −0.255) and joint health (rs = −0.325); mental health domains were linked with feelings of guilt and burden.
Related: 0012 — hemophilia carriers vs. hemophilia — the nomenclature these carrier categories come from.
How do you choose between steroids, cyclophosphamide, and rituximab for inhibitor elimination in acquired hemophilia A?¶
Answer: Most patients with acquired hemophilia A (AHA) require immunosuppressive therapy (IST) to eradicate the inhibitor. The choice is individualized, weighing the patient's risk factors for infection, the inhibitor titer, and whether rapid eradication is required.
- No high-quality trials compare regimens head-to-head. Where hemostatic therapy is available, the most common cause of morbidity is infection.
- Expert consensus stratifies by FVIII level and inhibitor titer:
- FVIII >1% and <20 BU/mL: steroids alone for 3–4 weeks (prednisone 1 mg/kg); add cyclophosphamide or rituximab if not responding.
- FVIII <1% or >20 BU/mL: steroids plus either rituximab (375 mg/m² weekly × 4) or cyclophosphamide (1–2 mg/kg/day).
- Other second-line options include CyDRi, cyclosporine, tacrolimus, and azathioprine.
- A small RCT found rituximab + steroids gave better response rates than cyclophosphamide + steroids (77% vs. 69%; Am J Hematol 2024).
- Our approach: individualize and optimize risk factors before starting IST, using emicizumab as a hemostatic bridge — it provides stable levels so IST can begin after optimization.
See also the BSH/UKHCDO guideline on acquired coagulation factor inhibitors.
Source: International recommendations on the diagnosis and treatment of acquired hemophilia A
What is your approach to the use of porcine FVIII in acquired hemophilia A?¶
Answer: Porcine FVIII (susoctocog alfa, Obizur) is a B-domain–deleted porcine FVIII product that shares 80–85% homology with human FVIII, so it may escape the anti-human FVIII antibodies seen in acquired hemophilia A (AHA). It is considered standard for hemostatic management of bleeding in AHA, alongside bypassing agents.
- Cross-reacting inhibitors are common. Stephen et al. found that 52% of one cohort had cross-reacting anti-porcine antibodies. A higher inhibitor titer (BU) predicted both a cross-reacting inhibitor and lack of response to Obizur. If an anti-porcine inhibitor is suspected, it should be quantified.
- Dosing. The FDA label and studies use 200 U/kg, then adjust to clinical response and FVIII activity.
- Lower doses may suffice. In our experience lower doses can still give an excellent response — consistent with other published reports that lower doses can be safe and product-sparing.
- Our approach: individualize to severity of bleeding, availability of rapid coagulation testing, staff familiarity, and the probability of a cross-reacting inhibitor.
Source: International recommendations on the diagnosis and treatment of acquired hemophilia A
What treatment options are available for patients with FVII deficiency?¶
Answer: Several hemostatic options exist; recombinant FVIIa (rFVIIa) is the preferred agent for bleeding and prophylaxis, given at doses far lower than those used in hemophilia A/B with inhibitors.
- Antifibrinolytics (TXA): usually effective for minor bleeding, procedures, and mucosal bleeding.
- rFVIIa: preferred for bleeding and prophylaxis; low doses of 15–30 mcg/kg every 4–6 h, with a single 20 mcg/kg dose for minor surgery.
- Plasma-derived FVII (pdFVII): effective but can be hard to access; 10–30 U/kg — in our experience most useful for prophylaxis.
- FFP / solvent-detergent plasma: ~10–15 mL/kg.
- 4-factor PCC: 20–30 U/kg (e.g. Octaplex, 180–480 IU/mL).
Background: FVII deficiency is the most common rare inherited coagulation disorder, with an autosomal recessive pattern (prevalence ~1:300,000–500,000 homozygous, ~1:350 heterozygous). Homozygotes or compound heterozygotes usually have severe deficiency (<10 IU/dL); heterozygotes have levels of 20–60 IU/dL. Bleeding correlates poorly with factor level — patients with severe deficiency may be asymptomatic, while heterozygotes may bleed significantly.
Source: Rare inherited coagulation disorders: no longer orphan and neglected
Are pre-medications required for IV iron empirically in a patient with a history of anaphylaxis unrelated to the IV iron?¶
Answer: Although a history of other allergies increases the risk of adverse reactions, routine pre-medication is not recommended.
- There is no evidence that pre-medication reduces the rate of a first reaction to IV iron. The panel instead advises a slow initial infusion rate for patients with risk factors or a first dose, and a lower dose in selected patients:
In patients with identified risk factors for hypersensitivity reactions, or in those receiving a first dose, the panel concurred that the infusion should be initiated at a slow infusion rate to minimize the risk of a reaction. In accordance with existing guidance documents that suggest initiating infusions at low rates (<50% of recommended rate), increasing it after a few minutes if no infusion reaction occurs, we also recommend using an initially slow infusion rate, particularly during the first infusion.
In addition to increasing the infusion time, the panel also noted that lower doses of IV iron are associated with lower rates of hypersensitivity reactions. Thus, in selected patients with identified risk factors for hypersensitivity reactions or previous isolated symptoms, a lower dose may be considered based on expert opinion.
- Test doses are not recommended based on post-marketing data; a successful test dose may give false assurance to the healthcare team.
Source: Canadian expert consensus: management of hypersensitivity reactions to intravenous iron in adults
Describe the natural history, definition, diagnosis, investigations, and management of patients with confirmed and suspected VWD.¶
Answer: For a comprehensive overview — natural history, definition, diagnosis, investigations, and management of confirmed and suspected von Willebrand disease — see the VWD module at The Blood Project, put together by hemophilia and VWD experts.
Source: von Willebrand Disease — The Blood Project
What is PIMT (persistent isolated mild thrombocytopenia), and is it clinically significant?¶
Answer: Persistent isolated mild thrombocytopenia (PIMT) is a common reason for referral, and data to guide management are scant.
- In one long-term report, the risk of developing a hematological disease was 26.4%, compared with 1.7% in matched healthy subjects.
- There may be value in yearly or interval CBC follow-up, but the management remains unclear.
- Patients with PIMT also have higher circulating levels of glycoprotein (GP)-specific antibodies; those with such antibodies have a 7-fold greater odds of developing ITP than those without (ASH abstract).
Where are iron and B12 absorbed in the GI tract?¶
Answer:
- Iron is absorbed mostly in the first part of the duodenum.
- B12 goes through several steps before final absorption in the terminal ileum:
- B12 binds R-factor, secreted by the salivary glands.
- The B12–R-factor complex is cleaved in the small intestine by pancreatic enzymes.
- Intrinsic factor (IF), secreted by gastric parietal cells, then binds B12.
- The B12–IF complex binds receptors in the ileum for absorption.
B12 references: Vitamin B12 Deficiency and Physiology, Gastric Intrinsic Factor (StatPearls).
Source: Iron Absorption: Molecular and Pathophysiological Aspects
How do you diagnose bleeding disorders of unknown cause (BDUC)?¶
Answer:
- The first step is a bleeding history and family history, using standardized tools such as the ISTH-BAT or MCMDM-1 BAT — to document the bleeding history, standardize communication, improve post-test probability, and outline the extent of testing.
- BDUC definition, from the ISTH SSC communication:
To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment.
— Standardization of definition and management for BDUC: communication from the SSC of the ISTH
- There is still uncertainty in how to approach these patients, given the limited evidence on testing.
- Around 50–60% may have no identifiable defect on hemostatic testing.
- See the review below for a proposed management approach.
Source: How I treat bleeding disorder of unknown cause